Methods and intermediates for preparing MCL1 inhibitors

Abstract

The present disclosure provides a method for preparing an MCL1 inhibitor or a salt thereof and related key intermediates.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 940,387, filed November 26, 2019. The entire contents of that application are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to methods and intermediates for the synthesis of certain compounds that inhibit MCL1 for use in treating cancer. Background Art

[0004] Apoptosis (programmed cell death) is a process that eliminates unwanted or potentially dangerous cells from an organism. Preventing apoptosis is crucial for the development and continued growth of tumors. Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic member of the Bcl-2 protein family. MCL1 is overexpressed in many cancers. Overexpression of MCL1 can prevent cancer cells from undergoing apoptosis. Studies have shown that MCL1 inhibitors can be used to treat cancer. Compounds that inhibit MCL1 have been described, but there remains a need for synthetic methods for preparing such compounds on a production scale.

[0005] PCT Application No. PCT / US2019 / 032053 (WO 2019 / 222112) discloses novel compounds that can be used as MCL1 inhibitors. This patent publication discloses compounds according to formula (A),

[0006]

[0007] and pharmaceutically acceptable salts thereof are effective as inhibitors of MCL1 and can be used to treat cancer.

[0008] There is a need for synthetic methods and intermediates that are useful in preparing compounds of formula I and their salts. There is also a need for methods for preparing intermediate compounds that are useful in preparing compounds of formula I and their salts. Summary of the Invention

[0009] The present disclosure provides methods for preparing compounds according to formula (A), as shown above. In some embodiments, the present disclosure provides compounds according to formula (I),

[0010]

[0011] in: Is a single bond or a double bond;

[0012] R 12 is hydrogen or -C(O)R 1 ;

[0013] R 1 It is C1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 or -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substitution;

[0014] R 2 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 group substitution;

[0015] R 3 It is hydrogen, C 1-6 Alkyl, -OR 7 、C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -C(O)R 7 or -CN, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 group substitution;

[0016] R 4 It is hydrogen;

[0017] R 5 It is C 1-6 Alkyl, -(CH2CH2O) p R 7 、C 1-6 Haloalkyl or C 3-10 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 The cycloalkyl group is optionally substituted with 1 to 5 R10 group substitution;

[0018] R 6 is hydrogen or a halogen;

[0019] Each R 7 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substitution;

[0020] Each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 group substitution;

[0021] Each R 10 Independently C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-OC(O)NR a R b 、-NR a R b 、-NR a C(O)R b 、-NR aC(O)OR b 、-S(O) q R a 、-S(O)2NR a R b 、-NR a S(O)2R b , -N3, -CN or -NO2, or two R 10 The groups form fused, spiro or bridged C 3-10 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl are optionally substituted by 1-5 R 20 group substitution;

[0022] Each R a and R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, or R a and R b Together with the atoms to which they are attached, they form a 3-12 membered heterocycloalkyl group, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl are optionally substituted by 1-5 R 20 group substitution;

[0023] Each R 20 Independently C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, hydroxyl, C 1-6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C- 1-6 alkyl), -C(O)N(C- 1-6 Alkyl)2, -COOH, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl or halogen;

[0024] p is 0, 1, or 2; and

[0025] q is 0, 1, or 2;

[0026] and pharmaceutically acceptable salts thereof. In some embodiments, the compound of formula I is a compound according to formula I(a):

[0027]

[0028] In a specific embodiment, the present disclosure provides a method for preparing Compound 1:

[0029]

[0030] The compounds of Formula A (as well as Formulas I and I(a)) can be schematically divided into four functional regions, as shown below, each separated by one of the four key synthetic bonds (dashed lines):

[0031]

[0032]

[0033] Thus, the compounds of formula A (as well as formulas I and I(a)) can be considered to contain four major sub-parts: a tetracyclic core (TC), and specifically, a 6′-substituted-3,4-dihydro-2H,2′H,4H-5λ 2 -spiro[benzo[b][1,4]oxazepane-3,1′-naphthene-7-yl moiety; a disubstituted cyclobutane moiety (CB); a polysubstituted sulfonimide moiety (SNO); and an N-linked side chain (SC).

[0034] In this structure, the TC and CB moieties are linked by a single N-C alkylamine bond (numbered 1), the TC and SNO moieties are linked by a single N-C amide bond (numbered 2), the CB and SNO moieties are linked by a C-C alkyl or C=C alkenyl bond (numbered 3), and the SC and SNO moieties are linked by an NH or N-C single bond (numbered 4), depending on the R 12 characteristics.

[0035] WO 2019 / 222112 discloses a method for preparing compounds of formula A (including formula I and I(a)). In this method, the key synthetic bonds are formed in the order of 1, 2, 4, and then 3. Therefore, the method can be schematically abbreviated as follows:

[0036]

[0037] It should be understood that in this nomenclature, when discussing synthetic routes in which key fragments are constructed and linked in a step-wise manner, there may be protecting groups and other temporary substituents in further intermediates that will not match the final substituents or structural motifs in the final compound of Formula A.

[0038] Method disclosed in WO 2019 / 222112

[0039]

[0040] Disclosed herein are methods for preparing compounds of formula A (e.g., compounds of formula I or I(a)), and methods for preparing key intermediates thereof. Specifically, in some embodiments, disclosed herein are methods for preparing compounds of formula A (e.g., compounds of formula I or I(a)), wherein the key synthetic bond is formed in one or more of the following orders: 1, 2, 3 then 4; 2, 1, 3 then 4; 1, 2, 4 then 3; 2, 1, 4 then 3; 2, 3, 1 then 4; or 3, 2, 1 then 4; provided that if the order of the key synthetic bond formation steps is 1, 2, 3, 4, then the method does not include the use of intermediates 1-J or 1-K as defined herein, wherein R 5 It’s H.

[0041] In some embodiments, the TC fragment is fully formed before being incorporated into the above method steps. In other embodiments, the TC fragment is initially prepared as a bicyclic phenoxy fragment and carried out in a protected state for one or more steps, followed by deprotection and ring closure to form a tetracyclic TC fragment. For example:

[0042]

[0043] Wherein PG represents a protected aldehyde, for example, PG is CH(OC 1-6 Alkyl)(OC 1-6 alkyl) or -O(C 2-10 Alkyl)O-. DETAILED DESCRIPTION

[0044] Thus, in a first aspect, the present disclosure provides a method (Method A) for preparing a compound of Formula A (e.g., a compound of Formula I or I(a)), as described above, wherein the method comprises the following steps:

[0045] (a) (1) synthesizing fragment TC (or BC), (2) synthesizing fragment CB, (3) linking fragment TC (or BC) to fragment CB by forming bond 1, (4) synthesizing fragment SNO, (5) linking fragment TC-CB (or BC-CB) to fragment SNO by forming bond 2, (6) linking the CB portion and the SNO portion of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 within the molecule, and (7) linking the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A;

[0046] Provided that at no time during the process is the TC-CB fragment a compound of formula intermediate 1-J or 1-K, as defined herein, wherein R 5 is H; or

[0047] (b) (1) synthesizing fragment SNO, (2) synthesizing fragment TC (or BC), (3) linking fragment SNO to fragment TC (or BC) by forming bond 2, (4) synthesizing fragment CB, (5) linking fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 1, (6) linking the CB portion and the SNO portion of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 3 within the molecule, and (7) linking the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; or

[0048] (c) (1) synthesizing fragment TC (or BC), (2) synthesizing fragment CB, (3) linking fragment TC (or BC) to fragment CB by forming bond 1, (4) synthesizing fragment CNO, (5) linking fragment TC-CB (or BC-CB) to fragment CNO by forming bond 2, (6) linking the SC moiety to the SNO-TC-CB (or SNO-BC-CB) moiety by forming bond 4, and (7) linking the CB moiety and the SNO moiety of the SC-SNO-TC-CB (or SNO-BC-CB) moiety by forming bond 3 within the molecule to form a compound of formula A; or

[0049] (d) (1) synthesizing fragment SNO, (2) synthesizing fragment TC (or BC), (3) linking fragment SNO to fragment TC (or BC) by forming bond 2, (4) synthesizing fragment CB, (5) linking fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 1, (6) linking the SC moiety to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4, and (7) linking the CB moiety and the SNO moiety of the SC-SNO-TC-CB (or SC-SNO-BC-CB) fragment by forming bond 3 within the molecule to form a compound of formula A; or

[0050] (e) (1) synthesizing fragment TC (or BC), (2) synthesizing fragment SNO, (3) linking fragment TC (or BC) to fragment SNO by forming bond 2, (4) synthesizing fragment CB, (5) linking fragment TC-SNO (or BC-SNO) to fragment CB by forming bond 3, (6) linking the CB portion and the SNO portion of the SNO-TC-CB (or SNO-BC-CB) portion by forming bond 2 within the molecule, and (7) linking the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A; or

[0051] (f) (1) synthesizing fragment SNO, (2) synthesizing fragment CB, (3) linking fragment SNO to fragment CB by forming bond 3, (4) synthesizing fragment TC (or BC), (5) linking fragment SNO-CB to fragment TC (or BC) by forming bond 2, (6) linking the CB portion and the TC (or BC) portion of the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 1 within the molecule, and (7) linking the SC portion to the SNO-TC-CB (or SNO-BC-CB) fragment by forming bond 4 to form a compound of formula A;

[0052] Optionally wherein any of the aforementioned methods further comprises the step of converting any intermediate comprising fragment BC into the same intermediate comprising fragment TC, e.g.

[0053] If step (3) links fragment SNO to fragment BC by forming bond 2, step (3') may convert fragment SNO-BC to fragment SNO-TC, and then proceed with the remaining steps (e.g., in method (b) or method (d)); or

[0054] If step (5) connects fragment SNO-CB to fragment BC to form fragment SNO-BC-CB, step (5′) can convert fragment SNO-BC-CB to fragment SNO-TC-CB (without bond 1) before performing the remaining steps, or alternatively, step (6′) can convert fragment SNO-BC-CB to fragment SNO-TC-CB (with bond 1) before performing the remaining steps (e.g., in method (f));

[0055] Among them, fragment BC is: The fragment TC is: Fragment CB is: The fragment SNO is: Fragment SC is R 12 ; and PG is a protecting group (e.g., CH(OC 1-6 Alkyl)(OC 1-6alkyl) or -O(C 2-10 alkyl)O-); and

[0056] wherein all other substituents are as defined herein for compounds of formula A.

[0057] In some embodiments, the product of Method A is Compound 1, Compound 1(a), or Compound 1, as defined herein. In some embodiments, Method A can include one or more steps, in any order and in any combination, as provided in any embodiment of Method 1, Method 2, Method 3, Method 4, and Method 5 described herein.

[0058] In a second aspect, the present disclosure provides a method for preparing a compound selected from the group consisting of compounds 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J, 1-K, 2-B, 2-C, 2-D, 2-E, 3-A, 3-B, 3-C, 3-D, 9-A, 9-B, 9-C, 9-D, 9-E, and one or more compounds 1 or 1(a) (Method 1), as described above, wherein the method comprises reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 1 generally involves the formation of a cyclobutyl moiety (CB), including advanced intermediates 1-I, 1-J, and 1-K, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 1 may include any of the steps shown in Schemes 1, 2, and 3.

[0059]

[0060] Solution 1

[0061]

[0062] Option 2

[0063]

[0064] Option 3

[0065] In a specific embodiment, the present disclosure provides the following method 1:

[0066] 1.1 Method 1, wherein the method comprises reacting compound 1-A with a suitable protecting agent in a suitable solvent (optionally with a suitable base and / or catalyst) and under conditions effective to produce compound 1-B for a period of time; wherein R′ is C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, or tert-butyl), optionally wherein R′ is methyl;

[0067] 1.2 Method 1.1, wherein the substituent PG is selected from a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1-6 alkyl groups such as acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 an alkyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butyloxycarbonyl group or a benzyloxycarbonyl group), an aryloxycarbonyl group (e.g., a phenoxycarbonyl group), a tert-alkyl group (e.g., a tert-butyl or trityl group), an alkoxyalkyl group (e.g., a methoxymethyl or ethoxymethyl group), or a C 1-6 alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl);

[0068] 1.3 Method 1.2, wherein the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl);

[0069] 1.4 Method 1.3, wherein the substituent PG is a tert-butyldiphenylsilyl group, optionally wherein the protecting agent is tert-butyldiphenylsilyl chloride;

[0070] 1.5 Any of methods 1.1-1.4, wherein the protecting agent is selected from silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, triphenylsilyl chloride), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl chloride), bromides (e.g., tert-butyldimethylsilyl bromide, dimethylphenylsilyl bromide, triphenylsilyl bromide), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride, 1-adamantanecarbonyl chloride), acid anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate), alkyl chlorides (e.g., trityl chloride), and alkoxymethyl chlorides (e.g., methoxymethyl chloride);

[0071] 1.6 Any of methods 1.1-1.5, wherein the reaction comprises a base;

[0072] 1.7 Method 1.6, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole) and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0073] 1.8 Method 1.7, wherein the base is triethylamine;

[0074] 1.9 Any of methods 1.1-1.8, wherein the reaction comprises a catalyst;

[0075] 1.10 Method 1.9, wherein the catalyst is selected from 4-(dimethylamino)pyridine, N-methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine and 9-azajulonidine;

[0076] 1.11 Method 1.10 wherein the catalyst is 4-(dimethylamino)pyridine;

[0077] 1.12 Any of methods 1.1-1.11, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0078] 1.13 Method 1.12, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0079] 1.14 Method 1.12, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0080] 1.15 Method 1.12, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0081] 1.16 Any of methods 1.1-1.15, wherein the reaction temperature is -30°C to 40°C, for example, -10°C to 30°C or about 0°C to 25°C;

[0082] 1.17 Method 1 or any of 1.1-1.16, wherein the method comprises reacting compound 1-B with an organometallic reagent in a suitable solvent and under conditions and for a time effective to form a 1-hydroxycyclopropane compound 1-C, wherein R′ is as defined in Method 1.1, and PG is defined as provided in Method 1.2, 1.3 or 1.4;

[0083] 1.18 Method 1.17, wherein the substituent R x Selected from H, C 1-6 Alkyl (eg, methyl) and C 6-10 Aryl (eg phenyl), wherein the alkyl group is optionally replaced by C 6-10 Aryl (e.g., phenyl) substitution;

[0084] 1.19 Method 1.18, where R x It is H;

[0085] 1.20 Method 1.17, 1.18 or 1.19, wherein the organometallic reagent is an organolithium reagent (e.g., C 1-6 alkyllithium) or Grignard reagents (e.g., C 1-6 alkylmagnesium halides);

[0086] 1.21 Method 1.20, wherein the organometallic reagent is selected from ethylmagnesium bromide, ethylmagnesium chloride, n-propylmagnesium bromide and 2-phenylethylmagnesium bromide, each optionally in an ether solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dimethyl ... Provided as a solution in alkane;

[0087] 1.22 Any of methods 1.17-1.21, wherein the reaction further comprises a transition metal promoter, such as a titanium(IV) compound;

[0088] 1.23 Method 1.22, wherein the promoter is titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, or titanium(IV) butoxide);

[0089] 1.24 Any of methods 1.20-1.23, wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide;

[0090] 1.25 Any of methods 1.17-1.24, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0091] 1.26 Method 1.25, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene);

[0092] 1.27 Method 1.25, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and a nitrile (e.g., acetonitrile);

[0093] 1.28 Method 1.25, wherein the non-polar solvent is an ethereal solvent, optionally wherein the solvent is tetrahydrofuran;

[0094] 1.29 Any of methods 1.17-1.28, wherein the reaction temperature is -20°C to 30°C, for example, -5°C to 15°C or about 0°C to 5°C;

[0095] 1.30 Method 1 or any of Methods 1.1-1.29, wherein the method comprises reacting Compound 1-C with a halogenating agent in a suitable solvent and under conditions and for a time effective to form a β-haloketone compound 1-D, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19;

[0096] 1.31 Method 1.30, wherein the substituent X is selected from bromine, chloride and iodine;

[0097] 1.32 Method 1.31, wherein X is bromine;

[0098] 1.33 Method 1.30, 1.31 or 1.32, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, hypobromous acid, N-chlorophthalimide, N-chlorosuccinimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, N-iodosuccinimide, N-iodophthalimide and iodine;

[0099] 1.34 Method 1.33, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, and hypobromous acid;

[0100] 1.35 Method 1.34, wherein the halogenating agent is N-bromosuccinimide;

[0101] 1.36 Any of methods 1.30-1.35, wherein the suitable solvent is a non-polar solvent;

[0102] 1.37 Method 1.36, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0103] 1.38 Method 1.37, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0104] 1.39 Any of methods 1.30-1.38, wherein the reaction temperature is -20°C to 30°C, for example, -5°C to 15°C or about 0°C to 5°C;

[0105] 1.40 Any of methods 1.30-1.39, wherein compound 1-C is mixed (e.g., stirred or agitated) with a halogenating agent in a suitable solvent for 0.25 to 5 hours, e.g., 0.5 to 3 hours, or 1 to 2 hours, or about 1.5 hours;

[0106] 1.41 Method 1 or any of Methods 1.1-1.40, wherein the method comprises reacting Compound 1-D with a base in a suitable solvent and under conditions and for a time effective to form an α,β-unsaturated ketone Compound 1-E, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R xAs defined in Method 1.18 or 1.19, and wherein X is chloro, bromo or iodo;

[0107] 1.42 Method 1.41 wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO) and aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole);

[0108] 1.43 Method 1.42, wherein the base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0109] 1.44 Method 1.43, wherein the base is triethylamine;

[0110] 1.45 Any of methods 1.41-1.44, wherein the suitable solvent is a non-polar solvent;

[0111] 1.46 Method 1.45, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0112] 1.47 Method 1.46, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0113] 1.48 Any of methods 1.41-1.47, wherein the reaction temperature is -20°C to 30°C, e.g., -5°C to 15°C or about 0°C to 5°C;

[0114] 1.49 Any of methods 1.30 to 1.48, wherein the conversion of compound 1-C to compound 1-D and the conversion of compound 1-D to compound 1-E occur continuously in the same vessel without isolating compound 1-D;

[0115] 1.50 Method 1 or any of Methods 1.1-1.49, wherein the method comprises the step of reducing an α,β-unsaturated ketone compound 1-E to an allyl alcohol compound 1-F and its stereoisomer 1-F′, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19;

[0116] 1.51 Method 1.50, wherein the reduction is carried out by reacting compound 1-E with a reducing agent and a Lewis acid catalyst in a suitable solvent;

[0117] 1.52 Method 1.51, wherein the reducing agent is selected from a borane agent (e.g., borane, a borane complex [e.g., BH3-THF, BH3-DMS, BH3-CBS], 9-BBN), a borohydride reagent (e.g., sodium borohydride, lithium borohydride, lithium triethylborohydride), an aluminum hydride reagent (e.g., lithium aluminum hydride, diisobutylaluminum hydride), a hydrogen source (e.g., isopropanol) with a transfer hydrogenating agent (e.g., RuCl[(R,R)-Tsdpen](p-cymene), RuCl[(S,S)-Tsdpen](p-cymene)), an aluminum alkoxide reagent in an alcohol solvent (e.g., aluminum triisopropoxide in ethanol), and a reductase (e.g., ketoreductase);

[0118] 1.53 Method 1.52, wherein the reducing agent is sodium borohydride;

[0119] 1.54 Method 1.51, 1.52, or 1.53, wherein the Lewis acid is selected from cerium(III) chloride, magnesium bromide, magnesium chloride, magnesium iodide, calcium chloride, calcium bromide, and calcium iodide;

[0120] 1.55 Method 1.54, wherein the Lewis acid is cerium(III) chloride, such as cerium(III) chloride heptahydrate or anhydrous cerium(III) chloride;

[0121] 1.56 Any of methods 1.50-1.55, wherein the suitable solvent is a polar protic solvent or a nonpolar solvent;

[0122] 1.57 Method 1.56, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol, butanol);

[0123] 1.58 Method 1.56, wherein the nonpolar solvent is an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) or halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0124] 1.59 Method 1.56, wherein the solvent is ethanol;

[0125] 1.60 Any of methods 1.50-1.59, wherein the reaction temperature is -30°C to 30°C, for example, -20°C to 20°C or -10°C to 0°C;

[0126] 1.61 Any of methods 1.50-1.60, wherein the products 1-F and 1-F′ are not separated prior to the next step of the method;

[0127] 1.62 Any of methods 1.50-1.60, wherein the products 1-F and 1-F′ are separated prior to the next step in the method;

[0128] 1.63 Method 1 or any of Methods 1.1-1.62, wherein the method comprises the step of treating a mixture of allyl alcohol compounds 1-F and 1-F′ with an acyl donor and an esterase, wherein PG is as defined in Method 1.2, 1.3 or 1.4, and R x As defined in method 1.18 or 1.19, wherein the acyl donor is an ester of an acid of formula RCOOH;

[0129] 1.64 Method 1.63, wherein the esterase selectively esterifies the (R)-allyl alcohol portion of compound 1-F' to form ester 1-F";

[0130] 1.65 Method 1.64, wherein the esterase is a bacterial esterase, e.g., Pseudomonas stutzeri lipase;

[0131] 1.66 Method 1.63, 1.64 or 1.65, wherein R is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 Alkyl (e.g., trifluoromethyl, trichloromethyl), C 1-6 alkylcarboxylates (e.g., 3-propionate, 4-butyrate), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl);

[0132] 1.67 Any of Methods 1.63-1.66, wherein the acyl donor is a vinyl ester, an isopropenyl ester, a methyl ester, an ethyl ester, a 2,2,2-trifluoroethyl ester, a 2,2,2-trichloroethyl ester, or a methoxyvinyl ester of an acid RCOOH, or an anhydride of an acid RCOOH (including mixed and unmixed linear anhydrides and cyclic anhydrides of dicarboxylic acids), wherein R is as defined in Method 1.66;

[0133] 1.68 Method 1.67, wherein the acyl donor is selected from the group consisting of succinic anhydride, vinyl acetate, isopropyl acetate, ethyl acetate, isopropyl acetate, acetic anhydride, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroethyl acetate, methoxyvinyl acetate, vinyl propionate, vinyl valerate, vinyl isobutyrate, vinyl trifluoroacetate, vinyl trichloroacetate, vinyl benzoate, 4-bromovinyl acetate, vinyl picolinate, glutaric anhydride, vinyl formate, vinyl butyrate, and butyric anhydride;

[0134] 1.69 Any of methods 1.63-1.68, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0135] 1.70 Method 1.69, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane) and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane);

[0136] 1.71 Method 1.69, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile);

[0137] 1.72 Method 1.69, wherein the nonpolar solvent is an ethereal solvent, optionally wherein the solvent is methyl tert-butyl ether;

[0138] 1.73 Any of methods 1.63-1.72, wherein the reaction temperature is 0°C to 50°C, for example, 10°C to 30°C or about 20°C

[0139] 1.74 Any of methods 1.63-1.73, wherein after the reaction is complete, the product mixture is purified to isolate compound 1-F and / or compound 1-F" is removed and discarded;

[0140] 1.75 Method 1 or any of Methods 1.1-1.74, wherein the method comprises reacting Compound 1-F with an alkylating agent and optionally a base in a suitable solvent and under conditions and for a time effective to form the ether compound 1-G, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19, and wherein R 5 Selected from C 1-6 Alkyl, -(CH2CH2O) p R 7 、C 1-6 Haloalkyl and C 3-10 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 The cycloalkyl group is optionally substituted with 1 to 5 R 10 Group substitution (R 7 and R 10 as defined for compounds of formula I);

[0141] 1.76 method 1.75, where R 5 Selected from C 1-6 Alkyl and C 1-6haloalkyl, each optionally substituted by 1-3 groups selected from halogen, oxo, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl group substitution;

[0142] 1.77 method 1.76, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0143] 1.78 method 1.77, where R 5 It is a methyl group;

[0144] 1.79 Any of methods 1.75-1.78, wherein the alkylating agent is of formula R 5 -X compound, wherein X is selected from Cl, Br, I, OS(O)2OR 5 and OSO2-L, where L is C 1-6 Alkyl, optionally substituted aryl or halogenated C 1-6 alkyl;

[0145] 1.80 Method 1.79, wherein the alkylating agent is selected from the group consisting of alkyl bromides, alkyl chlorides, alkyl iodides, alkyl trifluoromethanesulfonates, alkyl toluenesulfonates, alkyl methanesulfonates, alkyl nitrobenzenesulfonates, alkyl benzenesulfonates, and dialkyl sulfates;

[0146] 1.81 Method 1.80, wherein the alkylating agent is selected from methyl iodide, methyl trifluoromethanesulfonate, methyl tosylate, and dimethyl sulfate;

[0147] 1.82 Any of methods 1.75-1.81, wherein the reaction further comprises a base selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-amylate, sodium t-amylate, lithium t-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, or lithium hydroxide), and an amide base (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide);

[0148] 1.83 Method 1.82, wherein the base is sodium tert-butoxide;

[0149] 1.84 Any of methods 1.75-1.83, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0150] 1.85 Method 1.84, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0151] 1.86 Method 1.84, wherein the polar protic solvent is an alcohol solvent (e.g., tert-butyl alcohol or tert-amyl alcohol), optionally in combination with water;

[0152] 1.87 Method 1.84, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0153] 1.88 Method 1.84, wherein the suitable solvent is tetrahydrofuran;

[0154] 1.89 Any of methods 1.75-1.88, wherein the reaction temperature is -80°C to 50°C, for example, -45°C to 10°C, or -10°C to 10°C or about 0°C;

[0155] 1.90 Method 1 or any of Methods 1.1-1.89, wherein the method comprises the step of treating Compound 1-G with a deprotecting agent in a suitable solvent and for a time and under conditions effective to form alcohol Compound 1-H, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19, and wherein R5 is as defined in any one of Methods 1.75-1.78;

[0156] 1.91 Method 1.90, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0157] 1.92 Method 1.91, where R 5 is methyl, ethyl or isopropyl, optionally, wherein R 5 It is a methyl group;

[0158] 1.93 Any of methods 1.90-1.92, wherein the deprotecting agent is selected from an inorganic base (e.g., an aqueous solution thereof), an acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent;

[0159] 1.94 Any of methods 1.90-1.93, wherein the deprotecting agent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrochloric acid (e.g., aqueous HCl, HCl in diethyl ether, HCl in methanol, HCl in isopropanol), sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, 4-toluenesulfonic acid, hydrofluoric acid, pyridine hydrogen fluoride, triethylammonium hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, a combination of hydrogen and a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, a Ru complex, a Rh complex, PtO2, a Pt complex, a Pd complex, an Ir complex), and a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2);

[0160] 1.95 Any of methods 1.90-1.94, wherein the substituent PG is a silyl group and the deprotecting reagent is a fluoride reagent;

[0161] 1.96 Method 1.95, wherein the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl), and the deprotecting agent is selected from hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride;

[0162] 1.97 Method 1.96, wherein the substituent PG is tert-butyldiphenylsilyl and the deprotecting agent is selected from tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride;

[0163] 1.98 Any of methods 1.90-1.97, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0164] 1.99 Method 1.98, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0165] 1.100 Method 1.98, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol), optionally in combination with water, or wherein the polar protic solvent is water;

[0166] 1.101 Method 1.98, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0167] 1.102 Method 1.98, wherein the suitable solvent is tetrahydrofuran;

[0168] 1.103 Any of methods 1.90-1.102, wherein the reaction temperature is from -15°C to 50°C, e.g., from -5°C to 40°C, or from 0°C to 30°C, or from 10°C to 30°C;

[0169] 1.104 Method 1 or any of Methods 1.1-1.103, wherein the method comprises the step of treating Compound 1-H with an oxidizing agent in a suitable solvent to form an aldehyde Compound 1-I, wherein R x As defined in Method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.75-1.78;

[0170] 1.105 Method 1.104, wherein the reaction further comprises an additive, a catalyst, and / or a base;

[0171] 1.106 Method 1.104 or 1.105, wherein the oxidizing agent is selected from sodium hypochlorite, pyridine sulfur trioxide, dimethyl sulfoxide / oxalyl chloride, DMSO / acetic anhydride, DMSO / trifluoroacetic anhydride, diacetoxyiodobenzene (DAIB), tetrapropylammonium perruthenate (TPAP) / N-methylmorpholine oxide, Dess-Martin periodinane, pyridinium chlorochromate N-chlorosuccinimide / dimethyl sulfide, iodosobenzene, DMSO / dicyclohexylcarbodiimide, bis(trifluoroacetoxy)iodobenzene, and manganese dioxide;

[0172] 1.107 Method 1.106, wherein the oxidizing agent is selected from diacetoxyiodobenzene (DAIB), Dess-Martin periodinane, iodosobenzene, and bis(trifluoroacetoxy)iodobenzene;

[0173] 1.108 Method 1.107, wherein the oxidizing agent is diacetoxyiodobenzene (DAIB);

[0174] 1.109 Any of methods 1.104-1.108, wherein the reaction further comprises a catalyst selected from the group consisting of TEMPO((2,2,6,6-tetramethylpiperidin-1-yl)oxy), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, and 9-azaadamantane N-oxyl;

[0175] 1.110 Any of methods 1.104-1.109, wherein the reaction further comprises an additive selected from the group consisting of sodium bromide, lithium bromide, and potassium bromide;

[0176] 1.111 Any of methods 1.104-1.110, wherein the reaction further comprises a base selected from an inorganic base (e.g., disodium hydrogen phosphate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide) and an organic amine base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, DBU, DBN);

[0177] 1.112 Any of methods 1.104-1.109, wherein the oxidant is diacetoxyiodobenzene and the catalyst is TEMPO, wherein the reaction does not contain a base or additives;

[0178] 1.113 Any of methods 1.104-1.112, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0179] 1.114 Method 1.113, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0180] 1.115 Method 1.113, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0181] 1.116 Method 1.113, wherein the suitable solvent is dichloromethane;

[0182] 1.117 Any of methods 1.104-1.116, wherein the reaction temperature is from -80°C to 50°C, e.g., from -40°C to 40°C or from 10°C to 30°C;

[0183] 1.118 Method 1 or any of Methods 1.1-1.117, wherein the method comprises the step of treating Compound 1-I with a reducing agent and Compound 5-I in a suitable solvent for a period of time and under conditions effective to form the tertiary amine Compound 1-J, wherein R x As defined in Method 1.18 or 1.19, wherein R 5 As defined in any of Methods 1.75-1.78, and wherein R z As defined in any of Methods 2.129-2.131, and wherein R 6 is hydrogen or halogen. In one embodiment, R xis H. In one embodiment, R 5 It is a methyl group;

[0184] 1.119 Method 1.118, where R 6 selected from chlorine, bromine, fluorine and iodine;

[0185] 1.120 Method 1.119, where R 6 It is chlorine;

[0186] 1.121 Any of methods 1.118-1.120, wherein the reducing agent is selected from the group consisting of a hydride reducing agent, a silane reducing agent, and a zinc acid solution (e.g., a zinc acetic acid solution);

[0187] 1.122 Method 1.121, wherein the reducing agent is a hydride reducing agent;

[0188] 1.123 Method 1.122, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride;

[0189] 1.124 Method 1.123, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[0190] 1.125 Any of methods 1.122-1.124, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride);

[0191] 1.126 Method 1.121, the reducing agent is selected from silane (triisopropylsilane, triphenylsilane, diethylsilane, etc.), sodium borohydride, sodium borohydride / acetic acid, sodium triacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxide / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate, zinc borohydride / zinc chloride, tetramethylammonium triacetoxyborohydride. In one embodiment, the reducing agent is triethylsilane;

[0192] 1.127 Any of methods 1.121 to 1.126 wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid). In one embodiment, the acid is trifluoroacetic acid;

[0193] 1.128 Any of methods 1.118-1.128, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0194] 1.129 Method 1.128, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), acetonitrile, and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0195] 1.130 Method 1.128, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide;

[0196] 1.131 Method 1.128 wherein the suitable solvent is dichloromethane. In one embodiment, the solvent is acetonitrile;

[0197] 1.132 Any of methods 1.118-1.131 wherein the reaction temperature is from -30°C to 50°C, e.g., from -30°C to 0°C, or from -30°C to -10°C or about -20°C. In one embodiment, the temperature is from -10°C to 30°C;

[0198] 1.133 Method 1 or any of Methods 1.1-1.132, wherein the method comprises the step of hydrolyzing Compound 1-J in a suitable solvent and under conditions and for a time effective to form Carboxylic Acid Compound 1-K, wherein R x As defined in Method 1.18 or 1.19, wherein R 5 As defined in any of Methods 1.75-1.78, and wherein R z As defined in any of Methods 2.129-2.131, and wherein R 6 is hydrogen or a halogen;

[0199] 1.134 Method 1.133, wherein the reaction comprises treating Compound 1-J with an aqueous acid or base in an organic and / or aqueous solvent; or treating Compound 1-J with an enzyme (e.g., a bacterial or fungal lipase, such as a lipase from a Rhizopus species); or treating Compound 1-J with magnesium dibromide in a non-polar solvent; or treating Compound 1-J with a fluoride source (e.g., hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, fluorine) in a non-polar solvent. or treating compound 1-J with a combination of hydrogen and a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complex, Rh complex, PtO 2 , Pt complex, Pd complex, Ir complex) or a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO 2 );

[0200] 1.135 Method 1.134, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid;

[0201] 1.136 Method 1.134 wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, tetramethylammonium hydroxide, an alkoxide (lithium, sodium, potassium, magnesium or calcium salt of methanol, ethanol, isopropanol, t-butanol or t-amyl alcohol), trimethyltin hydroxide, sodium trimethylsilanolate, potassium trimethylsilanolate and pyridine;

[0202] 1.137 Any of methods 1.133-1.136, wherein the solvent is selected from water, an alcohol (e.g., methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, tert-amyl alcohol), a polar aprotic solvent (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile), an ether (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dimethyl ether, one or more of alkane), hydrocarbon solvents (e.g., toluene, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0203] 1.138 Any of methods 1.133-1.137 wherein the reaction temperature is from -10°C to 100°C, e.g., from 10°C to 80°C, or from 20°C to 80°C, or from 20°C to 50°C. In one embodiment, the temperature is from 20°C to 100°C. In one embodiment, the temperature is from 50°C to 70°C;

[0204] 1.139 Method 1 or any of Methods 1.1-1.138, wherein the method comprises treating (1S,5R)-3-oxabicyclo[3.2.0]heptan-2-one (Compound 2-A) with an organometallic reagent in a suitable solvent and under conditions and for a time effective to form 1-hydroxycyclopropane Compound 2-B, wherein the substituent R x Selected from H, C 1-6 Alkyl (eg, methyl) and C 6-10 Aryl (eg, phenyl), wherein alkyl is an optionally substituted aryl (eg, phenyl);

[0205] 1.140 method 1.139, where R x It is H;

[0206] 1.141 Method 1.139 or 1.140, wherein the organometallic reagent is an organolithium reagent (e.g., C 1-6 alkyllithium) or Grignard reagents (e.g., C 1-6 alkylmagnesium halides);

[0207] 1.142 Method 1.141 wherein the organometallic reagent is selected from ethylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium iodide, n-propylmagnesium bromide, and 2-phenylethylmagnesium bromide, each optionally in an ethereal solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dimethyl ... Provided as a solution in alkane;

[0208] 1.143 Any of methods 1.139-1.142, wherein the reaction further comprises a transition metal promoter, such as a titanium(IV) compound;

[0209] 1.144 Method 1.143, wherein the promoter is titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, titanium(IV) n-butoxide, titanium(IV) tert-butoxide, titanium(IV) benzyl alkoxide);

[0210] 1.145 Any of methods 1.139-1.144 wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide;

[0211] 1.146 Any of methods 1.139-1.145, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0212] 1.147 Method 1.146 wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene); or wherein the polar aprotic solvent is a nitrile (e.g., acetonitrile);

[0213] 1.148 Method 1.147, wherein the non-polar solvent is an ethereal solvent, optionally wherein the solvent is tetrahydrofuran;

[0214] 1.149 Any of methods 1.139-1.148, wherein the reaction temperature is from -20°C to 50°C, e.g., from -10°C to 10°C or from about 0°C to 5°C;

[0215] 1.150 Method 1 or any of 1.1-1.149, wherein the method comprises the step of reacting compound 2-B with a suitable protecting agent in a suitable solvent (optionally with a suitable base and / or catalyst) and under conditions and for a time effective to produce compound 2-C, wherein R x As defined in Method 1.139 or 1.140;

[0216] 1.151 Method 1.150, wherein the substituent PG is selected from a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1-6 alkyl groups such as acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tert-alkyl groups (e.g., tert-butyl or trityl), alkoxyalkyl groups (e.g., methoxymethyl or ethoxymethyl), and C 1-6 alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl);

[0217] 1.152 Method 1.151, wherein the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl);

[0218] 1.153 Method 1.152 wherein the substituent PG is a tert-butyldiphenylsilyl group, optionally wherein the protecting agent is TBDPS-chloride;

[0219] 1.154 Any of methods 1.150-1.153, wherein the protecting agent is selected from a silyl chloride (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, or triphenylsilyl chloride), a silyl triflate (e.g., trimethylsilyl triflate, triethylsilyl triflate, triisopropylsilyl triflate, tert-butyldimethylsilyl triflate, dimethylphenylsilyl triflate, or triphenylsilyl triflate), a silyl bromide (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl chloride, or triphenylsilyl chloride). silyl bromide, tert-butyldimethylsilyl bromide, dimethylphenylsilyl bromide or triphenylsilyl bromide), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halide (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chloride (e.g., pivaloyl chloride or 1-adamantanecarbonyl chloride), acid anhydride (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate or phenyl chloroformate), alkyl chlorides (e.g., trityl chloride) and alkoxymethyl chlorides (e.g., methoxymethyl chloride);

[0220] 1.155 Any of methods 1.150-1.154 wherein the reaction comprises a base;

[0221] 1.156 Method 1.155 wherein the base is selected from a tertiary amine (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine, imidazole or 1-methylimidazole) and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium hydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate) or sodium phosphate (monosodium hydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0222] 1.157 Method 1.156 wherein the base is triethylamine;

[0223] 1.158 Any of methods 1.150-1.157, wherein the reaction comprises a catalyst;

[0224] 1.159 Method 1.158 wherein the catalyst is selected from the group consisting of 4-(dimethylamino)pyridine, 2,6-lutidine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine;

[0225] 1.160 Method 1.159 wherein the catalyst is 4-(dimethylamino)pyridine;

[0226] 1.161 Any of methods 1.150-1.160, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0227] 1.162 Method 1.161 wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether or dihydrogen ether) alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0228] 1.163 Method 1.161, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile);

[0229] 1.164 Method 1.161, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0230] 1.165 Any of methods 1.150-1.161 wherein the reaction temperature is from -30°C to 40°C, for example, from -10°C to 30°C or from 0°C to 25°C;

[0231] 1.166 Method 1 or any of Methods 1.1-1.165, wherein the method comprises the step of reacting compound 2-C with a halogenating agent in a suitable solvent and under conditions and for a time effective to form a β-haloketone compound 2-D, wherein PG is as defined in any of Methods 1.151-1.153, and R x As defined in Method 1.139 or 1.140;

[0232] 1.167 Method 1.166, wherein the substituent X is selected from bromine, chloride and iodine;

[0233] 1.168 Method 1.167, wherein X is bromine;

[0234] 1.169 Method 1.166, 1.167, or 1.168, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, hypobromous acid, N-chlorophthalimide, N-chlorosuccinimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, N-iodosuccinimide, N-iodophthalimide, and iodine;

[0235] 1.170 Method 1.169, wherein the halogenating agent is selected from the group consisting of N-bromosuccinimide, N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, and hypobromous acid;

[0236] 1.171 Method 1.169 wherein the halogenating agent is M-bromosuccinimide;

[0237] 1.172 Any of methods 1.166-1.171, wherein the suitable solvent is a non-polar solvent;

[0238] 1.173 Method 1.172, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0239] 1.174 Method 1.172, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0240] 1.175 Any of methods 1.166-1.174, wherein the reaction temperature is from -20°C to 30°C, e.g., from -5°C to 15°C or from 0°C to 5°C;

[0241] 1.176 Any of methods 1.166-1.175, wherein compound 2-C is mixed (e.g., stirred or agitated) with a halogenating agent in a suitable solvent for 0.1 hour to 3 hours, e.g., 0.2 hour to 2 hours, or 0.3 hour to 1 hour, or about 0.5 hour;

[0242] 1.177 Method 1 or any of Methods 1.1-1.176, wherein the method comprises the step of reacting Compound 2-D with a base in a suitable solvent and under conditions and for a time effective to form an α,β-unsaturated ketone Compound 2-E, wherein PG is defined as provided in any of Methods 1.151-1.153, and R x As defined in Method 1.139 or 1.140, and wherein X is chloro, bromo or iodo;

[0243] 1.178 Method 1.177 wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole), and inorganic bases (e.g., alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate, alkali metal phosphates such as sodium dihydrogen phosphate, disodium hydrogen phosphate, or trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate, or lithium dihydrogen phosphate, dilithium hydrogen phosphate, or trilithium phosphate);

[0244] 1.179 Method 1.178 wherein the base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0245] 1.180 Method 1.179 wherein the base is triethylamine;

[0246] 1.181 Any of methods 1.177-1.180, wherein the suitable solvent is a non-polar solvent;

[0247] 1.182 Method 1.181 wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether or dihydrogen ether) alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0248] 1.183 Method 1.182, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0249] 1.184 Any of methods 1.177-1.183, wherein the reaction temperature is from -20°C to 30°C, e.g., from -5°C to 15°C or from 0°C to 5°C;

[0250] 1.185 Any of methods 1.166 to 1.184, wherein the conversion of compound 2-C to compound 2-D and the conversion of compound 2-D to compound 2-E occur continuously in the same vessel without isolating compound 2-D;

[0251] 1.186 Method 1 or any of Methods 1.1-1.185, wherein the method comprises the step of reacting Compound 2-E with a promoter in a suitable solvent and under conditions and for a time effective to form an epimerized α,β-unsaturated ketone Compound 1-E, wherein PG is defined as provided in any of Methods 1.151-1.153, and R xAs defined in Method 1.139 or 1.140;

[0252] 1.187 Method 1.186 wherein the promoter is selected from a tertiary amine (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, or DABCO), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine, or 1-methylimidazole), an inorganic base (e.g., an alkali metal carbonate such as sodium carbonate, potassium carbonate, and lithium carbonate, or an alkali metal phosphate such as sodium dihydrogen phosphate, disodium hydrogen phosphate, or trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, or tripotassium hydrogen phosphate, or lithium dihydrogen phosphate, dilithium hydrogen phosphate, or trilithium phosphate), an inorganic halide (e.g., lithium chloride, magnesium bromide, magnesium chloride), and an acid (e.g., titanium tetraisopropoxide, benzenesulfonic acid, toluenesulfonic acid, or methanesulfonic acid);

[0253] 1.188 Method 1.187 wherein the promoter is selected from triethylamine, N,M diisopropylethylamine, M methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU);

[0254] 1.189 Method 1.188, wherein the promoter is DBU;

[0255] 1.190 Any of methods 1.186-1.189, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, or a polar protic solvent;

[0256] 1.191 Method 1.190, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkanes) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0257] 1.192 Method 1.190, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0258] 1.193 Method 1.190, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, propanol, or isopropanol);

[0259] 1.194 Method 1.190, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0260] 1.195 Any of methods 1.186-1.194, wherein the reaction temperature is from -10°C to 50°C, e.g., from 0°C to 40°C, or from 10°C to 30°C or about 25°C;

[0261] 1.196 Method 1 or any of Methods 1.1-1.195, wherein the method comprises the step of thiolation of Compound 1-E by reacting Compound 1-E with a thiol and a base in a suitable solvent under conditions and for a time effective to form Compound 3-A, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19;

[0262] 1.197 Method 1.196, where R S Selected from optionally substituted C 1-6 alkyl (e.g., methyl) and optionally substituted aryl (e.g., phenyl);

[0263] 1.198 Method 1.197, where R S is optionally one or more selected from C 1-6 Alkoxy, halogen, C 1-6 Alkyl and aryl (eg, phenyl) groups substituted C 1-6 Alkyl, optionally wherein R S is methyl, ethyl or isopropyl;

[0264] 1.199 Method 1.197, where R S is optionally one or more selected from C 1-6 Alkoxy, halogen, C 1-6 alkyl and aryl (eg, phenyl) substituted aryl, optionally wherein R S is phenyl or tolyl;

[0265] 1.200 method 1.197, where R S is 4-tolyl;

[0266] 1.201 Any of Methods 1.196-1.200, wherein the thiol is R S -SH (e.g., methyl mercaptan, benzenethiol, or 4-methylbenzenethiol);

[0267] 1.202 Any of methods 1.196-1.201, wherein the base is selected from a tertiary amine (e.g., triethylamine, N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane) and an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine, imidazole, or 1-methylimidazole);

[0268] 1.203 Method 1.202, wherein the base is triethylamine or N,N-diisopropylethylamine;

[0269] 1.204 Any of methods 1.196-1.203, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0270] 1.205 Method 1.204, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether or dihydrogen ether) alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0271] 1.206 Method 1.204, wherein the polar aprotic solvent is selected from an ester (e.g., ethyl acetate, methyl acetate, or isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0272] 1.207 Method 1.204, wherein the non-polar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane;

[0273] 1.208 Any of methods 1.196-1.207, wherein the reaction temperature is from -20°C to 50°C, e.g., from 0°C to 30°C, or from 10°C to 20°C or about 25°C;

[0274] 1.209 Method 1 or any of Methods 1.1-1.208, wherein the method comprises the step of reducing the unsaturated thio compound 3-A to the thioalcohol compound 3-B, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19, and R S As defined in any of Methods 1.197-1.200;

[0275] 1.210 Method 1.209, wherein the reduction is carried out by reacting compound 3-A with a reducing agent and a Lewis acid catalyst in a suitable solvent;

[0276] 1.211 Method 1.210, wherein the reducing agent is selected from a borane agent (e.g., borane, a borane complex [e.g., BH3-THF, BH3-DMS, BH3-CBS], or 9-BBN), a borohydride reagent (e.g., sodium borohydride, lithium borohydride, or lithium triethylborohydride), an aluminum hydride reagent (e.g., lithium aluminum hydride, diisobutylaluminum hydride, or lithium tri-tert-butoxyaluminum hydride), a hydrogen source (e.g., isopropanol) with a transfer hydrogenating agent (e.g., RuCl[(R,R)-Tsdpen](p-cymene), RuCl[(S,S)-Tsdpen](p-cymene)), an aluminum alkoxide reagent in an alcohol solvent (e.g., aluminum triisopropoxide in ethanol), and a reductase (e.g., a ketoreductase);

[0277] 1.212 Method 1.211, wherein the reducing agent is sodium borohydride;

[0278] 1.213 Any of methods 1.209-1.212, wherein the Lewis acid is selected from cerium(III) chloride, magnesium bromide, magnesium chloride, magnesium iodide, calcium chloride, calcium bromide, and calcium iodide;

[0279] 1.214 Method 1.213, wherein the Lewis acid is cerium(III) chloride, such as cerium(III) chloride heptahydrate or anhydrous cerium(III) chloride;

[0280] 1.215 Any of methods 1.209-1.214, wherein the suitable solvent is a polar protic solvent or a nonpolar solvent;

[0281] 1.216 Method 1.215, wherein the suitable solvent is a polar protic solvent such as an alcohol (e.g., methanol, ethanol, propanol, isopropanol, or butanol);

[0282] 1.217 Method 1.215, wherein the suitable solvent is a non-polar solvent such as an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) or halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0283] 1.218 Method 1.215, wherein the solvent is ethanol;

[0284] 1.219 Any of methods 1.209-1.218, wherein the reaction temperature is from -30°C to 30°C, e.g., from -20°C to 20°C or from -10°C to 10°C;

[0285] 1.220 Method 1 or any of Methods 1.1-1.219, wherein the method comprises the step of reacting compound 3-B with an alkylating agent and optionally a base in a suitable solvent and under conditions and for a time effective to form the ether compound 3-C, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and R x As defined in Method 1.18 or 1.19, R S As defined in any of Methods 1.197-1.200, and wherein R 5 Selected from C 1-6 Alkyl, -(CH2CH2O) p R 7 、C 1-6 Haloalkyl or C 3-10 Cycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10The cycloalkyl group is optionally substituted with 1 to 5 R 10 Group substitution (R 7 and R 10 as defined for compounds of formula I);

[0286] 1.221 Method 1.220, where R 5 Selected from C 1-6 Alkyl and C 1-6 haloalkyl, each optionally substituted by 1-3 groups selected from halogen, oxo, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl group substitution;

[0287] 1.222 Method 1.221, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0288] 1.223 Method 1.222, where R 5 It is a methyl group;

[0289] 1.224 Any of methods 1.220-1.223 wherein the alkylating agent is of formula R 5 -X compound, wherein X is selected from Cl, Br, I, OS(O)2OR 5 and OSo2-L, where L is C 1-6 Alkyl, optionally substituted aryl or halogenated C 1-6 alkyl;

[0290] 1.225 Method 1.224 wherein the alkylating agent is selected from the group consisting of alkyl bromides, alkyl chlorides, alkyl iodides, alkyl trifluoromethanesulfonates, alkyl toluenesulfonates, alkyl methanesulfonates, alkyl nitrobenzenesulfonates, alkyl benzenesulfonates, and dialkyl sulfates;

[0291] 1.226 Method 1.224 wherein the alkylating agent is selected from the group consisting of methyl iodide, methyl trifluoromethanesulfonate, methyl tosylate, and dimethyl sulfate;

[0292] 1.227 Any of methods 1.220-1.226, wherein the reaction further comprises a base selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-amylate, sodium t-amylate, lithium t-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), and an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide);

[0293] 1.228 Method 1.227, wherein the base is sodium hydride;

[0294] 1.229 Any of methods 1.220-1.228, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0295] 1.230 Method 1.229, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0296] 1.231 Method 1.229, wherein the polar protic solvent is an alcohol solvent (e.g., tert-butyl alcohol, tert-amyl alcohol), optionally in combination with water;

[0297] 1.232 Method 1.229, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, optionally in combination with water;

[0298] 1.233 Method 1.229, wherein the suitable solvent is tetrahydrofuran;

[0299] 1.234 Any of methods 1.220-1.233, wherein the reaction temperature is from -80°C to 50°C, e.g., from -45°C to 10°C, or from -10°C to 10°C, or from 10°C to 20°C;

[0300] 1.235 Method 1 or any of Methods 1.1-1.234, wherein the method comprises the step of treating Compound 3-C with an S-oxidant in a suitable solvent and for a time and under conditions effective to form N-tosylsulfinylimidoyl Compound 3-D, wherein R s As defined in any of Methods 1.197-1.200, wherein PG is as defined in Methods 1.2, 1.3, or 1.4, and R x As defined in Method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.220-1.223;

[0301] 1.236 method 1.235, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl);

[0302] 1.237 method 1.236, where R 5 is methyl, ethyl or isopropyl, optionally, wherein R 5 It is a methyl group;

[0303] 1.238 Any of methods 1.235-1.237 wherein the S-oxidant is selected from N-chloro-4-methylbenzenesulfonamide or a salt thereof, N-chlorobenzenesulfonamide or a salt thereof, (tosylimido)iodobenzene, and p-toluenesulfonamide / phenyliododiacetate;

[0304] 1.239 Method 1.238, wherein the reagent is N-chloro-4-methylbenzenesulfonamide (chloramine-T);

[0305] 1.240 Any of methods 1.235-1.239, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0306] 1.241 Method 1.240, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane or n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene);

[0307] 1.242 Method 1.240, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, isopropanol, n-butanol, t-butanol, or t-amyl alcohol);

[0308] 1.243 Method 1.240, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile);

[0309] 1.244 Method 1.240, wherein the suitable solvent is acetonitrile;

[0310] 1.245 Any of methods 1.235-1.244, wherein the reaction temperature is 0°C to 50°C, e.g., 10°C to 30°C or about 25°C;

[0311] 1.246 Method 1 or any of Methods 1.1-1.245, wherein the method comprises the step of pyrolyzing Compound 3-D in a suitable solvent to form an allyl ether compound 1-G, wherein PG is defined as provided in Method 1.2, 1.3, or 1.4, and R x As defined in Method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.220-1.223;

[0312] 1.247 method 1.246, where R 5 is C optionally substituted by 1-3 halogens (eg, fluorine) 1-6alkyl (e.g., methyl, ethyl, isopropyl, propyl, or tert-butyl);

[0313] 1.248 method 1.247, where R 5 is methyl, ethyl or isopropyl, optionally, wherein R 5 It is a methyl group;

[0314] 1.249 Any of methods 1.246-1.248, wherein heat is applied without any chemical agent;

[0315] 1.250 Any of methods 1.246-1.249, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent, optionally wherein the boiling point of the solvent is at least 60°C;

[0316] 1.251 Method 1.250, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-heptane) and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene);

[0317] 1.252 Method 1.250, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, isopropanol, n-butanol, t-butanol, t-amyl alcohol, or any mixture thereof);

[0318] 1.253 Method 1.250 wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a nitrile (e.g., acetonitrile) and an ester (e.g., ethyl acetate, methyl acetate or isopropyl acetate);

[0319] 1.254 Method 1.250 wherein the suitable solvent is isopropyl acetate;

[0320] 1.255 Any of methods 1.246-1.254, wherein the reaction temperature is 70°C to 150°C, e.g., 80°C to 100°C or about 90°C;

[0321] 1.256 Any of Method 1 or Method 1.255, wherein the method produces a compound according to any one or more of Compound 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J, or 1-K;

[0322] 1.257 Method 1.256 wherein in one or more of said compounds, R' is methyl, R x is H, X is Cl or Br (e.g., Br), PG is a trialkylsilyl or dialkylarylsilyl group (e.g., TBDPS), Rz It is C 1-3 Alkyl (e.g., methyl), R 5 It is C 1-3 Alkyl (eg, methyl), and / or R 6 is a halogen (e.g., chlorine);

[0323] 1.258 Method 1 or any of Methods 1.1-1.257, wherein the method produces a compound according to any one or more of Compounds 2-B, 2-C, 2-D, or 2-E;

[0324] 1.259 Method 1.258 wherein in one or more of said compounds, R x is H, PG is trialkylsilyl or dialkylarylsilyl (e.g., TBDPS), and / or X is Cl or Br (e.g., Br);

[0325] 1.260 Method 1 or any of Methods 1.1-1.259, wherein the method produces a compound according to any one or more of Compounds 3-A, 3-B, 3-C, or 3-D;

[0326] 1.261 Method 1.260 wherein in one or more of said compounds, R x is H, PG is a trialkylsilyl or dialkylarylsilyl group (eg, TBDPS), R S is aryl (e.g., 4-tolyl), and / or R 5 It is C 1-3 alkyl (e.g., methyl);

[0327] 1.262 Method 1 or any of Methods 1.1-1.261, wherein the method produces a compound according to any one or more of Compounds 9-A, 9-B, 9-C, 9-D, 9-E;

[0328] 1.263 Method 1.262, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D, or 9-E are prepared according to any one or more of Method 4, Method 4.1, etc., or Method 5, Method 5.1, etc.;

[0329] 1.264 Method 1.262 or 1.263 wherein in one or more of said compounds, R x It is H, R y It is H, R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-3 Alkyl (e.g., methyl), R6 is halogen (e.g., chlorine), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6 alkoxy (e.g., (S)-1-phenylethoxy) or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0330] 1.265 Method 1.264 wherein in one or more of said compounds, R x It's H, R y It's H, R 2 and R 3 are independently H or methyl, R 4 It's H, R 5 is a methyl group, and R 6 It is chlorine;

[0331] 1.266 Method 1.265 wherein in one or more of said compounds, R 2 and R 3 It's H or R 2 and R 3

[0332] 1.267 is methyl, or R 2 is H and R 3 It is a methyl group;

[0333] 1.268 Method 1.266 wherein in one or more of said compounds, R 2 is H and R 3 It is a methyl group;

[0334] 1.269 Any of Methods 1.262-1.267, wherein in Compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0335] 1.270 Method 1.268, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[0336] 1.271 Method 1.269, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0337] 1.272 Method 1.269, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0338] 1.273 Method 1 or any of Methods 1.1-1.271, wherein the method produces a compound according to Compound 1;

[0339] 1.274 Method 1.272, wherein Compound 1 is Compound 1(a);

[0340] 1.275 Method 1.272 or 1.273, wherein compound I or I(a) is prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0341] 1.276 Any of Methods 1.272-1.274 wherein in Compound I or I(a), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0342] 1.277 Method 1.275 wherein in compound I or I(a), R 2and R 3 are independently H or methyl, R 4 It's H, R 5 is a methyl group, and R 6 It is chlorine;

[0343] 1.278 Method 1.276 wherein in compound I or I(a), R 2 and R 3 It's H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is a methyl group;

[0344] 1.279 Method 1.277 wherein in compound I or I(a), R 2 is H and R 3 It is a methyl group;

[0345] 1.280 Any of methods 1.275-1.278 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[0346] 1.281 Method 1.279 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0347] 1.282 Method 1.280 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0348] 1.283 Any of Methods 1.262-1.281, wherein in one or more of Compound 9-E, Compound 1, or Compound 1(a), It is a double bond;

[0349] 1.284 Method 1 or any of Methods 1.1-1.282, wherein the method produces Compound 1;

[0350] 1.285 Method 1 or any of Methods 1.1-1.283, wherein the method further comprises any of the steps described in any of Methods 2 et seq., Method 3 et seq., Method 4 et seq., and Method 5 et seq.

[0351] In a third aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 4-B, 4-C, 4-D, 4-E, 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H, 5-I, 1-J, 1-K, 9-A, 9-B, 9-C, 9-D, 9-E and compound I or I(a) (Method 2), as described herein, wherein the method comprises reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 2 generally involves the formation of a tetracyclic moiety (TC), including advanced intermediates 5-F and 5-I, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 2 may include any of the steps shown in Schemes 4 and 5.

[0352] In a specific embodiment, the present disclosure provides the following method 2:

[0353] 2.1 Method 2, wherein the method comprises the step of reacting compound 4-A (6-hydroxy-3,4-dihydronaphthalen-1(2H)-one) with a suitable triflation agent in a suitable solvent (with a suitable base) and for a period of time under conditions effective to produce compound 4-B;

[0354] 2.2 Method 2.1, wherein the triflation reagent is selected from trifluoromethanesulfonyl anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonyl fluoride, trifluoromethanesulfonic acid, N-trifluoromethanesulfonylimidazole and N-phenyltrifluoromethanesulfonimide;

[0355] 2.3 Method 2.1 or 2.2, wherein the base is selected from tertiary amines (e.g., N-methylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine) and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate), potassium bicarbonate, potassium carbonate, potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), potassium fluoride, lithium carbonate, cesium carbonate);

[0356]

[0357] Option 4

[0358]

[0359] Option 5

[0360] 2.4 Any of methods 2.1-2.3, wherein the reagent is trifluoromethanesulfonyl anhydride and the base is pyridine;

[0361] 2.5 Any of methods 2.1-2.4, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0362] 2.6 Method 2.5, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0363] 2.7 Method 2.5, wherein the polar aprotic solvent is selected from nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0364] 2.8 Method 2.5, wherein the non-polar solvent is dichloromethane;

[0365] 2.9 Any of methods 2.1-2.8, wherein the reaction temperature is -80°C to 40°C, for example, -30°C to 20°C, or -10°C to 10°C or about 0°C;

[0366] 2.10 Method 2 or any of Methods 2.1-2.9, wherein the method comprises the step of reacting compound 4-B with a halide source under conditions and for a time effective to form compound 4-C, wherein R6 is fluoro, chloro, bromo, or iodo;

[0367] 2.11 Method 2.10, where R 6Selected from chlorine and bromine (for example, wherein R 6 is chlorine);

[0368] 2.12 Method 2.10 or 2.11, wherein the halide source is selected from the group consisting of a chloride salt (e.g., lithium chloride, potassium chloride, cesium chloride, tetrabutylammonium chloride), triphenylphosphine dichloride, copper(II) chloride, copper(I) chloride, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, cyanuric chloride, methanesulfonyl chloride, phosgene, triphosgene, a bromide salt (e.g., lithium bromide, potassium bromide, cesium bromide, tetrabutylammonium bromide), triphenylphosphine dibromide, copper(II) bromide, copper(I) bromide, phosphorus tribromide, phosphorus oxybromide, thionyl bromide, sulfuryl bromide, an iodide salt (e.g., potassium iodide, cesium iodide, tetrabutylammonium iodide), copper(II) iodide, copper(I) iodide, a fluoride salt (e.g., lithium fluoride, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride), copper(II) fluoride, and copper(I) fluoride;

[0369] 2.13 Method 2.12, wherein the halide source is a chloride salt, such as lithium chloride;

[0370] 2.14 Any of methods 2.10-2.13, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0371] 2.15 Method 2.14, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene);

[0372] 2.16 Method 2.14, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0373] 2.17 Method 2.14, wherein the polar aprotic solvent is N-methyl-2-pyrrolidone;

[0374] 2.18 Any of methods 2.10-2.17, wherein the reaction temperature is 50°C to 250°C, for example, 100°C to 220°C, or 130°C to 150°C or about 140°C;

[0375] 2.19 Method 2 or any of Methods 2.1-2.18, wherein the method comprises the step of converting compound 4-C to compound 4-D, wherein R 6 as defined in Method 2.10 or 2.11;

[0376] 2.20 Method 2.19, where R 6 It is chlorine;

[0377] 2.21 Method 2.19 or 2.20, wherein the reaction comprises treating compound 4-C with a trimethylsulfonium salt and a base in a polar aprotic solvent;

[0378] 2.22 Method 2.21, wherein the trimethylsulfonium salt is trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium iodide, trimethylsulfonium tetrafluoroborate or trimethylsulfonium methylsulfate;

[0379] 2.23 Method 2.21 or 2.22, wherein the base is an inorganic base (e.g., sodium hydroxide, potassium hydroxide, or lithium hydroxide);

[0380] 2.24 Any of methods 2.21-2.23, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile);

[0381] 2.25 Any of methods 2.21-2.24, wherein the reaction temperature is 0°C to 50°C, for example, 10°C to 40°C or 20°C to 30°C;

[0382] 2.26 Any of methods 2.19-2.25, wherein the stereoisomers of compound 4-D are not separated prior to the next step of the method;

[0383] 2.27 Method 2 or any of Methods 2.1-2.26, wherein the method comprises the step of rearranging compound 4-D under conditions and for a time effective to form compound 4-E, wherein R 6 as defined in Method 2.10 or 2.11;

[0384] 2.28 Method 2.27, where R 6 It is chlorine;

[0385] 2.29 Method 2.27 or 2.28, wherein the reaction comprises treating compound 4-D with a Lewis acid in a nonpolar solvent;

[0386] 2.30 Method 2.29, wherein the Lewis acid is selected from boron trifluoride, boron trichloride reagent, boron tribromide, magnesium dibromide, indium chloride, bismuth trifluoromethanesulfonate, and copper trifluoromethanesulfonate;

[0387] 2.31 Method 2.30, wherein the boron trifluoride is boron trifluoride diethyl ether, boron trifluoride dimethyl sulfide or boron trifluoride tetrahydrofuran complex;

[0388] 2.32 Any of methods 2.29-2.31, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0389] 2.33 Method 2.32, wherein the nonpolar solvent is tetrahydrofuran;

[0390] 2.34 Any of methods 2.27-2.33, wherein the reaction temperature is -10°C to 50°C, for example, 0°C to 30°C or 0°C to 10°C;

[0391] 2.35 Any of methods 2.27-2.34, wherein the stereoisomers of compound 4-E are not separated prior to the next step of the method;

[0392] 2.36 Method 2 or any of Methods 2.1-2.35, wherein the method includes the step of converting compound 4-E to compound 5-A, wherein R 6 as defined in Method 2.10 or 2.11;

[0393] 2.37 Method 2.36, where R 6 It is chlorine;

[0394] 2.38 Method 2.35 or 2.36, wherein the reaction comprises treating compound 4-E with formaldehyde and a base in a polar protic solvent;

[0395] 2.39 Method 2.38, wherein the formaldehyde is provided as an aqueous solution;

[0396] 2.40 Method 2.38 or 2.39, wherein the base is a hydroxide base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, zinc hydroxide, or aluminum hydroxide);

[0397] 2.41 Any of methods 2.38-2.40, wherein the solvent is selected from methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, and water, or a combination thereof;

[0398] 2.42 Method 2.41, wherein the solvent further comprises tetrahydrofuran, 2-methyltetrahydrofuran, dihydrofuran, alkyl, methyl tert-butyl ether, cyclopentyl methyl ether and di One or more of alkanes;

[0399] 2.43 Any of methods 2.38-2.42, wherein the reaction comprises aqueous formaldehyde, aqueous sodium hydroxide or potassium hydroxide, and diethylene glycol solvent;

[0400] 2.44 Any of methods 2.36-2.43, wherein the reaction temperature is 0°C to 90°C, for example, 5°C to 50°C or 10°C to 40°C

[0401] 2.45 Method 2 or any of Methods 2.1-2.44, wherein the method comprises the step of acylating Compound 5-A with an acylating agent in a suitable solvent and under conditions and for a time effective to form Compound 5-B, wherein R 6 as defined in Method 2.10 or 2.11;

[0402] 2.46 Method 2.45, where R 6 It is chlorine;

[0403] 2.47 Method 2.45 or 2.46, where R m Selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 Alkyl (e.g., trifluoromethyl, trichloromethyl), carboxyl C 1-6 alkyl (e.g., 3-carboxypropyl), optionally substituted aryl (e.g., phenyl, 4-halophenyl), or optionally substituted heteroaryl (e.g., pyridyl, such as 2-pyridyl);

[0404] 2.48 Method 2.47, where R m It is C 1-6 Alkyl, optionally wherein R m It is a methyl group;

[0405] 2.49 Any of methods 2.45-2.48, wherein the acylation is asymmetric, e.g., the acylation produces a product in greater than 50% ee (e.g., greater than 75% ee, or greater than 85% ee, or greater than 90% ee, or greater than 95% ee) prior to any purification;

[0406] 2.50 Any of methods 2.45-2.49, wherein the acylation is enzymatic and the acylating agent is a combination of an enzyme and an acyl donor;

[0407] 2.51 Method 2.50, wherein the acyl donor is of formula R m -C(=O)-OZ ester or formula R m -C(=O)-OC(=O)-R m anhydride, wherein Z is selected from C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl), C2-6 Alkenyl (e.g., vinyl, allyl, methoxyvinyl, isopropenyl) and halogenated C 1-6 Alkyl (e.g., trifluoromethyl, 2,2,2-trichloroethyl);

[0408] 2.52 Method 2.50, wherein the acyl donor is selected from the group consisting of vinyl acetate, ethyl acetate, isopropyl acetate, acetic anhydride, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroethyl acetate, methoxyvinyl acetate, isopropenyl acetate, vinyl propionate, vinyl valerate, vinyl isobutyrate, vinyl trifluoroacetate, vinyl trichloroacetate, vinyl benzoate, 4-bromovinyl acetate, vinyl picolinate, glutaric anhydride, and vinyl formate;

[0409] 2.53 Any of methods 2.50-2.52, wherein the enzyme is a lipase, e.g., a bacterial or fungal lipase, such as from a Candida species (e.g., Lipozyme TL IM or Novozym 435);

[0410] 2.54 Any of methods 2.45-2.53, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0411] 2.55 Method 2.54, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane) and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane);

[0412] 2.56 Method 2.54, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, a nitrile (e.g., acetonitrile) and an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0413] 2.57 Method 2.54, wherein the polar aprotic solvent is ethyl acetate;

[0414] 2.58 Any of methods 2.45-2.57, wherein the reaction temperature is -10°C to 110°C, e.g., 10°C to 80°C or 0°C to 40°C; or 20°C to 30°C;

[0415] 2.59 Method 2 or any of Methods 2.1-2.58, wherein the method comprises the step of treating compound 5-B with an oxidizing agent in a suitable solvent and for a time and under conditions effective to form aldehyde compound 5-C, wherein R 6 As defined in Method 2.10 or 2.11, and R m As defined in Method 2.47 or 2.48;

[0416] 2.60 method 2.59, where R 6 is chlorine and R m It is a methyl group;

[0417] 2.61 Method 2.59 or 2.60, wherein the reaction further comprises an additive, a catalyst, and / or a base;

[0418] 2.62 Any of methods 2.59-2.61, wherein the oxidizing agent is selected from sodium hypochlorite, sulfur trioxide-pyridine, dimethyl sulfoxide and an activator (e.g., oxalyl chloride), tetrapropylammonium perruthenate (TPAP) / N-methylmorpholine oxide, Dess-Martin periodinane, pyridinium chlorochromate N-chlorosuccinimide / dimethyl sulfide, iodosobenzene, chromium trioxide, 2-iodooxybenzoic acid, bis(trifluoroacetoxy)iodobenzene, diacetoxyiodobenzene (DAIB), and manganese dioxide;

[0419] 2.63 Method 2.62, wherein the DMSO activating agent is selected from the group consisting of oxalyl chloride, trifluoroacetic anhydride, cyanuric chloride, N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide, N-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride, trichloroacetonitrile, 2-chloro-1,2-dimethylimidazolinium chloride, polyphosphoric acid, phosphorus trichloride, phosphorus pentoxide, triphenylphosphine dichloride, triphenylphosphine dibromide, phosphorus oxychloride, acetyl chloride, benzoyl chloride, acetyl bromide, phenyl dichlorophosphate, diphenyl chlorophosphate, diethyl chlorophosphate, and ethoxyacetylene;

[0420] 2.64 Any of methods 2.61-2.63, wherein the reaction further comprises a catalyst selected from the group consisting of TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxy), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, and 9-azaadamantane N-oxyl;

[0421] 2.65 Any of methods 2.61-2.64, wherein the reaction further comprises an additive selected from the group consisting of sodium bromide, lithium bromide, and potassium bromide;

[0422] 2.66 Any of methods 2.61-2.65, wherein the reaction further comprises a base selected from a tertiary amine (e.g., N,N-diisopropylethylamine, N-methylmorpholine, tri-n-propylamine, triethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, collidine), an inorganic base (e.g., sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, disodium hydrogenphosphate, or tribasic), sodium acetate, potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tripotassium phosphate), potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate), and a hydroxide base (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide);

[0423] 2.67 Any of methods 2.59-2.66, wherein the oxidizing agent is sulfur trioxide-pyridine;

[0424] 2.68 Method 2.67 wherein the base is N,N-diisopropylethylamine;

[0425] 2.69 Any of methods 2.59-2.68, wherein the suitable solvent is water, a nonpolar solvent, and / or a polar aprotic solvent;

[0426] 2.70 Method 2.69, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0427] 2.71 Method 2.69, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), nitriles (e.g., acetonitrile), and ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone);

[0428] 2.72 Method 2.69, wherein the suitable solvent is a mixture of ethyl acetate and dimethyl sulfoxide;

[0429] 2.73 Any of methods 2.59-2.72, wherein the reaction temperature is -80°C to 50°C, for example, -40°C to 40°C or -10°C to 10°C;

[0430] 2.74 Method 2 or any of Methods 2.1-2.73, wherein the method comprises the step of treating compound 5-C with a protecting agent in a suitable solvent and for a time and under conditions effective to form acetal compound 5-D, wherein R 6As defined in Method 2.10 or 2.11, and R m As defined in Method 2.47 or 2.48;

[0431] 2.75 method 2.74, where R 6 is chlorine and R m It is a methyl group;

[0432] 2.76 Method 2.74 or 2.75, where each R n Independently C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl), or two R n Parts are linked together to form C 2-10 Alkyl or C 2-10 an alkenyl bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted by one to four C 1-6 Alkyl, halogen or aryl substituted; or two R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge);

[0433] 2.77 Method 2.76, where each R n Independently C 1-6 Alkyl, optionally wherein each Rn is methyl;

[0434] 2.78 method 2.76, where two R n The moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-;

[0435] 2.79 Method 2.78, where two R nThe moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH2CH3)2CH2-, -CH(C6H5)CH(C6H5) and -CH2CH(C6H5)CH2-;

[0436] 2.80 method 2.76, where each R n is the same as C 1-6 alkyl moiety (e.g., methyl, ethyl, or isopropyl), and the protecting agent is C 1-6 Alcohol or tri(C 1-6 alkyl) esters, for example, wherein each R n is methyl, and the protecting reagent is methanol or trimethyl orthoformate;

[0437] 2.81 method 2.76, where two R n Partially formed C 2-10 Alkyl or C 2-10 The alkenyl bridge, and the protecting reagent is C 2-10 Alkyl-diol or C 2-10 Alkenyl-diols (e.g., ethylene glycol, propylene glycol);

[0438] 2.82 Method 2.81, wherein the protecting agent is selected from trimethyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate, triethyl orthoformate, an alcohol (e.g., MeOH) or a diol (e.g., ethylene glycol, pinacol, propylene glycol, butanediol, 2,2-dimethyl-1,3-propanediol, catechol, HOCH2CH2OH, HOCH(CH3)CH(CH3)OH, HOCH2CH(CH3)OH, HOCH2CH(Ph)OH, HOC(CH3)2C(CH3)2OH, H OCH2CH2CH2OH, HOCH2CBr2CH2OH, HOCH2(C=CH)CH2OH, HOCH2CH(Ph)CH2OH, HOCH(CH3)CH2CH(CH3)OH, HOCH2 CH(CH3)CH2OH, HOCH2C(CH3)2CH2OH, HOCH2C(CH2CH3)2CH2OH, HOCH2CH2CH2CH2OH, HOCH2CH2CH2CH2CH2OH);

[0439] 2.83 Any of methods 2.74-2.82, wherein the reaction further comprises, for example, a catalytic amount (e.g., 0.001 to 0.10 equivalents or 0.01 to 0.05 equivalents) of an acid;

[0440] 2.84 Method 2.83, wherein the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonic acid Sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, oxalic acid, fumaric acid, phthalic acid and formic acid; or an acidic resin in which the acid is immobilized (e.g., Amberlyst resin);

[0441] 2.85 Any of methods 2.74 to 2.84 wherein each Rn is methyl, the protecting reagent is trimethyl orthoformate, and the acid catalyst is p-toluenesulfonic acid;

[0442] 2.86 Any of methods 2.74 to 2.85, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0443] 2.87 Method 2.86, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0444] 2.88 Method 2.86, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and diols (e.g., ethylene glycol, propylene glycol), or combinations thereof, optionally wherein the solvent alcohol is the same as the protecting reagent;

[0445] 2.89 Method 2.86, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0446] 2.90 Method 2.86, wherein the suitable solvent is methanol;

[0447] 2.91 Any of Methods 2.74-2.87, wherein the reaction comprises refluxing in a hydrocarbon solvent (e.g., toluene) with azeotropic removal of water;

[0448] 2.92 Any of methods 2.74-2.91, wherein the reaction temperature is 0°C to 150°C, e.g., 25°C to 120°C, 0°C to 60°C, or 35°C to 55°C;

[0449] 2.93 Method 2 or any of Methods 2.1-2.92, wherein the method comprises the step of hydrolyzing compound 5-D in water with a base, optionally with a suitable cosolvent, for a period of time and under conditions effective to form acetal compound 5-E, wherein R 6As defined in Method 2.10 or 2.11, R m As defined in Method 2.47 or 2.48, and R n As defined in any of Methods 2.76-2.79;

[0450] 2.94 Method 2.93, where R 6 is chlorine, R m is a methyl group, and R n is each methyl group;

[0451] 2.95 Method 2.93 or 2.94, wherein the base is an inorganic base such as a hydroxide, bicarbonate, or carbonate base;

[0452] 2.96 Method 2.95, wherein the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate; in one embodiment, the base is potassium carbonate;

[0453] 2.97 Any of methods 2.93-2.96, wherein the suitable co-solvent is selected from a nonpolar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof;

[0454] 2.98 Method 2.97, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0455] 2.99 Method 2.98, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol);

[0456] 2.100 Method 2.98, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile);

[0457] 2.101 Method 2.97, wherein the suitable solvent is a combination of tetrahydrofuran and water;

[0458] 2.102 Any of methods 2.93-2.101, wherein the reaction further comprises a phase transfer catalyst, such as a quaternary ammonium halide salt (e.g., a chloride or bromide salt of tetrabutylammonium, tetraethylammonium, benzyltriethylammonium, methyltrioctylammonium, methyltributylammonium, or methyltrioctylammonium);

[0459] 2.103 Any of methods 2.93-2.102, wherein the reaction temperature is from -10°C to 70°C, e.g., from 10°C to 30°C or from 20°C to 30°C;

[0460] 2.104 Any of methods 2.74-2.103, wherein compound 5-C is converted to compound 5-E in two steps without isolating or purifying the intermediate compound 5-D;

[0461] 2.105 Method 2 or any of Methods 2.1-2.104, wherein the method comprises the step of treating compound 5-E with a transacetal reagent in a suitable solvent and for a period of time under conditions effective to form acetal compound 5-E', wherein R 6 As defined in Method 2.10 or 2.11, and wherein each R of compound 5-E n Independently C 1-6 alkyl (eg, methyl, ethyl, or isopropyl), and wherein both R n With the R of compound 5-E n different;

[0462] 2.106 Method 2.105, where R 6 It is chlorine;

[0463] 2.107 Method 2.105 or 2.106, wherein both R n It is a methyl group;

[0464] 2.108 Any of methods 2.105-2.107, wherein each R of compound 5-E' n Independently C 2-6 Alkyl (eg, ethyl or isopropyl), or wherein both R n The parts are connected together to form C 2-10 Alkyl or C 2-10 an alkenyl bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups; or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge);

[0465] 2.109 Method 2.108, wherein each R of compound 5-E′ n Independently C 2-6 Alkyl, optionally wherein each R n It is ethyl;

[0466] 2.110 Method 2.108, wherein both R nThe moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-;

[0467] 2.111 Method 2.110, wherein both R n The moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH2CH3)2CH2-, -CH(C6H5)CH(C6H5) and -CH2CH(C6H5)CH2-;

[0468] 2.112 Method 2.108, wherein each R of compound 5-E′ n is the same as C 2-6 alkyl moiety (e.g., ethyl or isopropyl), and the transamination reagent is C 2-6 alcohol, for example, where each R n is ethyl, and the reagent is ethanol;

[0469] 2.113 Method 2.108, wherein both R n Partially formed C 2-10 Alkyl or C 2-10 The alkenyl bridge, and the transversion reagent is C 2-10 Alkyl-diol or C 2-10 Alkenyl-diols (e.g., ethylene glycol, propylene glycol);

[0470] 2.114 Method 2.113, wherein the transcondensing agent is selected from an alcohol (e.g., ethanol and propanol) or a diol (e.g., ethylene glycol, 2,3-butanediol, pinacol, propylene glycol, 2,4-pentanediol, 2-methyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 2,2-diethyl-1,3-propanediol, 2-phenyl-1,3-propanediol, meso-1,2-diphenyl-1,2-ethanediol, and catechol);

[0471] 2.115 Any of methods 2.105-2.114, wherein the reaction further comprises a Lewis acid (e.g., boron trifluoride, titanium isopropoxide) or a Bronsted acid (e.g., p-toluenesulfonic acid);

[0472] 2.116 Method 2.115, wherein the Lewis acid is selected from boron trifluoride, boron trichloride, boron tribromide, magnesium dibromide, indium chloride, aluminum chloride, tin(IV) chloride, zinc chloride, bismuth trifluoromethanesulfonate, copper trifluoromethanesulfonate, titanium(IV) chloride, and titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, or titanium(IV) butoxide);

[0473] 2.117 Method 2.116, wherein the boron trifluoride is boron trifluoride diethyl ether, boron trifluoride dimethyl sulfide, or boron trifluoride tetrahydrofuran complex;

[0474] 2.118 Method 2.115, wherein the Bronsted acid is selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonic acid sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid, oxalic acid, fumaric acid, phthalic acid and formic acid; or wherein the acid is an immobilized acidic resin (e.g., Amberlyst resin); in one embodiment, the acid is boron trifluoride diethyl etherate (BF3·OEt2);

[0475] 2.119 Any of methods 2.105 to 2.118, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent, optionally a nonpolar solvent or a polar aprotic solvent in combination with a trace amount of a polar protic solvent (e.g., less than 10% v / v);

[0476] 2.120 Method 2.119, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0477] 2.121 Method 2.119, wherein the polar protic solvent is selected from alcohols (e.g., ethanol, propanol, isopropanol) and glycols (e.g., ethylene glycol, propylene glycol), or combinations thereof, optionally wherein the solvent alcohol is the same as the transduction reagent;

[0478] 2.122 Method 2.119, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0479] 2.123 Method 2.119 wherein the suitable solvent is 2-methyltetrahydrofuran;

[0480] 2.124 Any of methods 2.105-2.120, wherein the reaction comprises refluxing in a hydrocarbon solvent (e.g., toluene) with azeotropic removal of water;

[0481] 2.125 Any of methods 2.105-2.124, wherein the reaction temperature is 0°C to 100°C, e.g., 25°C to 120°C, or 50°C to 100°C, or 70°C to 80°C;

[0482] 2.126 Method 2 or any of Methods 2.1-2.125, wherein the method comprises the step of treating Compound 5-E or 5-E' with 4-fluoro-3-nitrobenzoic acid or ester in a suitable solvent and for a period of time under conditions effective to form the ether adduct Compound 5-F, wherein R 6 As defined in Method 2.10 or 2.11, and wherein each R n as defined in any of Methods 2.76-2.79 or 2.108-2.111;

[0483] 2.127 Method 2.126, where R 6 It is chlorine;

[0484] 2.128 Method 2.126 or 2.127, wherein both R n The moiety is methyl or ethyl, or the two R n The moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[0485] 2.129 Any of methods 2.126-2.128, where R z is H or optionally substituted C 1-6 alkyl;

[0486] 2.130 Method 2.129, where R z Selected from H, unsubstituted C 1-6 Alkyl (e.g., methyl), C 1-6 Alkoxy-substituted C 1-6 Alkyl (e.g., methoxyethyl, methoxymethyl), C 1-6 Alkoxy-substituted C 1-6 Alkoxy-substituted C 1-6 Alkyl (e.g., methoxyethoxyethyl, methoxyethoxymethyl), 5-6 membered heterocycloalkyl substituted C 1-6 Alkyl (e.g., 2-N-(morpholino)ethyl, 2-tetrahydropyranyl), aryloxy substituted C 1-6 Alkyl (e.g., benzyloxymethyl), halogen-substituted C 1-6 Alkyl (e.g., 2,2,2-trichloroethyl), trialkylsilyl substituted C 1-6 Alkyl (e.g., 2-(trimethylsilyl)ethyl, triisopropylsilylmethyl), trialkylsilyl-substituted C 1-6 Alkoxy-substituted C 1-6 Alkyl (e.g., 2-(trimethylsilyl)ethoxymethyl) and aryl substituted C 1-6 alkyl (e.g., benzyl, 4-methylbenzyl, 4-nitrobenzyl);

[0487] 2.131 Method 2.130, where R z is H or unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl);

[0488] 2.132 Any of methods 2.126-2.131, wherein compound 5-E or 5-m' is dissolved or suspended in a suitable solvent and treated with a strong base, and optionally with a promoter (e.g., sodium iodide, tetrabutylammonium iodide);

[0489] 2.133 Method 2.132, wherein the base is selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-amylate, sodium t-amylate, lithium t-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, ammonium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate, or trisodium phosphate));

[0490] 2.134 Method 2.133 wherein the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, and potassium diisopropylamide; optionally wherein the base is potassium tert-butoxide;

[0491] 2.135 Method 2.132, 2.133 or 2.134 wherein the 4-fluoro-3-nitrobenzoic acid or ester is added to the reaction about 1 to 60 minutes, e.g., about 1 to 30 minutes, or 1 to 20 minutes, or 1 to 15 minutes, or 1 to 10 minutes, or 1 to 5 minutes after the addition of the base;

[0492] 2.136 Any of methods 2.126-2.135, wherein the 4-fluoro-3-nitrobenzoic acid or ester has the formula 4-F-3-NO2-C6H4-COOR z ;

[0493] 2.137 Any of methods 2.126-2.136, wherein the suitable solvent is a nonpolar solvent;

[0494] 2.138 Method 2.137 wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0495] 2.139 Method 2.138, wherein the nonpolar solvent is tetrahydrofuran;

[0496] 2.140 Any of methods 2.126-2.139, wherein the reaction temperature is -80°C to 100°C, e.g., -45°C to 10°C, or -30°C to 10°C, or -10°C to 5°C, or about 0°C, or -10°C to 50°C, or -10°C to 30°C, or 10°C to 30°C, or 30°C to 80°C;

[0497] 2.141 Method 2 or any of Methods 2.1-2.140, wherein the method comprises the step of treating the nitro compound 5-F or 5-G' with a reducing agent in a suitable solvent and for a time and under conditions effective to produce the aniline compound 5-G or 5-H, respectively, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, and wherein R zAs defined in any of Methods 2.129 to 2.131;

[0498] 2.142 Method 2.141, where R 6 It is chlorine;

[0499] 2.143 Method 2.141 or 2.142, wherein both R n The moiety is methyl or ethyl, or the two R n The moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[0500] 2.144 Any of methods 2.141-2.143, where R z is unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl);

[0501] 2.145 Any of methods 2.141-2.144, wherein the reducing agent is selected from a solution of a zinc, tin, or iron acid (e.g., formic or acetic acid or HCl in a suitable solvent);

[0502] 2.146 Any of methods 2.141-2.144, wherein the reducing agent is a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system);

[0503] 2.147 Method 2.146, wherein the hydrogenating agent is a combination of hydrogen gas and a palladium, platinum, rhodium, iridium, ruthenium, or nickel catalyst (e.g., Pd, Pd / C, Pd(OAc)2, Pt / C, PtO2, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO2, Pt complexes, Pd complexes, Ir complexes) or a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt / C, PtO2);

[0504] 2.148 Method 2.147, wherein the hydrogenating agent is hydrogen in combination with a Pd, Pd / C, Pd(OAc)2, Pt / C, or PtO2 catalyst, optionally at a pressure of 1-5 bar (e.g., 1-2 bar);

[0505] 2.149 Method 2.145, wherein the reducing agent is a solution of iron in acetic acid;

[0506] 2.150 Any of methods 2.141 to 2.149, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0507] 2.151 Method 2.150, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0508] 2.152 Method 2.150, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid);

[0509] 2.153 Method 2.150 wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0510] 2.154 Method 2.150 wherein the suitable solvent is ethyl acetate or isopropyl acetate or acetic acid;

[0511] 2.155 Any of methods 2.141-2.154 wherein the reaction temperature is from 0°C to 100°C, e.g., from 20°C to 50°C, or from 20°C to 30°C, or from 50°C to 80°C;

[0512] 2.156 Method 2 or any of Methods 2.1-2.155, wherein the method comprises treating the acetal compound 5-F or 5-G′ with a deprotecting agent in a suitable solvent and for a period of time under conditions effective to produce the aldehyde compound 5-G or 5-H, respectively, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any one of Methods 2.76-2.79 or 2.108-2.111, and wherein R z As defined in any of Methods 2.129 to 2.131;

[0513] 2.157 Method 2.156, where R 6 It is chlorine;

[0514] 2.158 Method 2.156 or 2.157, where both R n is methyl or ethyl, or two R n The moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[0515] 2.159 Any of methods 2.156-2.158, where R z is unsubstituted C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl);

[0516] 2.160 Any of methods 2.156-2.159, wherein the deprotecting reagent comprises an acid;

[0517] 2.161 Method 2.160, wherein the acid is selected from HCl (e.g., aqueous HCl or HCl / methanol, HCl / isopropanol or HCl / diethanol). alkane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium toluenesulfonate trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium trifluoromethanesulfonate), and acidic resins (e.g., Amberlyst);

[0518] 2.162 Method 2.161, wherein the acid is selected from HCl (e.g., HCl / dihydrochloric acid) alkane), p-toluenesulfonic acid, methanesulfonic acid, and acidic resins (e.g., Amberlyst);

[0519] 2.163 Any of methods 2.156 to 2.162, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof;

[0520] 2.164 Method 2.163, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0521] 2.165 Method 2.163, wherein the polar protic solvent is water and / or an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid);

[0522] 2.166 Method 2.163, wherein the polar aprotic solvent is selected from ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile);

[0523] 2.167 Method 2.163, wherein the suitable solvent is acetone or distilled water. alkyl;

[0524] 2.168 Any of methods 2.156-2.167, wherein the reaction temperature is 0°C to 100°C, e.g., 20°C to 50°C or 20°C to 30°C;

[0525] 2.169 Any of methods 2.141-2.168, as appropriate, wherein the desired product compound 5-H undergoes spontaneous condensation partially or completely to form the intermediate imine 5-H′, and the mixture of 5-H and 5-H′ is subjected to the next step, or the isolated product is 5-H′ used in the next step;

[0526] 2.170 Method 2 or any of Methods 2.1-2.169, wherein the method comprises the step of treating the aniline / acetal compound 5-H (and / or 5-H′) with a reducing agent in a suitable solvent and for a time and under conditions effective to produce the secondary amine compound 5-I, wherein R 6 As defined in Method 2.10 or 2.11, and wherein R z As defined in any of Methods 2.129 to 2.131;

[0527] 2.171 Method 2.170, where R 6 It is chlorine;

[0528] 2.172 Method 2.170 or 2.171, where R z is unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl);

[0529] 2.173 Any of methods 2.170-2.172, wherein the reducing agent is selected from the group consisting of a hydride reducing agent, a silane reducing agent, and a zinc acid solution (e.g., a zinc acetic acid solution);

[0530] 2.174 Method 2.173, wherein the reducing agent is a hydride reducing agent;

[0531] 2.175 Method 2.174, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride;

[0532] 2.176 Method 2.175, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[0533] 2.177 Any of methods 2.174-2.176, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride);

[0534] 2.178 Method 2.173, wherein the silane reducing agent is triethylsilane;

[0535] 2.179 Any of methods 2.173 to 2.178 wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid);

[0536] 2.180 Any of methods 2.170-2.179, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0537] 2.181 Method 2.180, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0538] 2.182 Method 2.180, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide;

[0539] 2.183 Method 2.180, wherein the suitable solvent is dichloromethane or dichloroethane;

[0540] 2.184 Any of methods 2.170-2.183, wherein the reaction temperature is -30°C to 80°C, e.g., 0°C to 50°C, or 20°C to 30°C or about 20°C;

[0541] 2.185 Method 2 or any of Methods 2.1-2.184, wherein the method produces a compound according to any one or more of Compounds 4-B, 4-C, 4-D, and 4-E;

[0542] 2.186 Method 2.185 wherein in any one or more of said compounds, R 6 is a halogen (e.g., chlorine);

[0543] 2.187 Method 2 or any of Methods 2.1-2.186, wherein the method produces a compound according to any one or more of Compounds 5-A, 5-B, 5-C, 5-D, 5-E, 5-E′, 5-F, 5-G, 5-G′, 5-H, and 5-I;

[0544] 2.188 Method 2.187 wherein in one or more of said compounds, R m It is C 1-3 Alkyl (e.g., methyl), two R n is methyl or ethyl, or two R nThe moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-, R z It is C 1-3 Alkyl (eg, methyl), and / or R 6 is a halogen (e.g., chlorine);

[0545] 2.189 Method 2 or any of Methods 2.1-2.188, wherein the method produces a compound according to any one or more of Compounds 1-J or 1-K;

[0546] 2.190 Method 2.189 wherein in one or more of said compounds, R x It is H, R z Is H or C 1-3 Alkyl (e.g., methyl), R 5 It is C 1-3 Alkyl (eg, methyl), and / or R 6 is a halogen (e.g., chlorine);

[0547] 2.191 Method 2 or any of Methods 2.1-2.190, wherein the method produces a compound according to any one or more of Compounds 9-A, 9-B, 9-C, 9-D, or 9-E;

[0548] 2.192 Method 2.191, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D, or 9-E are prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0549] 2.193 Method 2.191 or 2.192 wherein in one or more of the compounds, R x It is H, R y It is H, R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6alkoxy (e.g., (S)-1-phenylethoxy) or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0550] 2.194 Method 2.193 wherein in one or more of said compounds, R x It's H, R y It's H, R 2 and R 3 are independently H or methyl, R 4 It's H, R 5 is a methyl group, and R 6 It is chlorine;

[0551] 2.195 Method 2.194 wherein in one or more of said compounds, R 2 and R 3 It's H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is a methyl group;

[0552] 2.196 Method 2.195 wherein in one or more of said compounds, R 2 is H and R 3 It is a methyl group;

[0553] 2.197 Any of Methods 2.191-2.196 wherein in Compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0554] 2.198 Method 2.197, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[0555] 2.199 Method 2.198, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0556] 2.200 Method 2.198, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0557] 2.201 Method 2 or any of Methods 2.1-2.200, wherein the method produces a compound according to Compound 1;

[0558] 2.202 Method 2.201, wherein Compound 1 is Compound 1(a);

[0559] 2.203 Method 2.201 or 2.202, wherein compound I or I(a) is prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0560] 2.204 Any of Methods 2.201-2.203 wherein in Compound I or I(a), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0561] 2.205 Method 2.204 wherein in compound I or I(a), R 2 and R 3 are independently H or methyl, R 4 It's H, R 5 is a methyl group, and R 6 It is chlorine;

[0562] 2.206 Method 2.205 wherein in compound I or I(a), R 2 and R3 It's H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is a methyl group;

[0563] 2.207 Method 2.206 wherein in compound I or I(a), R 2 is H and R 3 It is a methyl group;

[0564] 2.208 Any of methods 2.204-2.207 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[0565] 2.209 Method 2.208 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0566] 2.210 Method 2.209 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0567] 2.211 Any of Methods 2.191-2.210, wherein in one or more of Compound 9-E, Compound 1, or Compound 1(a), It is a double bond;

[0568] 2.212 Method 2 or any of Methods 2.1-2.211, wherein the method produces Compound 1;

[0569] 2.213 Method 2 or any of Methods 2.1-2.212, wherein the method further comprises any of the steps described in any of Methods 1 et seq., Method 3 et seq., Method 4 et seq., and Method 5 et seq.

[0570] In a fourth aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A, 8-B, 9-A, 9-B, 9-C, 9-D, 9-E, and compounds I or I(a) (Method 3), as described herein, wherein the method comprises reacting a precursor compound with one or more reagents in a suitable solvent and under conditions and for a time effective to form a product compound. Method 3 generally involves the formation of a sulfonimide moiety (SNO), including advanced intermediates 6-H, 6-L, and 8-B, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 3 may include any of the steps shown in Schemes 6, 7, and 8.

[0571]

[0572] Option 6

[0573]

[0574] Option 7

[0575]

[0576] Option 8

[0577] In a specific embodiment, the present disclosure provides the following method 3:

[0578] 3.1 Method 3, wherein the method comprises the step of reacting alcohol compound 6-A with an activating agent in a suitable solvent (with a suitable base) and under conditions and for a period of time effective to produce activated compound 6-B;

[0579] 3.2 Method 3.1, where R y Selected from H, C 1-6 alkyl (e.g., methyl) and optionally substituted aryl (e.g., phenyl);

[0580] 3.3 Method 3.2, where R y It is H;

[0581] 3.4 Any of the methods 3.1-3.3, where R 2 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 Group substitution (R 10 As defined for Compound 1);

[0582] 3.5 Method 3.4, where R 2 is hydrogen or C 1-6 alkyl (e.g., methyl);

[0583] 3.6 Any of the methods 3.1-3.5, where R 3 It is hydrogen, C 1-6 Alkyl, -OR 7 、C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -C(O)R 7 or -CN, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted by 1-5 R 10 Group substitution (R 7 and R 10 As defined for Compound 1);

[0584] 3.7 Method 3.6, where R 3 It is hydrogen, C 1-6 Alkyl (eg, methyl) or -OR 7 , where R 7 It is C 1-6 Alkyl groups (e.g., methyl);

[0585] 3.8 Method 3.7, where R 3 is hydrogen or C 1-6 alkyl (e.g., methyl);

[0586] 3.9 Any of the methods 3.1-3.9, wherein R 2 and R 3 are all hydrogen, or R 2 is hydrogen and R 3 It is C 1-6 Alkyl (eg, methyl), or wherein R 2 and R3 All C 1-6 alkyl (e.g., methyl);

[0587] 3.10 Method 3.9, where R 2 is hydrogen and R 3 It is C 1-6 alkyl (e.g., methyl);

[0588] 3.11 Any of methods 3.1-3.10, wherein the group X of compound 6-B is selected from the group consisting of halides (e.g., chloride, bromide, iodide), sulfonates (e.g., 4-toluenesulfonate, methanesulfonate, nitrobenzenesulfonate, benzenesulfonate, trifluoromethanesulfonate), and oxy groups. (e.g., oxytriphenyl ), optionally wherein the group X is 4-toluenesulfonate;

[0589] 3.12 Any of methods 3.1-3.11, wherein the activating agent is selected from p-toluenesulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonic anhydride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenyltrifluorocarboximide, triphenylphosphine dihalide, triphenylphosphine with a tetrahalomethane (e.g., tetrabromomethane), and combinations thereof with metal halide salts (e.g., sodium bromide, potassium iodide);

[0590] 3.13 Method 3.12, wherein the activating agent is p-toluenesulfonyl chloride;

[0591] 3.14 Any of methods 3.1-3.13, wherein the base is selected from tertiary amines (e.g., triethylamine, N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, picoline, indole, isoindole, quinoline, isoquinoline), and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, disodium hydrogenphosphate, or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tripotassium phosphate), potassium fluoride, lithium carbonate, cesium carbonate);

[0592] 3.15 Method 3.14, wherein the base is triethylamine;

[0593] 3.16 Any of methods 3.1-3.15, wherein the reaction further comprises a catalyst;

[0594] 3.17 Method 3.16, wherein the catalyst is selected from 4-dimethylaminopyridine, N-methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulonidine, optionally wherein the catalyst is 4-dimethylaminopyridine;

[0595] 3.18 Any of methods 3.1-3.17, wherein the activator is p-toluenesulfonyl chloride, the base is triethylamine, and the catalyst is 4-dimethylaminopyridine;

[0596] 3.19 Any of methods 3.1-3.18, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0597] 3.20 Method 3.19, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0598] 3.21 Method 3.19, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a nitrile (e.g., acetonitrile) and an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0599] 3.22 Method 3.19, wherein the nonpolar solvent is dichloromethane;

[0600] 3.23 Any of methods 3.1-3.22, wherein the reaction temperature is -20°C to 80°C, for example, -10°C to 30°C or 0°C to 20°C;

[0601] 3.24 Method 3 or any of 3.1-3.23, wherein the method comprises the step of reacting compound 6-B with a thiol in a suitable solvent (optionally with a suitable base) and under conditions and for a time effective to form thioether 6-C, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 as defined in any of Methods 3.4-3.10, and X is as defined in Method 3.11;

[0602] 3.25 Method 3.24, where R e is selected from optionally substituted 5-10 membered heteroaryl (eg, optionally substituted pyridinyl or pyrimidinyl), -C(=NH)NH(C 1-6 alkyl), -C(=NH)N(C 1-6 alkyl)2 and -C(=NH)NH2;

[0603] 3.26 Method 3.25, where R e is a 5-10 membered heteroaryl group, for example a 6 membered heteroaryl group (for example, 2-pyridyl or 2-pyrimidinyl);

[0604] 3.27 Any of methods 3.24-3.26, wherein the thiol is a thiol having the formula R e -SH compound, optionally in the form of a salt thereof (e.g., lithium, sodium or potassium) or a tautomeric equivalent thereof (e.g., thiourea or thiopyridone);

[0605] 3.28 Method 3.27, wherein the thiol is selected from 2-mercaptopyrimidine, 2-mercaptopyridine, thiourea, N-methylthiourea, N,N-dimethylthiourea, each optionally in the form of a salt (e.g., sodium or potassium salt);

[0606] 3.29 Any of methods 3.24-3.28, wherein the reaction comprises an organic hydride (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, bases such as sodium diisopropylamide, potassium diisopropylamide), tertiary amines (e.g., triethylamine, N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, N,N-diisopropylethylamine, tri-n-butylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, quinoline, isoquinoline), and inorganic bases (e.g., lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate, or trisodium phosphate), potassium bicarbonate, potassium carbonate, potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate));

[0607] 3.30 Method 3.29, wherein the base is an inorganic hydride (e.g., sodium hydride or potassium hydride) or an alkoxide base (e.g., sodium ethoxide or sodium methoxide);

[0608] 3.31 Any of methods 3.27-3.29, wherein the thiol is 2-mercaptopyrimidine and the base is sodium ethoxide;

[0609] 3.32 Any of methods 3.24-3.31, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0610] 3.33 Method 3.32, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0611] 3.34 Method 3.32, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol);

[0612] 3.35 Method 3.32, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0613] 3.36 Method 3.32, wherein the suitable solvent is methanol or ethanol, optionally wherein the suitable solvent is ethanol;

[0614] 3.37 Any of methods 3.24-3.36, wherein the reaction temperature is 0°C to 100°C, e.g., 20°C to 80°C, or 55°C to 75°C, or about 65°C;

[0615] 3.38 Method 3 or any of Methods 3.1-3.37, wherein the method comprises the step of oxidizing the sulfide compound 6-C with an oxidizing agent in a suitable solvent and under conditions and for a time effective to form the sulfone compound 6-D, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 As defined in any of Methods 3.4-3.10, and R e As defined in Method 3.25 or 3.26;

[0616] 3.39 Method 3.38, wherein the oxidizing agent is selected from peroxides (e.g., hydrogen peroxide, sodium peroxide, potassium peroxide), organic peroxides and peroxy compounds (e.g., tert-butyl hydroperoxide, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, magnesium monoperoxyphthalate), hypochlorites (e.g., sodium hypochlorite, potassium hypochlorite, calcium hypochlorite), periodates (e.g., sodium periodate, potassium periodate), perborates (e.g., sodium perborate), peroxymonosulfates (e.g., potassium peroxymonosulfate, potassium hydrogen persulfate), permanganates (e.g., potassium permanganate), tetramethyl perruthenate (TPAP), and any combination thereof;

[0617] 3.40 Method 3.39, wherein the oxidizing agent is a peroxide (e.g., hydrogen peroxide);

[0618] 3.41 Any of methods 3.38-3.40, wherein the reaction further comprises a catalyst selected from, for example, sodium tungstate, tungsten tetrachloride, tetrabutylammonium hexafluorotungstate, ammonium molybdate, vanadium acetylacetonate, manganese sulfate, phosphotungstic acid, ceric ammonium nitrate, ruthenium trichloride, methylrhenium trioxide, scandium trifluoromethanesulfonate, iron, and any combination thereof;

[0619] 3.42 Any of methods 3.38-3.41, wherein the oxidant is hydrogen peroxide and the catalyst is sodium tungstate;

[0620] 3.43 Any of methods 3.38-3.42, wherein the reaction further comprises an optional catalytic amount (e.g., 0.01 eq. to 0.1 eq.) of an acid such as phosphoric acid;

[0621] 3.44 Method 3.43, wherein the phosphoric acid is selected from phenylphosphonic acid, methylphosphonic acid, phenylphosphinic acid, methylphosphinic acid, phosphoric acid, polyphosphoric acid (PPA), phosphonic acid, phosphinic acid, and combinations thereof; 3.45 Any of Methods 3.38-3.44, wherein the reaction further comprises an optional catalytic amount (e.g., 0.01 equivalents to 0.1 equivalents) of a phase transfer reagent, such as a tetraalkylammonium salt (e.g., tetraethylammonium or tetrabutylammonium salt);

[0622] 3.46 Method 3.45, wherein the phase transfer reagent is selected from tetrabutylammonium hydrogen sulfate, tetrabutylammonium sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, and tetrabutylammonium iodide;

[0623] 3.47 Any of methods 3.42-3.46, wherein the reaction further comprises phenylphosphonic acid and tetrabutylammonium hydrogen sulfate each in an optionally catalytic amount (e.g., 0.01 eq. to 0.1 eq.);

[0624] 3.48 Any of methods 3.38-3.47, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0625] 3.49 Method 3.48, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0626] 3.50 Method 3.48, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol), water, or a combination thereof;

[0627] 3.51 Method 3.48, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0628] 3.52 Method 3.48, wherein the suitable solvent is toluene;

[0629] 3.53 Any of methods 3.38-3.52, wherein the reaction temperature is 0°C to 100°C, e.g., 0°C to 60°C or 10°C to 30°C;

[0630] 3.54 Method 3 or any of Methods 3.1-3.53, wherein the method comprises the step of reacting compound 6-D with a base in a suitable solvent and under conditions and for a time effective to form compound 6-E, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 As defined in any of Methods 3.4-3.10, and R e As defined in Method 3.25 or 3.26;

[0631] 3.55 Method 3.54, wherein M is selected from hydrogen and an alkali metal or alkaline earth metal, for example, wherein M is selected from H, Li, Na, K, Mg, and Ca;

[0632] 3.56 Method 3.54 or 3.55, wherein the base is selected from an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, ammonium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), an organic lithium base (e.g., methyllithium, ethyllithium, propyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium), and an inorganic carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate);

[0633] 3.57 Method 3.56, wherein the base is selected from the group consisting of an inorganic hydride, an alkoxide, and an inorganic hydroxide;

[0634] 3.58 Method 3.57, wherein the base is selected from sodium methoxide and potassium methoxide;

[0635] 3.59 Any of methods 3.54-3.58, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0636] 3.60 Method 3.59, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0637] 3.61 Method 3.59, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or water or a mixture of the two; optionally wherein the base is an alkoxide corresponding to the alcohol (e.g., a methoxide base and a methanol solvent), or the base is a hydroxide base and the solvent is water;

[0638] 3.62 Method 3.59, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0639] 3.63 Any of methods 3.58 to 3.61 wherein the base is sodium methoxide or potassium methoxide and the solvent is methanol;

[0640] 3.64 Any of methods 3.54-3.63, wherein the reaction temperature is 0°C to 100°C, e.g., 0°C to 60°C or 10°C to 30°C;

[0641] 3.65 Any of Methods 3.54-3.64, wherein the solvent is removed from the reaction and the crude compound 6-E is washed with water and / or an organic solvent and used in the next step without further purification;

[0642] 3.66 Method 3 or any one of 3.1-3.65, wherein the method comprises the step of oxidizing compound 6-E with a suitable oxidizing agent and a base in a suitable solvent to form a sulfonamide compound 6-F, wherein R y As defined in Method 3.2 or 3.3, and wherein R 2 and R 3 as defined in any of Methods 3.4-3.10, and M as defined in Method 3.55;

[0643] 3.67 Method 3.66, wherein the oxidizing agent is hydroxylamine-O-sulfonic acid, or the oxidizing agent is a mixture of ammonia and an oxidizing agent selected from iodine, N-chlorosuccinimide, N-bromosuccinimide, t-butyl hydroperoxide, and m-chloroperbenzoic acid;

[0644] 3.68 Method 3.67, wherein the oxidizing agent is hydroxylamine-O-sulfonic acid;

[0645] 3.69 Any of methods 3.66-3.68, wherein the base is selected from alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide), inorganic bases (e.g., lithium acetate, sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, disodium hydrogenphosphate, or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic, or tripotassium phosphate), lithium carbonate, cesium carbonate), other alkali metal carboxylates (e.g., potassium propionate), and combinations thereof;

[0646] 3.70 Method 3.69, wherein the base is sodium acetate or potassium acetate;

[0647] 3.71 Any of methods 3.66-3.70, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0648] 3.72 Method 3.71, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0649] 3.73 Method 3.71, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or water or a mixture of the two;

[0650] 3.74 Method 3.71, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0651] 3.75 Method 3.71, wherein the suitable solvent is water;

[0652] 3.76 Any of methods 3.66-3.71, wherein the reaction temperature is 0°C to 100°C, e.g., 20°C to 80°C, or 35°C to 55°C, or about 45°C;

[0653] 3.77 Method 3 or any of Methods 3.1-3.76, wherein the method comprises the step of reacting compound 6-F with a protecting agent in a suitable solvent and under conditions and for a time effective to form N-protected compound 6-G, wherein R yAs defined in Method 3.2 or 3.3, and wherein R 2 and R 3 As defined in any of Methods 3.4-3.10;

[0654] 3.78 Method 3.77, wherein the protecting group R k Selected from silyl groups, alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl (aryl), such as 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tertiary alkyl groups (e.g., tert-butyl or trityl), C 1-6 Alkoxy C 1-6 Alkyl groups (e.g., C 1-6 alkoxymethyl, such as methoxymethyl or ethoxymethyl), C 1-6 Alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., C 1-6 Alkyl (aryl) (aryl), such as diphenylmethyl), alkylsulfonyl groups (e.g., SO2C 1-6 alkyl, such as methylsulfonyl or isopropylsulfonyl) and arylsulfonyl groups (e.g., SO2-aryl, such as phenylsulfonyl, toluenesulfonyl);

[0655] 3.79 method 3.78, where R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0656] 3.80 method 3.79, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0657] 3.81 Method 3.80, where R kis tert-butyldimethylsilyl;

[0658] 3.82 Any of methods 3.77-3.81, wherein the protecting agent is selected from silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, triphenylsilyl chloride), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, dimethylphenylsilyl bromide, triphenylsilyl bromide), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride, acetyl chloride, benzoyl chloride), acid anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane), and alkoxymethyl halides (e.g., methoxymethyl chloride);

[0659] 3.83 Any of methods 3.77-3.82, wherein the reaction further comprises a base;

[0660] 3.84 Method 3.83, wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), Inorganic hydrides (e.g., sodium hydride, potassium hydride, lithium hydride), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organic lithium bases (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0661] 3.85 Method 3.84, wherein the protecting reagent is tert-butyldimethylsilyl chloride and the base is triethylamine;

[0662] 3.86 Any of methods 3.77-3.85, wherein the reaction further comprises a catalyst selected from the group consisting of 4-(dimethylamino)pyridine, 2,6-lutidine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulonidine;

[0663] 3.87 Any of methods 3.77-3.86, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0664] 3.88 Method 3.87, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0665] 3.89 Method 3.87, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0666] 3.90 Method 3.87, wherein the nonpolar solvent is an ether, optionally wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran;

[0667] 3.91 Any of methods 3.77-3.90, wherein the reaction temperature is -30°C to 100°C, e.g., -10°C to 30°C, 0°C to 25°C, 0°C to 100°C, e.g., 20°C to 80°C, or 35°C to 55°C or about 45°C;

[0668] 3.92 Method 3 or any of Methods 3.1-3.91, wherein the method comprises the steps of treating the protected sulfonamide 6-G with (1) a chlorinating agent and a base in a suitable solvent, followed by treating with (2) an ammonia source in a suitable solvent and for a period of time under conditions effective to form compound 6-H, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R k As defined in any of Methods 3.78-3.81;

[0669] 3.93 Method 3.92, wherein the chlorinating agent is selected from triphenylphosphine dichloride (Ph3PCl2) (optionally prepared in situ from triphenylphosphine and oxalyl chloride), phosphorus oxychloride (optionally prepared in situ from phosphorus pentoxide and a chloride salt such as sodium chloride, potassium chloride or tetrabutylammonium chloride), phenyldichlorophosphate, triphenyldichlorophosphorane, phenylphosphine dichloride, oxalyl chloride, thionyl chloride, sulfuryl chloride, triphenylphosphite dichloride complex ((PhO)3PCl2) (optionally prepared in situ from chlorine and triphenylphosphite), phosphorus(V)oxychloride, phosphorus trichloride, phosphorus pentachloride and hydrogen chloride;

[0670] 3.94 Method 3.93 wherein the chlorinating agent is triphenylphosphine dichloride, optionally wherein the triphenylphosphine dichloride is prepared in situ from triphenylphosphine oxide and oxalyl chloride;

[0671] 3.95 Any of methods 3.92-3.94, wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane) and aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine);

[0672] 3.96 Method 3.95 wherein the base is N,N-diisopropylethylamine;

[0673] 3.97 Any of methods 3.92-3.96, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0674] 3.98 Method 3.97, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0675] 3.99 Method 3.97, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0676] 3.100 Method 3.97, wherein the nonpolar solvent is dichloromethane;

[0677] 3.101 Any of methods 3.92-3.100, wherein the ammonia source is selected from ammonia gas, aqueous ammonia, inorganic ammonium salts (e.g., ammonium chloride, ammonium bromide, ammonium sulfate, ammonium acetate), ammonia surrogates (e.g., hexamethyldisilazane), amides (e.g., acetamide), and carbamates (e.g., t-butyl carbamate) dissolved in any of the solvents provided in methods 3.97-3.100;

[0678] 3.102 Method 3.101, wherein the ammonia source is ammonia dissolved in a solvent, optionally wherein the solvent is the same solvent as the reaction solvent from step (1) (e.g., wherein the reaction solvent is dichloromethane and the ammonia source is ammonia gas dissolved in dichloromethane);

[0679] 3.103 Any of methods 3.92-3.102, wherein the reaction temperature of step (1) and step (2) is independently selected from -40°C to 60°C, -25°C to 30°C, -20°C to 30°C, -20°C to 10°C, -10°C to 30°C, -10°C to 10°C, -20°C to 0°C, -10°C to 0°C, and 0°C to 30°C;

[0680] 3.104 Any of methods 3.92-3.103, wherein step (1) comprises mixing compound 6-G with a base and a suitable solvent at a temperature of -20°C to 0°C, then adding a chlorinating agent (or forming the chlorinating agent in situ), and stirring the reaction for a period of 0.5 hour to 10 hours (e.g., 1 to 5 hours), followed by step (2) comprising cooling the reaction to -40°C to -10°C, adding an ammonia source, and stirring the reaction at a temperature in the range of -10 to 10°C for a period of 0.1 to 5 hours (e.g., 0.1 to 2 hours);

[0681] 3.105 Method 3 or any of Methods 3.1-3.104, wherein the method comprises the step of reacting the mono-protected sulfonyl imide compound 6-H with a protecting reagent in a suitable solvent and under conditions and for a time effective to produce the di-protected sulfonyl imide compound 6-I, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R k As defined in any of Methods 3.78-3.81, provided that R p With R k different;

[0682] 3.106 Method 3.105, where R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0683] 3.107 Method 3.106, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0684] 3.108 Method 3.107, where R k is tert-butyldimethylsilyl;

[0685] 3.109 Any of methods 3.105-3.108, wherein the protecting group R p Selected from silyl groups, alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl (aryl), such as 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tertiary alkyl groups (e.g., tert-butyl or trityl), C 1-6 Alkoxy C 1-6Alkyl groups (e.g., C 1-6 alkoxymethyl, such as methoxymethyl or ethoxymethyl), C 1-6 Alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., C 1-6 Alkyl (aryl) (aryl), such as diphenylmethyl), alkylsulfonyl groups (e.g., SO2C 1-6 alkyl, such as methylsulfonyl or isopropylsulfonyl) and arylsulfonyl groups (e.g., SI2-aryl, such as phenylsulfonyl, toluenesulfonyl);

[0686] 3.110 Method 3.109, where R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[0687] 3.111 Method 3.110, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0688] 3.112 Method 3.111, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0689] 3.113 Any of methods 3.105-3.112, wherein the protecting agent is selected from silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, dimethylphenylsilyl chloride, triphenylsilyl chloride), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide) , dimethylphenylsilylbromosilane, triphenylsilylbromosilane), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride, acetyl chloride, benzoyl chloride), acid anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane), and alkoxymethyl halides (e.g., methoxymethyl chloride);

[0690] 3.114 Any of methods 3.105-3.112 wherein the protecting agent is 1H-imidazole-1-carboxylic acid C 1-6 Alkyl or C 1-6 Alkyl (aryl) esters, optionally by reacting the corresponding C 1-6 Alkyl alcohol or C 1-6 Alkyl (aryl) alcohol reacts with carbonyldiimidazole (CDI) in a suitable solvent, and then compound 6-H is added for in situ preparation;

[0691] 3.115 Method 3.113 or 3.114, wherein the protecting agent is selected from symmetrical or unsymmetrical carbonates (eg, di-tert-butyl dicarbonate or 4-nitrophenyl(1-phenylethyl) carbonate), C 1-6 Alkyl or C 1-6 Alkyl (aryl) chloroformate (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethyl chloroformate) or 1H-imidazole-1-carboxylic acid C 1-6 Alkyl or C 1-6 Alkyl (aryl) esters;

[0692] 3.116 Method 3.115, wherein the protecting reagent is selected from 1-phenylethyl-1H-imidazole-1-carboxylate (optionally prepared in situ from 1-phenylethanol and CDI), 4-nitrophenyl-(1-phenylethyl) carbonate, and 1-phenylethyl chloroformate, wherein each of said reagents is optionally in the (R) or (S) form;

[0693] 3.117 Any of methods 3.105-3.116, wherein the reaction further comprises a base;

[0694] 3.118 Method 3.117, wherein the base is selected from a tertiary amine (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), an aromatic amine (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine) , inorganic hydrides (e.g., sodium hydride, potassium hydride, lithium hydride), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organic lithium bases (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate));

[0695] 3.119 Method 3.118, wherein the base is an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), or an organic lithium base (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium);

[0696] 3.120 Method 3.119, wherein the protecting reagent is (S)-1H-imidazole-1-carboxylic acid 1-phenylethyl ester (optionally prepared in situ from (S)-1-phenylethanol and CDI), and the base is lithium hexamethyldisilazide;

[0697] 3.121 Any of methods 3.105-3.120, wherein the reaction further comprises a mixture selected from the group consisting of 4-(dimethylamino)pyridine, 2,6-lutidine, N-methylimidazole, imidazole, 4-

[0698] catalysts for pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulonidine;

[0699] 3.122 Any of methods 3.105-3.121, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0700] 3.123 Method 3.122, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0701] 3.124 Method 3.122, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0702] 3.125 Method 3.122, wherein the nonpolar solvent is an ether, optionally wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran;

[0703] 3.126 Any of methods 3.105-3.125, wherein the reaction temperature is -30°C to 100°C, e.g., -20°C to 60°C, -20°C to 10°C, 0°C to 25°C, 0°C to 100°C, e.g., 20°C to 80°C, or 35°C to 55°C;

[0704] 3.127 Method 3 or one of Methods 3.1-3.126, wherein the method comprises reacting compound 6-I with a deprotecting agent in a suitable solvent and under conditions and for a time effective to form compound 6-J, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R k As defined in any of Methods 3.78-3.81, and wherein R p As defined in any of Methods 3.109-3.112, provided that R p With R k different;

[0705] 3.128 Method 3.127, where R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0706] 3.129 Method 3.128, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0707] 3.130 Method 3.129, where R k is tert-butyldimethylsilyl;

[0708] 3.131 Any of Methods 3.127-3.130, R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[0709] 3.132 Method 3.131, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0710] 3.133 Method 3.132, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0711] 3.134 Method 3.133, where R k is tert-butyldimethylsilyl, and R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0712] 3.135 Any of methods 3.127-3.134, wherein the deprotecting agent is selected from an inorganic base (e.g., an aqueous solution thereof), an inorganic acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent;

[0713] 3.136 Method 3.135, wherein the deprotecting agent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate), potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), hydrochloric acid (e.g., aqueous HCl, HCl in diethyl ether, HCl in methanol, HCl in isopropanol), sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, hydrofluoric acid, hydrogen fluoride, pyrrolidone ... ammonia, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, a combination of hydrogen and a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complex, Rh complex, PtO2, Pt complex, Pd complex, Ir complex), and a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2);

[0714] 3.137 Any of methods 3.127-3.136, where R k is a silyl group, and the deprotecting reagent is a fluoride reagent or an inorganic base;

[0715] 3.138 Method 3.137, where R k is a trialkylsilyl group (e.g., tripropylsilyl, triisopropylsilyl, tert-butyldiethylsilyl, tert-butyldimethylsilyl), and the deprotecting agent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium bicarbonate, potassium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, lithium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine trihydrofluoride, tetrabutylammonium fluoride, tetrabutylammonium difluorotriphenylsilicate, and tetrabutylammonium difluorotriphenylsilicate;

[0716] 3.139 Method 3.138, where R k is tert-butyldimethylsilyl, and the deprotecting agent is selected from sodium carbonate, potassium carbonate and cesium carbonate;

[0717] 3.140 Any of methods 3.127-3.139, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent, or a combination thereof;

[0718] 3.141 Method 3.140, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0719] 3.142 Method 3.140, wherein the polar protic solvent is an alcohol solvent (e.g., methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol), optionally in combination with water, or wherein the polar protic solvent is water;

[0720] 3.143 Method 3.140, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile), optionally in combination with water;

[0721] 3.144 Method 3.140, wherein the suitable solvent is tetrahydrofuran or 2-methyltetrahydrofuran, optionally in combination with water;

[0722] 3.145 Any of methods 3.127-3.144, wherein the reaction temperature is -15°C to 70°C, e.g., -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C, or 20°C to 70°C, 40°C to 60°C, or about 50°C;

[0723] 3.146 Method 3 or any of Methods 3.1-3.145, wherein the method comprises the step of acylating compound 6-J with an acylating agent and a base under conditions and for a time effective to form compound 6-K, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0724] 3.147 Method 3.146, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0725] 3.148 Method 3.147, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0726] 3.149 Any of methods 3.146-3.148, wherein R″ is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl);

[0727] 3.150 Method 3.149, where R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0728] 3.151 Method 3.150, wherein R″ is methyl;

[0729] 3.152 Any of methods 3.146-3.151, wherein the acylating agent is an acyl chloride (e.g., R″—C(═O)—Cl), an anhydride (e.g., R″—C(═O)—O—(C═O)—R″), or a carboxylic acid (e.g., R″—COOH) in combination with an activating or coupling agent (e.g., oxalyl chloride, thionyl chloride, phosphorus oxychloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling agent (e.g., HATU, T3P, isobutyl chloroformate);

[0730] 3.153 Method 3.152, where R″ is C 1-6 an alkyl group (e.g., methyl), and the acylating agent is an acid chloride (e.g., R"-C(=O)-Cl) or an acid anhydride (e.g., R"-C(=O)-O-(C=O)-R");

[0731] 3.154 Any of methods 3.146-3.153 wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane) and aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine);

[0732] 3.155 Method 3.154 wherein the base is pyridine;

[0733] 3.156 Any of methods 3.146-3.155, wherein the reaction further comprises a catalyst, for example, selected from 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, and N,N-dimethylformamide;

[0734] 3.157 Any of methods 3.146-3.156, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0735] 3.158 Method 3.157, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0736] 3.159 Method 3.157, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile);

[0737] 3.160 Method 3.157, wherein the nonpolar solvent is dichloromethane;

[0738] 3.161 Any of Methods 3.146-3.160, wherein the reaction temperature is from -20°C to 60°C, e.g., from -5°C to 40°C, or from 0°C to 30°C, or from 10°C to 30°C, or about 25°C; 3.162 Method 3 or any of Methods 3.1-3.161, wherein the method comprises the step of stereoselectively (e.g., enantioselectively or diastereoselectively) hydrolyzing compound 6-K in a suitable solvent for a period of time and under conditions effective to produce a mixture of hydrolyzed stereoisomer 6-L and unreacted stereoisomer 6-L′, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0739] 3.163 Method 3.162, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0740] 3.164 Method 3.163, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0741] 3.165 Method 3.164, where R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0742] 3.166 Method 3.165, wherein R″ is methyl;

[0743] 3.167 Any of methods 3.162-3.166, wherein the reacting comprises treating compound 6-K with an enzyme such as a lipase or protease, e.g., a bacterial or fungal lipase or protease;

[0744] 3.168 Method 3.167, wherein the lipase or protease is derived from a Candida species (e.g., Candida rugosa), a Pseudomonas species (e.g., Pseudomonas stutzeri), or a Rhizomucor species (e.g., Rhizomucor miehei);

[0745] 3.169 Any of methods 3.162-3.168, wherein the reaction further comprises an aqueous buffer, such as sodium phosphate buffer or potassium phosphate buffer, optionally at a pH of 5-8 (e.g., about pH 7);

[0746] 3.170 Any of methods 3.162-3.169, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, water, or a combination thereof;

[0747] 3.171 Method 3.170, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0748] 3.172 Method 3.170, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone) and a nitrile (e.g., acetonitrile);

[0749] 3.173 Method 3.170, wherein the nonpolar solvent is methyl isobutyl ketone, in combination with aqueous sodium phosphate buffer (pH about 7);

[0750] 3.174 Any of methods 3.162-3.173, wherein the reaction temperature is 0°C to 50°C, e.g., 10°C to 40°C, or 10°C to 30°C or about 20°C;

[0751] 3.175 Any of Methods 3.162-3.174, wherein Compound 6-L and Compound 6-L' are purified and separately isolated;

[0752] 3.176 Method 3 or any of Methods 3.1-3.175, wherein the method comprises the step of converting compound 6-B to compound 6-B' by replacing group X with a different group X, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 as defined in any of Methods 3.4-3.10, wherein the group X of compound 6-B is a sulfonate (e.g., 4-toluenesulfonate, methanesulfonate, nitrobenzenesulfonate, benzenesulfonate, trifluoromethanesulfonate);

[0753] 3.177 Method 3.176 wherein the group X of compound 6-B′ is a halide (eg, chloride, bromide, or iodide);

[0754] 3.178 Method 3.177 wherein the group X of compound 6-B is 4-toluenesulfonate and the group X of compound 6-B′ is bromide;

[0755] 3.179 Method 3.176, 3.177, or 3.178, wherein the method comprises treating compound 6-B with an inorganic halide salt (e.g., a lithium, sodium, potassium, or cesium salt of chloride, bromide, or iodide) in a suitable solvent;

[0756] 3.180 Method 3.179, wherein the inorganic halide is lithium bromide;

[0757] 3.181 Any of methods 3.176-3.180, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0758] 3.182 Method 3.181, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0759] 3.183 Method 3.181, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a nitrile (e.g., acetonitrile) and an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0760] 3.184 Method 3.181, wherein the polar aprotic solvent is N-methyl-2-pyrrolidone;

[0761] 3.185 Any of methods 3.176-3.184, wherein the reaction temperature is from 20°C to

[0762] 120°C, e.g., 20°C to 100°C, or 40°C to 60°C;

[0763] 3.186 Method 3 or any of 3.1 to 3.185, wherein the method comprises the step of treating compound 6-B or 6-B' with a sulfite source for a period of time and under conditions effective to produce sulfonic acid 7-A, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any one of methods 3.4-3.10, wherein the group X of compound 6-B is selected from halide (e.g., chloride, bromide, iodide), sulfonate (e.g., 4-toluenesulfonate, methanesulfonate, nitrobenzenesulfonate, benzenesulfonate, trifluoromethanesulfonate) and oxy (e.g., oxytriphenyl ), or the group X of compound 6-B′ is a halide ion (e.g., bromide ion, chloride ion or iodide ion);

[0764] 3.187 Method 3.186, wherein the group X of compound 6-B or 6-B' is a halide ion, optionally wherein the halide ion is bromide or iodide;

[0765] 3.188 Method 3.186 or 3.187, wherein the sulfite source is an inorganic sulfite or bisulfite, such as a lithium, sodium, potassium, or cesium salt of sulfite or bisulfite;

[0766] 3.189 Method 3.188, wherein the sulfite source is sodium sulfite;

[0767] 3.190 Any of methods 3.186-3.189, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, water, or a combination thereof;

[0768] 3.191 Method 3.190, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0769] 3.192 Method 3.190, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a nitrile (e.g., acetonitrile), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate);

[0770] 3.193 Method 3.190, wherein the solvent is a mixture of acetone and water;

[0771] 3.194 Any of methods 3.186-3.193, wherein the reaction temperature is 20°C to 120°C, e.g., 40°C to 100°C or 50°C to 70°C;

[0772] 3.195 Method 3 or any of Methods 3.1-3.194, wherein the method comprises the steps of treating the sulfonic acid 7-A with (1) a chlorinating agent and optionally a catalyst in a suitable solvent, followed by treating with (2) an ammonia source in a suitable solvent and for a period of time under conditions effective to form the sulfonamide compound 6-F, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10;

[0773] 3.196 Method 3.195, wherein the chlorinating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, sulfuryl chloride, phosphorus(V) oxychloride, phosphorus trichloride, and phosphorus pentachloride;

[0774] 3.197 Method 3.196, wherein the chlorinating agent is oxalyl chloride;

[0775] 3.198 Any of methods 3.195-3.197, wherein reaction step (1) further comprises a catalyst, such as 4-dimethylaminopyridine or N,N-dimethylformamide;

[0776] 3.199 Any of methods 3.195-3.198, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, or wherein the solvent is a pure chlorinating agent (e.g., thionyl chloride);

[0777] 3.200 Method 3.199, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0778] 3.201 Method 3.199, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and a nitrile (e.g., acetonitrile);

[0779] 3.202 Method 3.199, wherein the solvent is tetrahydrofuran;

[0780] 3.203 Any of methods 3.195-3.302, wherein the ammonia source is selected from ammonia gas, gaseous ammonia, aqueous ammonia, and an ammonia substitute (e.g., hexamethyldisilazane) dissolved in any of the solvents provided in methods 3.199-3.202;

[0781] 3.204 Method 3.203, wherein the ammonia source is aqueous ammonia;

[0782] 3.205 Any of methods 3.195-3.204, wherein the reaction temperature of step (1) and step (2) is independently selected from -10°C to 100°C, 0°C to 50°C, 0°C to 30°C, and 20°C to 30°C;

[0783] 3.206 Any of methods 3.195-3.205, wherein step (1) comprises mixing compound 7-A with a catalyst and a suitable solvent at a temperature of 0°C to 30°C, followed by adding a chlorinating agent and stirring the reaction for a period of 0.1 to 2 hours (e.g., 0.5 to 1 hour), followed by step (2) comprising adding the reaction mixture from step (1) to a reactor containing an ammonia source and stirring the reaction at a temperature in the range of 10°C to 30°C for a period of 0.1 to 2 hours (e.g., 0.1 to 0.5 hours);

[0784] 3.207 Method 3 or any of Methods 3.1-3.206, wherein the method comprises the step of acylating compound 6-H with an acylating agent and a base in a suitable solvent and for a period of time under conditions effective to form diacyl compound 8-A, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R k is a silyl group;

[0785] 3.208 Method 3.207, where R k is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl);

[0786] 3.209 Method 3.208, where R k Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl;

[0787] 3.210 Method 3.209, where R k is tert-butyldimethylsilyl;

[0788] 3.211 Any of methods 3.207-3.210, wherein R″ is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl),

[0789] 3.212 Method 3.211, where R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0790] 3.213 Method 3.212, wherein R″ is methyl;

[0791] 3.214 Any of methods 3.207-3.213, wherein the acylating agent is an acyl chloride (e.g., R″—C(═O)—Cl), an anhydride (e.g., R″—C(═O)—O—(C═O)—R″), or a carboxylic acid (e.g., R″—COOH) in combination with an activating or coupling agent (e.g., oxalyl chloride, thionyl chloride, phosphorus oxychloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling agent (e.g., HATU, T3P, isobutyl chloroformate);

[0792] 3.215 Method 3.214, where R″ is C 1-6 an alkyl group (e.g., methyl), and the acylating agent is an acid chloride (e.g., R"-C(=O)-Cl), an acid anhydride (e.g., R"-C(=O)-O-(C=O)-R");

[0793] 3.216 Method 3.215 wherein R″ is methyl and the acylating agent is acetyl chloride;

[0794] 3.217 Any of methods 3.207-3.216, wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, pyrimidine, pyridazine, pyrazine, 2,6-lutidine, picoline, coltidine, imidazole), , 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), amide bases (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide) and alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide);

[0795] 3.218 Method 3.217, wherein the base is an aromatic amine selected from pyridine, pyrimidine, pyridazine, and pyrazine;

[0796] 3.219 Any of methods 3.207-3.218, wherein the reaction further comprises a catalyst, for example, selected from 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, and N,N-dimethylformamide;

[0797] 3.220 Any of methods 3.207-3.219, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0798] 3.221 Method 3.220, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0799] 3.222 Method 3.220, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile);

[0800] 3.223 Method 3.220, wherein the solvent is acetonitrile;

[0801] 3.224 Any of methods 3.207-3.223, wherein the reaction temperature is -20°C to 50°C, e.g., -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C or about 20°C; 3.225 Method 3 or any of methods 3.1-3.224, wherein the method comprises the step of stereoselectively (e.g., enantioselectively or diastereoselectively) hydrolyzing compound 8-A in a suitable solvent for a period of time and under conditions effective to produce the hydrolyzed stereoisomer 8-B, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R″ is as defined in any of Methods 3.211-3.213;

[0802] 3.226 Method 3.225, where R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0803] 3.227 Method 3.226, wherein R″ is methyl;

[0804] 3.228 Any of methods 3.225-3.227, wherein the reacting comprises treating compound 8-B with an enzyme such as a lipase or protease, eg, a bacterial or fungal lipase or protease;

[0805] 3.229 Method 3.228, wherein the lipase or protease is derived from a Carica species (e.g., Carica papaya);

[0806] 3.230 Any of methods 3.225-3.229, wherein the reaction further comprises an aqueous buffer, such as sodium phosphate buffer or potassium phosphate buffer, optionally at a pH of 5-8 (e.g., about pH 7);

[0807] 3.231 Any of methods 3.225-3.230, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, water, or a combination thereof;

[0808] 3.232 Method 3.231 wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0809] 3.233 Method 3.231, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone) and a nitrile (e.g., acetonitrile);

[0810] 3.234 Method 3.231, wherein the nonpolar solvent is methyl isobutyl ketone, in combination with an aqueous sodium phosphate buffer (pH about 7);

[0811] 3.235 Any of methods 3.225-3.234, wherein the reaction temperature is 0°C to 50°C, e.g., 10°C to 40°C, or 20°C to 40°C or about 30°C;

[0812] 3.236 Method 3 or any of Methods 3.1-3.235, wherein the method produces a compound according to any one or more of Compounds 6-B, 6-B′, 6-C, 6-D, 6-E, 6-F, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L′, 7-A, 8-A, and 8-B;

[0813] 3.237 Method 3.236 wherein in any one or more of said compounds, R y It's H, R 2 Is H or C 1-3 Alkyl (e.g., methyl), R 3 Is H or C 1-3 Alkyl (e.g., methyl), X is 4-toluenesulfonyl or bromine, R e is 2-pyrimidinyl, M is Na, R k is a trialkylsilyl group (e.g., tert-butyldimethylsilyl), R p is -C(=O)-OC 1-6 Alkyl (aryl) (e.g., 1-phenylethoxycarbonyl, optionally in the (R) or (S) form), and R" is C 1-3 alkyl (e.g., methyl);

[0814] 3.238 Method 3.237 wherein in one or more of said compounds, R 2 and R 3 It's H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is a methyl group;

[0815] 3.239 Method 3.238 wherein in one or more of said compounds, R 2 is H and R 3 It is a methyl group;

[0816] 3.240 Method 3 or any of Methods 3.1-3.239, wherein the method produces a compound according to any one or more of Compounds 9-A, 9-B, 9-C, 9-D, or 9-E;

[0817] 3.241 Method 3.240, wherein one or more of compounds 9-A, 9-B, 9-C, 9-D, or 9-E are prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0818] 3.242 Method 3.240 or 3.241 wherein in one or more of said compounds, R x It is H, R y It is H, R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6 alkoxy (e.g., (S)-1-phenylethoxy) or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0819] 3.243 Method 3.242, wherein in one or more of said compounds, R x It's H, R y It's H, R 2 and R 3 are independently H or methyl, R 4 It's H, R 5 is a methyl group, and R 6 It is chlorine;

[0820] 3.244 Method 3.243 wherein in one or more of said compounds, R 2 and R 3 It's H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is a methyl group;

[0821] 3.245 Method 3.244, wherein in one or more of said compounds, R 2is H and R 3 It is a methyl group;

[0822] 3.246 Any of methods 3.240-3.245, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0823] 3.247 Method 3.246, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[0824] 3.248 Method 3.247, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0825] 3.249 Method 3.247, wherein in compound 9-C, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0826] 3.250 Method 3 or any of Methods 3.1-3.249, wherein the method produces a compound according to Compound 1;

[0827] 3.251 Method 3.250 wherein Compound I is Compound I(a);

[0828] 3.252 Method 3.251 or 3.251, wherein compound I or I(a) is prepared according to any one or more of Method 4 or Method 4.1, etc. or Method 5 or Method 5.1, etc.;

[0829] 3.253 Any of Methods 3.250-3.252 wherein in Compound I or I(a), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and / or R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0830] 3.254 Method 3.253 wherein in compound I or I(a), R 2 and R 3 are independently H or methyl, R 4 It's H, R 5 is a methyl group, and R 6 It is chlorine;

[0831] 3.255 Method 3.254 wherein in compound I or I(a), R 2 and R 3 It's H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is a methyl group;

[0832] 3.256 Method 3.255 wherein in compound I or I(a), R 2 is H and R 3 It is a methyl group;

[0833] 3.257 Any of Methods 3.253-3.256 wherein in Compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy and halogen;

[0834] 3.258 Method 3.257 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0835] 3.259 Method 3.258 wherein in compound I or I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0836] 3.260 Any of methods 3.240-3.259, wherein in one or more of compound 9-E, compound 1, or compound 1(a), It is a double bond;

[0837] 3.261 Method 3 or any of Methods 3.1-3.260, wherein the method produces Compound 1;

[0838] 3.262 Method 3 or any of Methods 3.1-3.261, wherein the method further comprises any of the steps described in any of Method 1 et seq., Method 2 et seq., Method 4 et seq., and Method 5 et seq.

[0839] In a fifth aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 9-A, 9-B, 9-C, 9-D, 9-E and compound 1 or 1 (a) (Method 4), as described herein, wherein the method comprises reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 4 generally involves the formation of a SNO-CB-TC cyclic fragment (including a ring-closing metathesis step) and the attachment of a side chain fragment (SC), including advanced intermediates 9-B, 9-C and 9-E, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 4 may include any of the steps shown in Scheme 9.

[0840]

[0841] Option 9

[0842] In a specific embodiment, the present disclosure provides the following method 4:

[0843] 4.1 Method 4, wherein the method comprises the step of deprotecting compound 6-L′ with a deprotecting agent in a suitable solvent and under conditions effective to produce the reverse stereoisomer 8-B for a period of time, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112, and wherein R″ is as defined in any of Methods 3.211-3.213;

[0844] 4.2 Method 4.1, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0845] 4.3 Method 4.2, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0846] 4.4 Any of methods 4.1-4.3, wherein R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0847] 4.5 Method 4.4, wherein R″ is methyl;

[0848] 4.6 Any of methods 4.1-4.5, wherein the deprotecting agent is selected from an inorganic base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate), potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), optionally in the form of their aqueous solutions), an inorganic acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride , tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, optionally in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) such as Pd, Pd / C, Pt, Ru / C, Raney nickel, a Ru complex, a Rh complex, PtO2, a Pt complex, a Pd complex, an Ir complex, or a phase transfer hydrogenation system such as ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2), optionally further comprising a phase transfer agent or an enzyme;

[0849] 4.7 Method 4.6, wherein the deprotecting agent is an acid, for example selected from trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonic acid sulfuric acid, hydrochloric acid (e.g., aqueous HCl, HCl in diethyl ether, HCl in methanol, HCl in isopropanol), hydrobromic acid, acetic acid, formic acid, phosphoric acid, and oxalic acid, optionally wherein the acid is trifluoroacetic acid;

[0850] 4.8 Any of methods 4.1-4.7, wherein the suitable solvent is a non-polar solvent or a polar aprotic solvent;

[0851] 4.9 Method 4.8, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0852] 4.10 Method 4.8, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0853] 4.11 Method 4.8, wherein the solvent is dichloromethane;

[0854] 4.12 Any of methods 4.1-4.11, wherein the reaction temperature is -50°C to 50°C, e.g., 0°C to 40°C, or 10°C to 30°C or about 20°C;

[0855] 4.13 Method 4 or any of 4.1-4.12, wherein the method comprises the step of condensing sulfonimide compound 8-B or sulfonimide compound 6-L with carboxylic acid 1-K using an acid activator, a base, and optionally a promoter in a suitable solvent and under conditions and for a time effective to form N-acylsulfonimide compound 9-A, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of methods 3.4-3.10, and wherein R of compound 6-L p As defined in any one of Methods 3.109-3.112, wherein R″ of Compound 8-B is as defined in any one of Methods 3.211-3.213, wherein R x As defined in Method 1.18 or 1.19, wherein R 5 As defined in any of Methods 1.75-1.78, and wherein R 6 is hydrogen or a halogen;

[0856] 4.14 Method 4.13, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0857] 4.15 Method 4.14, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0858] 4.16 Any of methods 4.13-4.15, wherein R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0859] 4.17 Method 4.16, wherein R″ is methyl;

[0860] 4.18 Any of methods 4.13-4.17, wherein the acid activator is selected from N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC-HCl), carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholine chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N′N′-tetramethylchloroformamidine hexafluorophosphate (TCFH), N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), (PhO)2POCl, oxalyl chloride ((COCl)2) and thionyl chloride (SOCl2);

[0861] 4.19 Method 4.18, wherein the acid activator is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC HCl);

[0862] 4.20 Any of methods 4.13-4.19, wherein the base is selected from tertiary amines (e.g., N-methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, imidazole, 1-methylimidazole), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and bicarbonate derivatives, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and tripotassium phosphate, and sodium dihydrogen phosphate, disodium hydrogen phosphate, and trisodium phosphate);

[0863] 4.21 Method 4.20, wherein the base is imidazole; or in one embodiment, the base is 1-methylimidazole;

[0864] 4.22 Any of methods 4.13-4.21, wherein the reaction comprises a promoter selected from 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), and 1-hydroxybenzotriazole (HOBt);

[0865] 4.23 Any of methods 4.13-4.22, wherein the acid activator is EDC-HCl, the base is 1-methylimidazole, and the accelerator is DMAP;

[0866] 4.24 Any of methods 4.13-4.23, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, or a combination thereof with water;

[0867] 4.25 Method 4.24, wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0868] 4.26 Method 4.24, wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP)), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), ketones (acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (2-propanol); halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[0869] 4.27 Method 4.24, wherein the solvent is N,N-dimethylformamide. In one embodiment, the solvent is acetonitrile;

[0870] 4.28 Any of methods 4.13-4.27, wherein the reaction temperature is -50°C to 50°C, e.g., 0°C to 40°C, or 10°C to 30°C, or 0°C to 80°C, or about 20°C;

[0871] 4.29 Method 4 or any of Methods 4.1-4.28, wherein the method comprises the step of deprotecting Compound 9-A using a deprotecting reagent in a suitable solvent under conditions effective to form Compound 9-B for a period of time or deprotecting Compound 9-D under conditions effective to form Compound 9-E for a period of time, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112 or as -C(=O)-R", wherein R" is as defined in any of Methods 3.211-3.213, wherein R x As defined in Method 1.18 or 1.19, wherein R 5 As defined in any of Methods 1.75-1.78, and wherein R 6 is hydrogen or a halogen;

[0872] 4.30 Method 4.29, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0873] 4.31 Method 4.30, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0874] 4.32 Any of the methods in 4.31, where R p is -C(=O)-R", and R" is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[0875] 4.33 Method 4.32, wherein R″ is methyl;

[0876] 4.34 Any of methods 4.29-4.33, wherein the deprotecting agent is selected from an inorganic base (e.g., an aqueous solution thereof), an inorganic acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent or an enzyme;

[0877] 4.35 Method 4.34, wherein the deprotecting agent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (sodium dihydrogen phosphate, disodium hydrogen phosphate or trisodium phosphate), potassium phosphate (potassium dihydrogen phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, pyridine p-toluenesulfonic acid sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, formic acid, phosphoric acid, oxalic acid, citric acid, hydrochloric acid (e.g., aqueous HCl, HCl in diethyl ether, HCl in methanol, HCl in isopropanol), methanesulfonic acid, hydrofluoric acid, pyridine hydrogen fluoride, triethylammonium hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, hydrogen in combination with a catalyst (e.g., Pd, Pd / C, Pt, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO2, Pt complexes, Pd complexes, Ir complexes), and ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt, PtO2); in one embodiment, the deprotecting agent is sodium isopropoxide; in one embodiment, the deprotecting agent is trifluoroacetic acid;

[0878] 4.36 Method 4.34, wherein the deprotecting agent is an enzyme, such as a lipase or protease, for example a bacterial or fungal lipase or protease;

[0879] 4.37 Method 4.36, wherein the lipase or protease is derived from a Candida species (e.g., Candida rugosa), a Pseudomonas species (e.g., Pseudomonas stutzeri), or a Rhizomucor species (e.g., Rhizomucor miehei);

[0880] 4.38 Method 4.37, wherein the enzyme is a lipase from Pseudomonas stutzeri;

[0881] 4.39 Methods 4.36-4.38, wherein the reaction further comprises an aqueous buffer, such as sodium phosphate buffer or potassium phosphate buffer, optionally at a pH of 5-8 (e.g., about pH 7);

[0882] 4.40 Any of methods 4.29-4.39, wherein the suitable solvent is a nonpolar solvent, a polar aprotic solvent, a polar protic solvent, water, or a combination thereof;

[0883] 4.41 Method 4.40, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); in one embodiment, the non-polar solvent is toluene;

[0884] 4.42 Method 4.40, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone) and a nitrile (e.g., acetonitrile);

[0885] 4.43 Method 4.40, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol) and water, or a combination thereof;

[0886] 4.44 Method 4.40, wherein the nonpolar solvent is methyl tert-butyl ether, in combination with an aqueous sodium phosphate buffer (pH about 7). In one embodiment, the solvent is a combination of tetrahydrofuran (THF) and 2-propanol (IPA);

[0887] 4.45 Any of methods 4.29-4.44, wherein the reaction temperature is 0°C to 100°C, e.g., 10°C to 80°C, or 20°C to 60°C, or 20°C to 40°C, or 40°C to 80°C, or 60°C to 80°C, or about 30°C; in one embodiment, the reaction temperature is 10°C to 30°C. In one embodiment, the reaction temperature is 60°C to 80°C;

[0888] 4.46 Method 4 or any of 4.1-4.45, wherein the method includes the step of acylating compound 9-B under conditions and for a time effective to form compound 9-C or acylating compound 9-E under conditions and for a time effective to form compound I, the step comprising treating the starting material compound with a suitable acylating agent and a base in a suitable solvent, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R x As defined in Method 1.18 or 1.19, wherein R 5 As defined in any of Methods 1.75-1.78, and wherein R 6 is hydrogen or a halogen;

[0889] 4.47 Method 4.46, where R 12 As defined in compound I or I(a);

[0890] 4.48 Method 4.46, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0891] 4.49 Method 4.48, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[0892] 4.50 method 4.49, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0893] 4.51 Method 4.50, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 pyrazolyl substituted with an alkoxy group (e.g., methoxy);

[0894] 4.52 Method 4.51, where R 12 Yes-C(O)-R 1 , and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0895] 4.53 Any of methods 4.46-4.52, where R 12 Yes-C(O)-R 1 , and R 1 is any optionally substituted C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl, and the acylating agent is an acyl chloride (e.g., R 1 -C(=O)-Cl), anhydrides (e.g., R 1 -C(=O)-O-(C=O)-R 1 ) or carboxylic acid (e.g., R 1 -COOH) in combination with an activating or coupling agent (e.g., oxalyl chloride, thionyl chloride, phosphorus oxychloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling agent (e.g., HATU, T3P, isobutyl chloroformate);

[0896] 4.54 Method 4.53, wherein the activating agent is selected from N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC-HCl), carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholine chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethylimine chloride, isobutyl chloroformate, N,N,N,N′N′-tetramethylchloroformamidine hexafluorophosphate (TCFH), N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT);

[0897] 4.55 Method 4.54 wherein the activating agent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC HCl);

[0898] 4.56 Any of methods 4.46-4.52, where R 12 Yes-C(O)-R 1 , and R 1 is any optionally substituted -OR 7 , and the acylating agent is a chloroformate (e.g., R 7 -OC(=O)-Cl) or carbonate (e.g., R 7 -OC(=O)-OR 7 ).

[0899] 4.57 Any of methods 4.46-4.52, where R 12 Yes-C(O)-R 1 , and R 1 is any optionally substituted -NR 8 R 9 , and the acylating agent is an isocyanate (e.g., R 8 R 9 -NC(=O));

[0900] 4.58 Any of methods 4.46-4.57, wherein the base is selected from a tertiary amine (e.g., N-methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), an aromatic amine (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), an inorganic base (lithium carbonate, Sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate or tripotassium phosphate), sodium phosphate (monopotassium phosphate, disodium hydrogen phosphate or trisodium phosphate)), amide bases (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide) and alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, sodium isopropoxide, potassium isopropoxide and lithium isopropoxide). In one embodiment, the base is 1-methylimidazole;

[0901] 4.59 Any of methods 4.46-4.58, wherein the reaction further comprises a catalyst / promoter selected from, for example, 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, N,N-dimethylformamide, N,N-dimethylacetamide, and dichloromethylene-dimethyliminium chloride; in one embodiment, the catalyst / promoter is 4-dimethylaminopyridine;

[0902] 4.60 Any of methods 4.46-4.59, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent, optionally further comprising water;

[0903] 4.61 Method 4.60, wherein the nonpolar solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform and chlorobenzene);

[0904] 4.62 Method 4.60, wherein the solvent is selected from esters (e.g., ethyl acetate, isopropyl acetate), carbonates (e.g., dimethyl carbonate), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), chlorinated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform), hydrocarbon solvents (e.g., toluene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone), and nitriles (e.g., propionitrile);

[0905] 4.63 Method 4.60, wherein the solvent is acetonitrile;

[0906] 4.64 Any of methods 4.46-4.63, wherein the reaction temperature is -20°C to 60°C, e.g., -5°C to 40°C, or 0°C to 30°C, or 10°C to 30°C, or about 20°C;

[0907] 4.65 Method 4 or any of Methods 4.1-4.64, wherein the reaction comprises the step of subjecting Compound 9-A to ring-closing metathesis using a suitable catalyst in a suitable solvent under conditions and for a period of time effective to form Compound 9-D, or subjecting Compound 9-B to ring-closing metathesis under conditions and for a period of time effective to form Compound 9-E, or subjecting Compound 9-C to ring-closing metathesis under conditions and for a period of time effective to form Compound I, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R x As defined in Method 1.18 or 1.19, wherein R 5 As defined in any of Methods 1.75-1.78, wherein R 6 is hydrogen or a halogen, and wherein It is a double bond;

[0908] 4.66 Method 4.65, where R x and R y It's all hydrogen;

[0909] 4.67 Method 4.65 or 4.66, where R 12 As defined in compound I or I(a);

[0910] 4.68 Method 4.67, R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[0911] 4.69 method 4.68, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy and halogen;

[0912] 4.70 method 4.69, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0913] 4.71 Method 4.70, R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 pyrazolyl substituted with an alkoxy group (e.g., methoxy);

[0914] 4.72 Method 4.71, where R 12 Yes-C(O)-R 1 , and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0915] 4.73 Any of methods 4.65-4.72, wherein the catalyst is a ruthenium catalyst or a platinum catalyst;

[0916] 4.74 Method 4.73, wherein the catalyst is selected from dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) , dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl][3-(2-pyridyl)propylene]ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro(phenylmethylene)bis(3-bromopyridine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl] imidazolidinyl](2-isopropoxyphenylmethylene)ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro[3-(2-pyridyl)propylene]-ruthenium(II), (1,3-dimesityl-2-imidazolidinyl)dichloro(2-isopropoxy-5-nitrobenzylidene)ruthenium(II), tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazolidinyl][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazolidinyl][2-thienylmethylene]ruthenium(II) dichloride 1H-inden-1-yl]ruthenium(II) dichloride, tricyclohexylphosphino[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphino[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-yl]ruthenium(II) dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) and bis(tricyclohexylphosphino)-3-phenyl-1H-inden-1-ylruthenium(II) dichloride;

[0917] 4.75 Method 4.73, wherein the catalyst is selected from 2,6-diisopropyl-phenylimino-neophenylene [(S)-(-)-BIPHEN] platinum (VI), dichlorobis[(2,6-diisopropylphenyl)imino](1,2-dimethoxyethane) platinum (VI), and (T-4)-chloro(2,2-dimethylpropylene)[2,2″,4,4′,6,6′-hexa(1-methylethyl)[1,1′:3′,1-terphenyl]-2′olato][2-methyl-2-propylaminoester(2-)] platinum (VI);

[0918] 4.76 Method 4.73, wherein the suitable catalyst is Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II));

[0919] 4.77 Any of methods 4.65-4.76, wherein the solvent is a nonpolar solvent or a polar aprotic solvent;

[0920] 4.78 Method 4.77, wherein the solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); in one embodiment, the solvent is toluene;

[0921] 4.79 Method 4.77, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone) and carbonates (e.g., dimethyl carbonate, diethyl carbonate, diisopropyl carbonate);

[0922] 4.80 Any of methods 4.65-4.79, wherein the reaction temperature is 0°C to 150°C, e.g., 20°C to 90°C, or 40°C to 90°C, or 20°C to 60°C, or 40°C to 80°C, or about 80°C; in one embodiment, the reaction temperature is 70°C to 90°C;

[0923] 4.81 Method 4 or any of Methods 4.1-4.80, wherein the method further comprises forming a compound 9-D, 9-E, I or I(a) (wherein is a double bond) for a period of time, wherein is a double bond, the step comprising treating the compound with hydrogen gas in a suitable solvent (e.g., acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene) over a suitable catalyst (e.g., Pd / C, Pt, PtO2, Raney nickel, nickel boride, RhCl(Ph3P)3);

[0924] 4.82 Method 4 or any of Methods 4.1-4.81, wherein the method produces a compound according to one or more of Compound 8-B, 9-A, 9-B, 9-C, 9-D, 9-E, or Compound I or I(a);

[0925] 4.83 Method 4.82, wherein in any one or more of said compounds, R x It's H, R y It's H, R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-3 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), R p is -C(=O)-OC 1-6 Alkyl (aryl) (e.g., 1-phenylethoxycarbonyl, optionally in the (R) or (S) form), R' is C 1-3 Alkyl (eg, methyl), and / or R 12 is H or -C(O)-R 1 , where R 1 Selected from optionally substituted C 1-6 Alkyl (eg, methyl), optionally substituted C 1-6 alkoxy (e.g., (S)-1-phenethoxy) or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4-yl);

[0926] 4.84 Method 4.83, wherein in one or more of said compounds, R 2 and R 3 It's H or R 2 and R 3 is methyl, or R 2 is H and R 3 It is a methyl group;

[0927] 4.85 Method 4.84, wherein in one or more of said compounds, R 2 is H and R 3 It is a methyl group;

[0928] 4.86 Any of Methods 4.82-4.85, wherein in one or more of Compound 9-C, Compound I, and Compound I(a), R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[0929] 4.87 method 4.86, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[0930] 4.88 method 4.87, where R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 Alkoxy (eg, methoxy) substituted pyrazolyl, such as R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[0931] 4.89 Any of Methods 4.82-4.88, wherein in one or more of Compound 9-D, 9-E, Compound I, or Compound I(a), It is a double bond;

[0932] 4.90 Method 4 or any of Methods 4.1-4.89, wherein the product of the method is Compound 1;

[0933] 4.91 Method 4 or any of Methods 4.1-4.90, wherein the method further comprises any of the steps described in any of Methods 1 et seq., Method 2 et seq., Method 3 et seq., and Method 5 et seq.

[0934] In a sixth aspect, the present disclosure provides a method for preparing a compound selected from one or more of compounds 5-F, 5-F', 10-A, 10-B, 10-C, 10-C', 10-D, 10-E, 9-A, and 9-D (Method 5), as described herein, wherein the method comprises reacting a precursor compound with one or more reagents in a suitable solvent and under conditions effective to form a product compound for a period of time. Method 5 generally involves an alternative route for forming a SNO-CB-TC cyclic fragment (including a ring-closing metathesis step) and attaching side chain fragments, including advanced intermediates 10-C, 10-C', and 10-E, and the evolution of these intermediates to compound 1. Without being limited by the order or combination of steps employed, potential embodiments of Method 5 may include any of the steps shown in Scheme 10.

[0935]

[0936] Plan 10

[0937] In a specific embodiment, the present disclosure provides the following method 5:

[0938] 5.1 Method 5, wherein the method includes any steps described in any one of Method 1 etc., Method 2 etc., Method 3 etc. and Method 4 etc.;

[0939] 5.2 Method 5 or 5.1, wherein the method comprises the steps of: (1) reacting compound 5-E or 5-E′ with 4-fluoro-3-nitrobenzoic acid or ester under conditions and for a time effective to form compound 5-F, as defined in any of Methods 2.126-2.2.140, wherein R 6 、R n and R z As defined in any of Methods 2.126-2.131, and optionally (2) in an amount effective to form compound 5-F' (wherein R z Compound 5-F (wherein R is H) is treated with a compound 5-F as provided in any one of Methods 1.134-1.138 for a period of time under conditions of z Not H) hydrolyzed to the corresponding compound 5-F'; in one embodiment, R n Each independently is CH3, or two of R nThe moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-;

[0940] 5.3 Method 5.2, wherein R of compound 5-F z is unsubstituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl);

[0941] 5.4 Method 5.3, wherein R of compound 5-F or 5-F′ z It is H;

[0942] 5.5 Method 5 or any of Methods 5.1 or 5.2, wherein the method comprises the step of acylating Compound 6-L with 4-fluoro-3-nitrobenzoic acid for a period of time and under conditions effective to form Compound 10-A or acylating Compound 6-L with benzoic acid compound 5-F / 5-F′ for a period of time and under conditions effective to form Compound 10-B using an acid activator and a base in a suitable solvent, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, wherein R of compound 5-F or 5-F' is z is H, where R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0943] 5.6 Method 5.5, where R 6 It is chlorine;

[0944] 5.7 Method 5.5 or 5.6, where two R n is methyl or ethyl, or two Rn The moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH2CH3)2CH2-, -CH(C6H5)CH(C6H5) and -CH2CH(C6H5)CH2-;

[0945] 5.8 Any of the methods 5.5-5.7, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0946] 5.9 Method 5.8, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0947] 5.10 Any of methods 5.5-5.9, wherein the acid activator is selected from N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC HCl), (PhO)2POCl, carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholine chloride (DMTMM), thionyl chloride, oxalyl chloride, and sulfuryl chloride;

[0948] 5.11 Method 5.10, wherein the acid activator is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC HCl);

[0949] 5.12 Any of methods 5.5-5.11, wherein the base is selected from tertiary amines (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate, or trisodium phosphate));

[0950] 5.13 Method 5.12, wherein the base is imidazole or 1-methylimidazole;

[0951] 5.14 Any of methods 5.5-5.13, wherein the reaction further comprises a promoter selected from 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), and 1-hydroxybenzotriazole (HOBt);

[0952] 5.15 Any of methods 5.5-5.14, wherein the acid activator is EDC-HCl, the base is 1-methylimidazole, and the accelerator is DMAP;

[0953] 5.16 Any of methods 5.5-5.15, wherein the suitable solvent is a nonpolar solvent or a polar aprotic solvent;

[0954] 5.17 Method 5.16, wherein the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0955] 5.18 Method 5.16, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[0956] 5.19 Method 5.16, wherein the solvent is acetonitrile;

[0957] 5.20 Any of methods 5.5-5.19, wherein the reaction temperature is -50°C to 50°C, e.g., 0°C to 40°C, or 10°C to 30°C or about 20°C;

[0958] 5.21 Method 5 or any of Methods 5.1-5.20, wherein the method comprises the step of treating a fluorophenyl compound 10-A with an alcohol compound 5-E or 5-E' in a suitable solvent and for a time and under conditions effective to form an ether adduct compound 10-B, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0959] 5.22 Method 5.21, where R 6 It is chlorine;

[0960] 5.23 Method 5.21 or 5.22, wherein both R n is methyl or ethyl, or both R n The moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[0961] 5.24 Any of methods 5.21-5.23, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0962] 5.25 Method 5.24, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0963] 5.26 Any of methods 5.21-5.25, wherein compound 5-E or 5-E' is dissolved or suspended in a suitable solvent and treated with a strong base, and optionally with a promoter (e.g., sodium iodide, tetrabutylammonium iodide);

[0964] 5.27 Method 5.26, wherein the base is selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, ammonium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monopotassium phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate), sodium phosphate (monosodium phosphate, disodium hydrogen phosphate, or trisodium phosphate));

[0965] 5.28 Method 5.27, wherein the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, and potassium diisopropylamide; optionally wherein the base is potassium tert-butoxide;

[0966] 5.29 Any of methods 5.21-5.28, wherein compound 10-A is added to the reaction about 1 to 60 minutes, e.g., about 1 to 30 minutes, or 1 to 20 minutes, or 1 to 15 minutes, or 1 to 10 minutes, or 1 to 5 minutes after the addition of the base;

[0967] 5.30 Any of methods 5.21-5.29, wherein the suitable solvent is a non-polar solvent;

[0968] 5.31 Method 5.30, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0969] 5.32 Method 5.30, wherein the nonpolar solvent is tetrahydrofuran;

[0970] 5.33 Any of methods 5.21-5.32, wherein the reaction temperature is -80°C to 100°C, e.g., -45°C to 10°C, or -30°C to 10°C, or -10°C to 5°C, or about 0°C, or -10°C to 50°C, or -10°C to 30°C, or 10°C to 30°C, or 30°C to 80°C;

[0971] 5.34 Method 5 or any of 5.1-5.33, wherein the method comprises treating the acetal compound 10-B or 10-C′ with a deprotecting agent in a suitable solvent and for a period of time under conditions effective to form the aldehyde compound 10-C or 10-D, respectively, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112;

[0972] 5.35 Method 5.34, where R6 It is chlorine;

[0973] 5.36 Method 5.34 or 5.35, wherein both R n is methyl or ethyl, or both R n The moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[0974] 5.37 Any of methods 5.34-5.36, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0975] 5.38 Method 5.37, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0976] 5.39 Any of methods 5.34-5.38, wherein the acid is selected from HCl (e.g., aqueous HCl or HCl / methanol, HCl / isopropanol or HCl / diethanol). alkane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium toluenesulfonate trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium trifluoromethanesulfonate), and acidic resins (e.g., Amberlyst);

[0977] 5.40 Method 5.39, wherein the acid is methanesulfonic acid;

[0978] 5.41 Any of methods 5.34-5.40, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, a polar aprotic solvent, or a combination thereof;

[0979] 5.42 Method 5.41, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0980] 5.43 Method 5.41, wherein the polar protic solvent is water and / or an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid);

[0981] 5.44 Method 5.41, wherein the polar aprotic solvent is selected from ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile);

[0982] 5.45 Method 5.41, wherein the suitable solvent is tetrahydrofuran and water;

[0983] 5.46 Any of methods 5.34-5.45, wherein the reaction temperature is 0°C to 100°C, e.g., 20°C to 50°C, or 20°C to 30°C, or 60°C to 70°C;

[0984] 5.47 Any of methods 5.34-5.46, wherein the method results in R p The cleavage of the protecting group makes the reaction R p The product compound 10-C or 10-D is hydrogen;

[0985] 5.48 Method 5 or any of 5.1-5.47, wherein the method includes the step of reducing the nitro / aldehyde compound 10-C to the aniline / aldehyde compound 10-D or reducing the nitro / acetal 10-B to the aniline / acetal 10-C′, wherein R 6 As defined in Method 2.10 or 2.11, where each R n As defined in any of Methods 2.76-2.79 or 2.108-2.111, wherein R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112, or R p is hydrogen; and wherein each R n as defined in any of Methods 2.76-2.79 or 2.108-2.111;

[0986] 5.49 Method 5.48, where R 6 It is chlorine;

[0987] 5.50 Method 5.48 or 5.49, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[0988] 5.51 Method 5.50, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[0989] 5.52 Method 5.48 or 5.49, where R p It is hydrogen;

[0990] 5.53 Any of methods 5.48-5.52, wherein the reducing agent is selected from a solution of a zinc, tin, or iron acid (e.g., formic acid or acetic acid or HCl in a suitable solvent, or ammonium chloride);

[0991] 5.54 Method 5.53, wherein the reducing agent is a solution of iron (e.g., powder) in acetic acid;

[0992] 5.55 Any of methods 5.48-5.52, wherein the reducing agent is a hydrogenating agent (e.g., hydrogen gas in combination with a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer

[0993] hydrogenation system);

[0994] 5.56 Method 5.55, wherein the hydrogenating agent is a combination of hydrogen gas and a palladium, platinum, rhodium, iridium, ruthenium, or nickel catalyst (e.g., Pd, Pd / C, Pd(OAc)2, Pt / C, PtO2, Ru / C, Raney nickel, Ru complexes, Rh complexes, PtO2, Pt complexes, Pd complexes, Ir complexes) or a combination of ammonium formate and a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt / C, PtO2);

[0995] 5.57 Method 5.56, wherein the hydrogenating agent is a combination of hydrogen and a Pd, Pd / C, Pd(OAc)2, Pt / C, or PtO2 catalyst, optionally at a pressure of 1-5 bar (e.g., 1-2 bar);

[0996] 5.58 Any of methods 5.48-5.57, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[0997] 5.59 Method 5.58, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[0998] 5.60 Method 5.58, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or an acid (e.g., formic acid, acetic acid) or an aqueous acid solution (e.g., aqueous HCl);

[0999] 5.61 Method 5.58, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate) and nitriles (e.g., acetonitrile);

[1000] 5.62 Method 5.58, wherein the suitable solvent is acetic acid;

[1001] 5.63 Any of methods 5.48-5.62, wherein the reaction temperature is 0°C to 100°C,

[1002] For example, 20°C to 50°C, or 20°C to 30°C, or 50°C to 90°C, or 65°C to 85°C;

[1003] 5.64 Any of methods 5.34-5.63, wherein the desired product compound 10-D of this step undergoes spontaneous condensation to partially or completely form the intermediate imine 10-D′, and the mixture of 10-D and 10-D′ is subjected to the next step, or the isolated product is 10-D′ used in the next step;

[1004] 5.65 Method 5 or any of 5.1-5.64, wherein the method comprises the step of treating the aniline / acetal compound 10-D (and / or 10-D′) with a reducing agent in a suitable solvent and under conditions and for a time effective to produce the secondary amine compound 10-E, wherein R 6 As defined in Method 2.10 or 2.11, where R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, and wherein R p As defined in any of Methods 3.109-3.112, or R p It is hydrogen;

[1005] 5.66 Method 5.65, where R 6 It is chlorine;

[1006] 5.67 Method 5.65 or 5.66, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1007] 5.68 Method 5.67, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1008] 5.69 Method 5.65 or 5.66, where R p It is hydrogen;

[1009] 5.70 Any of methods 5.65-5.69, wherein the reducing agent is selected from the group consisting of a hydride reducing agent, a silane reducing agent, a hydrogenating agent, a combination of iron powder (Fe) and sodium triacetoxyborohydride (NaBH(OAc)3), a combination of tin or zinc and an acid (e.g., hydrochloric acid, acetic acid, ammonium chloride), a combination of a transition metal (e.g., Pd, Pt, or Rh) and H2 or a formate salt, a poisoned heterogeneous catalyst (e.g., Pt / S / C), a silane (triisopropylsilane, triphenylsilane, diethylsilane, etc.), sodium borohydride, sodium borohydride / acetic acid, sodium cyanoborohydride, titanium isopropoxide / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate, zinc borohydride / zinc chloride, tetramethylammonium triacetoxyborohydride; in one embodiment, the reducing agent is a combination of iron powder (Fe) and sodium triacetoxyborohydride (NaBH(OAc)3);

[1010] 5.71 Method 5.70, wherein the reducing agent is a hydride reducing agent;

[1011] 5.72 Method 5.71, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride;

[1012] 5.73 Method 5.72, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[1013] 5.74 Any of methods 5.71-5.73, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, titanium ethoxide, a borate, magnesium perchlorate, or zinc chloride);

[1014] 5.75 Method 5.70, wherein the silane reducing agent is triethylsilane;

[1015] 5.76 Any of methods 5.70-5.75, wherein the reaction further comprises an acid (e.g.,

[1016] from formic acid, acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid and hydrochloric acid);

[1017] 5.77 Any of methods 5.65-5.76, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[1018] 5.78 Method 5.77, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[1019] 5.79 Method 5.77, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and acids (e.g., acetic acid, formic acid, trifluoroacetic acid);

[1020] 5.80 Method 5.77, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., methyl acetate, ethyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[1021] 5.81 Method 5.77, wherein the suitable solvent is acetic acid;

[1022] 5.82 Any of methods 5.65-5.81, wherein the reaction temperature is -30°C to 100°C, e.g., 0°C to 80°C, or 20°C to 30°C, 20°C to 50°C, 50°C to 90°C, or 60°C to 80°C;

[1023] 5.83 Method 5 or any of Methods 5.1-5.82, wherein the method comprises the step of treating Compound 10-E with a reducing agent and Compound 1-I in a suitable solvent for a period of time under conditions effective to form the tertiary amine Compound 9-A, wherein R 6 As defined in Method 2.10 or 2.11, where R y As defined in Method 3.2 or 3.3, where R 2 and R 3 As defined in any of Methods 3.4-3.10, wherein R p As defined in any of Methods 3.109-3.112, or R p is hydrogen, where R x As defined in Method 1.18 or 1.19, and wherein R 5 As defined in any of Methods 1.75-1.78;

[1024] 5.84 Method 5.83, where R 6 It is chlorine;

[1025] 5.85 Method 5.83 or 5.84, where R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1026] 5.86 method 5.85, where R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1027] 5.87 Method 5.83 or 5.84, where Rp It is hydrogen;

[1028] 5.88 Any of methods 5.83-5.87, wherein the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or a hydrogenating agent;

[1029] 5.89 Method 5.88, wherein the reducing agent is a hydride reducing agent;

[1030] 5.90 Method 5.89, wherein the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride;

[1031] 5.91 Method 5.90, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride;

[1032] 5.92 Any of methods 5.89-5.91, wherein the hydride reducing agent is combined with an agent that modulates hydride reducing activity (e.g., titanium isopropoxide, titanium ethoxide, a borate, magnesium perchlorate, or zinc chloride);

[1033] 5.93 Method 5.88, wherein the silane reducing agent is triethylsilane;

[1034] 5.94 Any of methods 5.83-5.93, wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid);

[1035] 5.95 Any of methods 5.83-5.94, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent;

[1036] 5.96 Method 5.95, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dihydrogen ether, alkane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene);

[1037] 5.97 Method 5.95, wherein the polar protic solvent is selected from alcohols (e.g., methanol, ethanol, propanol, isopropanol) and acids (e.g., acetic acid, formic acid, trifluoroacetic acid);

[1038] 5.98 Method 5.95, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, an ester (e.g., methyl acetate, ethyl acetate, isopropyl acetate) and a nitrile (e.g., acetonitrile);

[1039] 5.99 Method 5.95, wherein the suitable solvent is dichloromethane;

[1040] 5.100 Any of methods 5.83-5.95, wherein the reaction temperature is from -30°C to 80°C, e.g., from 0°C to 80°C or from 10°C to 30°C;

[1041] 5.101 Method 5 or any of Methods 5.1-5.100, wherein the method produces a compound according to one or more of Compounds 10-A, 10-B, 10-C, 10-C′, 10-D, 10-E, or 9-A;

[1042] 5.102 Method 5 or any of 5.1-5.101, wherein the product, Compound 9-A, is further refined to Compound I, Compound I(a), or Compound 1, as provided by any step described in Method 4.

[1043] In another aspect, the disclosure provides compounds 1-A, 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 2-A, 2-B, 2-C, 2-D, 2-E, 3-A, 3-B, 3-C, 3-D, 4-A, 4-B, 4-C, 5-A, 5-B, 5-C, 5-D, 5-E, 5-E', 5-F, 5-G, 5-G', 5-H, 5-A, 6-B, 6-B', 6-C, 6-D, 6-E, 6-F, 6- Each of Compound 1, 6-G, 6-H, 6-I, 6-J, 6-K, 6-L, 6-L', 7-A, 8-A, 8-B, 9-A, 9-B, 9-C, 9-D, 9-E, 10-A, 10-B, 10-C, 10-C', 10-D, or 10-E, in each of their disclosed embodiments, for all purposes, as well as methods for making Compound 1, Compound 1(a), or Compound 1, and methods for making any other compound disclosed herein. In specific embodiments, the disclosure provides:

[1044] 6.1 Compound 9-A, wherein R x and R y Each independently is H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 5 It is C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R pSelected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1045] 6.2 Compound 9-A, as provided in Formula 6.1, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1046] 6.3 Compound 9-A, as provided in Formula 6.2, wherein R p is -C(=O)-OC 1-6 Alkyl (aryl);

[1047] 6.4 Compound 9-A, as provided in Formula 6.3, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1048] 6.5 Compound 9-A, as provided in Formula 6.4, wherein R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1049] 6.6 Compound 9-A, as provided in Formula 6.5, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1050] 6.7 Compound 9-A, provided by any one of Formulas 6.1-6.6, wherein R x and R y Each is H;

[1051] 6.8 Compound 9-A, provided by any one of Formulas 6.1-6.7, wherein R 2 is H and R 3 It is a methyl group;

[1052] 6.9 Compound 9-A, provided by any one of Formulas 6.1-6.8, wherein R 5 It is a methyl group;

[1053] 6.10 Compound 9-A, provided by any one of Formulas 6.1-6.9, wherein R 6 It is chlorine;

[1054] 6.11 Compound 9-B, wherein R x and R y Each independently is H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It is H, R 5 It is C 1-6 alkyl (eg, methyl), and R 6 is a halogen (e.g., chlorine);

[1055] 6.12 Compound 9-B, as provided in Formula 6.11, wherein R x and R y Each is H;

[1056] 6.13 Compound 9-B, as provided in Formula 6.11 or 6.12, wherein R 2 is H and R 3 It is a methyl group;

[1057] 6.14 Compound 9-B, provided by any one of Formulas 6.11-6.13, wherein R 5 It is a methyl group;

[1058] 6.15 Compound 9-B, provided by any one of Formulas 6.11-6.14, wherein R 6 It is chlorine;

[1059] 6.16 Compound 9-C, wherein R x and R y Each independently is H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R 2 and R3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R 12 Yes-C(O)-R 1 , and R 1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl and -NR 8 R 9 , wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein each R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, or R 8 and R 9 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic ring, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted by 1-5 R 10 Group substituted; wherein the R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C1-6 Haloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, oxo, -OR a and -NR a R b ; where R a and R b are independently hydrogen or C 1-6 alkyl;

[1060] 6.17 Compound 9-C, as provided in Formula 6.16, wherein R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 substituted 5-10 membered heteroaryl groups (e.g. Azolyl, iso oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl); wherein said R 10 Each of the groups is independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and halogen;

[1061] 6.18 Compound 9-C, as provided in Formula 6.17, wherein R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-5 R 10 a pyrazolyl or imidazolyl group substituted with a group; wherein said R 10 Each of the groups is independently C 1-6 Alkyl (eg, methyl) or C 1-6 alkoxy (e.g., methoxy);

[1062] 6.19 Compound 9-C, as provided in Formula 6.18, wherein R 12 Yes-C(O)-R 1 , and R 1 is optionally replaced by 1-3 C 1-6 Alkyl (eg, methyl) or C 1-6 pyrazolyl substituted with an alkoxy group (e.g., methoxy);

[1063] 6.20 Compound 9-C, as provided in Formula 6.19, wherein R 12 Yes-C(O)-R 1 , and R 1 is 3-methoxy-1-methyl-1H-pyrazolyl;

[1064] 6.21 Compound 9-C, provided by any one of Formulas 6.16-6.20, wherein R x and R y Each is H;

[1065] 6.22 Compound 9-C, provided by any one of Formulas 6.16-6.21, wherein R 2 is H and R 3 It is a methyl group;

[1066] 6.23 Compound 9-C, provided by any one of Formulas 6.16-6.22, wherein R 5 It is a methyl group;

[1067] 6.24 Compound 9-C, provided by any one of Formulas 6.16-6.23, wherein R 6 It is chlorine;

[1068] 6.25 Compound 9-E, wherein R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 4 It's H, R 5 It is C 1-6 alkyl (eg, methyl), and R 6 is a halogen (e.g., chlorine);

[1069] 6.26 Compound 9-E, as provided in Formula 6.25, wherein It is a double bond;

[1070] 6.27 Compound 9-E, as provided in Formula 6.25 or 6.26, wherein R 2 is H and R 3 It is a methyl group;

[1071] 6.28 Compound 9-E, provided by any one of Formulas 6.25-6.27, wherein R 5 It is a methyl group;

[1072] 6.29 Compound 9-E, provided by any one of Formulas 6.25-6.28, wherein R 6 It is chlorine;

[1073] 6.30 Compound 10-E, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R pSelected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1074] 6.31 Compound 10-E, as provided in Formula 6.30, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1075] 6.32 Compound 10-E, as provided in Formula 6.30 or 6.31, wherein R p is -C(=O)-OC 1-6 Alkyl (aryl);

[1076] 6.33 Compound 10-E, provided by any of Formulas 6.30-6.32, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1077] 6.34 Compound 10-E, as provided in Formula 6.33, wherein R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1078] 6.35 Compound 10-E, as provided in Formula 6.34, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1079] 6.36 Compound 10-E, provided by any one of Formulas 6.30-6.35, wherein R y It is H;

[1080] 6.37 Compound 10-E, provided by any one of Formulas 6.30-6.36, wherein R 2 is H and R 3 It is a methyl group;

[1081] 6.38 Compound 10-E, provided by any one of Formulas 6.30-6.37, wherein R 6 It is chlorine;

[1082] 6.39 Compound 10-B or 10-C′, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), each R n Independently C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl), or two R n Parts are linked together to form C 2-10 Alkyl or C 2-10 an alkenyl bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups, or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge), and R p Selected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1083] 6.40 Compound 10-B or 10-C', as provided in Formula 6.39, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1084] 6.41 Compound 10-B or 10-C', as provided in Formula 6.39 or 6.40, wherein R p is -C(=O)-OC 1-6 Alkyl (aryl);

[1085] 6.42 Compound 10-B or 10-C', provided by any of Formulas 6.39-6.41, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1086] 6.43 Compound 10-B or 10-C', as provided in Formula 6.42, wherein R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1087] 6.44 Compound 10-B or 10-C', as provided in Formula 6.43, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1088] 6.45 Compound 10-B or 10-C', provided by any of Formulas 6.39-6.44, wherein R y It is H;

[1089] 6.46 Compound 10-B or 10-C', provided by any one of Formulas 6.39-6.45, wherein R 2 is H and R 3 It is a methyl group;

[1090] 6.47 Compound 10-B or 10-C', provided by any one of Formulas 6.39-6.46, wherein each R n Independently C 1-6 Alkyl, optionally wherein each R n It is a methyl group;

[1091] 6.48 Compound 10-B or 10-C', as provided in Formula 6.47, wherein both R nThe moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -(o-C6H4)-;

[1092] 6.49 Compound 10-B or 10-C', as provided in Formula 6.48, wherein both R n The moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[1093] 6.50 Compound 10-B or 10-C', provided by any one of Formulas 6.39-6.49, wherein R 6 It is chlorine;

[1094] 6.51 Compound 10-C or 10-D, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 6 is a halogen (e.g., chlorine), and R p Selected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1095] 6.52 Compound 10-C or 10-D, as provided in Formula 6.51, wherein R p Selected from -C(=O)-C1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1096] 6.53 Compound 10-C or 10-D, as provided in Formula 6.51 or 6.52, wherein R p is -C(=O)-OC 1-6 Alkyl (aryl);

[1097] 6.54 Compound 10-C or 10-D, provided by any of Formulas 6.51-6.53, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1098] 6.55 Compound 10-C or 10-D, as provided in Formula 6.54, wherein R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1099] 6.56 Compound 10-C or 10-D, as provided in Formula 6.55, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1100] 6.57 Compound 10-C or 10-D, provided by any one of Formulas 6.51-6.56, wherein R y It is H;

[1101] 6.58 Compound 10-C or 10-D, provided by any of Formulas 6.51-6.57, wherein R 2 is H and R 3 It is a methyl group;

[1102] 6.59 Compound 10-C or 10-D, provided by any one of Formulas 6.51-6.58, wherein R 6 It is chlorine;

[1103] 6.60 Compound 10-A, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C1-6 alkyl (eg, methyl), and R p Selected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1104] 6.61 Compound 10-A, as provided in Formula 6.60, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1105] 6.62 Compound 10-A, as provided in Formula 6.61, wherein R p is -C(=O)-OC 1-6 Alkyl (aryl);

[1106] 6.63 Compound 10-A, as provided in Formula 6.62, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1107] 6.64 Compound 10-A, as provided in Formula 6.63, wherein R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1108] 6.65 Compound 10-A, as provided in Formula 6.64, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1109] 6.66 Compound 10-A, provided by any one of Formulas 6.60-6.65, wherein R y It is H;

[1110] 6.67 Compound 10-A, provided by any one of Formulas 6.60-6.66, wherein R 2 is H and R 3 It is a methyl group;

[1111] 6.68 Compound 5-F, wherein R 6 is a halogen (e.g., chlorine), each R n Independently C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl), or two R n Parts are linked together to form C 2-10 Alkyl or C 2-10 an alkenyl bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups, or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge), and R z selected from H and unsubstituted C 1-6 Alkyl (e.g., methyl or ethyl) and a C 1-6 Alkoxy, aryloxy, trialkylsilyl, aryl or halogenated C 1-6 Alkyl substituted C 1-6 an alkyl group (e.g., methyl or ethyl);

[1112] 6.69 Compound 5-F, as provided in Formula 6.68, wherein each R n Independently C 1-6 Alkyl, optionally wherein each R n It is a methyl group;

[1113] 6.70 Compound 5-F, as provided in Formula 6.69, wherein both R n The moieties are linked together to form a moiety selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CB r2 -, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and a bridge of -(o-C6H4)-;

[1114] 6.71 Compound 5-F, as provided in Formula 6.70, wherein both R n The moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[1115] 6.72 Compound 5-F, provided by any one of Formulas 6.68-6.71, wherein R z It is H;

[1116] 6.73 Compound 5-F, provided by any one of Formulas 6.68-6.72, wherein R z is unsubstituted C 1-6 an alkyl group (e.g., methyl or ethyl);

[1117] 6.74 Compound 5-F, provided by any one of Formulas 6.68-6.73, wherein R 6 It is chlorine;

[1118] 6.75 Compound 5-E, wherein R 6 is a halogen (e.g., chlorine), and both R n Parts are linked together to form C 2-10 Alkyl or C 2-10 an alkenyl bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted with 1-4 halogen or aryl groups, or wherein both R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge);

[1119] 6.76 Compound 5-E, as provided in Formula 6.75, wherein both R n The moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(Ph)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(Ph)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -(o-C6H4)-;

[1120] 6.77 Compound 5-E, as provided in Formula 6.76, wherein both R nThe moieties are linked together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2- and CH2C(CH3)2CH2-;

[1121] 6.78 Compound 5-E, provided by any one of Formulas 6.75-6.77, wherein R 6 It is chlorine;

[1122] 6.79 Compound 8-A or 8-B, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R 6 is halogen (e.g., chlorine), and R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[1123] 6.80 Compound 8-A or 8-B, as provided in Formula 6.79, wherein R y It is H;

[1124] 6.81 Compound 8-A or 8-B, as provided in Formula 6.79 or 6.80, wherein R 2 is H and R 3 It is a methyl group;

[1125] 6.82 Compound 8-A or 8-B, as provided by any of Formulas 6.79-6.81, wherein R″ is methyl;

[1126] 6.83 Compound 6-K, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C 1-6 Alkyl (e.g., methyl), R" is selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), halogenated C 1-6 alkyl (eg, trifluoromethyl, trichloromethyl), optionally substituted aryl (eg, phenyl, 4-bromophenyl), and optionally substituted heteroaryl (eg, 2-pyridyl), and R p Selected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1127] 6.84 Compound 6-K, as provided in Formula 6.83, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1128] 6.85 Compound 6-K, as provided in Formula 6.84, wherein R p is -C(=O)-OC 1-6 Alkyl (aryl);

[1129] 6.86 Compound 6-K, as provided in Formula 6.85, wherein R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1130] 6.87 Compound 6-K, as provided in Formula 6.86, wherein R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1131] 6.88 Compound 6-K, as provided in Formula 6.87, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1132] 6.89 Compound 6-K, provided by any one of Formulas 6.83-6.88, wherein R y It is H;

[1133] 6.90 Compound 6-K, provided by any one of Formulas 6.83-6.89, wherein R 2 is H and R 3 It is a methyl group;

[1134] 6.91 Compound 6-K, provided by any one of Formulas 6.83-6.90, wherein R″ is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl);

[1135] 6.92 Compound 6-K, provided by any one of Formulas 6.83-6.91, wherein R″ is methyl;

[1136] 6.93 Compound 6-L, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C 1-6 alkyl (eg, methyl), and R p Selected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1137] 6.94 Compound 6-L, as provided in Formula 6.93, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 Alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl);

[1138] 6.95 Compound 6-L, as provided in Formula 6.94, wherein R p is -C(=O)-OC 1-6 Alkyl (aryl);

[1139] 6.96 Compound 6-L, as provided in Formula 6.95, wherein R pis selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl;

[1140] 6.97 Compound 6-L, as provided in Formula 6.96, wherein R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form;

[1141] 6.98 Compound 6-L, as provided in Formula 6.97, wherein R p is 1-phenylethoxycarbonyl, in the (S) form;

[1142] 6.99 Compound 6-L, provided by any one of Formulas 6.93-6.98, wherein R y It is H;

[1143] 6.100 Compound 6-L, provided by any one of Formulas 6.93-6.99, wherein R 2 is H and R 3 It is a methyl group;

[1144] 6.101 Compound 6-J, wherein R y Is H or C 1-6 Alkyl (e.g., methyl), R 2 and R 3 are independently H or C 1-6 alkyl (eg, methyl), and R p Selected from alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl(aryl), such as 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and aryloxycarbonyl groups (e.g., phenoxycarbonyl);

[1145] 6.102 Compound 6-J, as provided in Formula 6.101, wherein R p Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1-6Alkyl (e.g., methoxycarbonyl, ethoxycar...

Claims

1. A compound selected from: Wherein PG is selected from tri-C 1-6 Alkylsilyl group, di-C 1-6 Alkyl-phenylsilyl group, C 1-6 Alkyl-diphenylsilyl groups and triphenylsilyl groups; R' is C 1-6 alkyl; R x Is H or C 1-6 Alkyl; and X is Br, Cl or I.

2. The compound according to claim 1, selected from:

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