FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) “6H-DIBENZ0 [B, E] OXEPINE DERIVED NONSTEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONISTS” ELI LILLY AND COMPANY, of Lilly Corporate Center Indianapolis, IN 46285, United States of America, The following specification particularly describes the invention and the manner in which it is to be performed. 6H-DIBENZ0[B,E]0XEPINE DERIVED NONSTEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONISTS The present invention relates to tricyclic compounds that are useful as therapeutic agents in the treatment of physiological disorders responsive to mineralocorticoid receptor antagonists, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders in patients, and to intermediates and processes useful in the synthesis of the compounds. Aldosterone, the primary endogenous mineralocorticoid, regulates hemodynamic homeostasis by promoting sodium and water reabsorption and potassium excretion following interaction with the mineralocorticoid receptor (MR). Because of aldosterone's role in maintaining electrolyte and water balance, MR antagonists have been used for the treatment of numerous physiological disorders including hypertension, hypokalemia, myocardial arrhythmias, Bartter's Syndrome, as well as disorders of primary or secondary hyperaldosteronism such as Conn's Syndrome. More recently, MR antagonists have been used in the treatment of congestive heart failure and acute myocardial infarction. In addition, MR antagonists have also proven effective in preclinical models of kidney disease and in combination with standard therapy to reduce proteinuria in patients suffering from renal disorders such as chronic kidney disease including diabetic nephropathy. However, existing MR antagonists produce concomitant effects which limit their safety and / or effectiveness. For example, spironolactone, a potent MR antagonist, is nonselective and cross reacts with other nuclear hormone receptors (e.g. the androgen receptor (AR), the progesterone receptor (PR), or the glucocorticoid receptor (GR)) which mediate other physiological processes. Spironolactone therapy has been associated with hyperkalemia as well as gynecomastia, erectile dysfunction, reduced libido, irregular menses, as well as gastric distress. Eplerenone, though selective for MR relative to the other nuclear hormone receptors, has also been associated with hyperkalemia. Thus, there remains a need in the art for alternatives to current MR antagonist therapy. The object of the present invention is to provide nonsteroidal MR ligands which possess MR antagonist activity. As a preferred embodiment, it is an object to provide nonsteroidal MR antagonists which bind to MR with greater affinity relative to AR, PR, and GR. As a more preferred embodiment, it is an object of the present invention to provide nonsteroidal MR antagonists which bind to MR with greater affinity relative to AR, PR, and GR, and which posses potent reno- or cardio-protective activity. As an even more preferred embodiment, it is an object of the present invention to provide nonsteroidal MR antagonists which bind to MR with greater affinity relative to AR, PR, and GR, and which posses potent reno- or cardio-protective activity, but with a reduced incidence or likelihood of producing hyperkalemia. An important consideration for any therapeutic agent is whether the agent is likely to cause a prolongation of the QT interval. A central mechanism by which therapeutic agents may induce a prolongation of the QT interval is by blocking the hERG channels in cardiac muscle. Blockage of the the hERG channel prevents passage of potassium ions across cardiac cell membranes resulting in prolongation of the action potentials of the cells, which could lead to dangerous cardiac arrhythmias. Thus, a further preferred embodiment of the present invention is to provide MR antagonists with a reduced incidence or likelihood of blocking hERG channels. Tricyclic MR ligands are known in the art. For example WO 04/052847 and WO 05/066161 disclose tricyclic steroid hormone receptor modulators which are useful for treating disorders susceptible to mineralocorticoid receptor or glucocorticoid receptor modulation. The present invention is directed to the discovery that certain novel tricyclic compounds, as given by Formula (I) below, have particular profiles of activity, as evidenced by in vitro and in vivo testing, which indicate that they have utility in the treatment or prevention of disorders responsive to mineralocorticoid receptor antagonist therapy. In particular, exemplified compounds of Formula (I) are potent MR ligands which antagonize the mineralocorticoid receptor. Accordingly, the present invention provides a compound of Formula (I) Formula (I) wherein, R1 and R2 each independently represent hydrogen or fluoro; L represents -(CH2)2- , -CH(CH3)-CH2-, or a direct bond; R3 represents hydrogen or a group of the formula: N— 0 ■N 0 -+-N N— (a) (b) (c) (d) 0 -N N— (g) (h) 0 / N— (i) or 0 HO 0) ; and R represents -CN or -C(0)NH2, or a pharmaceutical^ acceptable salt thereof. In another embodiment, the present invention provides a method of treating or preventing congestive heart failure, diabetic nephropathy, chronic kidney disease, hypertension, hypokalemia, myocardial arrhythmia, Bartter's Syndrome, primary or secondary hyperaldosteronism, or Conn's Syndrome, comprising -4- administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof As a more particular aspect, the present invention provides a method for treating or preventing congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease. Further, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of congestive heart failure, diabetic nephropathy, chronic kidney disease, hypertension, hypokalemia, myocardial arrhythmia, Bartter's Syndrome, primary or secondary hyperaldosteronism, or Conn's Syndrome. More particularly, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease. In addition, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of congestive heart failure, diabetic nephropathy, chronic kidney disease, hypertension, hypokalemia, myocardial arrhythmia, Bartter's Syndrome, primary or secondary hyperaldosteronism, or Conn's Syndrome. More particularly, the present invention provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease. In addition, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one of more pharmaceutically acceptable carriers, diluents, or excipients. More particularly, the present invention provides a pharmaceutical composition for the treatment or prevention of congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one of more pharmaceutically acceptable carriers, diluents or excipients. The present invention also encompasses novel intermediates and processes useful for the synthesis of a compound of Formula (I). The present invention also relates to solvates of the compound of Formula (I) or pharmaceutically acceptable salts of compounds of Formula (I). As such, when used herein the term "Formula (I)", or any particular compound of Formula (I), includes within its meaning any solvate of the compound. Examples of pharmaceutically acceptable salts and methods for their preparation are well within the knowledge of those skilled in the art. See for example, Stahl et al, "Handbook of Pharmaceutical Salts: Properties, Selection and Use," VCHA/Wiley-VCH, (2002); Gould, P.L., "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Berge et al, "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66, No. 1, (January 1977); and Bastin et al "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4: 427-435 (2000). Particular mention is made of the hydrochloride, maleate, and mesylate salts of compounds of Formula (I). The compounds of the present invention may have one or more chiral centers and may, therefore, exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers the compounds of the present invention may occur as racemates, mixtures of enantiomers, and as individual enantiomers as well as diastereomers and mixtures of diastereomers. Except where specifically set forth herein, all such racemates, enantiomers, and diastereomers are within the scope of the present invention. Enantiomers of the compounds provided by the present invention can be resolved, for example, by one of ordinary skill in the art using standard techniques such as those described by J. Jacques, et al, "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, as well as those techniques provided in the Schemes, Preparations, and Examples herein. Specific stereoisomers and enantiomers of compounds of Formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, Chapter 7; Separation of Stereoisomers, Resolution, Racemization; and by Collet and Wilen, "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981, as well as those techniques provided in the Schemes, Preparations, and Examples herein. For example, specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configurations of a chiral center. The terms "(+)", "R/S" or "RS" refer to a racemic configuration of a chiral center. A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, etal, eds., 1974). As will be appreciated by one of ordinary skill in the art, molecules containing a carbon-carbon or carbon-nitrogen double bond may exist as geometric isomers. Two methods are commonly used to designate the specific isomers, the "cis-trans" method and the "E and Z" method depending on whether the groups attached to each of the double bonded atoms are the same or different. A discussion of geometric isomerism and the naming of specific isomers is found in March, "Advanced Organic Chemistry", John Wiley & Sons, 1992, Chapter 4. All such geometric isomers, as well as mixtures of individual isomers, are contemplated and provided by the present invention. Compounds of the present invention may be formulated as part of a pharmaceutical composition. As such, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient is an important embodiment of the invention. Examples of pharmaceutical compositions and methods for their preparation are well known in the art. See, e.g. REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et ah, eds., 19th ed., Mack Publishing (1995)). Illustrative compositions comprising compounds of Formula (I) include, for example: A compound of Formula (I) in suspension with 0.5% carboxy methylcellulose, 0.25% Polysorbate 80 and 2.7% NaCl; or a compound of Formula I in suspension with 1% carboxy methylcellulose and 0.25% Polysorbate 80; or a compound of Formula I in suspension with 1% carboxy methylcellulose, 0.25% Polysorbate 80, and 0.05% AntiFoam 1510™ in purified water. It will be understood, however, that a preferred composition of the present invention comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, formulated in a capsule or tablet. A compound of Formula (I), or a composition comprising a compound of Formula (I) can be administered by any route which makes the compound bioavailable, including oral and parenteral routes. One of skill in the art will appreciate that particle size can affect the in vivo dissolution of a pharmaceutical agent which, in turn, can affect absorption of the agent. "Particle size" as used herein, refers to the diameter of a particle of a pharmaceutical agent as determined by conventional techniques such as laser light scattering, laser diffraction, Mie scattering, sedimentation field flow fractionation, photon correlation spectroscopy, and the like. Where pharmaceutical agents have poor solubility, small or reduced particle sizes may help dissolution and, thus, increase absorption of the agent. Amidon et ah, Pharm.Research, 12; 413-420 (1995). Methods for reducing or controlling particle size are conventional and include milling, wet grinding, micronization, and the like. Another method for controlling particle size involves preparing the pharmaceutical agent in a nanosuspension. A particular embodiment of the present invention comprises a compound of Formula (I), or a pharmaceutical composition comprising a compound of Formula (I), wherein said compound has a d90 particle size (i.e. the size of which 90% of the particles are smaller than or equal to) of less than about 50 µm. A more particular embodiment comprises a compound of Formula I having a d90 particle size of less than about 10 µm. As used herein the term "patient" refers to a human or nonhuman mammal such as a dog, cat, cow, monkey, horse, or sheep. More particularly, the term "patient" refers to a human. The term "treating" (or "treat" or "treatment") as used herein includes prohibiting, preventing, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. The term "preventing" (or "prevent" or "prevention") as used herein refers to prohibiting, restraining, or inhibiting the incidence or occurrence of a symptom or disorder. As appreciated by one of skill in the art, physiological disorders may present as a "chronic" condition, or as an "acute" episode. Thus, the treatment of disorders contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear, whereas a chronic condition is treated throughout the course of the disease. As used herein the term "effective amount" refers to the amount or dose of a compound of Formula (I) which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by considering a number of factors such as the species of mammal; its size, age, and general health; the specific disease involved; the degree or severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of any concomitant medications. When used in conjunction with the methods and uses of the present invention, the compounds and compositions of the present invention may be administered either alone, or in combination with conventional therapeutic agents used to treat the particular disorder or condition. Where the compounds or compositions of the present invention are used as part of a combination, the compound or composition comprising Formula (I) may be administered separately or as part of a formulation comprising the therapeutic agent with which it is to be combined. As used herein, the designation refers to a bond that protrudes forward out of the plane of the page, whereas the designation " refers to a bond that protrudes backward out of the plane of the page. Particular Aspects of the Invention The following lists set out several groupings of particular configurations, substituents and variables for compounds of Formula (I). It will be understood that compounds of Formula (I) having such particular configurations, substituents or variables, as well as methods, uses, and compositions comprising such compounds, represent particular aspects of the present invention. Thus, a particular aspect of the present invention is one wherein the compound of Formula (I) is one wherein L, R3 and R4 have any of the values defined herein, and: (a) R1 represents hydrogen and R2 represents hydrogen or fluoro; or (b) R1 represents fluoro and R2 represents hydrogen or fluoro; or (c) R1 represents hydrogen or fluoro and R2 represents hydrogen; or (d) R1 represents hydrogen or fluoro and R2 represents fluoro; or (e) R1 and R2 each independently represent hydrogen. Additional particular aspects of the present invention are those wherein the compound of Formula (I) is one wherein R1, R2, R3, and R4 have any of the values defined herein, and: (a) L represents -CH(CH3)-CH2- or a direct bond; or (b) L represents -CH(CH3)-CH2-; or (c) L represents a direct bond. Additional particular aspects of the present invention are those wherein the compound of Formula (I) is one wherein R1, R2, L and R4 have any of the values defined herein, and: (a) R3 represents hydrogen or a group of the formula (b) R3 represents a group of the formula Further particular aspects of the present invention are those wherein the compound of Formula (I) is one wherein R1, R2, L and R4 have any of the values defined herein, and: (a) R represents hydrogen or a group of the formula (b) R3 represents a group of the formula (c) R3 represents a group of the formula -rN 0 (a) (c) N-CH3 4 - or (d) H0 (i.) Additional particular aspects of the present invention are those wherein the compound of Formula (I) is one wherein R1, R2, L and R3 have any of the values defined herein, and: (a) R4 represents -CN or (b) R4 represents -C(0)NH2. A more particular aspect of the present invention is one wherein the compound of Formula (I), is one wherein, R1 and R2 each independently represent hydrogen or fluoro; L represents -CH(CH3)-CH2- or a direct bond; R represents hydrogen or a group of the formula: R4 represents -CN or -C(0)NH2, or a pharmaceutically acceptable salt thereof. An even more particular aspect of the present invention is one wherein the compound of Formula (I) is one wherein, R1 and R2 each independently represent hydrogen or fluoro; L represents -CH(CH3)-CH2- or a direct bond, provided that when L represents -CH(CH3)-CH2- , then R3 represents a group of the formula: -J-N 0 and when L represents a direct bond, then R3 represents a group of the formula: R represents -CN or -C(0)NH2, or a pharmaceutically acceptable salt thereof. Additional particular aspects of the present invention are provided by the compounds of Formula 1(a) and Formula 1(b) below. It will be understood that compounds of Formula 1(a) and Formula 1(b), as well as methods and uses employing such compounds, and compositions comprising such compounds represent particular further aspects of the present invention. Thus, a particular aspect of the present invention is provided by a compound of Formula 1(a): Formula 1(a) wherein, R1 and R2 each independently represent hydrogen or fluoro; L represents -CH(CH3)-CH2- or a direct bond; and R3 represents hydrogen or a group of the formula: or a pharmaceutically acceptable salt thereof. An even more particular aspect of the present invention is a compound of Formula 1(a), wherein R1 and R2 each independently represent hydrogen or fluoro; and L represents -CH(CH3)-CH2- or a direct bond, provided that when L represents -CH(CH3)-CH2- , then R3 represents a group of the formula: and when L represents a direct bond, then R3 represents a group of the formula: or a pharmaceutically acceptable salt thereof. Yet another particular aspect of the present invention is provided by a compound of Formula 1(b): Formula 1(b) wherein, R1 and R2 each independently represent hydrogen or fluoro; L represents -CH(CH3)-CH2- or a direct bond; and R3 represents a group of the formula: HO HO (a) (e) (f) (d) or a pharmaceutically acceptable salt thereof. An even more particular aspect of the present invention is a compound of Formula 1(b), wherein R1 and R2 each independently represent hydrogen or fluoro; and L represents -CH(CH3)-CH2- or a direct bond, provided that when L represents -CH(CH3)-CH2-, then R3 represents a group of the formula: -j-N 0 and when L represents a direct bond, then R3 represents a group of the formula: CH ^-^ +pv+f>.+cO-«+100%). JH NMR (400 MHz, DMSO-d6) 8 5.11 (s, 2H), 6.81 (t, 1H), 7.13 (t, 1H), 7.19 (dd, 1H), 7.46 (t, 1H), 7.59 (d, 1H), 7.62 (t, 1H), 7.93 (d, 1H). Preparation 2 3-[2-(2-Bromo-5-fluoro-phenoxymethyl)-phenyl]-acrylic acid ethyl ester To a mixture of l-bromo-4-fluoro-2-(2-iodo-benzyloxy)-benzene (0.29 mol, 117.4 g), sodium acetate (0.44 mol, 36.1 g, 1.5 equiv.), tetra-n-butylammonium bromide (0.29 mol, 90.3 g), palladium (II) acetate (8 mmol, 1.8 g, 3 mol %), and N-methylpyrrolidinone (900 mL) at 55-60 °C, add drop wise a solution of ethyl acrylate (0.32 mol, 34.3 mL) in N-methylpyrrolidinone (200 mL). Cool the reaction mixture to room temperature and treat with water (2 L) and methyl tert-butyl ether (2 L). Pass through diatomaceous earth, add ethyl acetate (1 L), separate the layers, and wash with water (2 L). Dry the organic portion over anhydrous sodium sulfate, filter, and concentrate. Suspend the resulting solid in hexanes (1 L), refrigerate for 2 h, filter, and wash with cold hexanes (500 mL). Dry in a vacuum oven (50 °C/20 mm Hg) to obtain the title compound as a pale yellow solid (104.4 g, 95%). LC-MS m/z 381.0 [M+H]+. Preparation 3 (E)- (3-Fluoro-6H-dibenzo[b,e]oxepin-ll-ylidene)-acetic acid ethyl ester Heat a mixture of 3-[2-(2-bromo-5-fluoro-phenoxymethyl)-phenyl]-acrylic acid ethyl ester (0.25 mol, 94 g), sodium acetate (0.37 mol, 30 g, 1.5 equiv.), tetra-n-butylammonium bromide (0.25 mol, 81 g), and palladium (II) acetate (7 mmol, 1.7 g, 3 mol %) in N-methylpyrrolidinone (850 mL) at 100-110 °C for 6 h. Cool to room temperature, dilute with water (1 L), filter through diatomaceous earth, and wash with ethyl acetate (2 L). Transfer the filtrate to a separatory funnel, add water (500 mL) and separate the layers. Wash the organic layer with water (2 x 1.5 L), dry over anhydrous sodium sulfate, filter through a silica pad, wash with ethyl acetate (1.5 L) and concentrate to dryness. To the residual solid add hexanes (1 L), refrigerate for 2 h, filter, rinse with hexanes (500 mL), and dry at 50 °C/20 mm Hg to obtain the title compound (64.3 g, 87%). LC-MS m/z 299.0 [M+H]+. Preparation 4 (E)-l l-Bromomethylene-3-fluoro-6,l l-dihydro-dibenzo[b,e]oxepine To a suspension of (3-fluoro-6H-dibenzo[b,e]oxepin-ll-ylidene)-acetic acid ethyl ester (0.23 mol, 69.5 g) in isopropanol (725 mL) add a solution of lithium hydroxide (0.53 mol, 12.0 g) in water (125 mL) and warm to 70 °C for 4 h. Allow the mixture to cool to 40 °C and then treat with glacial acetic acid (0.44 mol, 25 mL). After stirring for 15 min, add N-bromosuccinimide (0.25 mol, 44 g). Bubbling ensues, the temperature rises to 45 °C, and solids form after a few min. Stir the mixture at 40-45 °C for one hour and cool to room temperature. Add sodium bisulfite (4.5 g) in water (150 mL), saturated aqueous sodium bicarbonate (150 mL), and water (450 mL). Filter the resulting suspension and rinse with cold 1:1 isopropanol/water (300 mL). Dry the solid at 60 °C/20 mm Hg overnight to obtain the title compound (65.8 g, 93%). 1H NMR (400 MHz, DMSO-d6) 8 4.9-5.4 (br d, 2H), 6.63 (dd, 1H), 6.77 (dt, 1H), 7.13 (s, 1H), 7.32-7.46 (m, 4H), 7.52 (dd, 1H). Preparation 5 (£)-2-((3-fluorodibenzo[b,e]oxepin-ll(6H)-ylidene)methyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane To a stirred mixture of (E)-l l-(bromomethylene)-3-fluoro-6,l 1-dihydrodibenzo[b,e]oxepine (49 mmol, 15 g) and bis(pinacolato)diboron (64 mmol, 16 g) in 1,4-dioxane (250 mL) add potassium acetate (150 mmol, 15 g). Flush the mixture with nitrogen, add dichloro[l,l'-bis(diphenylphosphino)-ferrocene] palladium(II) dichloromethane adduct (2.46 mmol, 1.80 g), and heat at 65 °C overnight. Cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate and concentrate the filtrate in vacuo. Add methanol (200 mL) and rotate the mixture for one hour on a rotory evaporator without vacuum causing a brown solid to form. Collect the dark brown crystals by filtration and dry under vacuum overnight to obtain the title compound (7.28 g, 42%). Concentrate the filtrate and purify by column chromatography eluting with 0% to 16% ethyl acetate in hexanes to obtain the title compound as a yellow solid (3.46 g, 20%). Total yield for the reaction is 10.7 g (62%). lR NMR (300 MHz, CDC13) 8 7.36 (dd, ,7=8.8, 6.8 Hz, 1H), 7.32-7.27 (m, 4H), 6.64-6.57 (m, 1H), 6.48 (dd, 7=10.3, 2.6 Hz, 1H), 5.98 (s, 1H), 5.20 (br s, 1H), 1.15 (s, 12H). Preparation 6 1 -Bromo-3-fluorobenzaldehyde To a solution of diisopropylamine (2.27 mol, 320 mL) in anhydrous tetrahydrofuran (800 mL) in a 5 L flask at 0 °C add 1.6 M butyllithium (1.16 L, 1.86 mol) in hexanes dropwise over 1.5 h. Stir the resulting yellow solution at 0 °C for 30 min. In a separate 12 L flask dissolve l-bromo-3-fluorobenzene (203 mL, 1.86 mol) in anhydrous tetrahydrofuran (650 mL) and cool to -78 °C. Transfer the preformed LDA solution to an addition funnel via cannula and add dropwise to the l-bromo-3-fluorobenzene solution over 2 h so the temperature does not rise above -70 °C. Stir the resulting slurry at -78 °C for 30 min. Add a solution of N-methyl-N-phenyl formamide (230 mL, 1.86 moles, 1.00 equiv.) in anhydrous tetrahydrofuran (1.15 L) dropwise at -78 °C over one hour while maintaining the temperature below -70 °C. Stir the reaction cold for 2 h while slowly allowing it to rise to room temperature overnight. Dilute the reaction with methyl tert-buiyl ether (3 L), quench with 1M hydrochloric acid (4 L) and stir vigorously for 3 h. Separate the layers and extract the aqueous layer with methyl tert-butyl ether (1 L). Wash the combined organic phases with 1M hydrochloric acid (2 x 1 L), water (1 L), brine (1 L), dry over magnesium sulfate, filter and concentrate to an orange oil that slowly solidifies to obtain the title compound (394 g, 105%). lR NMR (CDC13) 8 10.37 (s, 1 H), 7.50 (d, 1 H), 7.44 (m, 1 H), 7.17 (t, 1 H). Preparation 7 l-Bromo-3-fluorobenzyl alcohol To l-bromo-3-fluorobenzaldehyde (1.60 kg, 7.91 mol) in methanol (14 L) at 0 °C add sodium borohydride (284 g, 7.93 mol) in portions over 30 min to control the exotherm and gas evolution. After 15 min, quench with water (500 mL) and concentrate to obtain a yellow oil. Dissolve the oil in ethyl acetate (6 L) and wash with water (3 L). Extract the aqueous layer with ethyl acetate (1 L). Wash the combined organic phases with brine (2 L), dry over sodium sulfate, filter, and concentrate to obtain the title compound as an orange oil (1614 g, 100%). JH NMR (CDC13) 5 7.40 (d, 1 H), 7.18 (m, 1 H), 7.07 (t, 1 H), 4.86 (s, 2 H). Preparation 8 l-Bromo-3-fluorobenzyl bromide To a solution of l-bromo-3-fluorobenzyl alcohol (1.61 kg, 7.85 mol) in chloroform (14 L) at 0 °C add pyridine (770 mL, 9.52 mol) in one portion (slight exotherm) and stir at 0 °C for 5 min. Add phosphorus tribromide (900 mL, 9.49) dropwise while maintaining the internal temperature below 20 °C and stir the resulting solution overnight while allowing to warm to room temperature. Cool the reaction to 0 °C and quench slowly with ice water (2 L). Transfer to a 50 L flask, separate the layers and then extract the aqueous layer with chloroform (1 L). Wash the combined organic phases with 5% sulfuric acid (2 L), saturated aqueous sodium bicarbonate (2 L), brine (2 L), dry over magnesium sulfate, filter, and concentrate to obtain the title compound as a yellow oil (1753 g, 83%). lR NMR (CDCI3) 8 7.43 (d, 1 H), 7.21 (m, 1 H), 7.09 (t, 1 H), 4.68 (s, 2 H). Preparation 9 l-Bromo-2-(2-bromo-6-fluoro43enzyloxy)-4-fiuoro4)enzene To a solution of l-bromo-3-fluorobenzyl bromide (1.75 kg, 6.52 mol) and 2-bromo-5-fluorophenol (730 mL, 16.56 mol, 1.01 eq) inN, N-dimethylformamide (14 L) at 0 °C add potassium carbonate (1.36 kg, 9.80 mol) in one portion and stir the resulting slurry cold for one hour and then at room temperature overnight. Transfer the reaction mixture to a 50 liter flask, add water (14 L) drop wise over 30 min and ice periodically to control the exotherm of the crystallization. Stir at room temperature for one hour, collect off-white solids by filtration, wash with water, and dry overnight at 50 °C to obtain the title compound (2.22 kg, 90%). JH NMR (CDC13) 5 7.51 (m, 2 H), 7.30 (m, 1 H), 7.14 (t, 1 H), 6.89 (dd, 1 H), 6.67 (m, 1 H), 5.26 (d, 2 H). Preparation 10 (£)- (3,7-Difluoro-6H-dibenzo[b,e]oxepin-l l-ylidene)-acetic acid ethyl ester Degas a mixture of l-bromo-2-(2-bromo-6-fluoro-benzyloxy)-4-fluoro-benzene (886 mmol, 335 g), ethyl acrylate (931 mmol, 101 mL, 1.05 eq), Pd(OAc)2 (22.2 mmol, 4.97 g), tetrabutylammonium bromide (886 mmol, 286 g), and sodium acetate (4.40 mol, 363.5 g) in N-methylpyrrolidinone (3.3 L) by evacuating and back-filling with nitrogen five times. Heat the mixture to 120 °C for 2 h. Cool to 35 °C and add water (5.5 L) over 40 min. Filter the precipitate, rinse with water (2 x 500 mL) and air dry for 30 min. Reslurry the in isopropanol (1 L) for 2 h and cool on ice for one hour. Collect the dark gray solid by filtration, rinse with cold isopropanol (5 x 100 mL) and dry at 50 °C in vacuo to obtain the title compound (191 g, 68%). Preparation 11 (£)-ll-Bromomethylene-3,7-difluoro-6,ll-dihydro-dibenzo[b,e]oxepine Heat a stirred slurry of (£)-(3,7-difluoro-6H-dibenzo[b,e]oxepin-l 1-ylidene)-acetic acid ethyl ester (601 mmol, 190 g) in methanol (1.9 L) and 5 N sodium hydroxide (1.20 mol, 240 mL) to 50 °C for 2 h. Remove the methanol in vacuo and reslurry the resulting black sludge in water (3 L). Add 5 N hydrochloride acid (250 mL) over 45 min, stir for 2.5 h, filter, and rinse the residue with water (4 x 200 mL). Dry the gray solid in vacuo at 60 °C overnight, and 80 °C for 6 h. Dissolve the solid (still wet, contains approximately 95 g of water) and lithium acetate (60.1 mmol, 4 g, 0.1 eq) in acetonitrile (1.7 L) and stir for 15 min. Add N-bromosuccinimide (661 mmol, 118 g) in one portion and stir for 2.5 h. Add 0.25 M sodium thiosulfate (400 mL), followed by saturated aqueous sodium bicarbonate (400 mL), and water (900 mL). Stir the mixture for one hour at room temperature and then stir for 2 h on an ice bath. Filter the mixture and rinse with cold acetonitrile (300 mL). Dry overnight in vacuo at 50 °C to obtain the title compound as a light beige solid (173.3 g, 89%). *H NMR (DMSO-d6) 8 5.25 (s, 2H), 6.67 (dd, 1H), 6.81 (dt, 1H), 7.20 (s, 1H), 7.22 (d, 1H), 7.28 (t, 1H), 7.36 (dd, 1H), 7.48 (m, 1H). Preparation 12 (£)-2-((3,7-difluorodibenzo[b,e]oxepin-ll(6H)-ylidene)methyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane To a mixture of (E)-l l-(bromomethylene)-3,7-difluoro-6, 11-dihydrodibenzo[b,e]oxepine (46.4 mmol, 15.0 g) and bis(pinacolato)diboron (50.3 mmol, 15.3 g) in 1,4-dioxane (150 mL) add potassium acetate (74.3 mmol, 7.29 g), tricyclohexyl phosphine (6.03 mmol, 1.69 g) and Pd2(dba)3 (2.32 mmol, 2.13 g). Flush by bubbling with nitrogen, then stir with heating at 65 °C overnight. After cooling to room temperature, filter the mixture through a pad of diatomaceous earth, wash the pad with ethyl acetate, and remove the solvent to obtain a brown oil. Dilute the oil with methanol (180 mL) and swirl the resulting mixture on a rotory evaporator without vacuum for 3 h causing a white precipitate to form. Collect the precipitate by vacuum filtration to obtain the title compound (10.8 g, 63%) as a white solid. JHNMR (300 MHz, CDC13) 8 7.34 (dd, .7=8.8, 6.7 Hz, 1H), 7.24-7.18 (m, 1H), 7.08-7.01 (m, 2H), 6.65-6.59 (m, 1H), 6.50 (dd, .7=10.3, 2.6 Hz, 1H), 5.99 (s, 1H), 5.31 (d, .7=0.9 Hz, 2H), 1.16 (s, 12 H). Preparation 13 (E)-11-Bromomethylene-3,8-difluoro-6,11-dihydro-dibenzo[b,e]oxepine Prepare the title compound essentially as described in Preparations 9, 10 and 11, starting with l-bromo-2-bromomethyl-4-fluoro-benzene and 2-bromo-5-fluoro-phenol. Preparation 14 (E)-2-((3,8-difluorodibenzo[b,e]oxepin-ll(6H)-ylidene)methyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane To a mixture of (E)-l l-(bromomethylene)-3,8-difluoro-6,ll-dihydrodibenzo[b,e]oxepine (90.0 mmol, 29.0 g) and bis(pinacolato)diboron (117 mmol, 29.5 g) in 1,4-dioxane (295 mL), add potassium acetate (144 mmol, 14.1 g), tricyclohexyl phosphine (11.7 mmol, 3.28 g), and Pd2(dba)3 (4.14 mmol, 3.80 g). Flush by bubbling nitrogen through the mixture, then heat at 65 °C overnight. After cooling to room temperature, filter through a pad of diatomaceous earth and wash with ethyl acetate. Concentrate the filtrate in vacuo to obtain a brown oil. Dilute the oil with methanol (180 mL) and swirl the resulting mixture for 1.5 h on a rotory evaporator without vacuum, causing a brown precipitate to form. Collect the precipitate by vacuum filtration to obtain the title compound as a brown solid (24.2 g, 73%). !H NMR (300 MHz, CDC13) 8 7.35 (dd, .7=8.8, 6.7 Hz, 1H), 7.29-7.24 (m, 1H), 7.05-6.93 (m, 2H), 6.65-6.59 (m, 1H), 6.49 (dd, ,7=10.2, 2.6 Hz, 1H), 5.99 (s, 1H), 5.15 (br s, 2H), 1.16 (s, 12H). Preparation 15 (R)-Methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester Add methanesulfonyl chloride (0.128 mol, 14.7 g, 1.5 equiv.) drop wise to a solution of (R)-(+)- 2- te/t-butoxy-carbonylamino-1-propanol (0.085 mol, 15.0 g) and triethylamine (0.12 mol, 17.3 g, 2.0 equiv.) in dichloromethane (150 mL) at 0 °C under nitrogen. Upon complete addition, warm the reaction mixture to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane, wash with 0.1 N hydrochloric acid and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (20.8 g, 96%) as white solid. JH NMR (400 MHz, CDC13)8 1.24 (d, 3H), 1.43 (s, 9H), 3.03 (s, 3H), 3.97 (br s, 1H), 4.14 (dd, 1H), 4.21 (br s, 1H), 4.64 (br s, 1H, Boc-NH). Preparation 16 (R)-(l-Methyl-2-morpholin-4-yl-ethyl)-carbamic acid tot-butyl ester Heat a mixture of (R)-methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester (0.083 mol, 20 g) and morpholine (0.83 mol, 72.2 g) in acetonitrile (210 mL) to 65°C for 16 h. Concentrate the reaction mixture, dilute the residue with water, extract with dichloromethane, combine organic layer and wash with water. Dry the organic layer over anhydrous sodium sulfate, filter and concentrate under vacuum to obtain the title compound (12 g, 62%) as yellow thick oil. JH NMR(400 MHz, CDC13)5 1.13 (d, 3H), 1.43 (s, 9H), 2.21 (dd, 1H), 2.26-2.32 (m, 1 H), 2.35-2.39 (m, 2 H), 2.48-2.55 (m, 2 H), 3.63-3.70 (m, 5 H), 4.68 (br s, 1H, -NH). Preparation 17 (R)-1 -Methyl-2-morpholin-4-yl-ethylaminehydrochloride Add 1.6 M hydrogen chloride in dioxane (120 mL) to a solution of (R)-(l-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-buiyl ester (0.05 mol, 12 g) in dry dichloromethane (75 mL) at 0 °C. Warm the reaction mixture to room temperature and stir for 2 h. Filter the precipitate and dry under vacuum to obtain the title compound (9.2 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 1.29 (d, 3H), 3.10 (br s, 2H), 3.38 (br s, 4H), 3.79 (br s, 5H). Preparation 18 (i?)-(4-Bromo-2-nitro-phenyl)-(l-methyl-2-morpholin-4-yl-ethyl)-amine Reflux a mixture of (i?)-l-methyl-2-morpholin-4-yl-ethylaminehydrochloride (0.04 mol, 8.7 g), 5-bromo-2-fluoronitrobenzene (0.048 mol, 10.5 g), triethylamine (0.20 mol, 20.2 g) and dimethylaminopyridine (0.0004 mol, 0.048 g) in ethyl acetate (220 mL) for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 10% ethyl acetate in hexanes as eluent to obtain the title compound (12.8 g, 95%) as an orange solid. *H NMR (400 MHz, CDC13) 8 1.29 (d, 3H), 2.47-2.51 (m, 5 H), 2.53-2.58 (m, 1 H), 3.64-3.69 (m, 4 H), 3.72-3.78 (m, 1H), 6.78 (d, 1H), 7.46 (dd, 1H), 8.30(d, 1H), 8.33 (d, 1H). Prepare the intermediates in the table below by essentially following the procedures as described in Preparations 15, 16, 17, and 18 starting from (E)-(-)- 2- tert-butoxy-carbonylamino-1-propanol or terf-butyl-N-(2-hydroxyethyl)carbamate respectively. Prep Chemical Name Physical Data 19 (S)-(4-Bromo-2-nitro-phenyl)-(l-methyl-2-morpholin-4-yl-ethyl)-amine !H NMR (400 MHz, CDC13) 5 1.29 (d, 3H), 2.46-2.58 (m, 6 H), 3.63-3.69 (m, 4 H), 3.71-3.79 (m, 1H), 6.77 (d, 1H), 7.45 (dd, 1H), 8.29 (d, 1H), 8.33 (d, 1H). Preparation 20 (4-Bromo-2-nitro-phenyl)-(4-methyl-piperazin-1 -yl)-amine Heat a mixture of l-amino-4-methyl piperazine (0.217 mol, 25.0 g), 5-bromo-2-fluoronitrobenzene (0.239 mol, 52.6 g) and triethylamine (0.46 mol, 46 g) in ethyl acetate (900 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 5% methanol in dichloromethane as eluent to give the title compound (43.2g, 63%). ES-MS m/z 315 [M+l]+. Preparation 21 3-(4-Bromo-2-nitro-phenylamino)-azetidine-l-carboxylic acid tert-butyl ester Dissolve 5-bromo-2-fluoronitrobenzene (28.8 mmol, 3.55 mL), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (28.8 mmol, 4.96 g), and triethylamine (35.9 mmol, 5.00 mL) in ethyl acetate (100 mL) and reflux under nitrogen for 48 h. Cool to room temperature. Wash with 0.5 M hydrochloric acid twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain a bright orange solid (11.04 g, >100%). LC-MS m/z (79Br/81Br) 394.0/396.0 [M+H]+. Preparation 22 Azetidin-3-yl-(4-bromo-2-nitro-phenyl)-amine, hydrochloride Stir a solution of 3-(4-bromo-2-nitro-phenylamino)-azetidine-l-carboxylic acid tert-butyl ester (29.66 mmol, 11.04 g) in 4.0 M hydrogen chloride in dioxane (40 mL) at room temperature under nitrogen overnight. Solids crash out of solution. Dilute with ether (200 mL), filter off solids, rinse with ample ether and dry (8.54 g, 93%). lR NMR (400 MHz, CD3OD): 4.12 (dd, 2H), 4.45 (dd, 2H), 4.72 (m, 1H), 6.76 (d, 1H), 7.62 (dd, 1H), 8.30 (d, 1H). LC-MS m/z (79Br/81Br) 272.0/274.0 [M+H]+. Preparation 23 (4-Bromo-2-nitro-phenyl)-(1-methyl-azetidin-3-yl)-amine To a mixture of azetidin-3-yl-(4-bromo-2-nitro-phenyl)-amine, hydrochloride (27.7 mmol, 8.54 g) in acetonitrile (100 mL) and 37% aqueous formaldehyde (83.0 mmol, 6.28 mL, 3.00 equiv.) at 0 °C add sodium triacetoxyborohydride (88.6 mmol, 18.8 g) slowly. Stir at room temperature under nitrogen overnight. Remove volatiles under reduced pressure. Dilute with ethyl acetate, wash with 10% aqueous sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 8.5 g of an orange solid. Purify on a 120 g silica column eluting with 5% methanol in dichloromethane to obtain the title compound (5.92 g, 75%>). LC-MS m/z (79Br/81Br) 286.0/288.0 [M+Hf. Preparation 24 (2S, 4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Addthionyl chloride (1.07 mol, 128.2 g) drop wise to a solution of (25, 4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (0.70 mol, 93.0 g) in dry methanol (2 L) at 0 °C under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 6 h. Concentrate the reaction mixture under reduced pressure to obtain the corresponding methyl ester hydrochloride. Add triethylamine (1.56 mol, 157.5 g) to a solution of methyl ester hydrochloride in dry dichloromethane (2 L) at 0 °C and stir for 30 min. Then add N, N-dimethylaminopyridine (0.10 mol, 13 g) and di-tot-butyl dicarbonate (0.85 mol, 185.7 g) consecutively. Warm the reaction mixture to room temperature and stir for 18 h. Quench the reaction mixture with water, separate the organic layer, and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (160 g, 91%) as viscous oil. ES-MS m/z 246.1 [M+l]+. Preparation 25 (2R, 4i?)-4-Hydroxy-pyrrolidine-2-carboxylic acid, hydrochloride To a mixture of acetic anhydride (408 g) and acetic acid (1.2 L) at 50 °C add trans-4-hydroxy-L-proline (0.36 mol, 94 g) in a single portion. Heat the reaction mixture for 5.5 h at 90 °C and then concentrate it. Dissolve the residue in 2 N hydrochloric acid and reflux for 3 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum until white needles form. Filter the crystals, wash with ether, and dry under vacuum to obtain the title compound (90.0 g, 75%). [α]D20 + 10.0 (c = 1.0 in methanol). 1H NMR (400 MHz, D20O), δ 2.34-2.39 (m, 1H), 2.45-2.53 (m, 1H), 3.38 (dd, 1H), 3.45 (d, 1H), 4.50 (dd, 1H), 4.58 (br s, 1H). Preparation 26 (2R, 4R)-4-Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Add thionyl chloride (1.81 mol, 213.8 g, 1.5 eq) drop wise to a solution of (2R, 4K)-4-hydroxy-pyrrolidine-2-carboxylic acid hydrochloride (1.19 mol, 200 g) in dry methanol (2 L) at 0 °C under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 6 h. Concentrate the reaction mixture under reduced pressure to obtain the corresponding methyl ester hydrochloride. Add triethylamine (265.9 g, 2.63 mol) to a solution of methyl ester hydrochloride in dry dichloromethane (2 L) at 0 °C and stir for 30 min. Then add N,N-dimethylaminopyridine (0.18 mol, 21.9 g) and di-tot-butyl dicarbonate (1.43 mol, 313.5 g) consecutively. Warm the reaction mixture to room temperature and stir for 18 h. Quench the reaction mixture with water, separate the organic layer and wash with water and NaHCC>3 solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (260 g, 88%>) as a thick oil. 1H NMR (400 MHz, CDC13) 5 1.43 (s, 9H), 1.46 (s, 9 H), 2.05-2.10 (m, 2H), 2.26-2.35 (m, 2H), 3.48-3.56 (m, 2H), 3.58-3.61 (m, 1H), 3.64-3.70 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 4.27-4.29 (m, 1H), 4.34-4.38 (m, 2H). Preparation 27 (2S, 4/?)-4-Methanesulfonyloxy-pyrrolidine-l,2-dicarboxylic acid l-tert-buty\ ester 2-methyl ester Add methanesulfonyl chloride (1.56 mol, 179 g) drop wise to a solution of (2S, 4R)-4-hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-te/t-butyl ester 2-methyl ester (0.65 mol, 160 g) in pyridine (600 mL) at 0 °C under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane, wash with 0.1 N hydrochloric acid solution and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (185 g, 91%) as a thick oil. ES-MS m/z 324.1 [M+lf, 224.0 [M-Boc]+. Preparation 28 (2R, 4i?)-4-Methanesulfonyloxy-pyrrolidine-l,2-dicarboxylic acid l-tert-butyl ester 2-methyl ester Prepare the title compound essentially as described in Preparation 27 from (2R, 4i?)-4-hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. ES-MS m/z 324.1 [M+l]+. Preparation 29 (2S, 4S)-Bromo-pyrrolidine-l^-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Add triphenylphosphine (0.88 mol, 231 g) in portions to a solution of (2S, 4R)-4-hydroxy-pyrrolidine-l,2-dicarboxylic acid l-tert-buty\ ester 2-methyl ester (0.58 mol, 144 g) and CBr4 (0.88 mol, 292 g) in dry dichloromethane (1.44 L) at 0 °C. Upon complete addition, warm the reaction mixture to room temperature and stir for 4 h. Add ethanol (1.44 L) and stir for an additional 2 h. Add diethyl ether (1.44 L) to the reaction mixture, filter the precipitated triphenylphosphine oxide, and concentrate the filtrate under reduced pressure. Purify by column chromatography using 5% ethyl acetate in hexanes as eluent to obtain the title compound (155 g, 85%) as a thick oil. ES-MS m/z 308 [M+lf. Preparation 30 (2R, 4S)-4-Bromo-pyrrolidine-l,2-dicarboxylic acid l-tert-butyl ester 2-methyl ester Prepare the title compound essentially as described in Preparation 29 from (2R, 4R)-4-hydroxy-pyrrolidine-l,2-dicarboxylic acid l-tert-butyl ester 2-methyl ester. 1HNMR(400 MHz, CDC13) 8 1.45-1.47 (s, 9H), 2.38-2.45 (m, 1H), 2.54-2.59 (m, 1H), 3.72-3.74 (s, 3H), 3.84-3.87 (m, 1H), 3.92-3.94 (m, 1H), 4.44-4.54 (m, 2H). Preparation 31 (2S, 4S)-4-Azido-pyrrolidine-l,2-dicarboxylic acid l-tert-butyl ester 2-methyl ester Heat a mixture of (2S, 4R)-4-methanesulfonyloxy-pyrrolidine-l, 2-dicarboxylic acid l-tert-butyl ester 2-methyl ester (0.60 mol, 185 g) and sodium azide (1.20 mol, 78 g,) in N,N-dimethylformamide (1 L) to 80 °C for 16 h. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution, and brine. Dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (140 g, 88%) as a thick, yellow oil. ES-MS m/z 271.2 [M+l]+, 171.0 [M-Boc]+. Prepare the intermediates in the table below by essentially following the procedures as described in Preparation 31 starting from the appropriate bromo or mesyl-pyrolidine. Prep Chemical Name Physical Data 32 (2S, 4R)-4-Azido-pyrrolidine-1,2-dicarboxylic acid l-tert-butyl ester 2-methyl ester 33 (2R, 4R)-4-Azido-pyrrolidine-1,2-dicarboxylic acid 1-tert- !H NMR (400 MHz, CDC13) 5 1.40-1.41 (s,9H), 2.09-2.13 (m,lH), 2.40-2.44 (m, 1H), 3.37-3.45 (m, Prep Chemical Name Physical Data butyl ester 2-methyl ester 1H), 3.61-3.65 (m, 1H), 3.67-3.69 (s, 3H), 4.09-4.15 (m,lH), 4.25-4.38 (m, 1H). 34 (2R, 4S)-4-Azido-pyrrolidine-1,2-dicarboxylic acid 1-tot-butyl ester 2-methyl ester ES-MSm/z271 [M+l]+, 171.1 [M-Boc]+ base peak 65 °C for 161 I Preparation 35 (2S, 4S)-4-Azido-2-hydroxymethyl-pyrrolidine-l-carboxylic acid tot-butyl ester Add lithium borohydride (0.16 mol, 3.6 g) to a solution of (2S, 4S)-4-azido-pyrrolidine-l,2-dicarboxylic acid 1-tot-butyl ester 2-methyl ester (0.16 mol, 40 g) in anhydrous diethyl ether (400 mL) at -10 to -20 °C under a nitrogen atmosphere. Upon complete addition, stir the reaction mixture for 30 min at the same temperature. Quench the reaction mixture with saturated sodium bicarbonate solution at -70 °C and allow it to come to room temperature slowly. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (32 g, crude) as a thick, yellow oil. 1H NMR (400 MHz, CDC13) 8 1.46 (s, 9H), 2.32-2.35 (m, 1H), 3.30 (dd, 1H), 3.65-3.79 (m, 4H), 4.07-4.29 (m, 2H). Prepare the intermediates in the table below by essentially following the procedures as described in Preparation 35 starting from the appropriate pyrrolidine-2-carboxylic acid methyl ester. Prep Chemical Name 36 (2S, 4R)-4-Azido-2-hydroxymethyl-pyrrolidine-1 -carboxylic acid tot-butyl ester 37 (2R, 4R)-4-Azido-2-hydroxymethyl-pyrrolidine-1 -carboxylic acid tot-butyl ester 38 (2R, 4S)-4-Azido-2-hydroxymethyl-pyrrolidine-1 -carboxylic acid tot-butyl ester Preparation 39 (2S, 45)-4-Amino-2-hydroxymethyl-pyrrolidine-l-carboxylic acid tert-buty\ ester H2N N Boc 0H Dissolve (25, 45)-4-azido-2-hydroxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (32 g) in methanol (150 mL). Add 10% palladium on carbon (3.2 g) and hydrogenate (1 atm) at room temperature for 16 h. Filter off the catalyst through a plug of diatomaceous earth and concentrate under vacuum to obtain the title compound (28 g, crude) as a thick, yellow oil. Prepare the intermediates in the table below by essentially following the procedures as described in Preparation 39 starting from the appropriate azido-pyrrolidine. Prep Chemical Name Structure 40 (2S, 4R)-4-Amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester Boc 0H 41 (2R, 4R)-4-Amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester H2N N \ Boc 0H 42 (2R, 4S)-4-Amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester H2N Boc 0H Preparation 43 (25, 45)-4-(4-Bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1 -carboxylic acid tot-butyl ester Boc Heat a mixture of (25, 45)-4-amino-2-hydroxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (0.14 mol, 31 g), 5-bromo-2-fluoronitrobenzene (0.29 mol, 64.0 g) and triethylamine (0.58 mol, 59 g) in ethyl acetate (320 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (42 g, crude) as a thick, dark, orange oil. Preparation 44 (25, 45)-[4-(4-Bromo-2-nitro-phenylamino)-pyrrolidin-2-yl]-methanol, hydrochloride H NO2 Add 4.0 M hydrogen chloride in dioxane (950 mL) slowly to a solution of (25, 45)-4-(4-bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1 -carboxylic acid tert-butyl ester (0.22 mol, 95 g) in dry dichloromethane (475 mL) at room temperature and stir for 2 h. Filter the precipitated solid and dry under vacuum to obtain the title compound (70 g, 87%) as an orange solid. lR NMR (400 MHz, CD3OD)5 1.98-2.05 (m, 1H), 2.71-2.79 (m, 1H), 3.36 (dd, 1H), 3.58-3.63 (m, 1H), 3.76 (dd, 1H), 3.88-3.95 (m, 2H), 4.55-4.58 (m, 1H), 7.03 (d, 1H), 7.66 (dd, 1H), 8.30 (d, 1H). Prepare the intermediates in the table below by essentially following the procedures as described in Preparations 43 and 44 starting from the appropriate amino-pyrrolidine. Prep Chemical Name Physical Data 45 (25, 4R)-[4-(4-Bromo-2-nitro-phenylamino)-pyrrolidin-2-yl]-methanol, hydrochloride *H NMR (400 MHz, DMSO-d6) 8 2.01-2.10 (m, 2H), 3.06-3.10 (m, 2H), 3.47-3.60 (m, 3H), 3.62-3.71 (m, 2H), 3.83 (brs, 1H), 4.49-4.50 (m, 1H), 7.09 (d, 1H), 7.72 (dd, 1H), 7.94 (d, 1H), 8.2 (d, 1H), 9.10 (br s, 1H, HC1), 9.60 (br s, 1H, HC1). 46 (2R, 4R)-[4-(4-Bromo-2-nitro-phenylamino)-pyrrolidin-2-yl]-methanol, hydrochloride lR NMR (400 MHz, DMSO-J6) 8 1.80-1.85 (m, 1H), 2.54-2.59 (m, 1H), 3.43-3.51 (m, 3H), 3.56-3.63 (m, 1H), 3.69-3.72 (m, 2 H), 4.50 - 4.5 l(m, 1H), 7.10 (d, 1H), Prep Chemical Name Physical Data 7.55 (dd, 1H), 8.14 (d, 1H, -NH), 8.20 (d, 1H). 47 (2R, 4S)-[4-(4-Bromo-2-nitro-phenylamino)-pyrrolidin-2-yl]-methanol, hydrochloride 'H NMR (400 MHz, DMSO-d6) 8 2.08-2.21 (m, 2H), 3.27 ( d, 1H), 3.57-3.61 (m, 2H), 3.68-3.71 (m, 1H), 3.83 (brs, 1H), 4.47-4.51 (m, 1H), 5.44 (br s, 1H), 7.08 (d, 1H), 7.72 (dd, 1H), 7.94 (d, 1H), 8.20 (d, lH),9.06(brs,lH), 9.59 (brs, 1H). Preparation 48 (7S, &5)-7-(4-Bromo-2-nitro-phenylamino)-tetrahydro-pyrrolo[2,l-c][l,4]oxazin- 4-one Add chloroacetyl chloride (0.49 mol, 55.7 g) drop wise to a solution of (2S, 45)-[4-(4-bromo-2-nitro-phenylamino)-pyrrolidin-2-yl]-methanol, hydrochloride (0.22 mol, 79 g) in tetrahydrofuran/water (1:1) mixture (1180 mL) at room temperature. Maintain the reaction pH between 10-12 by continuous addition of 4 M sodium hydroxide solution. After complete addition of chloroacetyl chloride, stir the reaction mixture for 4 h at room temperature. Remove tetrahydrofuran under reduced pressure and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (50 g, 62%) as an orange solid. lH NMR (400 MHz, CDC13) 8 1.59-1.67 (m, 1H), 2.58-2.64 (m, 1H), 3.40 (t, 1H), 3.71 (dd, 1H), 3.91-4.01 (m, 2H), 4.09 (d, 1H), 4.20 (dd, 1H), 4.29-4.35 (m, 2H), 6.75 (d, 1H), 7.54 (dd, 1H), 8.05 (d, 1H), 8.32 (d, 1H). Preparation 49 (4-Bromo-2-nitro-phenyl)-((7Sr, &5)-hexahydro-pyrrolo[2,l-c][l,4]oxazin-7-yl)- amine Add BH3.THF (1.0 M in tetrahydrofuran, 0.056 mol, 56 mL) drop wise to a solution of (7S,8αS)-7-(4-bromo-2-nitro-phenylamino)-tetrahydro-pyrrolo [2,1-c][l,4] oxazin-4-one (0.028 mol, 10 g) in tetrahydrofuran (150 mL) at 0 to -5 °C under nitrogen. After complete addition, reflux the reaction mixture for 3 h. Cool the reaction mixture to 0 °C, quench with 1 N hydrochloric acid, and then add 1 N aqueous sodium hydroxide solution. Remove tetrahydrofuran under reduced pressure and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in methanol (160 mL), add 4 N hydrogen chloride in dioxane (160 mL) and heat the reaction mixture for 4 h at 80 °C. Cool to room temperature and adjust the pH between 10-12 by adding 4 N aqueous sodium hydroxide solution. Remove the methanol under reduced pressure and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the title compound as a crystalline, yellow solid (8.0 g, 83%). JH NMR (400 MHz, CDC13) 5 1.32-1.38 (m, 1H), 2.19-2.22 (m, 1H), 2.34 (dt, 1H), 2.42-2.47 (m, 1H), 2.54-2.58 (m, 1H), 2.92 (d, 1H), 3.07 (d, 1H), 3.34 (t, 1H), 3.61 (dt, 1H), 3.85 (dd, 1H), 3.97 (dd, 1H), 4.01-4.07 (m, 1H), 6.67 (d, 1H), 7.48 (dd, 1H), 8.17 (d,lH), 8.35 (d,lH). Prepare the intermediates in the table below by essentially following the procedures as described in Preparations 48 and 49 starting from the appropriate phenyl-amino-pyrrolidine. Perform the reduction of the tetrahydro-pyrrolo[2,l-c][l,4]oxazin-4-one with borane-tetrahydrofuran complex or borane-dimethyl sulfide complex, for example, with Preparations 50 and 51. Prep Chemical Name Physical data 50 (7R, &zS)-(4-Bromo-2-nitro-phenyl)-(hexahydro-pyrrolo [2,1-c][l,4]oxazin-7-yl)-amine !H NMR (400 MHz, CDC13) 8 1.30-1.36 (m, 1H), 2.18-2.25 (m, 1H), 2.31-2.38 (m, 1H), 2.42-2.47 (m, 1H), 2.53-2.58 (m, 1H), 2.90 (d, 1H), 3.06 (d, 1H), 3.34 (t, 1H), 3.62 (dt, 1H), 3.86 (dd, 1H), 3.97 (dd, 1H), 4.01-4.09 (m, 1 H), 6.67 (d, 1H), 7.49 (dd, 1H), 8.16 (d, 1H, -NH), 8.32 (d, 1H). 51 (7R, 8aR)-(4-Bvomo-2-nitro-phenyl)-(hexahydro-pyrrolo [2,1-c][l,4]oxazin-7-yl)-amine JH NMR (400 MHz, CDCI3) 8 1.30-1.36 (m, 1H), 2.18-2.25 (m, 1H), 2.31-2.38 (m, 1H), 2.42-2.47 (m, 1H), 2.53-2.58 (m, 1H), 2.90 (d, 1H), 3.06 (d, 1H), 3.34 (t, 1H), 3.62 (dt, 1H), 3.86 (dd, 1H), 3.97 (dd, 1H), 4.01-4.09 (m, 1 H), 6.67 (d, 1H), 7.49 (dd, 1H), 8.16 (d, 1H, -NH), 8.32 (d, 1H). 52 (7S, 8aR)-(4-Bromo-2-nitro-phenyl)-(hexahydro-pyrrolo [2,1-c][l,4]oxazin-7-yl)-amine JH NMR (400 MHz, CDC13) 8 1.69 (dd, 1H), 1.88-1.96 (m, 1H), 2.17-2.24 (m, 1H), 2.42-2.48 (m, 2H), 2.93 (d, 1H), 3.27 (t, 1H), 3.57 (t, 1H), 3.68-3.75 (m, 1H), 3.87 (d, 1H), 3.97 (d, 1H), 4.09-4.17 (m, 1H), 6.69 (d, 1H), 7.50 (d, 1H), 8.07 (d, 1H), 8.32 (d, 1H). Preparation 53 Tert-buty\ 2,5-dihydro- \H-pyno\e-1 -carboxylate Add a solution of di-tert-butyl dicarbonate (0.69 mol, 151.0 g) in methylene chloride (200 mL) dropwise to a solution of 3-pyrroline (40.0 g, 0.57 mol) in methylene chloride (400 mL) over a period of 1.5 h at 0 °C and stir at room temperature for 10 h. Remove the solvent and carry the crude product on to the next step, Preparation 47 (95.0 g, 98%). Preparation 54 Rac-trans-3-Bromo-4-hydroxy-pyrrolidine- 1-carboxylie acid tert-butyl ester To a stirred mixture of tert-butyl 2,5-dihydro-1H-pyrrole-l-carboxylate (0.29 mol, 50.0 g) in dimethylsulfoxide (360 mL) and water (18 mL) add N-bromosuccinimide (0.325 mol, 58.0 g) gradually over 15 min at 0 °C. After stirring at room temperature for 2 h, add water (500 mL) and extract with ethyl acetate. Wash the organic layer with brine, dry over sodium sulfate and concentrate in vacuo to obtain the title compound as a light brown oil (75.0 g, 95%). 1H NMR (500 MHz, CDC13) 5 4.43-4.53 (m, 1H), 4.12-4.20 (m, 1H), 3.96-4.11 (m, 2H), 3.68-3.94 (m, 2H), 3.32-3.48 (m, 1H), 1.47 (s, 9H). Preparation 55 Rac-trans-3-Benzylamino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester Stir a mixture of crude rac-trans-3-bromo-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (75.0 g) and aqueous 1 N sodium hydroxide (400 mL) at room temperature for 2 h. Add benzylamine (0.86 mol, 80.0 g,), stir at 65 °C for 4.5 h and then cool to 0 °C. Collect the resultant precipitates by filtration, wash with water and isopropyl ether and dry to obtain the title compound as a white solid (50.0 g, 63%). 1H NMR (300 MHz, CDC13) 8 7.21-7.38 (m, 5H), 4.06-4.15 (m, 1H), 3.84 (d, .7=5.0 Hz, 2H), 3.57-3.75 (m, 2H), 3.10-3.35 (m, 3H), 1.65 (br s, 2H), 1.46 (s, 9H). Preparation 56 (3S, 45)-3-Benzylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester, (+)-mandelic acid salt Heat a mixture of rac-trans-3-benzylamino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (0.343 mol, 100.0 g) and (+)-mandelic acid (0.378 mol, 57.83 g) in acetonitrile (1 L) and water (10 mL) at 70 °C for one hour and then cool to room temperature during 4 h. Collect the resultant crystalline precipitate by filtration, wash with acetonitrile, and recrystallize from acetonitrile/ water (20:1) to give the title compound as a white crystalline solid (62.0 g, 40%). 1H NMR (500 MHz, CDCI3) 5 7.19-7.44 (m, 8H), 5.05 (br s, 2H), 4.97 (s, 1H), 3.95-4.02 (m, 1H), 3.73 (s, 2H), 3.28-3.50 (m, 4H), 2.95-3.18 (m, 3H), 1.39 (s, 9H),; mp 185-188, [a]23D +50.0° (c 0.50, MeOH). Preparation 57 (3S, 4S)-3-Benzylamino-4-hydroxy-pyrrolidine- 1-carboxylic acid te/t-butyl ester To (3S, 4S)- 3-benzylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (+)-mandelic acid salt (60.0 g) add 3% aqueous potassium carbonate (300 mL) and extract the free amine with ethyl acetate (3 x 250 mL). Wash the combined organic layer with brine and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to obtain the (S,S)-enantiomer as a white solid (34.0 g, 65%). APCI MS m/z 293 [M + H]+; mp 69-70 °C, [a]23D +18.0° (c, 0.50, MeOH). Preparation 58 (3S, 4S)-3-Amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-buty\ ester To a solution of (3S, 4S)-3-benzylamino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (0.054 mol, 16.0 g) in «-butanol (225 mL) add 10% Pd/C (5.0 g) and hydrogenate the mixture at 50 psi for 10 h. Filter the reaction mixture thorough a plug of diatomaceous earth and wash with ethanol. Evaporate the filtrate to obtain the title compound as a white solid (11.10 g, 99%). APCI MS m/z 203 [M + H]+; [α]23D +7.8° (c, 0.50, MeOH). Preparation 59 (3S, 4S)-3 -(4-Bromo-2-nitro-phenylamino)-4-hydroxy-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of l-bromo-4-fluoro-3-nitrobenzene (0.125 mol, 26.0 g) in ethyl acetate (300 mL) add (3S, 4S)-3-benzylamino-4-hydroxy-pyrrolidine-l-carboxylic acid tot-butyl ester (0.113 mol, 23.0 g) and triethylamine (0.339 mol, 35.0 g), reflux for 14 h, cool to room temperature, and wash with water and brine. Dry over anhydrous sodium sulfate, evaporate the solvent, and purify by flash column chromatography to give the title compound as a yellow solid (43.0 g, 90%). APCI MS m/z 403 [M + H]+. Preparation 60 (3R, 4R)-3-Benzylamino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester, (-)-mandelic acid salt Mix racemic trans-3-benzylamino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (0.085 mol, 25.0 g) and (-)-mandelic acid (0.094 mol, 14.45 g, 1.1 eq) in acetonitrile (200 mL) and water (5 mL) at 70 °C for one hour. Cool to room temperature during 4 h. Collect the resulting crystalline precipitate by filtration, wash with acetonitrile, and recrystallize from acetonitrile/water (20:1) to obtain the (-)-mandelic acid salt as a white crystalline solid (34.0 g, 88%). JH NMR (500 MHz, CDC13) 8 7.19-7.44 (m, 8H); 5.05 (br s, 2H), 4.97 (s, 1H), 3.95-4.02 (m, 1H), 3.73 (s, 2H), 3.28-3.50 (m, 4H), 2.95-3.18 (m, 3H), 1.39 (s, 9H); [af D-58.0° (c 0.50, MeOH). Preparation 61 (3R,4R)-3-(4-Bromo-2-nitro-phenylamino)-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester Prepare the title compound by essentially following the procedures as described in Preparations 58, 59, and 60 starting from (3R, 4R)- 3-benzylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (-)-mandelic acid salt. Preparation 62 (3S, 4R)-tert-b\xty\ 3-(4-bromo-2-nitrophenylamino)-4-(2-chloroacetoxy)pyrrolidine-1 -carboxylate To a mixture of (3S, 4S)-tert-buty\ 3-(4-bromo-2-nitrophenylamino)-4-hydroxypyrrolidine-1-carboxylate (2.50 mmol, 1.0 g), chloroacetic acid (3.0 mmol, 300 mg) and triphenylphosphine (3.0 mmol, 850 mg) in tetrahydrofuran (40 mL) add diethylazodicarboxylate (3.0 mmol, 600 mg) and stir at room temperature for 12 h. Remove the solvent, add ethyl acetate (50 mL) to the residue and wash with water and brine. Dry over anhydrous sodium sulfate and evaporate. Purify the residue by column chromatography, eluting with 20% ethyl acetate in methylene chloride to obtain the title compound as a yellow solid (1.10 g, 98%). XH NMR (500 MHz, CDCI3) 5 8.35 (s, 1H), 8.20 (m, 1H), 7.60 (m, 1H), 6.82 (m, 1H), 5.55 (d, .7=6.8 Hz, 1H), 4.32 (m, 1H), 4.13 (bd, .7=8.2 Hz, 2H), 3.90 (m, 1H), 3.79 (m, 1H), 3.74 (dd, .7=4.2, 10.4 Hz, 1H), 3.25 (t, .7=7.20 Hz, 1H), 1.41 (s, 9H). Preparation 63 (3S, 4R)-tert-buty\ 3 -(4-bromo-2-nitrophenylamino)-4-hydroxypyrrolidine-1 - carboxylate To a solution of the (3S,4R)-tert-buty\ 3-(4-bromo-2-nitrophenylamino)-4-(2-chloroacetoxy)pyrrolidine-l-carboxylate (2.20 mmol, 1.0 g) in methanol add 2.0 M aqueous lithium hydroxide (5 mL) and stir at room temperature for 3.5 h. Remove the solvent, dilute the residue with ethyl acetate (50 mL), and wash with water and brine. Dry over anhydrous sodium sulfate, filter, and evaporate the solvent. Purify by column chromatography eluting with 50% ethyl acetate in methylene chloride to obtain the title compound as a yellow solid (900 mg, 98%). APCI MS m/z 462 [M + H]+. Preparation 64 (3R, 4S)-tert-butyl 3 -(4-bromo-2-nitrophenylamino)-4-hydroxypyrrolidine-1 - carboxylate Prepare the title compound by essentially following the procedures as described in Preparations 62 and 63 starting from (3R,4R)-tert-butyl 3-(4-bromo-2-nitrophenylamino)-4-hydroxypyrrolidine-1 -carboxylate. Preparation 65 (3S, 4S)-4-(4-Bromo-2-nitro-phenylamino)-pyrrolidin-3-ol, hydrochloride To a suspension of the (3S, 45)-3-(4-bromo-2-nitro-phenylamino)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.106 mol, 43.0 g) in ethyl acetate (500 mL) at 0 °C bubble anhydrous hydrogen chloride gas for 10 min and stir at room temperature for one hour. Remove the solvent and dry the resultant solid under vacuum to give the title compound as a yellow solid (35.0 g, 98%). APCI MS m/z 302 [M + H]+. Preparation 66 (3S, 4S)-4-(4-Bromo-2-nitro-phenylamino)-l-methyl-pyrrolidin-3-ol To (3S, 4S)-4-(4-Bromo-2-nitro-phenylamino)-pyrrolidin-3-ol hydrochloride (0.104 mol, 35.0 g) in acetonitrile add sodium triacetoxyborohydride (0.37 mol, 78.0 g) at 0 °C. To this mixture, add slowly 37 % aqueous formaldehyde (30 mL) over 10 min and stir at room temperature for 10 h. Add saturated aqueous sodium bicarbonate and stir for one hour. Extract with ethyl acetate, and wash with water and brine. Dry over anhydrous sodium sulfate, filter, and evaporate the solvent to obtain the title compound as a yellow solid (34.0 g, 98%). APCI MS m/z 302 [M + H]+; [a]23D +58.6° (c, 0.50, MeOH). Prepare the intermediates in the table below by essentially following the procedures as described in Preparations 65 and 66 wherein the appropriate tert-butyl 3-(4-bromo-2-nitrophenylamino)-4-hydroxypyrrolidine-l-carboxylate is treated with anhydrous HC1 gas for 10 - 30 min and then stirred for 1 - 4 h. Treat the resulting deprotected pyrrolidine with formaldehyde for 15 min to 10 h. Prep Chemical Name Physical Data 67 (3R,4R)-H4- Bromo-2-nitro- phenylamino)-l- methyl-pyrrolidin- 3-ol *H NMR (300 MHz, CDC13) 5 8.21 (d, .7=7.9 Hz, 1H), 7.57 (dd, .7=3.5, 8.8 Hz, 1H), 7.08 (d, .7=8.1 Hz, 1H), 4.11 (m, 1H), 3.92 (m, 1H), 3.21 (dd, .7=3.8, 7.9 Hz, 1H), 3.12 (dd, .7=4.8, 8.9 Hz, 1H), 2.71 (dd, .7=3.8, 8.8 Hz, 1H), 2.59 (dd, .7=4.8, 8.9 Hz, lH),2.41(s,3H) 68 (3R,4S)-4-(4-bromo-2- nitrophenylamino)-1- methylpyrrolidin-3-ol ESI MS m/z 318[M + Hf 69 (3S,4R)-4-(4-bromo-2- lR NMR (300 MHz, CDC13) 8 8.66 (d, .7=5.4 Hz, 1H), 8.33 (d, .7=2.4 Hz, 1H), Prep Chemical Name Physical Data nitrophenylamino)-1- methylpyrrolidin-3-ol 7.48 (dd, 7=9.2, 2.1 Hz, 1H), 6.67 (d, 7=9.3 Hz), 4.43-4.41 (m, 1H), 4.05-4.00 (m, 1H), 2.90-2.73 (m, 3H), 2.68-2.63 (m, lH),2.38(s,3H) Preparation 70 4-Hydroxy-piperidine-l-carboxylic acid tert-butyl ester Add sodium borohydride (0.82 mol, 31.3 g) in portions to a solution of 1-(tert-butoxycarbonyl)-4-piperidone (0.74 mol, 150 g) and triethylamine (1.5 mol, 151.6 g) in dichloromethane (1 L) at 0 °C. Upon complete addition, warm the reaction mixture to room temperature and stir for 4 h. Quench the reaction mixture with saturated ammonium chloride solution and remove the ethanol under reduced pressure. Dissolve the residue in water and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (150 g, 99%) as a viscous solid. lR NMR (400 MHz, CDC13) 8 1.45 (s, 9H), 1.53 (d, 2H), 1.83-1.87 (m, 2H), 3.02 (dt, 2H), 3.8-3.85 (m, 3H). Preparation 71 4-Methanesulfonyloxy-piperidine-l-carboxylic acid tert-butyl ester Add methanesulfonyl chloride (1.12 mol, 128.8 g) drop wise to a solution of 4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (0.74 mol, 150 g) and triethylamine (1.5 mol, 151.6 g) in dichloromethane (1 L) at 0 °C. Upon complete addition, warm the reaction mixture to room temperature and stir for 16 h. Dilute the reaction mixture with dichloromethane, wash with saturated sodium bicarbonate solution and water. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (192 g, 92%) as a brown solid. H NMR (400 MHz, CDCI3) 8 1.45 (s, 9H), 1.78-1.85 (m, 2H), 1.93-1.98 (m, 2H), 3.03 (s, 3H), 3.26-3.32 (m, 2H), 3.68-3.71 (m, 2H), 4.85-4.90 (m 1H). Preparation 72 3, 6-Dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester Heat a solution of 4-methanesulfonyloxy-piperidine-l-carboxylic acid tert-butyl ester (0.69 mol, 193g) in DBU (400 mL) at 80 °C for 16 h. Dilute the reaction mixture with water, extract with diethyl ether, and wash the organic layer with 1 N hydrochloric acid and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (116 g, 92%) as a brown oil. lR NMR (400 MHz, CDC13) 8 1.46 (s, 9H), 2.12 (br s, 2H), 3.47 (t, 2H), 3.87 (s, 2H), 5.65 (br s, 1H), 5.81 (br s, 1H). Preparation 73 Rac cis-7-Oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid tert-butyl ester Add a solution of m-chloroperoxybenzoic acid (0.77 mol, 133.1 g) in dichloromethane (200 mL) drop wise to a solution of 3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (0.64 mol, 117.8 g) in dichloromethane (1 L) at 0 °C. Upon complete addition, warm the reaction mixture to room temperature and stir for 16 h. Dilute the reaction mixture with dichloromethane and wash with 4 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (112 g, 87%) as a light yellow oil. JH NMR (400 MHz, CDC13) 8 1.44 (s, 9H), 1.87-1.93 (m s, 1H), 2.04 (br s, 1H), 3.11 (br s, 1H), 3.20 (br s, 1H), 3.28 (s, 1H), 3.44 (br s, 1H), 3.68 (br s 1H). 3.81-3.92 (m, 1H). ES-MS m/z 204 [M+H]+. Preparation 74 Rac trans-4-Azido-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester Heat a mixture of racemic zra«s-7-oxa-3-aza-bicyclo [4.1.0] heptane-3-carboxylic acid tert-butyl ester (0.56 mol, 112 g), sodium azide (1.12 mol, 73.08 g), ammonium chloride (0.56 mol, 30.07 g) and methanol/water (3:1) (1 L) at 65 °C for 16 h. Dilute the reaction mixture with water, extract with dichloromethane, and wash the organic layer with saturated sodium bicarbonate and brine solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify the residue on a silica gel column using 6%> ethyl acetate in hexanes as eluent to obtain the title compound (42.3 g, 42%) as a light yellow oil. 1H NMR (400 MHz, CDC13) 8 1.48 (s, 9H), 1.84 (br s 1H), 1.97-2.01 (m, 1H), 2.74-2.82 (m, 1H), 2.88 (br s, 1H), 3.37-3.40 (m, 1H), 3.50 (br s, 1H), 3.91 (br s, 1H), 4.09 (dd, 1H). ES-MS m/z 143 [M-Bocf. Preparation 75 Rac trans-4-Amino-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester Dissolve racemic trans-4-azido-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (0.23 mol, 56.6 g) in methanol (500 mL), add 10% palladium on carbon (12.0 g) and hydrogenate (1 atm) at room temperature for 16 h. Filter off the catalyst through a plug of diatomaceous earth and concentrate the filtrate to obtain the title compound (53.7 g, 99%) as a thick, light yellow oil. Preparation 76 Rac trans- 4-Benzylamino-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester Add benzaldehyde (0.24 mol, 26.3g) to a solution of racemic trans-4-amino-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (0.24 mol, 53.7 g), and acetic acid (92 mL) in ethanol (400 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.49 mol, 31.2 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in a minimum amount of dichloromethane and add 0.1 N aqueous hydrochloric acid to maintain the pH between 4-5. Discard the organic layer. Wash the acidic aqueous layer three times with dichloromethane and discard the organic layer. Adjust the pH of the aqueous layer between 10-12 and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (35.7 g, 46%) as a light yellow oil. 1H NMR (400 MHz, CDC13) 8 1.35-1.40 (m, 2H), 1.45 (s, 9H), 2.05 (br s 1H), 2.43 (t, 1H), 2.57 (t, 1H), 2.69 (br s, 1H), 3.27 (br s, 1H), 3.70 (d, 1H), 3.94 (d, 1H), 4.15 (br s, 1H), 4.26 (d, 1H), 7.23-7.29 (m, 1H), 7.30-7.32 (m, 2H), 7.33-7.36 (m, 2H). -62- Preparation 77 (3R,4R)-4-Benzylamino-3-hydroxy-4-piperidine-l-carboxylic acid tert-butyl ester, L-(+)-tartaric acid salt Heat a mixture of racemic trans-4-benzylamino-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (0.11 mol, 35.0 g) and L-(+)-tartaric acid (0.12 mol, 18.9 g, 1.2 eq) and acetonitrile/water (20:1) (175 mL) at 75 °C for 4 h. Concentrate the reaction mixture under reduced pressure to obtain the tartaric acid salt (53.0 g). Crystallize the residue from acetonitrile three times. Filter the crystals and dry under vacuum to obtain the title compound (18.3 g, 67%). HPLC (Column: Chiralcel OD-H(250 mm*4.6 mm); solvent system: isopropanol/0.1% triethylamine in hexanes (8:92); flow rate: 0.800 ml/min; wavelength: 258 nm): 99.9% ee. tR 9.502 min. tR for opposite enantiomer ((3S,4S)-3-Hydroxy-4-phenethyl-piperidine-1-carboxylic acid tert-butyl ester.L-(-)-tartaric acid salt) 8.714 min. Preparation 78 (3R, 4R)-4-Amino-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester Dissolve the (3R,4R)-4-benzyl-3-hydroxy-4-phenethyl-piperidine-l-carboxylic acid tert-butyl ester, L-(+)-tartaric acid salt (0.04 mol, 18.3 g) in 4% potassium carbonate solution (500 mL) and stir for 30 min. Extract the free amine with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the free amine (11.3 g, 92%). Dissolve the amine in methanol (110 mL), add 10% palladium on carbon (2.5 g) and hydrogenate (1 atm) at room temperature for 16 h. Filter off the catalyst through a plug of diatomaceous earth and concentrate the filtrate to obtain the title compound (7.6 g, 95%) as thick, 26.1 light yellow oil. [a] +2.141 (c 1.0, methanol). H NMR (400 MHz, DMSO-d6) 8 1.08 (dq, 1H), 1.38 (s, 9H), 1.67 (dd, 1H), 1.80 (br s, 1H), 2.37-2.45 (m, 2H), 2.67 (br s, 1H), 2.90 (br s, 1H), 3.79 (br s, 1H), 3.88 (br s, 1H), 5.0 (br s, 1H). ES-MS m/z217[M+H]+. Preparation 79 (3R,4R)-4-(4-Bromo-2-nitro-phenylamino)-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester Heat a mixture of (3R,4R)-4-ammo-3 -hydroxy-piperidine- 1-carboxylic acid tert-butyl ester (0.02 mol, 6.0 g), 5-bromo-2-fluoronitrobenzene (0.03 mol, 6.71 g) and triethyl amine (0.058 mol, 5.88 mL) in ethyl acetate (180 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (12.35 g, crude). 1H NMR (400 MHz, CDC13) 5 1.46 (s, 9H), 1.50-1.51 (m, 1H), 2.08-2.12 (m, 1H), 2.93 (dd, 1H), 3.01 (brs, 1H), 3.55-3.61 (m, 1H), 3.62-3.68 (m, 1H), 3.68 (brs, 1H), 4.13-4.18 (m, 1H), 6.97 (d, 1H), 7.48 (dd, 1H), 8.08 (d, 1H), 8.30 (d, 1H). ES-MS m/z 316 [M-Boc]+. Preparation 80 (3i?,^i?)-4-(4-Bromo-2-nitro-phenylamino)-piperidin-3-ol.hydrochloride salt Add 4.0 M hydrogen chloride in dioxane (70 mL) slowly to a solution of (3R, 4R)-4-(4-bromo-2-nitro-phenylamino)-3-hydroxy-piperidine-1 -carboxylic acid tert-butyl ester (0.027 mol, 11.5 g) in dry dichloromethane (40 mL) at room temperature and stir for 16 h. Filter the precipitate and dry under vacuum to obtain the title compound (8.68 g, 89%) as a yellow solid. lR NMR (400 MHz, CD3OD) 8 1.81-1.86 (m, 1H), 2.39-2.44 (m, 1H), 3.02-3.07 (m, 1H), 3.18-3.26 (m, 1H), 3.34-3.40 (m, 1H), 3.45 (dd, 1H), 3.87-3.91(m, 2H), 7.17 (d, 1H), 7.61 (dd, 1H), 8.28 (d, 1H). Preparation 81 (3i?,4i?)-4-(4-Bromo-2-nitro-phenylamino)-l-methyl-piperidin-3-ol Add formaldehyde (20.5 mL, 37-41% aqueous solution) to a solution of (3R,4R)-4-(4-bromo-2-nitro-phenylamino)-piperidin-3-ol.hydrochloride salt (0.0.024 mol, 8.68 g) and acetic acid (10.2 mL) in water (42 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.073 mol, 4.6 g) and stir the reaction mixture for 3 h. Quench the reaction -64- mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (7.8 g, 97%). 1H NMR (400 MHz, CDC13) 8 1.63-1.71 (m, 1H), 2.16-2.21 (m, 2H), 2.33 (s, 3H), 2.35-2.38 (m, 1H), 2.60 (br s, 1H), 2.80 (d, 1H), 3.54-3.56 (m, 1H), 3.75-3.79 (m, 1H), 6.92 (d, 1H), 7.48 (dd, 1H), 8.14 (d, 1H), 8.30 (d, 1H). Preparation 82 (35,¥5)-4-Benzylamino-3-hydroxy-4-piperidine-l-carboxylic acid tert-butyl ester, D-(-)-tartaric acid salt Concentrate the mother liquor of Preparation 77 to obtain enantio enriched (35,45)-3-hydroxy-4-phenethyl-piperidine-l-carboxylic acid tert-buty\ ester L-(+)-tartaric acid salt (0.0377 mol, 17.2 g). Add 4% aqueous potassium carbonate solution (500 mL) and stir for 30 min. Extract the free amine with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the free amine (11.0 g). Heat a mixture of 4-benzylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.0361 mol, 11.0 g) and D-(-)-tartaric acid (0.0397 mol, 5.97 g, 1.1 equiv.) in acetonitrile/water (20:1) (100 ml) at 75 °C for 4 h. Concentrate the reaction mixture under reduce pressure to obtain crude tartaric acid salt. Crystallize the residue from acetonitrile three times. Filter the crystals and dry under vacuum to obtain the title compound (14.8 g, 90%). HPLC (Column: Chiralcel OD-H(250 mm*4.6 mm); solvent system: isopropanol/0.1% triethylamine in hexanes (8:92); flow rate: 0.800 ml/min; wavelength: 258 nm): 96.4% ee. tR 8.714 min. tR for opposite enantiomer ((3i?,4i?)-3-Hydroxy-4-phenethyl-piperidine-l-carboxylic acid tert-butyl ester.L-(+)-tartaric acid salt) 9.502 min. Preparation 83 (35,45)-4-Amino-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester Dissolve (35,45)-4-Benzylamino-3 -hydroxy-4-phenethyl-piperidine-1 -carboxylic acid tert-butyl ester, D-(-)-tartaric acid salt (0.036 mol, 16.4 g) in 4% aqueous potassium carbonate solution (500 mL) and stir for 30 min. Extract with -65- dichloromethane, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the free amine (11.0 g, 99%). Dissolve the amine in methanol (110 mL), add 10% palladium on carbon (5.5 g) and hydrogenate (50 psi) at room temperature for 2 h. Filter off the catalyst through diatomaceous earth and concentrate to obtain the title compound (7.7 g, 99%) as a thick, light yellow oil. Preparation 84 (35',4S)-4-(4-Bromo-2-nitro-phenylamino)-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester Heat a mixture of (3S,45)-4-amino-3-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (0.035 mol, 7.5 g), 5-bromo-2-fluoronitrobenzene (0.038 mol, 8.48 g) and triethyl amine (0.073 mol, 7.44 g) in ethyl acetate (250 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (16.16 g, crude). Preparation 85 (35,,4S)-4-(4-Bromo-2-nitro-phenylamino)-piperidin-3-ol, hydrochloride Add 4 M hydrogen chloride in dioxane (90 mL) slowly to a solution of (35',4S)-4-(4-bromo-2-nitro-phenylamino)-3-hydroxy-piperidine-l-carboxylicacid tert-butyl ester (0.035 mol, 14.6 g) in dry dichloromethane (50 mL) at room temperature and stir for 16 h. Filter the precipitate and dry under vacuum to obtain the title compound (9.84 g, 80%) as a yellow solid. Preparation 86 (3S, 4S)-4-(4-Bromo-2-nitro-phenylamino)-1 -methyl-piperidin-3-ol Add formaldehyde (24 mL, 37-41% aqueous solution) to a solution of (3S,4S)-4-(4-bromo-2-nitro-phenylamino)-piperidin-3-ol, hydrochloride (0.028 mol, 9.8 g) and acetic acid (12 mL) in water (46 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.083 mol, 5.26 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (8.4 g, 92%). 'HNMR (400 MHz, CDC13) 8 1.63-1.71 (m, 1H), 2.16-2.21 (m, 2H), 2.33 (s, 3H), 2.35-2.38 (m, 1H), 2.60 (br s, 1H), 2.80 (d, 1H), 3.54-3.56 (m, 1H), 3.75-3.79 (m, 1H), 6.92 (d, 1H), 7.48 (dd, 1H), 8.14 (d, 1H), 8.30 (d, 1H). Preparation 87 (R)- [4-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-2-nitro-phenyl]-(l-methyl-2-morpholin-4-yl-ethyl)-amine Degas three times a mixture of (i?)-(4-bromo-2-nitro-phenyl)-(l-methyl-2-morpholin-4-yl-ethyl)-amine (0.037 mol, 12.8 g), (£)-3,8-difluoro-11 -(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-ylmethylene) -6,11-dihydro-dibenzo[b,e] oxepine (0.037 mol, 13.7 g), triphenylphosphine (0.007 mol, 2.02 g) and potassium acetate (0.074 mol, 7.29 g) in dioxane/water (3:1) (450 mL) with nitrogen. Add palladium (II) acetate (0.001 mol) to the reaction mixture and degas again three times with nitrogen. Heat the resulting reaction mixture at 85 °C for 16 h. Cool the reaction mixture to room temperature, dilute with water, extract with ethyl acetate, combine organic layer, wash with water and brine. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 7% ethyl acetate in hexanes as eluent to obtain the title compound (9.1 g, 48%) as an orange solid. JH NMR (400 MHz, CDC13), 8 1.26 (d, 3H), 2.44-2.57 (m, 6H), 3.66-3.68 (m, 4H), 3.71-3.78 (m, 1H), 4.89 (br s, 1H), 5.63 (brs, 1H), 6.52 (dd, 1H), 6.61 (d, 1H), 6.67 (dt, 1H), 6.76 (s, 1H), 6.89 (d, 1H), 6.95 (dt, 1H), 7.06-7.10 (m, 1H), 7.19 (dd, 1H), 7.29-7.41 (m, 1H), 7.95 (d, 1H), 8.35 (d, 1H, -NH). Example 1 (E)-N-((R)-5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-l-(l-methyl-2-morpholin-4-yl-ethyl)-l,3-dihydro-benzoimidazol-2-ylidene)-cyanamide Dissolve (R)-[4-((E)-3,8-diffuoro-6H-dibenzo [b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(l-methyl-2-morpholin-4-yl-ethyl)-amine (0.017mol, 9.0 g) in tetrahydrofuran (35 mL) and isopropanol (90 mL). Add triethylamine (0.039 mol, 3.9 ) and 10% platinum on carbon (1.5 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 2 h. Filter off the catalyst through a plug of diatomaceous earth. Dilute the filtrate with dioxane (35 mL), add diphenyl N-cyanocarbonimidate (0.019 mol, 4.61 g) and stir at room temperature for 48 h. Concentrate the reaction mixture under reduced pressure. Purify on a silica gel column using 0.5% methanol in dichloromethane as eluent to obtain the title compound (6.0 g, 64%) as an off-white solid. LC-MS m/z 528.2 [M+H]+. Prepare the following examples in the table below, essentially as described in Preparation 87 and Example 1, using the appropriate phenyl bromide and the appropriate vinyl dioxaborolane. Ex Chemical Name Structure Physical Data 2 (E)-N-((S)-5-((E)- 3-Fluoro-6H- dibenzo [b,e]oxepin-ll- ylidenemethyl)-l- (l-methyl-2- morpholin-4-yl- ethyl)-l,3-dihydro- benzoimidazol-2- ylidene)- cyanamide ' N N LC-MS m/z 510.2 [M+Hf 3 (E)-K-((R)-5-((E)-3-Fluoro-6H- dibenzo [b,e]oxepin-ll- ylidenemethyl)-l- (l-methyl-2- morpholin-4-yl- ethyl)-l,3-dihydro- benzoimidazol-2- ylidene)- cyanamide y-NH N N LC-MS m/z 510.4 [M+H]+ 4 3,8-Difluoro-6H- dibenzo[b,e]oxepin -11- ylidenemethyl)-l- (l-methyl-2- morpholin-4-yl- ethyl)-l,3-dihydro- benzoimidazol-2- ylidene)- cyanamide ' N—v 0 7 V A^ ^ / N 1 y-NH N N LC-MS m/z 528.5 [M+H]+ 5 (E)-N-((R)-5-((E)- 3,7-Difluoro-6H- dibenzo [b,e]oxepin-ll- ylidenemethyl)-l- (l-methyl-2- morpholin-4-yl- ethyl)-l,3-dihydro- benzoimidazol-2- ylidene)- cyanamide 0 J V A^ y-NH N N LC-MS m/z 528.5 [M+Hf Ex Chemical Name Structure Physical Data 6 3,7-Difluoro-6H- dibenzo [b,e]oxepin-ll- ylidenemethyl)-l- (l-methyl-2- morpholin-4-yl- ethyl)-l,3-dihydro- benzoimidazol-2- ylidene)- cyanamide F-0 / N—v 0 7 V A^ ^ / N I y-NH N N LC-MS m/z 528.2 [M+Hf Preparation 88 [4-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-2-nitro-phenyl]-(4- methyl-piperazin-1 -yl)-amine Degas three times a mixture of (4-bromo-2-nitro-phenyl)-(4-methyl-piperazin-l-yl)-amine (0.016 mol, 5.0 g), (F)-3,7-difluoro-ll-(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-ylmethylene) -6,ll-dihydro-dibenzo[b,e] oxepine (0.017 mol, 6.4 g), triphenylphosphine (0.0028 mol, 0.74 g) and potassium acetate (0.0317 mol, 3.11 g) in dioxane/water (3:1) (200 mL) with nitrogen. Add palladium (II) acetate (0.5 mmol, 113 mg) to the reaction mixture and degas again three times with nitrogen. Heat the resulting reaction mixture at 85 °C for 16 h. Cool the reaction mixture to room temperature and dilute with water. Extract the mixture with ethyl acetate, combine organic layers, and wash with water and brine. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Crystallize the crude material from methanol, filter, and dry under vacuum to obtain the title compound (4.2 g, 55%) as an orange solid. ES-MS m/z 479 [M+lf. Example 7 (E)-N-(5-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-l-(4-methyl-piperazin-l-yl)-l,3-dihydro-benzoimidazol-2-ylidene)-cyanamide N-N —N Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-2-nitro-phenyl]-(4-methyl-piperazin-l-yl)-amine (0.008 mol, 3.96 g) in tetrahydrofuran (150 mL). Add triethylamine (0.018 mol, 1.84 g) and 10% platinum on carbon (1.3 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 3 h. Filter off the catalyst through a plug of diatomaceous earth, and add pyridine (150 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.17 g). Stir at room temperature for 16 h and then heat to 70 °C for 8 h. Concentrate the reaction mixture under reduced pressure. Purify on a silica gel column using 60% acetone in hexanes as eluent to obtain the title compound (1.8 g, 43%>) as an off-white solid. LC-MS m/z 499.2 [M+H]+. Prepare the following examples in the table below, essentially as described in Preparation 88 and Example 7, using the appropriate phenyl bromide and the appropriate vinyl dioxaborolane. Ex Chemical Name Structure Physical Data 8 (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-1 -(4-methyl-piperazin-1 -yl)-l,3-dihydro-benzoimidazol-2-ylidene)-cyanamide y—O — N N-N'^T N CN LC-MS m/z 481.08 [M+H]+ Ex Chemical Name Structure Physical Data N-N (E)-N-(5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-1 -(4-methyl-piperazin-1 -yl)-l,3-dihydro-benzoimidazol-2-ylidene)-cyanamide —N LC-MS m/z 499.3 [M+H]+ Example 10 5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-l,3-dihydro-benzoimidazol-2-ylidene-cyanamide -0 Isolate the title compound as a side-product during the final purification of (E)-N-(5-((E)-3,8-difluoro- 6H- dibenzo[b,e]oxepin-11-ylidenemethyl)-1-(4-methyl- piperazin- 1-yl)- l,3-dihydro-benzoimidazol-2-ylidene)-cyanamide (Example 9). LC-MS nVz 401.3 [M+H]+. Preparation 89 [4-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-2-nitro-phenyl]-(l- methyl-azetidin-3 -yl)-amine Purge with nitrogen for five min a mixture of (4-bromo-2-nitro-phenyl)-(l-methyl-azetidin-3-yl)-amine (709 µmol, 203 mg), (E)-3,7-difluoro-11-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-ylmethylene)-6,11-dihydro-dibenzo[b,e]oxepine (723 |imol, 268 mg) in methanol (1.0 mL)/tetrahydrofuran (3.0 mL) (1:3 solvent ratio) in a sealed tube. Add sodium methoxide (1.42 mmol, 77 mg), tetrakis(triphenylphosphine)palladium (35 µmol, 41 mg) and heat at 70 °C overnight. Dilute with ethyl acetate, wash with 10% sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain 377 mg of an orange oil residue. Purify on a 12 g silica gel column eluting with 5% methanol in dichloromethane to obtain the title compound (199 mg, 62%). LC-MS m/z 450.0 [M+H]+. Example 11 (E)-N-(5-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-l-(l-methyl-azetidin-3-yl)-l,3-dihydro-benzoimidazol-2-ylidene)-cyanamide F > Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(l-methyl-azetidin-3-yl)-amine (4.23 mmol, 1.90 g), triethylamine (9.31 mmol, 1.30 mL) in tetrahydrofuran (20 mL), add 5% platinum on carbon (200 mg) and hydrogenate (50 psi) at 35 °C for one hour. Filter off the catalyst, rinse with pyridine (20 mL), add diphenyl N-cyanocarbonimidate (4.65 mmol, 1.11 g) and stir at room temperature overnight under nitrogen. Dilute with ethyl acetate, wash with 5% aqueous sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain approximately 3 g of an orange oil. Purify on an 80 g silica gel column eluting with 5% methanol in dichloromethane to obtain -930 mg of a yellow semi-solid. Dissolve in a minimum amount of methanol and let sit. White solids form. After 30 min filter off the solids and rinse with methanol to obtain the title compound as a white solid (815 mg, 41%). LC-MS m/z 470.2 [M+H]+. Prepare the following Examples in the table below essentially as described in Preparation 89 and Example 11, using the appropriate phenyl bromide and the appropriate vinyl dioxaborolane. Ex Chemical Name Structure Physical Data 12 (E)-N-(5-((E)-3-Fluoro-6H- dibenzo[b,e]oxepin-l 1-ylidenemethyl)-l-(l-methyl-azetidin-3 -yl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide \—N N LC-MS m/z 452.2 [M+H]+ 13 (E)-N-(5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-l 1-ylidenemethyl)-l-(l-methyl-azetidin-3 -yl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide N N LC-MS m/z 470.2 [M+H]+ Preparation 90 [4-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7S, 8αS)-hexahydro-pyrrolo[2,1 -c][ 1,4]oxazin-7-yl)-amine F Degas three times a mixture of (4-bromo-2-nitro-phenyl)-((7,S, 8aS)-hexahydro-pyrrolo[2,l-c][l,4]oxazin-7-yl)-amine (0.011 mol, 4.0 g), (E)-3,7-difluoro-ll-(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-ylmethylene) - 6,11-dihydro-dibenzo[b,e] oxepine (0.012 mol, 4.76 g), triphenylphosphine (0.0031 mol, 0.8 g) and sodium methoxide (0.03 mol, 1.6 g) in tetrahydrofuran/methanol (3:1) (120 mL) with nitrogen. Add palladium (II) acetate (1.0 mmol, 240 mg) to the reaction mixture and degas again three times with nitrogen. Heat the reaction mixture at 70 °C for 4 h. Cool the reaction mixture to room temperature, filter through a plug of diatomaceous earth and concentrate the filtrate under reduced pressure to obtain the title compound (5.0 g, crude). Example 14 (E)-N-(5-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-l-((71S, 8aS)-hexahydro-pyrrolo[2,1 -c] [ 1,4]oxazin-7-yl)-1,3-dihydro-benzoimidazol-2-ylidene)- Dissolve [4-((E)-3,7-difluoro- 6H-dibenzo [b,e]oxepin-11- ylidenemethyl)- 2-nitro- phenyl]-((7S, 8α,S)-hexahydro-pyrrolo[2,l-c][l,4]oxazin-7-yl)-amine (0.009 mol, 5.0 g) in tetrahydrofuran (40 mL). Add triethylamine (0.009 mol, 0.9 g) and 10% platinum on carbon (1.0 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 3 h. Filter off the catalyst through a plug of diatomaceous earth, add pyridine (40 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.35 g) to the filtrate. Stir at room temperature for 16 h, then heat at 60-70 °C for 8 h. Remove the solvent under reduced pressure. Dissolve the resulting residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify on a silica gel column using 1% methanol in dichloromethane as eluent to give the title compound (1.9 g, 36%). LC-MS m/z 526.4 [M+H]+. Prepare the following Examples in the table below essentially as described in Preparation 90 and Example 14, using the appropriate phenyl bromide and the appropriate vinyl dioxaborolane and heating at about 70 °C for 4 to 16 h. Ex Chemical Name Structure Physical Data 15 (E)-N-(5-((F)-3-Fluoro-6H-dibenzo [b, e] oxepin-ll-ylidenemethyl)-l-((7S, #a4-hydroxy-l- methylpyrrolidin-3-yl)- 1 H-benzo [d] imidazol- 2(3H)- ylidene)cyanamide ESI MS m/z 500 [M + H]+ 23 [a]Dz +61.0 (c 0.24, CH3OH). Use potassium acetate in the Suzuki coupling reaction Example 32 (^-N-CS-C^-S-Fluoro-eH-dibenzo^^loxepin-ll-ylidenemethyO-l^CJ^^^- hydroxy-l-methyl-l-oxy-pyrrolidin-3-yl)-l,3-dihydro-benzoimidazol-2-ylidene)- cyanamide -o To a solution of (F)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-l 1(6H)-ylidene)methyl)-l-((3,S,,4S,)-4- hydroxy- 1- methylpyrrolidin- 3- yl)- 1H-benzo[d]imidazol-2(3H)-lidene) cyanamide (0.27 mmol, 130 mg) in dichloromethane (10 mL) add m-chloroperoxybenzoic acid (0.43 mmol, 93 mg) and stir at room temperature overnight. Load the solution on silica and purify by flash chromatography eluting with 0 to 20% methanol in dichloromethane to obtain the title compound (135 mg, 100%). LC-MS m/z 498.2 [M+H]+. Example 33 (F)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-ll(6H)-ylidene)methyl)-l-((55^5')-4-hydroxy-l-methylpyrrolidin-3-yl)-lH-benzo[d]imidazol-2(3H)-ylidene)cyanamide, Heat (F)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-ll(6H)-ylidene)methyl)-l-((3S,4S)-4-hydroxy- 1-methylpyrrolidin-3-yl)- lH-benzo[d] imidazol-2 (3H)-ylidene) cyanamide (7.10 mmol, 3.42 g) in acetonitrile (60 mL) at 50 °C for 30 min and add (Z)- 2-butenedioic acid (7.10 mmol, 837 mg) at once. After a few minutes, the suspension becomes homogeneous and then precipitates start forming. Cool the resulting suspension to room temp. Collect the solid by filtration, wash with acetonitrile (50 mL), and dry in a vacuum oven at 50 °C for 2 h to obtain the title compound (4.1 g, 97 %). LC-MS m/z 488.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6): 2.80 (s, 3H), 3.77-3.72 (m, 8H), 4.66-4.63 (m, 1H), 4.96-4.91 (m, 1H), 5.16-5.10 (m, 1H), 5.72-5.67 (m, 1H), 5.89-5.82 (m, 1H), 6.00 (s, 2H), 6.59 (dd, J= 2.6, 10.5 Hz, 1H), 6.80-6.76 (m, 1H), 6.86 (s, 1H), 6.94-6.90 (m, 2H), 7.02 (s, 1H), 7.22 (td, J= 7.5, 1.3 Hz, 1H), 7.30 (d, J= 8.8 Hz, 1H), 7.36 (td, J= 7.5, 1.3 Hz, 1H), 7.61-7.57 (m, 2H). Alternate procedure: Dissolve (F)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-l 1(6H)-ylidene)methyl)-1 -((3S, ^lS)-4-hydroxy-1 -methylpyrrolidin-3 -yl)-1H-benzo[d]imidazol-2(3H)-ylidene)cyanamide (145 mg) in acetonitrile (5 mL) heat to -83- 50 °C to give a cloudy solution. Dissolve 2-butenedioic acid (35 mg) in THF (300 uL) and slowly add to the acetonitrile to provide a clear solution. Cool the solution to room temperature while stirring to give a precipitate. Continue stirring the solution overnight. Fast filter the resulting solids and dry under vacuum for 2 h at 40 °C. Residual acetonitrile was observed in the subsequent TGA (Thermo Gravimetric Analysis) thermogram and the material was dried further overnight. Preparation 92 (3R,4R)-4-[4-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-2-nitro-phenylamino]-l-methyl-piperidin-3-ol Degas three times a mixture of (3R,4R)-4-(4-bromo-2-nitro-phenylamino)-l-methyl-piperidin-3-ol (0.009 mol, 3.0 g), (E)-3,8-difluoro-11 -(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-ylmethylene) -6,ll-dihydro-dibenzo[b,e] oxepine (0.01 mol, 3.7 g, 1.1 equiv.), triphenylphosphine (0.002 mol, 0.61 g) and sodium methoxide (0.02 mol, 1.2 g) in tetrahydrofuran/methanol (3:1) (150 mL) with nitrogen. Add palladium (II) acetate (0.8 mmol, 183 mg) to the reaction mixture and degas again three times with nitrogen. Heat the reaction mixture at 70 °C for 16 h. Cool the reaction mixture to room temperature, filter through a plug of diatomaceous, and concentrate the filtrate under reduced pressure to obtain the title compound (6.6 g, crude). Example 34 (E)-N- (5-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-l-((3R,4R)-3 -hydroxy-1 -methyl-piperidin-4-yl)-1,3 -dihydro-benzoimidazol-2-ylidene)- cyanamide OH N N CN O Dissolve (3R,4R)-4-[4-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-2-nitro-phenylamino]-l-methyl-piperidin-3-ol (0.009 mol, 4.48 g) in tetrahydrofuran (100 mL). Add triethylamine (0.018 mol, 1.83 g) and 10% platinum on carbon (2.2 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 4 h. Filter off the catalyst through a plug of diatomaceous earth. Add pyridine (100 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.16 g) to the filtrate. Stir at room temperature for 16 h and then heat at 60-70 °C for 8 h. Remove the solvent under reduced pressure. Dissolve the residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify on a silica gel column using 5% methanol in dichloromethane as eluent to obtain the title compound (1.2 g, 26%) as an off-white solid. *H NMR (400 MHz, DMSO-d6) 8 1.66-1.8 (m, 1H), 1.75-1.78 (m, 1H), 1.87-1.90 (m, 1H), 2.03 (br s, 1H), 2.24 (s, 3H), 2.81 (br s, 1H), 2.96 (br s, 1H), 3.99 (br s, 1H), 4.31 (br s, 1H), 5.09 (s, 1H), 5.36 (br s, 1H), 5.46 (br s, 1H), 6.68 (dd, 1H), 6.82-6.87 (m, 3H), 6.99 (d, 1H), 7.09 (s, 1H), 7.26-7.35 (m, 3H), 7.62 (t, 1H), 12.49 (br s, 1H). Example 35 (E)N- (5-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-l -((3S,4S)-3 -hydroxy-1 -methyl-piperidin-4-yl)-1,3 -dihydro-benzoimidazol-2-ylidene)- cyanamide O CN Dissolve 4-[4-((ET)-3,7-difluoro-6H-dibenzo [b,e]oxepin-l 1-ylidenemethyl)-2-nitro-phenylamino]-l-methyl-piperidin-3-ol (0.012 mol, 5.97 g) in tetrahydrofuran (50 mL). Add triethylamine (0.024 mol, 2.44 g) and 10% platinum on carbon (2.9 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 4 h. Filter off the catalyst through diatomaceous earth. Add pyridine (50 mL) and diphenyl N-cyanocarbonimidate (0.012 mol, 2.88 g) to the filtrate. Stir at room temperature for 16 h and then heat at 60-70 °C for 8 h. Remove the solvent under reduced pressure, dissolve the residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue on a silica gel column using 5% methanol in dichloromethane as eluent to obtain the title compound (1.7 g, 27%) as an off-white solid. LC-MS m/z 514.4 [M+H]+. Prepare the examples below by following the procedures as essentially described for Preparation 92 and Example 34 and 35, using the appropriate phenyl bromide and vinyl dioxaborolane and heating at about 80 to 85 °C for 3 to 16 h. Use 5% or 10% platinum on carbon or palladium on carbon for the reduction for about 1-4 h. Ex Chemical Name Structure Physical Data 36 (E)-N- (5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-l 1-ylidenemethyl)-l-((3R,4R)-3 -hydroxy-1 -methyl-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide OH }rNH N CN LCMS m/z 496.5 [M +H]+ 37 (E)-N-(5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-l 1-ylidenemethyl)- l-((3R, 4R)-3 -hydroxy-1 -methyl-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide OH )rNH N CN LCMS m/z 514.5 [M +H]+ 38 (E)-N- (5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-l 1-ylidenemethyl)-l-((3S,45> 3 -hydroxy-1 -methyl-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide XN^I (iT OH y™ N CN LCMS m/z 496.5 [M +H]+ 39 (E)-N-(5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-l 1-ylidenemethyl)-l-((3S,4S> 3 -hydroxy-1 -methyl-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide OH ^NH N CN LCMS m/z 514.5 [M +H]+ Example 40 (E)-N-(5-((^)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-ll-ylidenemethyl)-l-p)-l-methyl-2-morpholin-4-yl-ethyl)-l,3-dihydro-benzoimidazol-2-ylidene)-urea o Prepare a solution of 4 M hydrogen chloride in dioxane by diluting 12 M hydrochloric acid (10 mL) with dioxane (20 mL). Slowly add this solution to (E)- N-((i?)-5-((E)-3,7-difluoro-6H-dibenzo [b,e]oxepin-ll-ylidenemethyl)-l-(l-methyl- 2-morpholin-4-yl-ethyl)-l,3-dihydro-benzoimidazol-2-ylidene)-cyanamide (0.005 mol, 3.0 g) at room temperature and stir for 48 hours. Quench the reaction mixture with aqueous 4 N potassium hydroxide solution, extract with dichloromethane and wash with saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduce pressure. Purify on silica gel column using 1% methanol in dichloromethane to obtain the title compound (1.2 g, 38%) as an off-white solid. lR NMR (400 MHz, DMSO-^) mixture of (is,Zj-N isomers. Major isomer: 8 1.44 (d, 3H), 2.23-2.26 (m, 2H), 2.32-2.33 (m 1H), 2.63 (dd, 1H), 2.77-2.82 (m 1H), 3.29-3.46 (m, 5H), 4.77-4.82 (m, 1H), 5.35-5.44 (br d, 2H), 6.65 (dd, 1H), 6.89 (dt, 3H), 7.13 (s 1H), 7.1 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.42 (m 1H), 7.55-7.62 (m, 1H), 9.95 (s, 1H). Minor isomer: 5 1.39 (d, 3H, E,Z-isomer), 2.23-2.26 (m, 2H), 2.32-2.33 (m 2H), 2.88-3.0 (m 1H), 3.29-3.46 (m, 5H), 4.80 - 4.99 (m, 1H), 5.35-5.44 (br d, 2H), 6.65 (dd, 1H), 6.89 (dt, 3H), 7.13 (s 1H), 7.1 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.42 (m 1H), 7.55- 7.62 (m, 1H), 9.95 (s, 1H). Example 41 (E)-N-(5)-((E)-3-Fluoro-6H-dibenzo|b,e]oxepin-11-ylideaemethyl)-l-((3S,4S)-4-hydroxy-1 -methyl-pyrrolidin-3 -yl)-1,3 -dihydro-benzoimidazol-2-ylidene)-urea To a mixture of trifluoroacetic acid (30 rnL) and water (6.0 eq, 100 mmol, 1.81 mL) in an ice bath add (E)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)- 1- ((35',4S)-4-hydroxy- 1-methylpyrrolidin- 3- yl)- 1H-benzo[d]imidazol- 2(3H)- ylidene) cyanamide maleate (16.73 mmol, 10.00 g). Allow the resulting suspension to warm up to room temperature and stir for 2 h. Dilute the solution with ethyl acetate (250 mL), cool the mixture in an ice bath for 30 min, and treat with 5 N sodium hydroxide to pH = 11. Wash the organic layer with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography eluting with 2.5 to 5% methanol in ethyl acetate to obtain a white solid. Dry in a vacuum oven at 40 °C overnight to obtain the title compound (6.74 g, 81%). LC-MS m/z 500.2 [M+H]+. Prepare the examples below by following the procedures as essentially described for Example 40 or 41, using the appropriate cyanoguanidine. Ex Chemical Name Structure Physical Data 42 (E)-N-(5-((E)-3-Fluoro- 6H-dibenzo[b,e]oxepin- 11 -ylidenemethyl)-1 - p)-l-methyl-2- morpholin-4-yl-ethyl)- 1,3-dihydro- benzoimidazol-2- ylidene)-urea )^NH2 O LCMS m/z 528.2 [M +H]+ Ex Chemical Name Structure Physical Data 43 (E)-N-(5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-l 1-ylidenemethyl)-1 -((R)-1 -methyl-2-morpholin-4-yl-ethyl)-1,3 -dihydro-benzoimidazol-2-ylidene)-urea 0 LCMS m/z 546.2 [M +H]+ 44 (E)-N-(5-((E)-3,8- Difluoro-6H- dibenzo[b,e]oxepin-l 1- ylidenemethyl)-l- ((3SWS>4-hydroxy-l- methyl-pyrrolidin-3-yl)- 1,3-dihydro- benzoimidazol-2- ylidene)-urea A-0 1 V-NH 0 LCMS m/z 518.5 [M +H]+ 45 (E)-N-(5-((E)-3,7- Difluoro-6H- dibenzo[b,e]oxepin-l 1- ylidenemethyl)-l- ((3S;4S>4-hydroxy-l- methyl-pyrrolidin-3-yl)- 1,3-dihydro- benzoimidazol-2- ylidene)-urea N^V (i T )^NH2 0 LCMS m/z 518.6 [M +H]+ 46 (E)-N-(5-((E)-3,7- Difluoro-6H- dibenzo[b,e]oxepin-l 1- ylidenemethyl)-l- ((3SWS>3-hydroxy-l- methyl-piperidin-4-yl)- 1,3-dihydro- benzoimidazol-2- ylidene)-urea 0 LCMS m/z 532.6 [M +H]+ Ex Chemical Name Structure Physical Data 47 (E)-N-(5-((iT)-3,8- Difluoro-6H- dibenzo[b,e]oxepin-l 1- ylidenemethyl)-l- ((3SWS>3-hydroxy-l- methyl-piperidin-4-yl)- 1,3-dihydro- benzoimidazol-2- ylidene)-urea A-0 \ W NH 0 LCMS m/z 532.6 [M + H]+ 48 (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-1 -((7S, &zi?)-hexahydro-pyrrolo[2,l- c][l,4]oxazin-7-yl)-l,3-dihydro-benzoimidazol-2-ylidene)-urea y-NH N )~NH2 0 LCMS m/z 526.6 [M + H]+ 49 (E)-N-(5-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-l 1-ylidenemethyl)-l -((7S, &zR)-hexahydro-pyrrolo[2,l- c][l,4]oxazin-7-yl)-l,3-dihydro-benzoimidazol-2-ylidene)-urea /—0 V—NH 0 LCMS m/z 544.6 [M + H]+ 50 (E)-N-(5-((i<)-3,7- Difluoro-6H- dibenzo[b,e]oxepin-l 1- ylidenemethyl)-l -((7S, 8aR)-hexahydro- pyrrolo[2,l- c][l,4]oxazin-7-yl)-l,3- dihydro-benzoimidazol- 2-ylidene)-urea F\ A-° o / \ /\^ V--NH )~NH2 0 LCMS m/z 544.6 [M + H]+ Ex Chemical Name Structure Physical Data 51 (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11 -ylidenemethyl)-1 -{(7R, &i?)-hexahydro-pyrrolo[2,l-c][l,4]oxazin-7-yl)-l,3-dihydro-benzoimidazol-2-ylidene)-urea A-0 o NH NH2 0 LCMS m/z 526.6 [M + H]+ We Claim: 1. A compound of the formula wherein, R1 and R2 each independently represent hydrogen or fluoro; L represents -(CH2)2- , -CH(CH3)-CH2- , or a direct bond; R3 represents hydrogen or a group of the formula: R4 represents -CN or -C(O)NH2, or a pharmaceutically acceptable salt thereof. 2. A compound or salt according to claim 1 selected from the group consisting of (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-(1-methyl- azetidin-3-yl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide; (E)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-1-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)cyanamide; (E)-N-(5-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-1-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)cyanamide maleate; (E)-N- [5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-((3S,4S)-4-hydroxy-1-methyl-pyrrolidin-3-yl)-1,3-dihydro-benzoimidazol-2-ylidene]-urea; (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-((R)-1-methyl-2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-ylidene)-urea; and (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-((7S, 8aR)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-1,3-dihydro-benzoimidazol-2-ylidene)-urea. 3. A compound according to claim 1 that is (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-((R)-1-methyl-2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-ylidene)-urea, or a pharmaceutically acceptable salt thereof. 4. A compound or salt according to any one of claims 1 through 3 for use in the treatment of congestive heart failure, diabetic nephropathy, chronic kidney disease, hypertension, hypokalemia, myocardial arrhythmia, Bartter’s Syndrome, primary or secondary hyperaldosteronism, or Conn’s Syndrome. 5. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 through 3 in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients. 6. A pharmaceutical composition according to Claim 5 comprising a compound that is (E)-N-(5-((E)-3-Fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-((R)-1-methyl-2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-ylidene)-urea, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.