Abstract:
Disclosed are syntheses of 11β-HSD1 inhibitors and corresponding intermediates that are promising for the treatment of a variety of disease states including diabetes, metabolic syndrome, obesity, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hypertension-related cardiovascular disorders, hyperlipidemia, deleterious gluco-corticoid effects on neuronal function (e.g. cognitive impairment, dementia, and/or depression), elevated intra-ocular pressure, various forms of bone disease (e.g., osteoporosis), tuberculosis, leprosy (Hansen&#39;s disease), psoriasis, and impaired wound healing (e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes).

Description:
RELATED APPLICATIONS 
     The present application is a U.S. national stage application claiming the benefit of International Application No. PCT/US2008/009048, filed on Jul. 25, 2008, which claims the benefit of U.S. Provisional Application No. 60/962,058, filed on Jul. 26, 2007, U.S. Provisional Application No. 61/001,253, filed Oct. 31, 2007 and U.S. Provisional Application No. 61/049,650, filed May 1, 2008. The entire teachings of the above applications are incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) are promising drugs for the treatment of a number of diseases and disorders as described in detail in U.S. Provisional Patent Application No. 60/962,058, filed Jul. 26, 2007; U.S. Provisional Patent Application No. 61/001,253, filed Oct. 31, 2007; U.S. Provisional Patent Application No. 61/049,650, filed May 1, 2008; and International Application No. PCT/US2008/009048, filed Jul. 25, 2008; all of which are herein incorporated by reference in their entirety. 
     For example, 11β-HSD1 inhibitors are promising for the treatment of diabetes, metabolic syndrome, obesity, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hypertension-related cardiovascular disorders, hyperlipidemia, deleterious gluco-corticoid effects on neuronal function (e.g. cognitive impairment, dementia, and/or depression), elevated intra-ocular pressure, various forms of bone disease (e.g., osteoporosis), tuberculosis, leprosy (Hansen&#39;s disease), psoriasis, and impaired wound healing (e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes). 
     There is a need for better, for example, more economical and more efficient methods for synthesis of the 11β-HSD1 inhibitors. 
     SUMMARY OF THE INVENTION 
     The present invention provides economical and efficient methods for the synthesis of 11β-HSD1 inhibitors, for example, oxazinone compounds and tertiary alcohol oxazinone compounds as disclosed herein. 
     One embodiment of the present invention is a method of preparing an oxazinone compound represented by structural formula (I): 
     
       
                 
         
             
             
         
      
     
     R 1  is (a) absent or (b) is selected from optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy, and optionally substituted (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl; 
     E is (a) a bond or (b) (C 1 -C 3 )alkylene or (C 1 -C 2 )alkoxy, wherein the O is attached to R 2 , each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, trifluoromethyl and oxo; 
     R 2  is selected from optionally substituted (C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; 
     R 3  is selected from optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 3 -C 5 )cycloalkyl(C 1 -C 4 )alkyl, optionally substituted (C 1 -C 3 )alkoxy(C 1 -C 3 )alkoxy and optionally substituted (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl; 
     A 1  is (a) a bond, or (b) (C 1 -C 3 )alkylene, CH 2 CH 2 O, wherein the oxygen is attached to Cy 1 ; 
     Cy 1  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted monocyclic cycloalkyl or optionally substituted monocyclic heterocyclyl; 
     A 2  is (a) a bond, O, S or NR 4 , wherein R 4  is (C 1 -C 3 )alkyl or (C 3 -C 6 )cycloalkyl; or (b) (C 1 -C 3 )alkylene or (C 1 -C 2 )alkoxy, each of which is optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, or trifluoromethyl. 
     Cy 2  is (a) hydrogen or (b) optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl. 
     The method comprises the step of reacting a β-haloalcohol compound, for example a β-haloalcohol compound represented by structural formula (II) 
                                
with an isocyanate compound represented by structural formula (III)
 
                                
X is a leaving group
 
     Another embodiment of the present invention is a method of preparing an epoxide compound represented by structural formula (IV): 
                                
The method comprises the step of oxidizing with an epoxidation reagent a 2-methyl-2-propenyl intermediate represented by the following structural formula:
 
                                
A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2  and E in structural formulas (IV) and (V) are as defined in structural formula (I).
 
     Another embodiment of the present invention is a method of preparing tertiary alcohol oxazinone compound represented by structural formula (VI): 
                                
The method comprises the step of reducing the epoxide group of the epoxide compound represented by structural formula (IV) with a reducing agent. A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2  and E in structural formula (VI) are as defined in structural formula (V).
 
     In an alternative embodiment, the tertiary alcohol oxazinone compound represented by structural formula (VI) can be prepared using the compound of structural formula VII: 
                                
following the synthetic scheme set forth in  FIG. 2 . Example 22 provides details of the synthetic steps of  FIG. 2  for the preparation of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one.
 
     A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2  and E in structural formula (VII) are as defined in structural formula (I). 
     Another embodiment of the present invention is an epoxide compound represented by structural formula (IV) or a salt thereof. 
     Yet another embodiment of the present invention is a 2-methyl-2-propenyl intermediate represented by structural formula (V) or a salt thereof. 
     Other embodiments of the present invention are the epoxide compounds and salts thereof, and 2-methyl-2-propenyl intermediates and salts thereof as prepared with the methods of the present invention, in particular, the epoxide compounds and 2-methyl-2-propenyl intermediates corresponding to the above described embodiments. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic, showing the synthesis of a specific tertiary alcohol oxazinone compound, a 11β-HSD1 inhibitor, using the methods disclosed herein. 
         FIG. 2  is a schematic, showing the synthesis of a specific tertiary alcohol oxazinone compound, a 11β-HSD1 inhibitor, using the methods disclosed herein. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides methods for synthesizing 11β-HSD1 inhibitors, for example, oxazinone compounds and tertiary alcohol oxazinone compounds as disclosed herein. 
     The oxazinone compound represented by structural formula (I), for example, compounds 5 and 6 (see Figure), can be prepared by reacting a β-haloalcohol compound represented by structural formula (II) with an isocyanate compound represented by structural formula (III). Both, the β-haloalcohol compound and the isocyanate compound can be prepared from commercially available compounds using methods known in the art (see, Exemplification section). 
     The tertiary alcohol oxazinone compound represented by structural formula (VI) such as, for example, compound 8 (see  FIG. 1 ) is prepared by first oxidizing 2-methyl-2-propenyl intermediate represented by structural formula (V) with an epoxidation reagent to obtain the epoxide compound represented by structural formula (IV). The 2-methyl-2-propenyl intermediate is an oxazinone compound that can be prepared using the method described in the previous paragraph, wherein R 3  is 2-methyl-2-propenyl. In a second step, the epoxide group of the epoxide compound is reduced with a reducing agent to form the tertiary alcohol oxazinone compound. 
     Oxazinone compounds and tertiary alcohol oxazinone compounds represented by structural formulas (I) and (VI), respectively, for which Cy 1  is phenyl substituted with a leaving group (e.g., —Br) and optionally substituted with one or more additional substituents, can be used to prepare biaryl group containing 11β-HSD1 inhibitors, for example, by using a “Suzuki” coupling reaction as described in Example 111 of U.S. Provisional Patent Application No. 60/962,058, filed Jul. 26, 2007. Alternatively, oxazinone compounds represented by structural formulas (I) and (VI), respectively, for which Cy 1  is phenyl substituted with a leaving group (e.g., —Br) and optionally substituted with one or more additional substituents, can be used to prepare biaryl group containing 11β-HSD1 inhibitors, by conversion of the leaving group (e.g. —Br) to a boronic acid or boronate ester, followed by using a “Suzuki” coupling reaction with Cy 2 -Cl or Cy 2 -Br (see EXAMPLE 23). Alternatively, biaryl group containing 11β-HSD1 inhibitors can be obtained from isocyanate compounds that already contain the biaryl group using the methods of the present invention. The synthesis of a variety of biaryl compounds is provided in the Exemplification section. 
     A detailed description of each reaction in the syntheses is provided below. In the discussion below, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2  and E have the meanings indicated above unless otherwise noted. In cases where the synthetic intermediates and final products described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol, sulfonamide, amide and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (T. W. Greene and P. G. M. Wuts “Protective Groups in Organic Synthesis” John Wiley &amp; Sons, Inc., New York 2007, herein incorporated by reference in its entirety). Such protecting group manipulations are assumed in the discussion below and not described explicitly. The term “protected” as used herein in combination with terms denoting chemical groups, for example, protected piperidinyl, refers to the chemical group with its functional groups that may interfere with a desired reaction having been reacted with a protective group, e.g., the ring nitrogen atom in the case piperidine. 
     Oxazinone Compounds 
     The oxazinone compound represented by structural formula (I) is prepared by reacting a β-haloalcohol compound represented by structural formula (II) with an isocyanate compound represented by structural formula (III) as shown above. Typically, the reaction of the a β-haloalcohol with the isocyanate compound is carried out in the presence of a base. More typically, the reaction is carried out in the presence of a non-nucleophilic base. Most typically, the reaction is carried out in the presence of a non-nucleophilic amine base. Suitable non-nucleophilic amide bases include, but are not limited to as lithium amide (LiNH 2 ), sodium amide (NaNH 2 ), lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, lithium dicyclohexylamide, silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, lithium tetramethylpiperidide, and lithium tetramethylpiperidine. Other non-nucleophilic bases include but are not limited to sodium hydride, sodium tert-pentoxide and sodium tert-butoxide. Examples of suitable non-nucleophilic amine bases include, but are not limited to, diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4-methylpyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane and the like. Most typically, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. Although an excess of either β-haloalcohol compound or isocyanate compound can be used, the isocyanate compound is more commonly used in excess. Typically, from about one to about ten equivalents of base relative to β-haloalcohol are used, more typically from about one to about six equivalents, and, even more typically, from one to about 5 equivalents. Typically the reaction is carried out in an anhydrous aprotic, non-nucleophilic solvent at β-haloalcohol compound concentrations between about 0.01 M and 5 M. β-Haloalcohol compound concentrations are more typically, however, between about 0.05 M and 2 M. Suitable solvents include, but are not limited to ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl-methyl ether and 1,4-dioxane, and non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like. Suitable reaction temperatures generally range from about 0° C. to about the boiling point of the solvent. More typically, temperatures are sufficiently high to allow refluxing, for example, about 68° C. for tetrahydrofuran. 
     Epoxide Compounds 
     The epoxide compound represented by structural formula (IV) is prepared by oxidizing the propenyl group of the 2-methyl-2-propenyl intermediate represented by structural formula (V) with an epoxidation reagent. The 2-methyl-2-propenyl intermediate is an oxazinone compound that can be prepared using the method described in the previous paragraphs (e.g., the reaction of a compound of Formula II with a compound of Formula III). Suitable epoxidation reagents include, but are not limited to peroxides (e.g., hydrogen peroxide, t-butyl hydroperoxide), peroxycarboxylic acids (e.g., 3-chloroperbenzoic acid (MCPBA), peracetic acid, pertrifluoroacetic acid), magnesium bis(monoperoxyphthalate) hexahydrate, potassium monoperoxysulfate optionally in the presence of 1,2:4,5-di-O-isopropylidene-β-D-erythro-2,3-hexodiulo-2,6-pyranose, dimethyldioxirane and the like. Typically, the epoxidation reagent is a peroxycarboxylic acid, and, most typically, it is 3-chloroperbenzoic acid. Typically, from about one to about ten equivalents of epoxidation reagent relative to 2-methyl-2-propenyl intermediate are used, more typically from about one to about six equivalents, and, most typically, from about one to about 2 equivalents. Typically the reaction is carried out in an aprotic, non-nucleophilic solvent at 2-methyl-2-propenyl intermediate concentrations between about 0.01 M and 5 M. 2-Methyl-2-propenyl intermediate concentrations are more typically, however, between about 0.05 M and 2 M. Suitable solvents include, but are not limited to, halogenated solvents (e.g., chloroform, dichloromethane and 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), or hexamethylphosphorus triamide and ethereal solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane. Typically, the solvent is a halogenated solvent. More typically, the solvent is dichloromethane or 1,2-dichloroethane. Most typically, the solvent is dichloromethane. Suitable reaction temperatures generally range from about 0° C. to about the boiling point of the solvent used. Most typically, the reaction is carried out at ambient temperature. 
     Tertiary Alcohol Oxazinone Compounds 
     The tertiary alcohol oxazinone compound represented by structural formula (VI) is prepared by reducing the epoxide group of the epoxide compound represented by structural formula (IV) with a reducing agent. Suitable reducing agents include, but are not limited to hydride reducing agents such as lithium triethylborohydride, LiAlH 4 , LiBH 4 , lithium tri-t-butoxyaluminum hydride in the presence of triethylborane, potassium tri-sec-butylborohydride or sodium bis(2-methoxyethoxy)aluminum hydride and the like. Other suitable reducing agents include, but are not limited to BH 3 .Et 3 N—LiClO 4 , lithium di-tert-butylbiphenyl, or hydrogen or sodium formate in the presence of palladium on charcoal. Most typically, the reducing agent is lithium triethylborohydride (super hydride). Typically, from about one to about ten equivalents of reducing agent relative to the epoxide compound are used, more typically from about one to about six equivalents, and, most typically, from about one to about 2 equivalents. Typically the reaction is carried out in an anhydrous aprotic, non-nucleophilic solvent at epoxide compound concentrations between about 0.01 M and 5 M. Epoxide compound concentrations are more typically, however, between about 0.05 M and 2 M. Suitable solvents include, but are not limited to ethereal solvents such as diethyl ether, tetrahydrofuran (THF), tert-butyl-methyl ether and 1,4-dioxane, and non-ethereal solvents such as dimethyl formamide and dimethyl sulfoxide and the like. Typically, the solvent is an ethereal solvent. Most typically, the solvent is anhydrous tetrahydrofuran. Suitable reaction temperatures generally range from about 0° C. to about ambient temperature. 
     The processes for preparing the oxazinone compound represented by structural formula (I), the epoxide compound represented by structural formula (IV) and the tertiary alcohol oxazinone compound represented by structural formula (VI) as described in the previous three paragraphs and for the compounds represented by structural formulas (I), (IV), (V), (VI) and (VII) can further be described according to the following preferred embodiments. Note that R 3  and X refer to the preparation of an oxazinone compound only. 
     In a first preferred embodiment, Cy 1 , Cy 2 , R 2 , R 3  and X are as defined in structural formulas (I) to (VI) (see summary of invention) and R 1  is absent or is (C 1 -C 6 )alkyl; A 1  is a bond, CH 2 , or CH 2 CH 2 , or CH when R 1  is present; A 2  is a bond, O, OCH 2 CO or CH 2 ; X is a Cl, Br, I or —OSO 2 R, wherein R is (C 1 -C 4 )alkyl optionally substituted with one or more F, or phenyl optionally substituted with halogen, (C 1 -C 4 )alkyl or NO 2 ; and E is a bond or (C 1 -C 3 )alkylene. 
     In a second preferred embodiment, R 1 , R 2 , R 3 , X and E are as defined in the first preferred embodiment and A 1  is a bond or CH when R 1  is present; A 2  is a bond; Cy 2  is hydrogen; Cy 1  is phenyl substituted with Cl, Br, I or OSO 2 CF 3 , and optionally substituted with one or more additional substituents. 
     In a third preferred embodiment, A 2 , Cy 2 , R 1 , R 2 , R 3 , X and E are as defined in the second preferred embodiment and A 1  is —CH, R 1  is present and Cy 1  is represented by the following structural formula: 
                                
Z is a Cl, Br, I, OSO 2 CF 3 , OSO 2 Me, or OSO 2 C 6 H 4 Me, r is 0, 1, 2 or 3; and each G′ is independently selected from the group consisting of (C 1 -C 4 )alkyl, halo(C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy, halogen, cyano and nitro.
 
     In a fourth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 2 , R 3 , X, E, r, G 1  and Z are defined as in the third preferred embodiment and R 1  is methyl or ethyl. 
     In a fifth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , X, E, r, G 1  and Z are defined as in the fourth preferred embodiment and R 2  is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (C 1 -C 6 )alkyl, protected hydroxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, protected CONH 2 , protected carboxylic acid and SO 2 Me; and with regard to the preparation of an oxazinone compound, R 3  is methyl, ethyl, propyl, butyl, vinyl, allyl, 2-methyl-2-propenyl, or ethoxyethyl, each optionally substituted with up to two groups independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, benzyloxycarbonyl, protected hydroxy(C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, protected (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, halogen, cyano, oxo, nitro, protected hydroxy, protected amino, MeSO 2 —, MeSO 2 N(Me)(C 1 -C 4 )alkyl, protected MeSO 2 NH(C 1 -C 4 )alkyl, protected H 2 NC(═O)CMe 2 (C 1 -C 4 )alkyl, protected H 2 NC(═O)CHMe(C 1 -C 4 )alkyl and protected H 2 NC(═O)CH 2 (C 1 -C 4 )alkyl. 
     In a sixth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X, E, r, G 1  and Z are defined as in the fifth preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3  is vinyl, allyl, 2-methyl-2-propenyl, MeSO 2 NHCH 2 CH 2 CH 2 , protected H 2 NC(═O)CH 2 CH 2 , protected H 2 NC(═O)CMe 2 CH 2 , 2-cyano-2-methylpropyl, 2-oxopropyl or (C 1 -C 4 )alkoxycarbonylmethyl. 
     In a seventh preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X, E, r, G 1  and Z are defined as in the sixths preferred embodiment and R 2  is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, protected CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and SO 2 Me. 
     In an eight preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X, E, r, G 1  and Z are defined as in the seventh preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3  is allyl, 2-methyl-2-propenyl, protected H 2 NC(═O)CMe 2 CH 2  or 2-cyano-2-methylpropyl. 
     In a ninth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X, A E, r, G 1  and Z are defined as in the seventh preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3  is 2-methyl-2-propenyl or 2-cyano-2-methylpropyl. 
     In a tenth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X, E, r, G 1  and Z are defined as in the ninth preferred embodiment and R 2  is phenyl or fluorophenyl. 
     In an eleventh preferred embodiment, A 1 , A 2 , R 1 , R 2 , R 3 , X and E are defined as in the first preferred embodiment and Cy 1  is phenyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, azepanyl, pyridyl, thiazolyl, pyrimidinyl, each optionally substituted with 1 to 4 groups; and Cy 2  is phenyl, thienyl, pyridyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, S,S-dioxothiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benztriazolyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl and oxodihydropyrazinyl, each optionally substituted by 1 to 4 groups; wherein substituents for a ring carbon atom of Cy 1  and Cy 2  are independently selected from halogen, cyano, oxo, nitro, protected hydroxy, protected amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, benzoxycarbonyl, protected CONH 2 , protected (C r  C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, protected (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and protected (C 1 -C 4 )alkylcarbonylamino, wherein suitable substituents for a substitutable ring nitrogen atom in Cy 2  are selected from the group consisting of (C r  C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkylcarbonyl and benzyloxycarbonyl. For the process of preparing an oxazinone compound, each substitutable ring nitrogen atom of Cy 2 , if present, is either bonded to A 2 , protected or substituted. 
     In a twelfth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 2 , R 3 , X and E are defined as in the eleventh preferred embodiment and R 1  is methyl or ethyl. 
     In a thirteenth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , X and E are defined as in the twelfth preferred embodiment and R 2  is phenyl, thienyl, or pyridyl, each optionally substituted with halogen, nitro, cyano, (C 1 -C 6 )alkyl, protected hydroxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, protected CONH 2 , protected carboxylic acid and SO 2 Me; and, with regard to the preparation of an oxazinone compound, R 3  is methyl, ethyl, propyl, butyl, vinyl, allyl, 2-methyl-2-propenyl, or ethoxyethyl each optionally substituted with up to two groups independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, benzyloxycarbonyl, protected hydroxy(C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, protected (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, halogen, cyano, oxo, nitro, protected hydroxy, protected amino, MeSO 2 —, MeSO 2 N(Me)(C 1 -C 4 )alkyl, protected MeSO 2 NH(C 1 -C 4 )alkyl, protected H 2 NC(═O)CMe 2 (C 1 -C 4 )alkyl, protected H 2 NC(═O)CHMe(C 1 -C 4 )alkyl and protected H 2 NC(═O)CH 2 (C 1 -C 4 )alkyl. 
     In a fourteenth preferred embodiment, A 1 , A 2 , Cy 1 , R 1 , R 2 , R 3 , X and E are defined as in the thirteenth preferred embodiment and Cy 2  is optionally substituted and selected from the group consisting of benzimidazolyl, benzotriazolyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl, oxodihydropyrazinyl, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl and thiadiazolyl. 
     In a fifteenth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are defined as in the fourteenth preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3  is vinyl, allyl, 2-propenyl-2-methyl, MeSO 2 NHCH 2 CH 2 CH 2 , protected H 2 NC(═O)CH 2 CH 2 , protected H 2 NC(═O)CMe 2 CH 2 , 2-cyano-2-methylpropyl, 2-oxopropyl or (C 1 -C 4 )alkoxycarbonylmethyl. 
     In a sixteenth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 3 , X and E are defined as in the fifteenth preferred embodiment and R 2  is phenyl optionally substituted with 1, 2 or 3 substituents selected from halo, cyano, protected CONH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and SO 2 Me. 
     In a seventeenth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are defined as in the sixteenth preferred embodiment and with regard to the preparation of an oxazinone compound, R 3  is allyl, 2-propenyl-2-methyl, protected H 2 NC(═O)CMe 2 CH 2  or 2-cyano-2-methylpropyl. 
     In an eighteenth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are defined as in the seventeenth preferred embodiment and, with regard to the preparation of an oxazinone compound, R 3  is 2-propenyl-2-methyl, or 2-cyano-2-methylpropyl. 
     In a nineteenth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , R 3 , X and E are defined as in the eighteenth preferred embodiment and R 2  is phenyl or fluorophenyl. 
     In a twentieth preferred embodiment, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , R 3 , X and E are are defined as in the nineteenth preferred embodiment and suitable substituents for a substitutable ring nitrogen atom in the group represented by Cy 2  are selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, (C 1 -C 4 )alkoxycarbonyl and (C 1 -C 4 )alkylcarbonyl; and suitable substituents for a substitutable ring carbon atom in the Cy 2  is selected from the group consisting fluorine, chlorine, cyano, protected hydroxy, protected amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, (C 1 -C 4 )alkoxy, protected CONH 2 , protected (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl, protected (C 3 -C 4 )cycloalkylaminocarbonyl, {(C 1 -C 4 )alkyl}{(C 3 -C 4 )cycloalkyl}aminocarbonyl and protected (C 1 -C 4 )alkylcarbonylamino. 
     In a twenty-first preferred embodiment, with regard to the preparation of an oxazinone compound, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and R 3  is 2-methyl-2-propenyl. 
     In a twenty-second preferred embodiment, with regard to the preparation of an oxazinone compound, A 1 , A 2 , Cy 1 , Cy 2 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and R 3  is 2-propenyl. 
     In a twenty-third preferred embodiment, A 1 , A 2 , Cy 1 , R 1 , R 2 , X and E are as defined in any one of the above preferred embodiments and Cy 2  is represented by one of the following structural formulas: 
     
       
                 
         
             
             
         
      
     
     G 2a  is (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl or (C 1 -C 4 )haloalkyl; G 2b  is hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, (C 3 -C 4 )cycloalkyl(C 1 -C 2 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, CONH 2 , (C 1 -C 4 )alkylaminocarbonyl, di(C 1 -C 4 )alkylaminocarbonyl or (C 1 -C 4 )alkylcarbonylamino. 
     Other embodiments of the present invention are the epoxide compounds and salts thereof, and 2-methyl-2-propenyl intermediates and salts thereof as prepared with the methods of the present invention, in particular, the epoxide compounds and 2-methyl-2-propenyl intermediates corresponding to the above described preferred embodiments. 
     The following individual compounds can be prepared by a suitable choice of starting materials: 
     
         
         (S)-3-((S)-1-(4-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile 
         (S)-3-((S)-1-(4-(1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         N-ethyl-5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)picolinamide 
         5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-methylpicolinamide 
         5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N-dimethylpicolinamide 
         (S)-3-((S)-1-(4-(1H-benzo[d][1,2,3]triazol-6-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methyl-1H-benzo[d]imidazol-6-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(1,5,6-trimethyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile 
         2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)isonicotinonitrile 
         N-tert-butyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide 
         (S)-3-((S)-1-(4-(2-ethoxy-6-methylpyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(6-ethoxy-5-methylpyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         N-cyclopropyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         6-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrazine-2-carboxamide 
         2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N-dimethylthiazole-5-carboxamide 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-ethyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1,6-dimethyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         6-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrazine-2-carbonitrile 
         (S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N-dimethylnicotinamide 
         (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)propyl)phenyl)-2,6-dimethylpyridine 1-oxide 
         5-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrazine-2-carbonitrile 
         5-fluoro-2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine 1-oxide 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-methylpyrazin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-methylnicotinamide 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide 
         (S)-3-((S)-1-(4-(5-fluoropyridin-2-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyrimidin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(pyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(pyrazin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile 
         (S)-3-((S)-1-(4-(2,6-dimethylpyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4-(2,6-dimethylpyridin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one 
         4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,6-dimethylpyridine 1-oxide 
         6-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile 
         4-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)-2,6-dimethylpyridine 1-oxide 
         4-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)-2-methylpyridine 1-oxide 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
         (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one 
       
    
     As used herein, “β-haloalcohol compound,” refers to compound represented by structural formula (II) 
                                
wherein X includes any suitable leaving group as described herein, not just halogen.
 
     Suitable leaving groups include, but are not limited to halides, alkylsulfonates, trifluoromethanesulfonate (triflate) and phenylsulfonates which are optionally substituted with a methyl, halogen, nitro and the like, for example, methanesulfonate (mesylate), p-toluenesulfonate (tosylate), p-bromobenzenesulfonate (brosylate), p-nitrobenzenesulfonate (nosylate) and the like. Typically, leaving groups are Cl, Br, I or —OSO 2 R, wherein R is (C 1 -C 4 )alkyl optionally substituted with one or more F, or phenyl optionally substituted with halogen, (C 1 -C 4 )alkyl or NO 2 . Most typically, leaving groups are Cl, Br, I or —OSO 2 R. 
     The term “biaryl group” as used herein refers to a group where an optionally substituted aryl or optionally substituted heteroaryl is bonded to another optionally substituted aryl or optionally substituted heteroaryl (e.g., biphenyl). 
     The term “alkyl” as used herein refers to a straight chain or branched saturated hydrocarbyl group having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. 
     The term “cycloalkyl” means a monocyclic, bicyclic or tricyclic, saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl (c-Pr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, spiro[4.4]nonane, adamantyl and the like. 
     The term “aryl” means an aromatic radical which is a phenyl group, a naphthyl group, an indanyl group or a tetrahydronaphthalene group. An aryl group is optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido. 
     The term “heteroaryl” means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a saturated or unsaturated ring containing 0-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-, or 5-imidazolyl. A heteroaryl is optionally substituted. Exemplary substituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO 2 H, CONH 2 , N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide. 
     The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. Exemplary heterocyclyls include pyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine, 1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine, 1,4-dihydro-4-oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one, imidazolidin-2-one, imidazolidine-2,4-dione, tetrahydropyrimidin-2(1H)-one, morpholine, N-methylmorpholine, morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-1,2,5-thiaoxazole 1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-dioxide, hexahydro-1,2,6-thiadiazine 1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide isothiazolidine 1,1-dioxide, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl and 5-oxo-4,5-dihydro-1H-imidazol-2-yl. A heterocyclyl can be optionally substituted with 1-4 substituents. Exemplary substituents include alkyl, haloalkyl, halogen and oxo. 
     The term “alkoxy group” (also herein referred to as “alkoxy”) as used herein, refers to an alkyl-O— group or a cycloalkyl-O— group, where the preferred alkyl and cycloalkyl groups and optional substituents thereon are those given above. An alkoxy group can be unsubstituted or substituted with one or more substituents. 
     The term “alkenyl group” (also herein referred to as “alkenyl”) as used herein, refers to a straight chain or branched hydrocarbyl group which includes one or more double bonds. Typically, an alkenyl group includes between 2 and 12 carbon atoms (i.e., (C 2 -C 12 )-alkenyl). Suitable alkenyl groups include but are not limited to n-butenyl, cyclooctenyl and the like. An alkenyl group can be unsubstituted or substituted with one or more substituents. 
     The term “alkynyl” group (also herein referred to as “alkynyl”) as used herein, refers to a straight chain or branched hydrocarbyl group which includes one or more triple bonds. The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to, (C 2 -C 8 )-alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl-, and 4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substituted with one or more substituents. 
     The term “alkylene group” (also herein referred to as “alkylene) as used herein, refers to a group represented by —[CH 2 ] z —, wherein z is a positive integer, preferably from one to eight, more preferably from one to four. 
     The terms “cycloalkyl alkyl”, “alkoxy alkyl” and the like, that is, terms that consist of a combination of terms as defined above refer to groups that contain the groups referred to by the terms. For example, a (C a -C b )alkoxy(C c -C d )alkyl is a group that includes an alkoxy group with between a and b carbon atoms that is covalently bonded to an alkyl group with between c and d carbon atoms. 
     The above groups can be unsubstituted or optionally substituted. Suitable substituents are those which do not substantially interfere with the reactions described herein, that is, that do not substantially decrease the yield (e.g., a decrease of greater than 50%) or cause a substantial amount of by-product formation (e.g., where by-products represent at least 50% of the theoretical yield). However, “interfering” substituents can be used, provided that they are first converted to a protected form. Suitable protecting groups are known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007). 
     Suitable substituents for above groups include, for example, unless otherwise indicated, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, benzyloxycarbonyl, hydroxy(C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, halogen, cyano, oxo, nitro, hydroxy, amino, MeSO 2 —, MeSO 2 N(Me)(C 1 -C 4 )alkyl, MeSO 2 NH(C 1 -C 4 )alkyl, H 2 NC(═O)CMe 2 (C 1 -C 4 )alkyl, H 2 NC(═O)CHMe(C 1 -C 4 )alkyl, H 2 NC(═O)CH 2 (C 1 -C 4 )alkyl, —OR, —NR 2 , —COOR, —CONR 2 , —SO k R (k is 0, 1 or 2), wherein each R is independently —H, an alkyl group, a cycloalkyl group or an aryl group. 
     When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that solvates or hydrates of the compound or its physiologically acceptable salts are also included. “Solvates” refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. 
     Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol “*” in a structural formula represents the presence of a chiral carbon center. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. Thus, “R*” and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms. 
     The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. 
     When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer. 
     When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound free from the corresponding optical isomer, a racemic mixture of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer. 
     When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has at least two chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s). 
     The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. 
     Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts. 
     Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. 
     Protecting groups for an hydroxyl group —OH and reactions and conditions for protecting and deprotecting the hydroxyl group are well known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007), Chapter 2 and references cited therein. For example, a protecting group may protect a hydroxyl group as ether. Such protecting groups include, but are not limited to methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, [3,4-dimethoxybenzyl)oxy]methyl, p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, [(R)-1-(2-nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, [(p-phenylphenyl)oxy]methyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, O-bis(2-acetoxyethoxy)methyl, tetrahydropyranyl, fluorous tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl, S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1-(4-chlorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahyrdo-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-hydroxyethyl, 2-bromoethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl, 1,1,-dianisyl-2,2,2,-trichloroethyl, 1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 1-(2-cyanoethoxy)ethyl, 2-trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, t-butyl, cyclohexyl, 1-methyl-1′-cyclopropylmethyl, allyl, prenyl, cinnamyl, 2-phenallyl, propargyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, pentadienylnitrobenzyl, pentadienylnitropiperonyl, halobenzyl, 2,6-dichlorobenzyl, 2,4-dichlorobenzyl, 2,6-difluorobenzyl, p-cyanobenzyl, fluorosbenzyl, 4-fluorousalkoxybenzyl, trimethylsilylxylyl, p-phenylbenzyl, 2-phenyl-2-propyl (cumyl), p-acylaminobenzyl, p-azidobenzyl, 4-azido-3-chlorobenzyl, 2- and 4-trifluoromethylbenzyl, p-(methylsulfinyl)benzyl, p-siletanylbenzyl, 4-acetoxybenzyl, 4-(2-trimethylsilyl)ethoxymethoxybenzyl, 2-naphthylmethyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, 2-quinolinylmethyl, 6-methoxy-2-(4-methylphenyl)-4-quinolinemethyl, 1-pyrenylmethyl, diphenylmethyl, 4-methoxydiphenylmethyl, 4-phenyldiphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, tris(4-t-butylphenyl)methyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″tris(benzoyloxyphenyl)methyl, 4,4′-dimethoxy-3″-[N-(imidazolylmethyl)trityl, 4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl, bis(4-methoxyphenyl)-1′-pyrenylmethyl, 4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4″-dimethoxytrityl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-phenylthioxanthyl, 9(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, 4,5-bis(ethoxycarbonyl-[1,3]-dioxolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsiyl, diethylisopropylsilyl, dimethylthexylsilyl, 2-norbornyldimethylsily, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-t-butylmethylsilyl, bis(t-butyl)-1-pyrenylmethoxysilyl, tris(trimethylsilyl)silyl, sisyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsily, t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl, fluorous silyl. Alternatively, suitable protecting groups protect the hydroxyl group as esters, for example, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetamidate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, phenylacetate, p-P-phenylacetate, diphenylacetate, 3-phenylpropionate, bisfluorous chain type propanoyl (Bfp-OR), 4-pentenoate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate, 5-[3-Bis(4-methoxyphenyl)hydroxymethylphenoxy]levulinate, pivaloate, 1-adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), 4-bromobenzoate, 2,5-difluorobenzoate, p-nitrobenzoate, picolinate, nicotinate, 2-(azidomethyl)benzoate, 4-azidobutyrate, (2-azidomethyl)phenylacetate, 2-{[(tritylthio)oxy]methyl}benzoate, 2-{[(4-methoxytritylthio)oxy]methyl}benzoate, 2-{[methyl(tritylthio)amino]methyl}benzoate, 2{{[4-methoxytrityl)thio]methylamino}-methyl}benzoate, 2-(allyloxy)phenylacetate, 2-(prenyloxymethyl)benzoate, 6-(levulinyloxymethyl)-3-methoxy-2- and 4-nitrobenzoate, 4-benzyloxybutyrate, 4-trialkylsiloxybutrate, 4-acetoxy-2,2-dimethylbutyrate, 2,2-dimethyl-4-pentenoate, 2-iodobenzoate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 4-methylthiomethoxy)butyrate, 2-methylthiomethoxymethyl)benzoate, 2-(chloroacetoxymethyl)benzoate, 2[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate, 2-[2-(4-methoxybenzyloxy)ethyl]benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, 2-chlorobenzoate, as sulfonates, sulfenates and sulfinates such as sulfate, allylsulfonate, ethanesulfonate (mesylate), benzylsulfonate, tosylate, 2-[(4-nitrophenyl)ethyl]sulfonate, 2-trifluoromethylsulfonate, 4-monomethoxytritylsulfenate, alkyl 2,4-initrophenylsulfenate, 2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinate, borate, dimethylphosphinothioyl, as carbonates such as alkyl methyl carbonate, methoxymethyl carbonate, 9-fluorenylmethyl carbonate, ethyl carbonate, bromoethyl carbonate, 2-(methylthiomethoxy)ethyl carbonate, 2,2,2-trichloroethyl carbonate, 1,1-dimethyl-2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-[dimethyl(2-naphthylmethypsilyl]ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, 2-(triphenylphosphonio)ethyl carbonate, cis-[4-[[(-methoxytrityl)sulfenyl]oxy]tetraydrofuran-3-yl]oxy carbonate, isobutyl carbonate, t-butyl carbonate, vinyl carbonate, allyl carbonate, cinnamyl carbonate, propargyl carbonate, p-chlorophenyl carbonate, p-nitrophenyl carbonate, 4-ethoxyl-1-naphthyl carbonate, 6-bromo-7-hydroxycoumarin-4-ylmethyl carbonate, benzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, anthraquinon-2-ylmethyl carbonate, 2-dansylethyl carbonate, 2-(4-nitrophenyl)ethyl, 2-(2,4-nitrophenyl)ethyl, 2-(2-nitrophenyl)propyl, 2-(3,4-methylenedioxy-6-nitrophenylpropyl, 2-cyano-1-phenylethyl carbonate, 2-(2-pyridyl)amino-1-phenylethyl carbonate, 2-[N-methyl-N-(2-pyridyl)]amino-1-phenylethyl carbonate, phenacyl carbonate, 3′,5′-dimethoxybenzoin carbonate, methyl dithiocarbonate, S-benzyl thiocarbonate, and carbamates such as dimethylthiocarbamate, N-phenylcarbamate, and N-methyl-N-(o-nitrophenyl) carbamate. 
     Protecting groups for a carbonyl group and reactions and conditions for protecting and deprotecting the carbonyl group are well known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007), Chapter 4 and references cited therein. For example, a protecting group may protect a carbonyl group as acetal or ketal. These acetals and ketals include acyclic acetals and ketals (e.g., dimethyl, diisopropyl, bis(2,2,2-trichloroethyl), cyclic acetals and ketals (e.g., 1,3-dioxanes, 1,3-dioxolanes, 1,3-dioxapane and the like), chiral acetals and ketals (e.g., (4R,5R)-diphenyl-1,3-dioxolane, 4,5-dimethyl-1,3-dioxolane, trans-1,2-cyclohexanediol ketal and the like), dithio acetals and ketals (e.g., S,S′-dimethyl, S,S′-diethyl, S,S′-dipropyl, 1,3-dithiane and the like), and monothio acetals and ketals. 
     Protecting groups for a carboxyl group and reactions and conditions for protecting and deprotecting the carboxyl group are well known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007), Chapter 5 and references cited therein. For example, a protecting group may protect a carboxyl group as ester. These esters include, but are not limited to substituted methyl esters (e.g., 9-fluorenylmethyl, methoxymethyl, methoxyethoxymethyl and the like), 2-substituted ethyl esters (e.g., 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl and the like), 2,6-dialkylphenyl esters (e.g., 2,6-dimethylphenyl, 2,6-di-t-butyl-4-methylphenyl, pentafluorophenyl and the like), substituted benzyl esters (e.g., triphenylmethyl, diphenylmethyl, 9-anthrylmethyl and the like), silyl esters (e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like. Alternatively, for example, a protecting group may protect a carboxyl group as amide (e.g., N,N-dimethyl, pyrrolidinyl, piperidinyl and the like) or hydrazide (e.g., N-phenyl). 
     Protecting groups for an amino group and reactions and conditions for protecting and deprotecting the amino group are well known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007), Chapter 7 and references cited therein. For example, a protecting group may protect an amino group as carbamate (e.g., 9-fluorenylmethyl, 2,2,2-trichloroethyl, 4-phenylacetoxybenzyl, 2-methylthioethyl, m-nitrophenyl, and the like) or amide (e.g., formamide, acetamide, 3-phenylpropanamide). 
     Protecting groups for an aromatic heterocycle such as, for example, imidazole, pyrrole, and indole, and reactions and conditions for protecting and deprotecting the aromatic heterocycles are well known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007), Chapter 7 and references cited therein. For example, a protecting group may protect an aromatic heterocycle as N-sulfonyl derivative (e.g., N,N-dimethylsulfonamide, methanesulfoneamide, mesitylenesulfonamide and the like), carbamate (e.g., benzyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl and the like), N-alkyl and N-aryl derivatives, N-trialkylsilyl, N-allyl, N-benzyl, amino acetal derivative, or amide. 
     Protecting groups for an amide group, and reactions and conditions for protecting and deprotecting the amide group are well known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007), Chapter 7 and references cited therein. For example, a protecting group may protect an amide group as N-methylamide, N-allylamide, N-t-butylamide and the like. 
     Protecting groups for a sulfonamide group, and reactions and conditions for protecting and deprotecting the sulfonamide group are well known in the art and are disclosed, for example, in Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &amp; Sons (2007), Chapter 7 and references cited therein. For example, a protecting group may protect a sulfonamide group as N-t-butylsulfonamide, N-diphenylmethylsulfonamide, N-benzylsulfonamide and the like. A description of example embodiments of the invention follows. 
     The following abbreviations have the indicated meanings: 
     
       
         
               
               
             
           
               
                   
               
               
                 Abbreviation 
                 Meaning 
               
               
                   
               
             
             
               
                 A % 
                 Area percentage 
               
               
                 Boc 
                 tert-butoxy carbonyl or t-butoxy carbonyl 
               
               
                 (Boc) 2 O 
                 di-tert-butyl dicarbonate 
               
               
                 Cbz 
                 Benzyloxycarbonyl 
               
               
                 CbzCl 
                 Benzyl chloroformate 
               
               
                 c-Pr 
                 cyclopropyl 
               
               
                 DAST 
                 diethylaminosulfur trifluoride 
               
               
                 DBU 
                 1,8-diazabicyclo[5.4.0]undec-7-ene 
               
               
                 DCC 
                 N,N′-dicyclohexylcarbodiimide 
               
               
                 DCU 
                 N,N′-dicyclohexylurea 
               
               
                 DIAD 
                 diisopropyl azodicarboxylate 
               
               
                 DIBAL-H 
                 diisobutylaluminum hydride 
               
               
                 DIEA 
                 N,N-diisopropylethylamine 
               
               
                 DMAP 
                 4-(dimethylamino)pyridine 
               
               
                 DMF 
                 N,N-dimethylformamide 
               
               
                 DMPU 
                 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 
               
               
                 2,4-DNP 
                 2,4-dinitrophenylhydrazine 
               
               
                 DPTBS 
                 Diphenyl-t-butylsilyl 
               
               
                 dr 
                 diastereomer ratio 
               
               
                 EDC•HCl, 
                 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide 
               
               
                 EDCI 
                 hydrochloride 
               
               
                 Equiv 
                 equivalents 
               
               
                 EtOAc 
                 ethyl acetate 
               
               
                 Fmoc 
                 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- 
               
               
                 Fmoc-OSu 
                 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- 
               
               
                   
                 pyrrolidinedione 
               
               
                 h, hr 
                 hour(s) 
               
               
                 HOBt 
                 1-hydroxybenzotriazole 
               
               
                 HATU 
                 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- 
               
               
                   
                 tetramethyluronium hexafluorophosphate 
               
               
                 HBTU 
                 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium 
               
               
                   
                 hexafluorophosphate 
               
               
                 KHMDS 
                 potassium hexamethyldisilazane 
               
               
                 LAH or 
                 lithium aluminum hydride 
               
               
                 LiAlH 4   
               
               
                 LC-MS 
                 liquid chromatography-mass spectroscopy 
               
               
                 LHMDS 
                 lithium hexamethyldisilazane 
               
               
                 m-CPBA 
                 meta-chloroperoxybenzoic acid 
               
               
                 Me 
                 methyl 
               
               
                 MsCl 
                 methanesulfonyl chloride 
               
               
                 Min 
                 minute 
               
               
                 MS 
                 mass spectrum 
               
               
                 NaH 
                 sodium hydride 
               
               
                 NaHCO 3   
                 sodium bicarbonate 
               
               
                 NaN 3   
                 sodium azide 
               
               
                 NaOH 
                 sodium hydroxide 
               
               
                 Na 2 SO 4   
                 sodium sulfate 
               
               
                 NMM 
                 N-methylmorpholine 
               
               
                 NMP 
                 N-methylpyrrolidinone 
               
               
                 Pd 2 (dba) 3   
                 tris(dibenzylideneacetone)dipalladium(0) 
               
               
                 PE 
                 petroleum ether 
               
               
                 Quant 
                 quantitative yield 
               
               
                 rt 
                 room temperature 
               
               
                 Satd 
                 saturated 
               
               
                 SOCl 2   
                 thionyl chloride 
               
               
                 SFC 
                 supercritical fluid chromatography 
               
               
                 SPA 
                 scintillation proximity assay 
               
               
                 SPE 
                 solid phase extraction 
               
               
                 TBAF 
                 tetrabutylammonium fluoride 
               
               
                 TBS 
                 t-butyldimethylsilyl 
               
               
                 TBDPS 
                 t-butyldiphenylsilyl 
               
               
                 TBSCl 
                 t-butyldimethylsilyl chloride 
               
               
                 TBDPSCl 
                 t-butyldiphenylsilyl chloride 
               
               
                 TEA 
                 triethylamine or Et 3 N 
               
               
                 TEMPO 
                 2,2,6,6-tetramethyl-1-piperidinyloxy free radical 
               
               
                 Teoc 
                 1-[2-(trimethylsilyl)ethoxycarbonyloxy]- 
               
               
                 Teoc-OSu 
                 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione 
               
               
                 T ext   
                 External temperature 
               
               
                 T int   
                 Internal temperature 
               
               
                 TFA 
                 trifluoroacetic acid 
               
               
                 Tlc, TLC 
                 thin layer chromatography 
               
               
                 TMS 
                 trimethylsilyl 
               
               
                 TMSCl 
                 chlorotrimethylsilane or trimethylsilyl chloride 
               
               
                 t R   
                 retention time 
               
               
                 TsOH 
                 p-toluenesulfonic acid 
               
               
                   
               
             
          
         
       
     
     EXEMPLIFICATION 
     Synthesis of Compound 8 of FIG.  1   
       FIG. 1  shows a preferred synthesis of a specific tertiary alcohol oxazinone compound (compound 8) known to be a 11β-HSD1 inhibitor. Compounds 3 to 8 of  FIG. 1  were synthesized as described in Examples 1 to 4. 
     Example 1 
     
       
                 
         
             
             
         
      
     
     1-Chloro-5-methyl-3-phenyl-hex-5-en-3-ol (3). To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500 mL of THF (KF&lt;100 ppm) was charged 53.0 mL of 1 M DIBAL-H in hexane under nitrogen at room temperature. Then beta-methylallylic chloride (160 g, 1.77 mol) was introduced while maintaining the internal temperature below 30° C. The resulting solution was agitated for 2 h at room temperature. The solution was titrated in the presence of 1,1′-bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry flask containing 307.0 g of anhydrous CeCl 3  (1.25 mol) at room temperature under nitrogen was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25 mol). The resulting slurry was cooled to −10° C. and agitated for 0.5 h. To the slurry was added 200 g of the ketone (1.19 mol) in 200 mL of THF while maintaining the internal temperature below 0° C. After the mixture was stirred for 0.5 h, 1200 mL of 1 M HCl was added to obtain a clear solution while maintaining the internal temperature below 30° C. After the phase cut, the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under vacuum produced the crude product, which was chased with THF to achieve KF&lt;500 ppm. The crude product (306 g, 83 wt %, 95% yield) was used directly for subsequent coupling. Analytical data for 3:  1 H-NMR spectroscopy (500 MHz, CDCl 3 ) δ 7.38-7.37 (d. J=7.8 Hz, 2H), 7.33 (t, 7.9 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 4.91 (s, 1H), 4.76 (s, 1H), 3.57 (ddd, J=5.6, 10.7, and 10.7, 1H), 3.13 (ddd, J=4.7, 10.7 and 10.7 Hz, 1H), 2.66 (d, J=13.3 Hz, 1H), 2.54 (d, J=11.3 Hz, 1H), 2.53 (s, 1H), 2.36 (ddd, J=5.4, 10.6 and 13.9 Hz. 1H), 2.29 (ddd, J=5.6, 11.3 and 13.3 Hz, 1H), 1.29 (s, 3H).  13 C-NMR spectroscopy (125 MHz, CDCl 3 ) δ 144.3, 141.4, 128.0, 126.6, 124.8, 116.1, 74.2, 51.2, 46.0, 39.9, 23.9. 
     Example 2 
     
       
                 
         
             
             
         
      
     
     1-Bromo-4-((S)-1-isocyanato-ethyl)-benzene (4). To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous). To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(−)-1-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An additional 4 L of dichloromethane was charged to the reactor. The biphasic solution was agitated and cooled to T int =2-3° C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ˜6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene. The resulting murky solution was agitated at T int =2-5° C. for 30 min, at which point HPLC analysis indicates &gt;99 A % conversion (220 nm). The dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ˜1.5 L which fine particles of a white solid developed. The solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of product (93.7 wt %, 79.4% yield). The material was used in the following coupling without further purification. Analytical data for 4:  1 H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7.53 (d, J=11.4 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H). 
     Example 3 
     
       
                 
         
             
             
         
      
     
     (R)-3-[(S)-1-(4-Bromo-phenyl)-ethyl]-6-(2-methyl-allyl)-6-phenyl-perhydro-1,3-oxazin-2-one (6) To a dried 10 L jacketed reactor under a nitrogen atmosphere was charged 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (3, 167 g, 81.7 wt %, 610 mmol, 1.00 equiv), 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (4, 219 g, 93.7 wt %, 911 mmol, 1.50 equiv), anhydrous tetrahydrofuran (3.00 L), and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 mL, 2.73 mol, 4.50 equiv). The resulting solution was agitated and refluxed (T int =67-69° C., T ext =75° C.) for 19 h, at which point HPLC analysis indicates ˜1A % (220 nm) of the 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (3) remains. The dark solution was cooled to Tint=20-25° C. Two liters of tetrahydrofuran were removed by distillation under reduced pressure. The remaining dark solution was diluted with 4.0 L of ethyl acetate and 1.0 L of hexanes. The resulting solution was washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note: the wash is slightly exothermic). The aqueous solution was cut and the remaining organic solution was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was subjected to flash silica chromatography (5-30% ethyl acetate/hexanes, 1.74 kg of silica) to produce 137.8 g of material (59 wt %, 3.1:1 diastereomeric ratio favoring the desired diastereomer 6, 32.3% yield). The material was used in the following epoxidation without further purification. 
     Analytical data for (R)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-allyl)-6-phenyl-perhydro-1,3-oxazin-2-one (6):  1 H-NMR spectroscopy (500 MHz, CD2Cl2) δ 7.42-7.35 (m, 3H), 7.33-7.31 (m, 2H), 7.25-7.23 (m, 2H), 6.80-6.74 (m, 2), 5.55 (q, J=7.1 Hz, 1H), 5.37-5.36 (m, 1H), 4.89 (s, 1H), 4.69 (s, 1H), 2.96-2.93 (m, 1H), 2.61 (dd, J=13.8 and 26.4 Hz, 2H), 2.37-2.25 (m, 3H), 1.68 (s, 3H), 1.50 (d, J=7.1 Hz, 3H).  13 C-NMR spectroscopy (125 MHz, CD2Cl2) δ 152.5, 141.5, 140.1, 138.3, 130.6, 128.1, 128.0, 126.9, 124.4, 120.2, 115.3, 82.4, 52.1, 50.1, 35.6, 29.8, 23.4, 14.5. 
     Analytical data for (S)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-allyl)-6-phenyl-perhydro-1,3-oxazin-2-one (5):  1 H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7.50-7.48 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.32 (m, 3H), 7.20-7.18 (m, 2H), 5.60 (q, J=7.1 Hz, 1H), 4.85 (s, 1H), 4.66 (s, 1H), 2.73-2.67 (m, 2H), 2.60 (dd, J=13.9 and 19.4 Hz, 2H), 2.28 (dt, J=3.3 and 13.7 Hz, 1H), 2.14-2.05 (m, 1H), 1.66 (s, 3H), 1.24 (d, J=7.2 Hz, 3H).  13 C-NMR spectroscopy (100 MHz, CD2Cl2) δ 153.4, 142.5, 141.0, 140.1, 131.8, 129.3, 128.9, 127.8, 125.3, 121.5, 116.3, 83.9, 53.2, 51.0, 36.6, 31.3, 24.3, 15.4. 
     Example 4 
     
       
                 
         
             
             
         
      
     
     (S)-3-[(S)-1-(4-Bromo-phenyl)-ethyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-perhydro-1,3-oxazin-2-one (8; BI00135541). To a 1.0 L 2-neck RBF was charged (R)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-allyl)-6-phenyl-perhydro-1,3-oxazin-2-one (6, 135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (MCPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at RT (T int =20-25° C.) for 1 h, which HPLC analysis indicates &gt;99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence were repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of MCPBA is &lt;2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (S)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-oxiranylmethyl)-6-phenyl-perhydro-1,3-oxazin-2-one (7) which was used directly in the following reduction. 
     To a 2.0 L 3-neck oven-dried RBF was charged the crude (S)-3-[(S)-1-(4-bromo-phenyl)-ethyl]-6-(2-methyl-oxiranylmethyl)-6-phenyl-perhydro-1,3-oxazin-2-one (7) and 750 mL of anhydrous tetrahydrofuran. The resulting solution was agitated and cooled to T int =2-3° C. To the agitated clear solution was charged 1.0 M lithium triethylborohydride in tetrahydrofuran (Super Hydride, 348 mL, 348 mmol, 1.8 equiv). The addition is exothermic and addition controlled to maintain T int =&lt;8° C. The resulting solution was agitated at T int =2-3° C. for 1.5 h and then allowed to warm to T int =10-13° C. over a 2.5 h, which HPLC analysis indicates ˜94 A % (220 nm) conversion. To the agitated solution was charged a solution of hydrogen peroxide (95.7 mL of a 35 wt % aqueous solution diluted with 400 mL of water, 1.08 mol, 5.60 equiv). The addition is highly exothermic and addition controlled to maintain T int =&lt;25° C. The resulting solution was diluted with 1.00 L of methyl tert-butyl ether (MTBE) and washed with 1.00 L of water followed by 500 mL of a ˜30 wt % solution of sodium thiosulfate. The organic solution was dried with anhydrous sodium sulfate, filtered, and then concentrated via reduced pressure. The resulting material was subjected to flash silica chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired diastereomer (&gt;99:1 dr). The material consisting of the mixed fractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g of product (95.7 A % at 220 nm, 74:1 dr). The two samples were combined to produce 72.3 g of product (83.6% yield for the two step operation). Analytical data for 8:  1 H-NMR spectroscopy (400 MHz, CDCl 3 ) δ 7.37-7.29 (m, 5H), 7.25-7.21 (m, 2H), 6.82-6.79 (m, 2H), 5.61 (q, J=6.9 Hz, 1H), 2.83 (ddd, J=2.5, 5.4 and 11.6 Hz, 1H), 2.39 (ddd, J=5.7, 12.0 and 14.1 Hz, 1H), 2.27 (ddd, J=2.6, 4.8 and 14.0 Hz, 1H), 2.21-2.14 (m, 3H), 2.08 (s, 1H), 1.49 (d, J=7.0 Hz, 3H), 1.18 (s, 3H), 1.13 (s, 3H).  13 C-NMR spectroscopy (100 MHz, CDCl 3 ) δ 153.2, 142.6, 138.5, 131.6, 129.13, 129.10, 128.0, 125.3, 121.6, 84.2, 71.4, 54.1, 53.3, 36.4, 33.6, 32.1, 30.8, 15.6. 
     Synthesis of Oxazinones: Reaction of a β-haloalcohol and an isocyanate 
     Example 5 
     6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one 
                                
Step 1. 1-Chloro-3-(4-fluorophenyl)hex-5-en-3-ol
 
     To a solution of 1,1′-bi-2-naphthol (0.2280 g, 0.80 mmol, 0.26 equiv), CH 2 Cl 2  (5 mL) and titanium(IV) isopropoxide (0.2243 g, 0.79 mmol, 0.26 equiv) were added 2-propanol (3.1620 g, 52.6 mmol, 17 equiv), tetraallylstannane (1.2538 g, 4.43 mmol, 1.43 equiv), and 3-chloro-1-(4-fluorophenyl)propan-1-one (0.5760 g, 3.09 mmol, 1.0 equiv) successively. The reaction mixture was stirred at rt under nitrogen for 22 h. The reaction was quenched with satd aq NH 4 Cl and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol as an oil. 
     Step 2. 6-Allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one 
     A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (0.0889 g, 0.39 mmol, 1.0 equiv), (S)-(−)α-methylbenzyl isocyanate (0.0823 g, 0.56 mmol, 1.44 equiv), and DBU (0.1397 g, 0.92 mmol, 2.36 equiv) in THF (2 mL) was heated to reflux for 17 h. After the solvent was removed, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to give 0.0990 g (75%) of the product as a mixture of diastereomers. Selected fractions contained the individual diastereomers. 
     Isomer 1: (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.89 min, m/z=340 (M+1).  1 H NMR (CDCl 3 ) 7.36-7.27 (m, 7H), 7.10-7.05 (m, 2H), 5.79-5.67 (m, 2H), 5.09-4.98 (m, 2H), 2.72-2.68 (m, 2H), 2.64-2.53 (m, 2H), 2.22-2.16 (m, 1H), 2.09-2.01 (m, 1H), 1.26 (d, J=7.3 Hz, 3H). 
     Isomer 2: (S)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =1.86 min, m/z=340 (M+1).  1 H NMR (CDCl 3 ) 7.29-7.24 (m, 2H), 7.14-7.08 (m, 3H), 7.05-7.00 (m, 2H), 6.88-6.85 (m, 2H), 5.77-5.63 (m, 2H), 5.10-5.00 (m, 2H), 2.93-2.88 (m, 1H), 2.65-2.52 (m, 2H), 2.32-2.17 (m, 3H), 1.51 (d, J=7.0 Hz, 3H). 
     Example 6 
     6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one 
                                
Step 1. 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol
 
     A 250-mL flask was charged with anhydrous CeCl 3  (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO 3 , extracted with EtOAc, and dried over Na 2 SO 4 . After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 t R =1.79 min, m/z 213, 211 (M-OH) + ;  1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H);  19 F NMR (376 MHz, CDCl 3 ) δ −116.52 (m). 
     Step 2. (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one 
     A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (0.4129 g, 1.8 mmol, 1.0 equiv), (S)-(−)-1-(4-bromophenyl)ethyl isocyanate (0.5005 g, 2.2 mmol, 1.2 equiv), and DBU (0.7375 g, 4.8 mmol, 2.7 equiv) in THF (10 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (2×). The combined organic phase was dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was directly used in the next step without further purification. 
     An analytical sample was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford the two diastereomers of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. 
     Isomer 1: (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =2.03 min, m/z 420, 418 (MH + );  1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J=8.2 Hz, 2H), 7.31-7.28 (m, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.07 (t, J=8.5 Hz, 2H), 5.76-5.66 (m, 2H), 5.10-4.99 (m, 2H), 2.75-2.52 (m, 4H), 2.23-2.19 (m, 1H), 2.08-2.00 (m, 1H), 1.24 (d, J=7.0 Hz, 3H);  19 F NMR (376 MHz, CDCl 3 ) δ −115.07 (m). 
     Isomer 2: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1 t R =1.98 min, m/z 420, 418 (MH + );  1 H NMR (400 MHz, CDCl 3 ) δ 7.25-7.20 (m, 4H), 7.05-7.01 (m, 2H), 6.71 (d, J=8.5 Hz, 2H), 5.74-5.64 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 5.09-4.99 (m, 2H), 2.92-2.87 (m, 1H), 2.63-2.50 (m, 2H), 2.33-2.16 (m, 3H), 1.47 (d, J=7.0 Hz, 3H);  19 F NMR (376 MHz, CDCl 3 ) δ −114.91 (m). 
     Example 7 
     6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one 
                                
Step 1. 2-Phenylpent-4-en-2-ol
 
     To a solution of acetophenone (30 g, 0.25 mol) in dry THF (250 mL) at −78° C. was added dropwise 1M allylmagnesium bromide (1.25 L, 1.25 mol). After addition was complete, the mixture was allowed to stir at rt for 3 h. The reaction was quenched with satd aq NH 4 Cl solution (30 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4  and concentrated to give 2-phenylpent-4-en-2-ol (40.2 g), which was used for the next step without purification. 
     Step 2. 3-Phenylbutane-1,3-diol 
     A solution of 2-phenylpent-4-en-2-ol (74 g, 0.457 mol) in dry CH 2 Cl 2  (1 L) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH 4 (42.8 g, 1.143 mol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2  (2×). The organic layers were combined, washed with brine, dried over anhydrous Na 2 SO 4  and concentrated to give 3-phenylbutane-1,3-diol (67.8 g), which was used for the next step without purification. 
     Step 3. 3-Hydroxy-3-phenylbutyl 4-methylbenzenesulfonate 
     To a solution of 3-phenylbutane-1,3-diol (68 g, 0.41 mol) in dry CH 2 Cl 2  (500 mL) was added dropwise a solution of TsCl (78 g, 0.41 mol) and triethylamine (71 mL, 0.45 mol) in dry CH 2 Cl 2  (500 mL) at 0° C. The mixture was stirred overnight. The mixture was poured into water and separated. The aqueous layer was extracted with CH 2 Cl 2  (200 mL) twice. The organic layer was combined, washed with brine, dried over anhydrous Na 2 SO 4  and concentrated to give the crude product. The crude product was purified by column chromatography to give 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (62 g, 42%).  1 H NMR (400 MHz, CDCl 3 ): δ=1.55 (s, 3H), 1.93 (w, 1H), 2.19˜2.24 (q, 2H), 2.45 (s, 3H), 3.87˜4.01 (m, 1H), 4.09˜4.16 (m, 1H), 7.19˜7.34 (m, 7H), 7.68˜7.76 (d, 2H). 
     Step 4. 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one 
     To a solution of 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (1 g, 3.12 mmol) and DBU (1.4 g, 9.26 mmol) in CH 2 Cl 2  (15 mL) was added a solution of 3-methylphenyl isocyanate (623 mg, 4.68 mmol) in CH 2 Cl 2  (5 mL) at 0° C. over 0.5 h. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography and then by preparative HPLC to afford 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one. LC-MS Method 2, t R =2.706 min, m/z=282.  1 H NMR (CDCl 3 ) 1.75 (s, 3H), 2.30 (s, 3H), 2.35-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 6.95 (m, 2H), 7.05 (m, 1H), 7.20-7.30 (m, 1H), 7.35 (m, 1H), 7.42-7.50 (m, 4H). 
     Step 5. Enantiomers of 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one 
     Chiral preparative SFC using a ChiralPak-AD, 400×25 mm I.D, 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35 C eluted with 70:30 supercritical CO 2 /0.1% diethylamine in MeOH at a flow rate of 70 mL min −1  and a nozzle pressure of 100 bar afforded two isomers. 
     Isomer 1 (90 mg) gave the following spectral data:  1 H NMR (400 MHz, CDCl 3 ): δ=1.62 (m, 1H), 1.76 (s, 3H), 2.31 (s, 3H), 2.48 (m, 2H), 3.28 (m, 1H), 3.50 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 7.23 (t, 1H), 7.35 (m, 1H), 7.44 (m, 4H); 
     Isomer 2 (100 mg) gave the following spectral data: (400 MHz, CDCl 3 ): δ=1.62 (m, 1H), 1.76 (s, 3H), 2.31 (s, 3H), 2.48 (m, 2H), 3.28 (m, 1H), 3.50 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 7.23 (t, 1H), 7.35 (m, 1H), 7.44 (m, 4H). 
     Example 8 
     6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one 
     
       
                 
         
             
             
         
      
     
     1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (126 mg, 0.55 mmol), (S)-(+)-1-cyclohexylethyl isocyanate (160 mg, 1.44 equiv.) and proton sponge (271 mg, 2.3 equiv.) were dissolved in dry THF (5 mL) and heated to reflux for 3 h. The mixture was then cooled to 0° C. and NaH (22 mg, 1.0 equiv.) was added slowly. After 5 min, the mixture was heated to reflux overnight. LC-MS showed the reaction was complete. The mixture was diluted with EtOAc (50 mL) and washed with 1% aq HCl (2×15 mL), satd aq NaHCO 3  (10 mL) and brine (10 mL), and dried over Na 2 SO 4 . After filtration and concentration, the residue was purified by chromatography on a 12-g silica cartridge eluted with a 10-45% EtOAc in hexanes gradient to afford two isomeric products. 
     Isomer 1: (R)-6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (57.5 mg, 30%). LC-MS Method 1, t R =2.05 min, m/z=346.  1 H NMR (CDCl 3 ) 7.29 (m, 2H), 7.02 (m, 2H), 5.70 (m, 1H), 5.05 (dd, 2H), 3.94 (m, 1H), 3.06 (m, 1H), 2.68-2.49 (m, 3H), 2.33 (m, 1H), 2.14 (m, 1H), 1.17 (d, 3H), 0.78 (m, 2H) 
     Isomer 2: (S)-6-allyl-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (56 mg, 29%). LC-MS Method 1, t R =2.06 min, m/z=346.  1 H NMR (CDCl 3 ) 7.27 (m, 2H), 7.03 (t, 2H), 5.71 (m, 1H), 5.05 (dd, 2H), 3.95 (m, 1H), 2.92 (m, 1H), 2.72 (m, 1H), 2.57 (m, 2H), 2.22 (m, 2H), 1.49 (d, 1H), 1.32 (m, 1H), 0.86 (d, 3H). 
     Example 9 
     6-(3-hydroxypropyl)-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one 
                                
Step 1
 
     To a solution of 2-phenylcyclopropanecarboxylic acid (1.0 g, 6.17 mmol) in dry toluene (20 mL) was added triethylamine (934 mg, 9.26 mmol) and DPPA (2.0 g, 7.41 mmol) under N 2 , and the reaction mixture was refluxed for 3 h. The solution was concentrated to give (2-isocyanatocyclopropyl)benzene (800 mg), which was used for the next step without further purification. 
     Step 2 
     To a solution of (2-isocyanatocyclopropyl)benzene (800 mg, 5.03 mmol) in THF (15 mL) was added DBU (1.61 g, 10.48 mmol) and 1-chloro-3-phenylhex-5-en-3-ol (880 mg, 4.19 mmol), and the mixture was refluxed overnight. The solution was diluted with EtOAc, and washed with 1 N HCl (2×15 mL). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude product, which was purified by preparative TLC to afford 6-allyl-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one (100 mg, 6%).  1 H NMR (CDCl 3 ): 1.05-1.21 (m, 3H), 1.36-1.42 (m, 1H), 2.13-2.34 (m, 1H), 2.39-2.61 (m, 2H), 2.92-3.15 (m, 1H), 3.76-4.01 (m, 1H), 4.95-5.10 (m, 2H), 5.42-5.73 (m, 1H), 6.95-6.99 (m, 1H), 7.10-7.24 (m, 10H). 
     Step 3 
     To a solution of 6-allyl-6-phenyl-3-(2-phenylcyclopropyl)-1,3-oxazinan-2-one (200 mg, 0.60 mmol) in dry THF (5 mL) was added dropwise 1 M of BH 3 /THF (1.8 mL, 1.8 mmol) at 0° C. under N 2 . After stirring at rt for 2 h, the reaction mixture was cooled to 0° C. again, and water (0.1 mL), 3 M of aqueous NaOH solution (0.1 mL), and 30% H 2 O 2  (0.3 mL) were added sequentially. After the mixture was stirred at rt for another 2 h, 1 N aqueous HCl (0.5 mL) was added. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product, which was purified by preparative TLC followed by preparative HPLC to afford two isomers. 
     Isomer 1 (20 mg, 9%): LC-MS Method 3 t R =1.151, min, m/z=352.2;  1 H NMR (CDCl 3 ) 0.83 (m, 2H), 1.12 (m, 1H), 1.23 (m, 4H), 1.68 (m, 1H), 1.97 (m, 2H), 2.16 (m, 1H), 2.21 (m, 1H), 2.84 (m, 1H), 3.13 (m, 1H), 3.52 (m, 2H), 4.14 (m, 1H), 7.03 (m, 2H), 7.11 (m, 1H), 7.17 (m, 2H), 7.29 (m, 4H), 7.46-7.63 (m, 1H). 
     Isomer 2 (15 mg, 7%): LC-MS Method 3 t R =1.149, min, ink=352.2;  1 H NMR (CDCl 3 ) 0.85 (m, 2H), 1.11 (m, 1H), 1.26 (m, 3H), 1.67 (m, 2H), 1.96 (m, 2H), 2.18 (m, 1H), 2.27 (m, 1H), 2.83 (m, 1H), 3.13 (m, 1H), 3.52 (m, 2H), 4.15 (m, 1H), 7.02 (m, 2H), 7.11 (m, 1H), 7.15 (m, 2H), 7.26 (m, 3H), 7.29 (m, 2H), 7.46-7.63 (m, 1H). 
     Example 10 
     (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-7-one 
                                
Step 1
 
     To a solution of (S)-1-phenylpropan-1-amine (3.00 g, 14 mmol) in the mixture of methylene chloride (50 mL) and saturated NaHCO 3  (50 mL) was added triphosgene (1.40 g, 4.60 mmol) at 0° C. The mixture was stirred for 15 minutes. The organic phase was separated, dried and concentrated to give (5)-(1-isocyanatopropyl)benzene (3.0 g, 88%).  1 H NMR (CDCl 3 ): δ=0.93 (q, 3H), 1.81 (m, 2H), 4.50 (m, 1H), 7.13 (m, 2H), 7.22 (m, 1H), 7.50 (m, 2H). 
     Step 2 
     A mixture of (S)-(1-isocyanatopropyl)benzene (3.0 g, 12.5 mmol), 1-chloro-3-phenylhex-5-en-3-ol (3.6 g, 12.5 mmol) and DBU (3.80 g, 25 mmol) in tetrahydrofuran (20 mL) was heated to reflux overnight. The mixture was washed by 1 N HCl and extracted with EtOAc. The organic phase was concentrated to give the crude product which was purified by column chromatography to give (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one (1.0 g, 20%).  1 H NMR (400 MHz, CDCl 3 ): δ=0.92 (t, 3H), 1.72-2.00 (m, 4H), 2.06-2.31 (m, 4H), 2.53 (m, 2H), 2.82 (m, 1H), 4.99 (m, 2H), 5.32 (m, 1H), 5.69 (m, 1H), 6.72 (m, 1H), 7.12 (m, 4H), 7.25 (m, 4H). 
     Step 3 
     To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.242 mmol) in tetrahydrofuran (10 mL) was added BH 3  THF (3 mL, 1 mol/L) at 0° C. under nitrogen. The formed mixture was stirred for 2 h. Then the reaction was quenched by water, followed by 3 mol/L NaOH and H 2 O 2  (3 mL). The PH of the mixture was adjusted to &lt;7 with 5% HCl. The organic phase was separated, extracted by EtOAc, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (15 mg, 15%). LC-MS Method 3 t R =1.36, min, m/z=432, 434;  1 H NMR (CDCl 3 ): δ=0.99 (t, 3H), 1.29 (m, 1H), 1.63 (m, 1H), 1.98 (m, 4H), 2.20-2.42 (m, 2H), 2.48 (m, 1H), 3.08 (m, 1H), 3.49 (m, 1H), 5.30 (m, 1H), 6.92 (m, 2H), 7.26 (m, 4H), 7.35 (m, 2H). 
     Example 11 
     (R)-3-((R)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one 
                                
Step 1
 
     TFAA (134 mL, 948 mmol) was dissolved in CH 2 Cl 2  (600 mL) and cooled in an ice water bath. A solution of (S)-1-phenylpropan-1-amine (112.8 g, 930 mmol) in CH 2 Cl 2  (200 mL) was added dropwise and then the ice bath was removed. The reaction mixture was stirred for 3 hrs at ambient temperature. Then the above mixture was cooled in an ice bath and MsOH (160 mL, 2.5 mol) was added dropwise followed by DBDMH (130 g, 454 mmol). The reaction mixture was left stirring overnight at rt and then quenched with water and brine. The combined organic phases were dried over NaSO 4 , filtered and concentrated to give (R)-N-(1-(4-bromophenyl)ethyl)-2,2,2-trifluoroacetamide (120 g, 44%) as a off-white solid.  1 H NMR (CDCl 3 ): 1.56 (m, 3H), 1.86 (m, 2H), 5.11 (m, 1H), 6.63 (m, 1H), 7.18 (m, 2H), 7.50 (m, 2H). 
     Step 2 
     (R)-N-(1-(4-bromophenyl)ethyl)-2,2,2-trifluoroacetamide (20 g, 68 mmol) was dissolved in methanol (200 mL) and cooled in an ice-water bath. Then aqueous NaOH (2 M, 100 mL) was added to the above mixture. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and then partitioned between CH 2 Cl 2  and water. The aqueous layer was extracted with addition CH 2 Cl 2  and the combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give (R)-1-(4-bromophenyl)ethan amine (9.8 g, 73%).  1 H NMR (DMSO): 1.19 (m, 3H), 3.92 (m, 1H), 7.28 (m, 2H), 7.42 (m, 2H). 
     Step 3 
     To a solution of (S)-1-(4-bromophenyl)propan-1-amine (5 g, 25 mmol) in CH 2 Cl 2  (10 mL) was added saturated aqueous NaHCO 3  (10 mL) and then triphosgene (2.45 g, 8 mmol) at 0□. Then the reaction mixture was stirred for 15 minutes at 0° C. under nitrogen. The reaction mixture was extracted with CH 2 Cl 2  twice. The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to afford (R)-1-bromo-4-(1-isocyanatoethyl)benzene (2.5 g, 44%), which was used for the next step without purification. 
     Step 4 
     To a solution of (R)-1-bromo-4-(1-isocyanatoethyl)benzene (2.5 g, 11 mmol) in THF anhydrous (40 mL) was added 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (1.69 g, 7 mmol) and DBU (5.68 g, 33 mmol) at ambient temperature and the reaction mixture was refluxed overnight. The reaction mixture was extracted with 1 N aq HCl and EtOAc. The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to afford the residue, which was purified by column chromatography to give two isomers. 
     Isomer 1: (R)-6-allyl-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (334 mg, 7%).  1 H NMR (CD 3 OD): 1.50 (m, 3H), 2.16-2.38 (m, 2H), 2.46 (m, 1H), 2.60 (m, 2H), 3.10 (m, 1H), 5.05 (m, 2H), 5.48 (m, 1H), 5.66 (m, 1H), 6.82 (m, 2H), 7.08 (m, 2H), 7.26 (m, 4H). 
     Isomer 2: (S)-6-allyl-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. 
     Step 5 
     A solution of (R)-6-allyl-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (334 mg, 0.80 mmol) in dry CH 2 Cl 2  (20 mL) was treated with ozone at −78° C. until the reaction mixture became blue. Then the mixture was flushed with oxygen to remove excess ozone. To the above mixture was added NaBH 4  (273 mg, 7 mmol) at 0° C. and the reaction mixture was stirred for 4 hrs at ambient temperature under nitrogen. The reaction mixture was washed with water and then extract with CH 2 Cl 2  twice. The combined organic phases were dried over NaSO 4 , filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (118 mg, 35%).  1 H NMR (CD 3 OD): 1.50 (m, 3H), 2.12 (m, 2H), 2.29 (m, 2H), 2.50 (m, 1H), 3.10 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 4.56 (m, 1H), 5.50 (m, 1H), 6.86 (m, 2H), 7.10 (m, 2H), 7.30 (m, 4H). 
     Step 6 
     To a solution of (S)-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (109 mg, 0.26 mmol), 2,4-difluorophenylboronic acid (49 mg, 0.31 mmol) and Pd(PPh 3 ) 4  (30 mg, 0.03 mmol) in dioxane (8 mL) was added a solution of CsCO 3  (2 M, 1 mL) at 0□. Then the reaction mixture was refluxed overnight under nitrogen. The reaction mixture was washed with water and then extract with CH 2 Cl 2  twice. The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((R)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (49 mg, 42%). LC-MS Method 3 t R =1.41, min, m/z=456;  1 H NMR (CD 3 OD): 1.55 (m, 3H), 2.12 (m, 2H), 2.22-2.46 (m, 3H), 2.52 (m, 1H), 3.12 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 5.56 (m, 1H), 7.08 (m, 6H), 7.08 (m, 2H), 7.35 (m, 5H). 443-155-3. 
     (R)-3-((R)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one was prepared from (S)-6-allyl-3-((R)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following procedures analogous to those described in Steps 5 and 6 immediately above. LC-MS Method 3 t R =1.47, min, m/z=456;  1 H NMR (CD 3 OD) 1.35 (m, 3H), 2.18 (m, 2H), 2.40 (m, 1H), 2.51 (m, 1H), 2.82 (m, 2H), 3.33 (m, 1H), 3.71 (m, 1H), 4.22-4.48 (m, 1H), 5.62 (m, 1H), 7.03 (m, 2H), 7.18 (m, 2H), 7.38 (m, 4H), 7.50 (m, 3H). 
     Example 12 
     (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one 
                                
Step 1
 
     To a solution of (S)-1-(4-bromophenyl)ethanamine (40 g, 0.2 mol) in methylene chloride (600 mL) and satd aq NaHCO 3  (600 mL) was added triphosgene (27 g, 0.025 mol) at 0° C. The mixture was stirred for 15 min. The organic phase was separated, dried and concentrated to give 1-bromo-4-(1-isocyanato-ethyl)-benzene (35 g, crude). 
     Step 2 
     A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (27.5 g, 130 mmol), (5)-(−)-1-(-bromophenyl)ethyl isocyanate (35 g, 160 mmol), and DBU (80 g, 325 mmol) in THF (400 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (3×). The combined organic phase was dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was purified by column chromatography to give (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (30 g, yield 45%). 
     Step 3 
     The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 78. LC-MS Method 2 t R =1.36 min, m/z=440.1;  1 H NMR (CDCl 3 ) 1.26-1.39 (m, 1H), 1.42 (d, 3H), 1.58-1.71 (m, 1H), 1.85-1.95 (m, 2H), 2.11-2.45 (m, 3H), 2.79 (m, 1H), 3.52 (m, 2H), 5.54 (m, 1H), 6.67 (d, 2H), 7.12-7.31 (m, 7H). 
     Synthesis of Biaryls Via Suzuki Synthesis 
     Example 13 
     3-(biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one 
     
       
                 
         
             
             
         
      
     
     To a solution of 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.14 mmol) and phenylboronic acid (35 mg, 0.29 mmol) in THF (2 mL) was added a solution of NaHCO 3  (31 mg, 0.29 mmol) in H 2 O (2 mL) followed by Pd(PPh 3 )Cl 2  (9 mg, 0.01 mmol). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography, followed by preparative HPLC to afford 3-(biphenyl-3-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%).  1 H NMR: (400 MHz, CDCl 3 ): δ 1.71 (s, 3H), 2.40 (m, 1H), 2.48 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 7.08 (m, 1H), 7.30 (m, 3H), 7.7.32-7.42 (m, 8H), 7.46 (m, 2H). LC-MS Method 3, t R =1.362 min, m/z=344.  1 H NMR (CDCl 3 ) 1.75 (s, 3H), 2.32-2.43 (m, 1H), 2.50 (m, 1H), 3.20 (m, 1H), 3.52 (m, 1H), 7.10 (d, 1H), 7.25-7.45 (m, 11H), 7.50 (d, 2H). 
     Example 14 
     6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one 
                                
Step 1. 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one
 
     To a solution of 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.134 mmol) and 2,4-difluorophenylboronic acid (40 mg, 0.215 mmol), K 2 CO 3  (0.5 mL, 2 M) in 1,4-dioxane (1.5 ml) was slowly added Pd(Ph 3 ) 2 Cl 2  (10 mg, 20%) at 0° C. under N 2 . The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 18%).  1 H NMR (400 MHz, CDCl 3 ): δ=2.40 (m, 2H), 2.55-2.72 (m, 2H), 3.26 (m, 1H), 3.47 (m, 1H), 5.05 (m, 2H), 5.76 (m, 1H), 6.76-6.90 (m, 2H), 7.04 (m, 1H), 7.28 (m, 4H), 7.36 (m, 2H). 
     Example 15 
     6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one 
                                
Step 1. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one
 
     To a solution of 3-(3-bromophenyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.538 mmol), 4-fluorophenylboronic acid (128 mg, 0.806 mmol), and aq. K 2 CO 3  (1 mL, 2 M) in 1,4-dioxane (3 ml) was slowly added Pd(Ph 3 ) 2 Cl 2  (20 mg, 10%) at 0° C. under N 2 . The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 91%).  1 H-NMR (400 MHz, CDCl 3 ): δ=2.12-2.35 (m, 2H), 2.51 (m, 2H), 3.26 (m, 1H), 3.47-3.6 (m, 2H), 4.25 (m, 1H), 6.83 (m, 2H), 7.06 (m, 1H), 7.26-7.51 (m, 8H). 
     Step 2. 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate 
     To a solution of 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.49 mmol) in dry CH 2 Cl 2  (4 mL) was added Et 3 N (0.234 mL, 1.46 mmol) at 0˜−5° C. A solution of methanesulfonyl chloride (67 mg, 0.59 mmol) in dry CH 2 Cl 2  (1 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. When the reaction was complete, water (10 mL) was added and the mixture was extracted with CH 2 Cl 2  (3×10 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO 3  and brine, then dried over Na 2 SO 4 , filtered and concentrated to give 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 97%), which was used in the next step without purification. 
     Step 3. 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one 
     To a solution of 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 0.47 mmol) in anhydrous DMF (5 mL) was added NaN 3  (92 mg, 1.42 mmol). The reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (30 mL), and water (20 ml). The organic phase was washed with water (3×20 mL), dried over Na 2 SO 4  and evaporated to give 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 49%). 
     Step 4. 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one 
     To a solution of 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol) in 20:1 THF/H 2 O (3 mL) was added PPh 3  (72 mg, 0.28 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel to afford 6-(2-aminoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (30 mg, 31%).  1 H NMR (400 MHz, CDCl 3 ): δ=2.20-2.51 (m, 2H), 2.51-2.60 (m, 2H), 2.72 (m, 1H), 3.00 (m, 1H), 3.24 (m, 1H), 3.53 (m, 1H), 6.85-6.99 (m, 2H), 7.14 (m, 1H), 7.31-7.50 (m, 8H). 
     Example 16 
     6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one 
                                
Step 1. 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one
 
     To a solution of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (0.3860 g, 0.92 mmol, 1.0 equiv) in THF (10 mL) were added, under a nitrogen atmosphere, 2,4-difluorophenylboronic acid (0.2708 g, 1.71 mmol, 1.86 equiv), 2 M aq Na 2 CO 3  (8 mL), and (Ph 3 P) 2 PdCl 2  (0.0308 g, 0.0438 mmol, 0.047 equiv). The mixture was stirred for 2 d at 100° C. Brine was then added, the mixture was extracted with Et 2 O (3×), and the combined ether extracts were dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was directly used in the next step without further purification. LC-MS t R =2.13, 2.17 min in 3 min chromatography, m/z 452 (MH + ). 
     Analytical samples were separated by silica gel chromatography. 
     Isomer 1: (S)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =2.17 min, m/z=452.  1 H NMR (CDCl 3 ) 7.47 (d, J=8.2 Hz, 2H), 7.42-7.30 (m, 5H), 7.08 (t, J=8.2 Hz, 2H), 6.98-6.88 (m, 2H), 5.82-5.68 (m, 2H), 5.08 (d, J=10.2 Hz, 1H), 5.02 (d, J=17.0 Hz, 1H), 2.78-2.71 (m, 2H), 2.66-2.54 (m, 2H), 2.25-2.20 (m, 1H), 2.13-2.05 (m, 1H), 1.30 (d, J=7.0 Hz, 3H). 
     Isomer 2: (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1, t R =2.13 min, m/z=452.  1 H NMR (CDCl 3 ) 7.33-7.23 (m, 5H), 7.03 (t, J=8.2 Hz, 2H), 6.96-6.86 (m, 4H), 5.77-5.67 (m, 2H), 5.10 (d, J=10.3 Hz, 1H), 5.04 (d, J=17.3 Hz, 1H), 2.99-2.94 (m, 1H), 2.66-2.54 (m, 2H), 2.41-2.34 (m, 1H), 2.30-2.17 (m, 2H), 1.55 (d, J=7.0 Hz, 3H). 
     Example 17 
     3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one 
     
       
                 
         
             
             
         
      
     
     To a solution of (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxy ethyl)-1,3-oxazinan-2-one (60 mg, 0.14 mmol), 2,4-difluorophenylboronic acid (26 mg, 0.17 mmol) and Pd(PPh 3 ) 4  (16 mg, 0.01 mmol) in dioxane (5 mL) was added a solution of CsCO 3  (2 M, 1 mL) at 0° C. Then the reaction mixture was refluxed overnight under nitrogen. The reaction mixture was washed with water and then extract with CH 2 Cl 2  twice. The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (17 mg, 26%).  1 H NMR (CD 3 OD): 0.96 (m, 3H), 2.01 (m, 2H), 2.12 (m, 2H), 2.30 (m, 2H), 2.48 (m, 1H), 3.10 (m, 1H), 3.33 (m, 1H), 3.65 (m, 1H), 5.38 (m, 1H), 7.02 (m, 4H), 7.08 (m, 2H), 7.28 (m, 4H), 7.42 (m, 1H). 443-114-3. 
     (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxy ethyl)-1,3-oxazinan-2-one following a procedure analogous to that described immediately above.  1 H NMR (CD 3 OD): 0.62 (m, 3H), 1.76 (m, 1H), 1.92 (m, 1H), 2.12 (m, 3H), 2.56 (m, 1H), 2.78 (m, 1H), 2.89 (m, 1H), 3.33 (m, 1H), 3.71 (m, 1H), 5.38 (m, 1H), 7.05 (m, 2H), 7.16 (m, 2H), 7.44 (m, 7H). 
     Example 18 
     (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one 
                                
Step 1
 
     Pd(PPh 3 ) 2 Cl 2  (100 mg) was added to the solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (1.0 g, 2.5 mmol), 4-fluorophenylboronic acid (420 mg, 3.0 mmol) in 1,4-dioxane. Cs 2 CO 3  (5 mL) was slowly added. The mixture was heated to reflux for 2 h. The mixture was quenched with water and separated, extracted with EtOAc twice, dried over anhydrous Na 2 SO 4  and concentrated to afford the residue, which was purified by TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (768 mg, 73%). 
     Step 2 
     To a solution of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (300 mg, 0.71 mmol) was added aqueous solution of KMnO 4  (66 mg, 0.42 mmol) and NaIO 4  (537 mg, 2.52 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was filtered and concentrated, then extracted with CH 2 Cl 2 . The organic phases was dried over Na 2 SO 4 , filtered and concentrated to afford 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-(thiophen-2-yl)-1,3-oxazinan-6-yl)acetic acid (218 mg, 70%). 
     Step 3 
     A solution of 2-((S′-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-(thiophen-2-yl)-1,3-oxazinan-6-yl)acetic acid (218 mg, 0.5 mmol) in THF anhydrous (10 mL) was added BH 3  (3.0 mL) at 0□ and then stirred at reflux for 2 h. Then the reaction mixture quenched by water and separated, extracted with EtOAc twice. The organic phases was dried over Na 2 SO 4 , filtered and concentrated to afford the residue, which was purified by TLC to give (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (85 mg, 40%). LC-MS Method 3 t R =1.35, min, m/z=426, 448;  1 H NMR (CD 3 OD): 1.50 (m, 3H), 2.15 (m, 2H), 2.30 (m, 1H), 2.40 (m, 1H), 2.60 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 3.70 (m, 1H), 5.60 (m, 1H), 6.90 (m, 1H), 7.00 (m, 1H), 7.10 (m, 4H), 7.35 (m, 3H), 7.55 (m, 2H). 
     (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one was prepared following a procedure analogous to that described immediately above. LC-MS Method 3 t R =1.4, min, m/z=426, 448;  1 H NMR (CD 3 OD) 1.38 (d, 3H), 2.01 (m, 1H), 2.18 (m, 3H), 2.41 (m, 1H), 2.86 (m, 1H), 3.02 (m, 1H), 3.41 (m, 1H), 3.72 (m, 1H), 5.62 (m, 1H), 6.98 (m, 1H), 7.03 (m, 1H), 7.15 (m, 1H), 7.36 (m, 3H), 7.58 (m, 4H). 
     Example 19 
     (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
                                
Step 1
 
     A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 0.375 mmol) and 6-aminopyridin-3-ylboronic acid (56 mg, 0.45 mmol), Pd(Ph 3 P) 2 Cl 2  (15 mg), and aqueous Cs 2 CO 3  solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 60%). 
     Step 2 
     To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 0.23 mmol) in tetrahydrofuran (10 mL) was added BH 3  THF (3.0 mL, 1 mol/L, 4 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched by water. Then NaOH (2 mL, 3 mol/L) and H 2 O 2  (1 mL) was added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 41%). 
     Step 3 
     (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 0.09 mmol.) was dissolved in 3.5 M H 2 SO 4  (10 mL), and 2 M NaNO 2  (10 mL) was added at 0° C. The reaction mixture was stirred at rt for 2 h and treated with NaOH solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated to afford the residue, which was purified by preparative HPLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). LC-MS Method 2 t R =1.66, min, m/z=433, 455;  1 H NMR (CDCl 3 ): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H), 2.10-2.30 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.12 (m, 1H), 6.62 (m, 1H), 6.86 (m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1H), 7.62 (m, 1H). 
     Example 20 
     (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
                                
Step 1
 
     A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.83 g, 15 mmol), 4-fluorophenylboronic acid (3 g, 22 mmol), PdCl 2 (PPh 3 ) 2  (1 g, 1.4 mmol), and aqueous Cs 2 CO 3  solution (2 M, 8.0 mL) in 1,4-dioxane (50 mL) was heated to reflux for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na 2 SO 4  and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5.3 g, 88%). 
     Step 2 
     To a solution of (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (3 g, 7.23 mmol) in acetone (20 mL) was added a solution of KMnO 4  (685 mg, 4.34 mmol) and NaIO 4  (5.6 g, 26 mmol) in H 2 O (15 mL) dropwise at 0° C. The mixture was stirred for 4 h. When TLC showed that the starting material had disappeared, the precipitate was removed by filtration, and the acetone was removed under reduced pressure. The resulting mixture was basified to pH=13 by the addition of 1 M aq NaOH, and then washed with ether (3×50 mL). The aqueous phase was acidified to pH=1 by addition of 1 N aq HCl, and extracted with CH 2 Cl 2  (3×15 mL). The organic layers were combined, washed with brine, dried over Na 2 SO 4  and concentrated in vacuo to give 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (2.8 g, 90%). 
     Step 3 
     To a solution of 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (1 g, 2.3 mmol) in MeOH (15 mL) was added thionyl chloride (408 mg, 3.5 mmol) dropwise at 0° C. under N 2  atmosphere. After refluxing overnight, the mixture was concentrated to give the crude product, which was purified by chromatography to give methyl 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate (680 mg, 68%). 
     Step 4 
     To a solution of methyl 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate (180 mg, 0.4 mmol) in dry THF (5 mL) under N 2  at −78° C. was added methylmagnesium bromide (1.5 mL, 3 M, 4.5 mmol) dropwise at −78° C. After addition, the mixture was stirred for 1 h at rt. Then the reaction was quenched with water and the mixture was extracted with ethyl acetate for three times (3×5 mL). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative HPLC to give (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (2.48 mg, 1%).  1 H NMR (CDCl 3 ): 1.05 (s, 1H), 1.13 (s, 3H), 1.50 (d, 3H), 2.14-2.23 (m, 2H), 2.25-2.40 (m, 1H), 2.80 (m, 1H), 5.63 (m, 1H), 6.94 (m, 2H), 7.02 (m, 2H), 7.18-7.30 (m, 7H), 7.38 (m, 2H). LC-MS Method 3 t R =1.51, min, m/z=448, 470. 
     Example 21 
     5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide 
                                
Step 1
 
     To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1 g, 2.4 mmol) in dry THF (15 mL) was added dropwise BH 3 .THF (5 mL, 1 M) at 0° C. After stirring for 2 h at rt, the reaction mixture was cooled to 0° C. and water (1 mL), aqueous NaOH (0.5 mL, 3 M) and H 2 O 2  (0.5 mL, 30%) were successively added. The mixture was stirred for 2-3 h at rt and diluted with water (8 mL). The pH was adjusted to 6-7 with 0.5 N HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with a satd aq NaHCO 3  (20 mL) and brine (20 mL), dried over Na 2 SO 4 , and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (400 mg, 38%). 
     Step 2 
     A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (250 mg, 0.6 mmol), 5-(methoxycarbonyl)pyridin-3-ylboronic acid (163 mg, 0.9 mmol), PdCl 2 (PPh 3 ) 2  (50 mg, 20%) and aqueous Cs 2 CO 3  solution (2 M, 2 mL) in 1,4-dioxane (6 mL) was heated to reflux at 100° C. overnight under N 2 . The mixture was filtered, and the filtrate was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na 2 SO 4  and concentrated to the crude product, which was purified by preparative HPLC to give methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (220 mg, crude). 
     Step 3 
     Methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (30 mg, 0.1 mmol) was dissolved in anhydrous NH 3  in EtOH (5 mL). Then the mixture was stirred at rt overnight. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to provide 5-(4-((S)-1-((R)-6-(4-luorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide (10 mg, 34%). LC-MS Method 2 t R =1.022 min, m/z=478;  1 H NMR (CD 3 OD): 1.31 (m, 1H), 1.56 (m, 3H), 1.59 (m, 1H), 1.91 (m, 2H), 2.17-2.28 (m, 1H), 2.33 (m, 1H), 2.44 (m, 1H), 3.14 (m, 1H), 3.44 (m, 2H), 5.60 (m, 1H), 7.04-7.17 (m, 4H), 7.29 (m, 2H), 7.49 (m, 2H), 8.41 (m, 1H), 8.86 (m, 1H), 8.97 (m, 1H). 
     Example 22 
     (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
                                
Step 1: (S)-1-bromo-4-(1-isocyanatoethyl)benzene
 
     To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) in methylene chloride (3 L) and satd aq NaHCO 3  (3 L) solution was added triphosgene (118 g, 0.396 mol) at 0° C. The mixture was stirred for 15 min. The organic phase was separated, dried over Na 2 SO 4  and concentrated to give 1-bromo-4-(1-isocyanato-ethyl)-benzene (170 g, 63%). 
     Step 2: 1-chloro-3-phenylhex-5-en-3-ol 
     To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1 mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 30 min at −78° C. The reaction was quenched with aqueous NaHCO 3  solution. The organic phase was separated, dried over Na 2 SO 4  and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol (180 g, 86%).  1 H NMR (CDCl 3 ): 2.27 (m, 2H), 2.51 (m, 1H), 2.74 (m, 1H), 3.22 (m, 1H), 3.58 (m, 1H), 5.16 (m, 2H), 5.53 (m, 1H), 7.23 (m, 1H), 7.39 (m, 4H). 
     Step 3: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 
     A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (105 g, 0.050 mmol), (S)-(−)-1-(-bromophenyl)ethyl isocyanate (170 g, 0.752 mol), and DBU (228 g, 1.5 mol) in THF (1700 mL) was heated to reflux overnight. The mixture was diluted with EtOAc and washed with 1N aq HCl. The aqueous phase was extracted with EtOAc (3×). The combined organic phase was dried over Na 2 SO 4 . After the solvents were evaporated, the crude product was purified by column chromatography (petroleum ether/EtOAc=20:1 to 5:1) to give (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (100 g, 34%).  1 H NMR (CDCl 3 ): 1.39 (d, 3H), 2.14 (m, 1H), 2.24 (m, 2H), 2.48-2.61 (m, 3H), 2.82 (m, 2H), 5.01 (m, 2H), 5.52 (q, 1H), 5.73 (m, 1H), 6.62 (d, 2H), 7.12 (m, 2H), 7.28 (m, 2H). 
     Step 4: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one and 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal 
     To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (31 g, 78 mmol) and CuCl (19.3 g, 195 mmol) in dry DMF (150 mL) was added H 2 O (50 mL) and PdCl 2  (4.10 g, 23 mmol) at rt. After addition, the mixture was stirred overnight under oxygen. After TLC showed the starting material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (200 mL) was added, the organic layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by column chromatography (petroleum ether/EtOAc=5:1 to 1:1) to give a mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one and 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal, (26 g, 81%). 
     Step 5: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one 
     To a mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one and 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal (20 g, 48.2 mmol) in t-BuOH (250 mL) and 2-methyl-2-butene (50 mL) was added a solution of NaClO 2  (19.3 g, 0.213 mol) and NaH 2 PO 4  (28 g, 0.179 mol) in H 2 O (300 mL) at 0° C. The formed mixture was stirred for 1 h at 0° C. The mixture was treated with water (100 mL) and extracted with CH 2 Cl 2 . The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated to leave a residue, which was purified by column chromatography (petroleum ether/EtOAc=5:1 to 2.5:1) to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (10.0 g, 83%).  1 H NMR (CDCl 3 ): 1.49 (d, 3H), 2.12 (s, 3H), 2.33 (m, 2H), 2.63 (m, 1H), 2.86-3.08 (m, 3H), 5.57 (q, 1H), 6.66 (d, 2H), 7.19 (m, 2H), 7.33 (m, 5H). 
     Step 6: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one 
     To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (20 g, 46.4 mmol) in anhydrous THF (200 mL) was added dropwise methylmagnesium bromide (31 mL, 144 mmol) at −78° C. under nitrogen. Then the mixture was stirred at rt for 1 h. The reaction mixture was quenched with aq NaHCO 3  (50 mL) under ice water bath. The organic layers were separated. The aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4  and concentrated in vacuo to give the crude product, which was purified column chromatography (petroleum ether/EtOAc=5:1 to 2:1) to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (13 g, 65%). After re-crystallization from EtOH, 4 g of the pure compound was obtained.  1 H NMR (CDCl 3 ): 1.06 (s, 3H), 1.12 (s, 3H), 1.44 (d, 3H), 2.14 (m, 3H), 2.21 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 5.54 (q, 1H), 6.74 (d, 2H), 7.16 (d, 2H), 7.28 (m, 5H). 
     Example 23 
     Reverse Suzuki 
     6-(4-{1-[6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-N-methyl-nicotinamide 
                                
Step 1
 
     To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (6.6 g, 15.2 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.1 g, 24.3 mmol) in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) and Pd(dppf)Cl 2  (372 mg, 0.46 mmol). After addition, the mixture was warmed to 100° C. for 20 h. After TLC showed the starting material had disappeared, the solid was filtered off. Water (60 mL) and EtOAc (20 mL) were added, the layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (4.4 g, 60%), which was purified by column. NMR (CDCl 3 ): 1.03 (s, 3H), 1.12 (s, 3H), 1.22 (s, 12H), 1.49 (d, 3H), 2.13 (m, 4H), 2.26 (m, 1H), 2.73 (m, 1H), 5.64 (q, 1H), 6.91 (d, 2H), 7.38 (m, 5H), 7.51 (d, 2H). 
     Step 2 
     To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.04 mmol) and methyl 6-bromonicotinate (292 mg, 1.35 mmol) in dry 1,4-dioxane (5 mL) was added CsCO 3  (1 mL, 2 mmol) and Pd(PPh 3 ) 2 Cl 2  (50 mg). After addition, the mixture was warmed to 110° C. for 30 min under microwave. After TLC showed the starting material had disappeared, the solid was filtered off. Water (20 mL) and EtOAc (10 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give methyl 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (507 mg, 89%), which was purified by preparative TLC.  1 H NMR (CDCl 3 ): 1.13 (s, 3H), 1.19 (s, 3H), 1.61 (d, 3H), 2.24 (m, 4H), 2.37 (m, 1H), 2.88 (m, 1H), 4.02 (s, 3H), 5.76 (q, 1H), 7.11 (d, 2H), 7.29-7.47 (m, 6H), 7.78 (m, 1H), 7.82 (m, 2H), 8.38 (d, 1H), 9.31 (s, 1H). 
     Step 3 
     Methyl 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (150 mg, 0.307 mmol) was dissolved in NH 2 Me/MeOH (10 mL). The mixture was stirred at rt overnight. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-methylnicotinamide (54 mg, 36%). LC-MS Method 2 t R =1.117 min, m/z=430.1;  1 H NMR (CD 3 OD) 0.93 (s, 3H), 1.27 (s, 3H), 1.59 (d, 3H), 2.16 (s, 2H), 2.22-2.37 (m, 1H), 2.41-2.60 (m, 2H), 2.99 (s, 3H), 3.11 (m, 1H), 5.60 (m, 1H), 7.12 (d, 1H), 7.29 (m, 5H), 7.80 (m, 2H), 8.01 (d, 1H), 8.41 (d, 1H), 9.03 (s, 1H). 
     The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety. 
     While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.