Processes and intermediates for preparing MCL1 inhibitors

Abstract

The present disclosure provides methods for preparing MCL1 inhibitors or a salt thereof and related key intermediates, for example [Image disponible dans le document PDF, Image available in the PDF document] or a salt thereof.

Description

PROCESSES AND INTERMEDIATES FOR PREPARING MCL1 INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application serial number 62 / 940,387 filed on November 26, 2019. FIELD

[0002] The present disclosure relates to methods and intermediates for the synthesis of certain compounds which inhibit MCL1, for use in the treatment of cancers. BACKGROUND

[0003] Apoptosis (programmed cell death) is a process for elimination of unwanted or potentially dangerous cells from an organism. Avoidance of apoptosis is critical for the development and sustained growth of tumors. Myeloid cell leukemia 1 protein (MCL1) is an antiapoptotic member of the Bcl-2 family of proteins. MCL1 is overexpressed in many cancers. Overexpression of MCL1 prevents cancer cells from undergoing apoptosis. Research has shown that MCL1 inhibitors can be used to treat cancers. Compounds that inhibit MCL1 have been disclosed, but there remains a need for synthetic methods for preparing such compounds on a manufacturing scale.

[0004] PCT Application No. PCT / US2019 / 032053 (WO 2019 / 222112) discloses novel compounds useful as MCL1 inhibitors. This patent publication discloses that compounds according to Formula (A), [Image disponible dans le document PDF, Image available in the PDF document] and pharmaceutically acceptable salts thereof, are effective as inhibitors of MCL1, and are useful in the treatment of cancers.

[0005] There is currently a need for synthetic methods and intermediates that can be used to prepare the compound of formula I and salts thereof. There is also a need for methods for preparing intermediate compounds that can be used to prepare the compound of formula I and salts thereof. SUMMARY

[0006] The present disclosure provides methods for making compounds according to Formula (A), as shown above. In some embodiments, the present disclosure provides compounds according to Formula (I), [Image disponible dans le document PDF, Image available in the PDF document] wherein: === is a single or double bond; <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is hydrogen or <semantics>−C(O)R1<annotation encoding="application / x-tex">-C(O)R^1< / annotation>< / semantics>; R1 is C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR7, or -NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; R2 is hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 3-12 membered heterocycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R10 groups; R3 is hydrogen, C1-6alkyl, -OR7, C1-6haloalkyl, C3-10cycloalkyl, 3-12 membered heterocycloalkyl, -C(O)R7, or -CN, wherein said C1-6alkyl, C1-6haloalkyl, C3- 10cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R10 groups; R4 is hydrogen; R5 is C1-6alkyl, –(CH2CH2O)pR7, C1-6haloalkyl, or C3-10cycloalkyl, wherein said C1-6alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>haloalkyl, or <semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>cycloalkyl, are optionally substituted with 1-5 <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> groups; R6 is hydrogen or halogen; each R7 is independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with from 1-5 R10 groups; each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3- 12 membered heterocycloalkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>aryl, or 5-10 membered heteroaryl, or <semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics> and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; each R10 is independently C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, -ORa, - <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, <semantics>−C(O)ORa<annotation encoding="application / x-tex">-C(O)OR^a< / annotation>< / semantics>, <semantics>−C(O)NRaRb<annotation encoding="application / x-tex">-C(O)NR^aR^b< / annotation>< / semantics>, <semantics>−OC(O)NRaRb<annotation encoding="application / x-tex">-OC(O)NR^aR^b< / annotation>< / semantics>, <semantics>−NRaRb<annotation encoding="application / x-tex">-NR^aR^b< / annotation>< / semantics>, <semantics>−NRaC(O)Rb<annotation encoding="application / x-tex">-NR^aC(O)R^b< / annotation>< / semantics>, <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> <semantics>NRaC(O)ORb<annotation encoding="application / x-tex">NR^{a}C(O)OR^{b}< / annotation>< / semantics>, <semantics>−S(O)qRa<annotation encoding="application / x-tex">-S(O)_{q}R^{a}< / annotation>< / semantics>, <semantics>−S(O)2NRaRb<annotation encoding="application / x-tex">-S(O)_{2}NR^{a}R^{b}< / annotation>< / semantics>, <semantics>−NRaS(O)2Rb<annotation encoding="application / x-tex">-NR^{a}S(O)_{2}R^{b}< / annotation>< / semantics>, <semantics>−N3<annotation encoding="application / x-tex">-N_{3}< / annotation>< / semantics>, <semantics>−CN<annotation encoding="application / x-tex">-CN< / annotation>< / semantics>, or <semantics>−NO2<annotation encoding="application / x-tex">-NO_{2}< / annotation>< / semantics>, or two R10 groups form a fused, spiro, or bridged C3-10cycloalkyl or 3-12 membered heterocycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3- 10cycloalkyl, C6-10aryl, 3-12 membered heterocycle, and 5-10 membered heteroaryl is optionally substituted with 1-5 <semantics>R20<annotation encoding="application / x-tex">R^{20}< / annotation>< / semantics> groups; each Ra and Rb is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C3-10cycloalkyl, C1-6 6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, or Ra and Rb together with the atoms to which they are attached form a 3-12 membered heterocycloalkyl, wherein said C1-6alkyl, C2-6alkenyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl is optionally substituted with 1-5 R20 groups; each R20 is independently C1-6 alkyl, C3-10 cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, hydroxyl, C1-6 alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C1-6 alkyl), -C(O)N(C1-6 alkyl)2, - COOH, <semantics>−C(O)C1−6<annotation encoding="application / x-tex">-C(O)C_{1-6}< / annotation>< / semantics> alkyl, <semantics>−C(O)OC1−6<annotation encoding="application / x-tex">-C(O)OC_{1-6}< / annotation>< / semantics> alkyl, or halogen; p is 0, 1, or 2; and q is 0, 1, or 2; and pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula I is a compound according to Formula I(a): [Image disponible dans le document PDF, Image available in the PDF document]

[0007] In particular embodiments, the present disclosure provides methods of making the Compound 1: [Image disponible dans le document PDF, Image available in the PDF document]

[0008] Compounds of Formula A (as well as formulae I and I(a)) can be schematically divided into four functional regions, as shown below, each separated by one of four critical synthetic bonds (dotted lines): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0009] Thus, the Compounds of Formula A (as well as formulae I and I(a)) can be considered to contain four main subparts: a tetracyclic core (TC), and in particular, a 6'-substituted-3,4- dihydro-<semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>,2'<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>,4<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>-<semantics>5λ2<annotation encoding="application / x-tex">5\lambda^2< / annotation>< / semantics>-spiro[benzo[<semantics>b<annotation encoding="application / x-tex">b< / annotation>< / semantics>][1,4]oxazepane-3,1'-napthenelene-7-acyl moiety; a disubstituted cyclobutane moiety (CB); a multi-substituted sulfonimidamide moiety (SNO); and sn N-linked side-chain (SC).

[0010] In this structure, the TC and CB moieties are connected by a single N-C alkylamine bond (numbered 1), the TC and SNO moieties are connected by a single N-C acylamide bond (numbered 2), the CB and SNO moieties are connected by a C-C alkyl or C=C alkenyl bond (numbered 3), and the SC and SNO moieties are connected by an N-H or N-C single bond (numbered 4), depending on the identity of <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics>.

[0011] WO 2019 / 222112 has disclosed a process of preparing the compounds of Formula A (including formula I and I(a)). In the process, the critical synthetic bonds are formed in the order 1, 2, 4 then 3. Thus, the process may be abbreviated schematically as follows: [Image disponible dans le document PDF, Image available in the PDF document]

[0012] It is understood that in this nomenclature, when discussing a synthetic route which will build up and connect the key fragments in a stepwise manner, there may be protecting groups and other temporary substituents present in more intermediates which will not match the final substituents or structural motifs seen in the final compound of Formula A. The process disclosed in WO 2019 / 222112 [Image disponible dans le document PDF, Image available in the PDF document]

[0013] Disclosed herein are methods of making Compounds of Formula A (e.g., compounds of Formula I or I(a)), as well as methods of making critical intermediates therefor. In particular, in some embodiments, disclosed herein are methods of making Compounds of Formula A (e.g., compounds of Formula I or I(a)), wherein the critical synthetic bonds are 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 critical synthetic bond formation steps is 1, 2, 3, 4, then the process does not comprise the use of an intermediate 1-J or 1-K, as defined herein, wherein R5 is H.

[0014] In some embodiments, fragment TC is fully formed before incorporation into the above process steps. In other embodiments fragment TC is initially prepared as a bicyclic phenoxy fragment and carried through one or more steps in a protected state, followed by deprotection and ring closure to form the tetracyclic TC fragment. For example: [Image disponible dans le document PDF, Image available in the PDF document] wherein PG represents a protected aldehyde, for example, PG is CH(OC1-6alkyl)(OC1-6alkyl) or <semantics>−O(C2−10alkyl)O−.<annotation encoding="application / x-tex">-O(C_{2-10}alkyl)O-.< / annotation>< / semantics> DETAILED DESCRIPTION

[0015] Therefore, in a first aspect, the present disclosure provides a Method (Method A) for making a Compound of Formula A (e.g., a compound of Formula I or I(a)), as described above, wherein the method comprises the steps of: (a) (1) Synthesizing fragment TC (or BC), (2) synthesizing fragment CB, (3) joining fragment TC (or BC) to fragment CB by forming Bond 1, (4) synthesizing fragment SNO, (5) joining fragment TC-CB (or BC-CB) to fragment SNO by forming Bond 2, (6) connecting the CB moiety and the SNO moiety of the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 3 intramolecularly, and (7) attaching the SC moiety to the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 4 to form the compound of Formula A; provided that at no point in the process is the TC-CB fragment a compound of formula intermediate 1-J or 1-K, as defined herein, wherein R5 is H; or (b) (1) Synthesizing fragment SNO, (2) synthesizing fragment TC (or BC), (3) joining fragment SNO to fragment TC (or BC) by forming Bond 2, (4) synthesizing fragment CB, (5) joining fragment TC-SNO (or BC-SNO) to fragment CB by forming Bond 1, (6) connecting the CB moiety and the SNO moiety of the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 3 intramolecularly, and (7) attaching the SC moiety to the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 4 to form the compound of Formula A; or (c) (1) Synthesizing fragment TC (or BC), (2) synthesizing fragment CB, (3) joining fragment TC (or BC) to fragment CB by forming Bond 1, (4) synthesizing fragment CNO, (5) joining fragment TC-CB (or BC-CB) to fragment CNO by forming Bond 2, (6) attaching the SC moiety to the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 4, and (7) connecting the CB moiety and the SNO moiety of the SC-SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 3 intramolecularly to form the compound of Formula A; or (d) (1) Synthesizing fragment SNO, (2) synthesizing fragment TC (or BC), (3) joining fragment SNO to fragment TC (or BC) by forming Bond 2, (4) synthesizing fragment CB, (5) joining fragment TC-SNO (or BC-SNO) to fragment CB by forming Bond 1, (6) attaching the SC moiety to the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 4, and (7) connecting the CB moiety and the SNO moiety of the SC-SNO- TC-CB (or SC-SNO-BC-CB) fragment by forming Bond 3 intramolecularly to form the compound of Formula A; or (e) (1) Synthesizing fragment TC (or BC), (2) synthesizing fragment SNO, (3) joining fragment TC (or BC) to fragment SNO by forming Bond 2, (4) synthesizing fragment CB, (5) joining fragment TC-SNO (or BC-SNO) to fragment CB by forming Bond 3, (6) connecting the CB moiety and the SNO moiety of the SNO-TC-CB (or SNO-BC-CB) moiety by forming Bond 2 intramolecularly, and (7) attaching the SC moiety to the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 4 to form the compound of Formula A; or (f) (1) Synthesizing fragment SNO, (2) synthesizing fragment CB, (3) joining fragment SNO to fragment CB by forming Bond 3, (4) synthesizing fragment TC (or BC), (5) joining fragment SNO-CB to fragment TC (or BC) by forming Bond 2, (6) connecting the CB moiety and the TC (or BC) moiety of the SNO-TC-CB (or SNO-BC- CB) fragment by forming Bond 1 intramolecularly, and (7) attaching the SC moiety to the SNO-TC-CB (or SNO-BC-CB) fragment by forming Bond 4 to form the compound of Formula A; optionally wherein any of the preceding processes further comprises the step of converting any intermediate comprising a fragment BC into the same intermediate comprising a fragment TC, for example, if step (3) joins fragment SNO to fragment BC by forming Bond 2, then step (3') may convert fragment SNO-BC to fragment SNO-TC, followed by the remaining steps (e.g., in process (b) or process (d); or if step (5) joins fragment SNO-CB to fragment BC to form fragment SNO-BC-CB, then step (5') may convert fragment SNO-BC-CB to fragment SNO-TC-CB (without Bond 1), followed by the remaining steps or, alternatively, step (6') may convert fragment SNO-BC-CB to fragment SNO-TC-CB (with Bond 1), followed by the remaining steps (e.g., in process (f)); [Image disponible dans le document PDF, Image available in the PDF document] wherein, fragment BC is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ; fragment SC is R12; and PG is a protecting group (e.g., [Image disponible dans le document PDF, Image available in the PDF document] wherein all other substituents are as defined for the compound of Formula A herein.

[0016] In some embodiments, the product of Method A is a Compound I, a Compound I(a), or Compound 1, as defined herein. In some embodiments, Method A may comprise one or more steps, in any order and any combination, as provided in any embodiments of Method 1, Method 2, Method 3, Method 4, and Method 5 as described herein.

[0017] In a second aspect, the present disclosure provides a method (Method 1) of making a compound selected from one or more 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 Compound I or I(a), as hereinbefore described, wherein the method comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form the product compound. Method 1 generally pertains to formation of the cyclobutyl moiety (CB), including advanced intermediates 1-I, 1-J, and 1-K, as well as the evolution of those intermediates to Compound 1. Without being limited in the order or combination of steps employed, the potential embodiments of Method 1 may include any steps shown in Schemes 1, 2 and 3. [Image disponible dans le document PDF, Image available in the PDF document] Scheme 2 [Image disponible dans le document PDF, Image available in the PDF document] Scheme 3

[0018] In particular embodiments, the present disclosure provides Method 1 as follows: 1.1 Method 1, wherein the method comprises the step of reacting a compound 1-A with a suitable protecting reagent in a suitable solvent, optionally with a suitable base and / or catalyst, for a time and under conditions effective to yield a compound 1-B; wherein R' is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, or t-butyl), optionally R' is methyl; 1.2 Method 1.1, wherein the substituent PG is selected from a silyl group, an alkylcarbonyl group (e.g., <semantics>−C(=O)−C1−6<annotation encoding="application / x-tex">-C(=O)-C_{1-6}< / annotation>< / semantics>alkyl, such as acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), an arylcarbonyl group (e.g. benzoyl), an alkoxycarbonyl group (e.g., -C(=O)-O-C1-6alkyl, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), an aryloxycarbonyl group (e.g., phenoxycarbonyl), a tertiary alkyl group (e.g., t-butyl or trityl), an alkoxyalkyl group (e.g., methoxymethyl or ethoxymethyl), or a C1-6alkylaryl group (e.g., benzyl, 3,5-dimethoxybenzyl); 1.3 Method 1.2, wherein the substituent PG is selected from a trialkyl silyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), a dialkylaryl silyl group (e.g., dimethylphenylsilyl), an alkyldiaryl silyl group (e.g., t-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl); 1.4 Method 1.3, wherein the substituent PG is a tert-butyldiphenyl silyl group, optionally wherein the protecting agent is tert-butyldiphenylsilyl chloride; 1.5 Any of Methods 1.1-1.4, wherein the protecting reagent is selected from silyl chlorides (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, bromotriphenylsilane), 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), 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); 1.6 Any of Methods 1.1-1.5, wherein the reaction comprises a base; 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 (monobasic, dibasic or tribasic), sodium phosphate (monobasic, dibasic or tribasic)); 1.8 Method 1.7, wherein the base is triethylamine; 1.9 Any of Methods 1.1-1.8, wherein the reaction comprises a catalyst; 1.10 Method 1.9, wherein the catalyst is selected from 4-(dimethylamino)pyridine, N- methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 1.11 Method 1.10, wherein the catalyst is 4-(dimethylamino)pyridine; 1.12 Any of Methods 1.1-1.11, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 1.13 Method 1.12, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.14 Method 1.12, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and nitriles (e.g., acetonitrile); 1.15 Method 1.12, wherein the nonpolar solvent is a halogenated solvent, optionally, wherein the solvent is dichloromethane; 1.16 Any of Methods 1.1-1.15, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to <semantics>40<annotation encoding="application / x-tex">40< / annotation>< / semantics> °C, e.g., from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to 30 °C, or about 0 °C to 25 °C; 1.17 Method 1, or any of 1.1-1.16, wherein the method comprises the step of reacting a compound 1-B with an organometallic reagent in a suitable solvent for a time and under conditions effective to form a 1-hydroxycyclopropane compound 1-C, wherein R' is defined as in Method 1.1, and PG is defined as provided in Method 1.2, 1.3 or 1.4; 1.18 Method 1.17, wherein the substituent Rx is selected from H, C1-6alkyl (e.g., methyl), and <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>aryl (e.g. phenyl), wherein the alkyl is optionally substituted with <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>aryl (e.g., phenyl); 1.19 Method 1.18, wherein <semantics>Rx<annotation encoding="application / x-tex">R^x< / annotation>< / semantics> is H; 1.20 Method 1.17, 1.18 or 1.19 wherein the organometallic reagent is an organolithium reagent (e.g., C1-6alkyl lithium) or a Grignard reagent (e.g., C1-6alkylmagnesium halide); 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 provided as a solution in an ethereal solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane); 1.22 Any of Methods 1.17-1.21, wherein the reaction further comprises a transition metal promoter, such as a titanium(IV) compound; 1.23 Method 1.22, wherein the promoter is a titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, or titanium(IV) butoxide); 1.24 Any of Methods 1.20-1.23, wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide; 1.25 Any of Methods 1.17-1.24, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 1.26 Method 1.25, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether. dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., 1,2- dichloroethane, chloroform, chlorobenzene); 1.27 Method 1.25, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and nitriles (e.g., acetonitrile); 1.28 Method 1.25, wherein the nonpolar solvent is an ethereal solvent, optionally, wherein the solvent is tetrahydrofuran; 1.29 Any of Methods 1.17-1.28, wherein the temperature of the reaction is from −20 to 30 °C, e.g., from -5 to 15 °C, or about 0 °C to 5 °C; 1.30 Method 1, or any of Methods 1.1-1.29, wherein the method comprises the step of reacting a compound 1-C with a halogenating agent in a suitable solvent for a time and under conditions effective to form beta-halo ketone compound 1-D, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19; 1.31 Method 1.30, wherein the substituent X is selected from bromo, chloro and iodo; 1.32 Method 1.31, wherein X is bromo; 1.33 Method 1.30, 1.31 or 1.32 wherein the halogenating agent is selected from 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-iodosucciminide, N-iodophthalimide, and iodine; 1.34 Method 1.33, wherein the halogenating agent is selected from N-bromosuccinimide, N- bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, and hypobromous acid; 1.35 Method 1.34, wherein the halogenating agent is N-bromosuccinimide; 1.36 Any of Methods 1.30-1.35, wherein the suitable solvent is a nonpolar solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.38 Method 1.37, wherein the nonpolar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.39 Any of Methods 1.30-1.38, wherein the temperature of the reaction is from <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to 30 °C, e.g., from -5 to 15 °C, or about 0 °C to 5 °C; 1.40 Any of Methods 1.30-1.39, wherein the compound 1-C is mixed (e.g., stirred or agitated) in the suitable solvent with the halogenating agent for 0.25 to 5 hours, e.g., 0.5 to 3 hours, or 1 to 2 hours, or about 1.5 hours; 1.41 Method 1, or any of Methods 1.1-1.40, wherein the method comprises the step of reacting a compound 1-D with a base in a suitable solvent for a time and under conditions effective to form an alpha, beta-unsaturated ketone compound 1-E, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19, and wherein X is chloro, bromo or iodo; 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); 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; 1.44 Method 1.43, wherein the base is triethylamine; 1.45 Any of Methods 1.41-1.44, wherein the suitable solvent is a nonpolar solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.47 Method 1.46, wherein the nonpolar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.48 Any of Methods 1.41-1.47, wherein the temperature of the reaction is from −20 to 30 °C, e.g., from <semantics>−5<annotation encoding="application / x-tex">-5< / annotation>< / semantics> to <semantics>15<annotation encoding="application / x-tex">15< / annotation>< / semantics> °C, or about 0 °C to 5 °C; 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 takes place consecutively in the same vessel without isolation of compound 1-D; 1.50 Method 1, or any of Methods 1.1-1.49, wherein the method comprises the step of reducing an alpha, beta-unsaturated ketone compound 1-E to an allylic 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 Rx is defined as in Method 1.18 or 1.19; 1.51 Method 1.50, wherein the reduction is carried out by reacting the compound 1-E with a reducing agent and a Lewis acid catalyst, in a suitable solvent; 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 agent (e.g., sodium borohydride, lithium borohydride, lithium triethylborohydride), an aluminum hydride agent (e.g., lithium aluminum hydride, diisobutylaluminum hydride), a hydrogen source (e.g., isopropanol) with a transfer hydrogenation agent (e.g., <semantics>RuCl[(R,R)−Tsdpen](p−cymene)<annotation encoding="application / x-tex">RuCl[(R,R)-Tsdpen](p-cymene)< / annotation>< / semantics>, <semantics>RuCl[(S,S)−Tsdpen]<annotation encoding="application / x-tex">RuCl[(S,S)-Tsdpen]< / annotation>< / semantics>(p-cymene), an aluminum alkoxide agent in an alcoholic solvent (e.g., aluminum triisopropoxide in ethanol), and a reductase enzyme (e.g., a ketoreductase); 1.53 Method 1.52, wherein the reducing agent is sodium borohydride; 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; 1.55 Method 1.54, wherein the Lewis acid is cerium(III) chloride, e.g., cerium(III) chloride heptahydrate or anhydrous cerium(III) chloride; 1.56 Any of Methods 1.50-1.55, wherein the suitable solvent is a polar protic solvent or nonpolar solvent; 1.57 Method 1.56, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol, butanol); 1.58 Method 1.56, wherein the nonpolar solvent is an ether (e.g., tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), a hydrocarbon solvent (e.g., toluene, n-hexane, n-heptane), or a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.59 Method 1.56, wherein the solvent is ethanol; 1.60 Any of Methods 1.50-1.59, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to <semantics>30<annotation encoding="application / x-tex">30< / annotation>< / semantics> °C, e.g., from <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to <semantics>20<annotation encoding="application / x-tex">20< / annotation>< / semantics> °C, or <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to <semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics> °C; 1.61 Any of Methods 1.50-1.60, wherein products 1-F and 1-F' are not separated before the next step of the method; 1.62 Any of Methods 1.50-1.60, wherein the products 1-F and 1-F' are separated before the next step in the method; 1.63 Method 1, or any of Methods 1.1-1.62, wherein the method comprises the step of treating a mixture of allylic alcohol compounds 1-F and 1-F' with an acyl donor and an esterase enzyme, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19, wherein the acyl donor is an ester of an acid of the formula RCOOH; 1.64 Method 1.63, wherein the esterase enzyme selectively esterifies the (R)-allylic alcohol moiety of compound 1-F' to form ester 1-F''; 1.65 Method 1.64, wherein the esterase is a bacterial esterase, e.g., Pseudomonas stutzeri lipase; 1.66 Method 1.63, 1.64 or 1.65 wherein R is selected from H, C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC1-6alkyl (e.g., trifluoromethyl, trichloromethyl), C1- 6alkylcarboxylate (e.g., 3-propionate, 4-butyrate), optionally substituted aryl (e.g., phenyl, 4- bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl); 1.67 Any of Methods 1.63-1.66, wherein the acyl donor is a vinyl ester, isopropenyl ester, methyl ester, ethyl ester, 2,2,2-trifluoroethyl ester, 2,2,2-trichloroethyl ester, or methoxyvinyl ester of an acid RCOOH, or is an anhydride of an acid RCOOH (including mixed and unmixed linear anhydrides and cyclic anhydrides of dicarboxylic acids), wherein R is defined as in Method 1.66; 1.68 Method 1.67, wherein the acyl donor is selected from succinic anhydride, vinyl acetate, isopropenyl 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, vinyl 4-bromoacetate, vinyl picolinate, glutaric anhydride, vinyl formate, vinyl butyrate, and butyric anhydride; 1.69 Any of Methods 1.63-1.68, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 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, dioxane), and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane); 1.71 Method 1.69, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and nitriles (e.g., acetonitrile); 1.72 Method 1.69, wherein the nonpolar solvent is an ethereal solvent, optionally, wherein the solvent is methyl tert-butyl ether; 1.73 Any of Methods 1.63-1.72, wherein the temperature of the reaction is from 0 to 50 °C, e.g., from 10 to 30 °C, or about 20 °C; 1.74 Any of Methods 1.63-1.73, wherein upon completion of the reaction, the product mixture is purified to isolate the compound 1-F and / or to remove and discard the compound 1-F"; 1.75 Method 1, or any of Methods 1.1-1.74, wherein the method comprises the step of reacting a compound 1-F with an alkylating agent, and optionally a base, in a suitable solvent for a time and under conditions effective to form an ether compound 1-G, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19, and wherein R5 is selected from C1-6alkyl, –(CH2CH2O)pR7, C1-6haloalkyl, and C3-10cycloalkyl, wherein said C1- 6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, are optionally substituted with 1-5 R10 groups (R7 and R10 are as defined for the Compound of Formula I); 1.76 Method 1.75, wherein <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is selected from <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl and <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>haloalkyl, each optionally substituted with 1-3 groups selected from halogen, oxo, C3-6cycloalkyl, and 4-6 membered heterocycloalkyl; 1.77 Method 1.76, wherein <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl) optionally substituted with 1-3 halogen (e.g., fluoro); 1.78 Method 1.77, wherein R5 is methyl; 1.79 Any of Methods 1.75-1.78, wherein the alkylating agent is a compound of the formula R5-X, wherein X is selected from Cl, Br, I, OS(O)2OR5, and OSO2-L wherein L is C1-6alkyl, optionally substituted aryl, or haloC1-6alkyl; 1.80 Method 1.79, wherein the alkylating agent is selected from an alkyl bromide, alkyl chloride, alkyl iodide, alkyl triflate, alkyl tosylate, alkyl mesylate, alkyl nosylate, alkyl benzenesulfonate, and dialkyl sulfate; 1.81 Method 1.80, wherein the alkylating agent is selected from methyl iodide, methyl triflate, methyl tosylate and dimethyl sulfate; 1.82 Any of Methods 1.75-1.81, wherein the reaction further comprises a base selected from inorganic hydrides (e.g., sodium hydride, potassium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t- pentoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, or lithium hydroxide), and amide bases (e.g., sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide); 1.83 Method 1.82, wherein the base is sodium t-butoxide; 1.84 Any of Methods 1.75-1.83, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.86 Method 1.84, wherein the polar protic solvent is an alcoholic solvent (e.g., tert-butanol, or tert-amyl alcohol), optionally in combination with water; 1.87 Method 1.84, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, optionally in combination with water; 1.88 Method 1.84, wherein the suitable solvent is tetrahydrofuran; 1.89 Any of Methods 1.75-1.88, wherein the temperature of the reaction is from -80 to 50 °C, e.g., from <semantics>−45<annotation encoding="application / x-tex">-45< / annotation>< / semantics> to <semantics>10<annotation encoding="application / x-tex">10< / annotation>< / semantics> °C, or <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> °C to <semantics>10<annotation encoding="application / x-tex">10< / annotation>< / semantics> °C, or about <semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics> °C; 1.90 Method 1, or any of Methods 1.1-1.89, wherein the method comprises the step of treating a compound 1-G in a suitable solvent with a deprotection reagent for a time and under conditions effective to form an alcohol compound 1-H, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19, and wherein R5 is defined as in any of Methods 1.75-1.78; 1.91 Method 1.90, wherein <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl) optionally substituted with 1-3 halogen (e.g., fluoro); 1.92 Method 1.91, wherein R5 is methyl, ethyl, or isopropyl, optionally, wherein R5 is methyl; 1.93 Any of Methods 1.90-1.92, wherein the deprotection reagent 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 hydrogenation agent (e.g., hydrogen in combination with a heterogenous 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; 1.94 Any of Methods 1.90-1.93, wherein the deprotection reagent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, 4-toluenesulfonic acid, hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, 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, <semantics>PtO2<annotation encoding="application / x-tex">PtO_2< / annotation>< / semantics>); 1.95 Any of Methods 1.90-1.94, wherein the substituent PG is a silyl group, and the deprotection agent is a fluoride agent; 1.96 Method 1.95, wherein the substituent PG is selected from a trialkyl silyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), a dialkylaryl silyl group (e.g., dimethylphenylsilyl), an alkyldiaryl silyl group (e.g., t-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl), and the deprotection reagent is selected from hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride; 1.97 Method 1.96, wherein the substituent PG is tert-butyldiphenylsilyl and the deprotection agent is selected from tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride; 1.98 Any of Methods 1.90-1.97, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.100 Method 1.98, wherein the polar protic solvent is an alcoholic 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; 1.101 Method 1.98, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, optionally in combination with water; 1.102 Method 1.98, wherein the suitable solvent is tetrahydrofuran; 1.103 Any of Methods 1.90-1.102, wherein the temperature of the reaction is from <semantics>−15<annotation encoding="application / x-tex">-15< / annotation>< / semantics> to 50 °C, e.g., from –5 to 40 °C, or 0 °C to 30 °C, or from 10 °C to 30 °C; 1.104 Method 1, or any of Methods 1.1-1.103, wherein the method comprises the step of treating a compound 1-H in a suitable solvent with an oxidizing agent to form an aldehyde compound 1-I, wherein Rx is defined as in Method 1.18 or 1.19, and wherein R5 is defined as in any of Methods 1.75-1.78; 1.105 Method 1.104, wherein the reaction further comprises an additive, a catalyst and / or a base; 1.106 Method 1.104 or 1.105, wherein the oxidizing agent is selected from sodium hypochlorite, sulfur trioxide pyridine, dimethyl sulfoxide / oxalyl chloride, DMSO / acetic anhydride, DMSO / trifluoroacetic anhydride, diacetoxyiodobenzene (DAIB), tetrapropylammonium perruthenate (TPAP) / N-methyl morpholine oxide, Dess-Martin Periodinane, pyridinium chlorochromate, N-chlorosuccinimide / dimethyl sulfide, iodosylbenzene, DMSO / dicyclohexylcarbodiimide, bis(trifluoroacetoxy)iodobenzene, and manganese dioxide; 1.107 Method 1.106, wherein the oxidizing agent is selected from diacetoxyiodobenzene (DAIB), Dess-Martin Periodinane, iodosylbenzene, and bis(trifluoroacetoxy)iodobenzene; 1.108 Method 1.107, wherein the oxidizing agent is diacetoxyiodobenzene (DAIB); 1.109 Any of Methods 1.104-1.108, wherein the reaction further comprises a catalyst selected from TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, and 9-azanoradamantane N-oxyl; 1.110 Any of Methods 1.104-1.109, wherein the reaction further comprises an additive selected from sodium bromide, lithium bromide and potassium bromide; 1.111 Any of Methods 1.104-1.110, wherein the reaction further comprises a base selected from an inorganic base (e.g., sodium phosphate dibasic, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide) and an organic amine base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, DBU, DBN); 1.112 Any of Methods 1.104-1.109, wherein the oxidizing agent is diacetoxyiodobenzene and the catalyst is TEMPO, wherein the reaction does not further comprise a base or an additive; 1.113 Any of Methods 1.104-1.112, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.115 Method 1.113, wherein the polar aprotic solvent is selected from N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, optionally in combination with water; 1.116 Method 1.113, wherein the suitable solvent is dichloromethane; 1.117 Any of Methods 1.104-1.116, wherein the temperature of the reaction is from -80 to 50 °C, e.g., from -40 to 40 °C, or 10 °C to 30 °C; 1.118 Method 1, or any of Methods 1.1-1.117, wherein the method comprises the step of treating a compound 1-I in a suitable solvent with a reducing agent and the compound 5-I, for a time and under conditions effective to form the tertiary amine compound 1-J, wherein Rx is defined as in Method 1.18 or 1.19, wherein R5 is defined as in any of Methods 1.75-1.78, and wherein <semantics>Rz<annotation encoding="application / x-tex">R^z< / annotation>< / semantics> is defined as in any of Methods 2.129-2.131, and wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is hydrogen or halogen. In one embodiment, <semantics>Rx<annotation encoding="application / x-tex">R^x< / annotation>< / semantics> is H. In one embodiment, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is methyl; 1.119 Method 1.118, wherein R6 is selected from chloro, bromo, fluoro and iodo; 1.120 Method 1.119, wherein R6 is chloro; 1.121 Any of Methods 1.118-1.120, wherein the reducing agent is selected from a hydride reducing agent, a silane reducing agent, and zinc in acid (e.g., zinc in acetic acid); 1.122 Method 1.121, wherein the reducing agent is a hydride reducing agent; 1.123 Method 1.122, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 1.124 Method 1.123, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 1.125 Any of Methods 1.122-1.124, wherein the hydride reducing agent is combined with a reagent to modulate the hydride reducing activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride); 1.126 Method 1.121, the reducing agent is selected from silanes (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; 1.127 Any of Methods 1.121 to 1.126, wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoracetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid). In one embodiment, the acid is trifluoroacetic acid; 1.128 Any of Methods 1.118-1.128, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), acetonitrile, and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.130 Method 1.128, wherein the polar aprotic solvent is selected from N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; 1.131 Method 1.128, wherein the suitable solvent is dichloromethane. In one embodiment, the solvent is acetonitrile; 1.132 Any of Methods 1.118-1.131, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to 50 °C, e.g., from -30 to 0 °C, or -30 to -10 °C, or about -20 °C. In one embodiment, the temperature is -10 to 30 °C; 1.133 Method 1, or any of Methods 1.1-1.132, wherein the method comprises the step of hydrolyzing the compound 1-J in a suitable solvent for a time and under conditions effective to form the carboxylic acid compound 1-K, wherein Rx is defined as in Method 1.18 or 1.19, wherein R5 is defined as in any of Methods 1.75-1.78, and wherein Rz is defined as in any of Methods 2.129-2.131, and wherein R6 is hydrogen or halogen; 1.134 Method 1.133, wherein the reaction comprises treating the compound 1-J in an organic and / or aqueous solvent with an aqueous acid or a base; or treating the compound 1-J with an enzyme (e.g., a bacterial or fungal lipase, such as lipase from Rhizopus species); or treating the compound 1-J with magnesium dibromide in a nonpolar solvent; or treating the compound 1-J with a fluoride source (e.g., hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride), in a nonpolar solvent; or treating the compound 1-J with 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), or ammonium formate in combination with a palladium or platinum catalyst (e.g., <semantics>Pd,Pd / C,Pt,PtO2);<annotation encoding="application / x-tex">Pd, Pd / C, Pt, PtO_2);< / annotation>< / semantics> 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; 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, alkoxides (lithium, sodium, potassium, magnesium, or calcium salts of methoxide, ethoxide, isopropoxide, t-butoxide, or t-pentoxide), trimethyltin hydroxide, sodium trimethylsilanolate, potassium trimethylsilanolate, and pyridine; 1.137 Any of Methods 1.133-1.136, wherein the solvent is selected from one or more of water, alcohols (e.g., methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, tert-amyl alcohol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N- methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile), ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2- dichloroethane, chloroform, chlorobenzene); 1.138 Any of Methods 1.133-1.137, wherein the temperature of the reaction is from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to 100 °C, e.g., from 10 to 80 °C, or 20 to 80 °C, or from 20 to 50 °C. In one embodiment, the temperature is from 20 to 100 °C. In one embodiment, the temperature is from 50 to 70 °C; 1.139 Method 1, or any of Methods 1.1-1.138, wherein the method comprises the step of treating (1S,5R)-3-oxabicyclo[3.2.0]heptan-2-one (compound 2-A) with an organometallic reagent in a suitable solvent for a time and under conditions effective to form a 1- hydroxycyclopropane compound 2-B, wherein the substituent Rx is selected from H, C1-6alkyl (e.g., methyl), and <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl (e.g. phenyl), wherein the alkyl is optionally substituted aryl (e.g., phenyl); 1.140 Method 1.139, wherein Rx is H; 1.141 Method 1.139 or 1.140 wherein the organometallic reagent is an organolithium reagent (e.g., C1-6alkyl lithium) or a Grignard reagent (e.g., C1-6alkylmagnsium halide); 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 provided as a solution in an ethereal solvent (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane); 1.143 Any of Methods 1.139-1.142, wherein the reaction further comprises a transition metal promoter, such as a titanium(IV) compound; 1.144 Method 1.143, wherein the promoter is a titanium(IV) alkoxide (e.g., titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) propoxide, titanium(IV) isopropoxide, titanium(IV) n-butoxide, titanium(IV) t-butoxide, titanium(IV) benzoxide); 1.145 Any of Methods 1.139-1.144, wherein the organometallic reagent is ethylmagnesium bromide and the promoter is titanium(IV) isopropoxide; 1.146 Any of Methods 1.139-1.145, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 1.147 Method 1.146, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), 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); 1.148 Method 1.147, wherein the nonpolar solvent is an ethereal solvent, optionally, wherein the solvent is tetrahydrofuran; 1.149 Any of Methods 1.139-1.148, wherein the temperature of the reaction is from -20 to 50 °C, e.g., from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to <semantics>10<annotation encoding="application / x-tex">10< / annotation>< / semantics> °C, or about <semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics> °C to <semantics>5<annotation encoding="application / x-tex">5< / annotation>< / semantics> °C; 1.150 Method 1, or any of 1.1-1.149, wherein the method comprises the step of reacting a compound 2-B with a suitable protecting reagent in a suitable solvent, optionally with a suitable base and / or catalyst, for a time and under conditions effective to yield a compound 2-C, wherein Rx is defined as in Method 1.139 or 1.140; 1.151 Method 1.150, wherein the substituent PG is selected from a silyl group, an alkylcarbonyl group (e.g., <semantics>−C(=O)−C1−6<annotation encoding="application / x-tex">-C(=O)-C_{1-6}< / annotation>< / semantics>alkyl, such as acetyl, isobutyryl, pivaloyl, adamantanecarbonyl), an arylcarbonyl group (e.g. benzoyl), an alkoxycarbonyl group (e.g., - <semantics>C(=O)<annotation encoding="application / x-tex">C(=O)< / annotation>< / semantics>-O-C1-6alkyl, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), an aryloxycarbonyl group (e.g., phenoxycarbonyl), a tertiary alkyl group (e.g., t-butyl or trityl), an alkoxyalkyl group (e.g., methoxymethyl or ethoxymethyl), and a C1- 6alkylaryl group (e.g., benzyl, 3,5-dimethoxybenzyl); 1.152 Method 1.151, wherein the substituent PG is selected from a trialkyl silyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), a dialkylaryl silyl group (e.g., dimethylphenylsilyl), an alkyldiaryl silyl group (e.g., t-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl); 1.153 Method 1.152, wherein the substituent PG is a tert-butyldiphenyl silyl group, optionally wherein the protecting agent is TBDPS-chloride; 1.154 Any of Methods 1.150-1.153, wherein the protecting reagent is selected from silyl chlorides (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chlorodimethylphenylsilane, or chlorotriphenylsilane), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, or triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, or bromotriphenylsilane), 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, or 1-adamantanecarbonyl chloride), anhydrides (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); 1.155 Any of Methods 1.150-1.154, wherein the reaction comprises a base; 1.156 Method 1.155, 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, or 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, imidazole, or 1-methylimidazole), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic or tribasic), or sodium phosphate (monobasic, dibasic or tribasic)); 1.157 Method 1.156, wherein the base is triethylamine; 1.158 Any of Methods 1.150-1.157, wherein the reaction comprises a catalyst; 1.159 Method 1.158, wherein the catalyst is selected from 4-(dimethylamino)pyridine, 2,6- dimethylpyridine, N-methylimidazole, imidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 1.160 Method 1.159, wherein the catalyst is 4-(dimethylamino)pyridine; 1.161 Any of Methods 1.150-1.160, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 1.162 Method 1.161, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, or n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.163 Method 1.161, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and nitriles (e.g., acetonitrile); 1.164 Method 1.161, wherein the nonpolar solvent is a halogenated solvent, optionally, wherein the solvent is dichloromethane; 1.165 Any of Methods 1.150-1.161, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to 40 °C, e.g., from −10 to 30 °C, or 0 °C to 25 °C; 1.166 Method 1, or any of Methods 1.1-1.165, wherein the method comprises the step of reacting a compound 2-C with a halogenating agent in a suitable solvent for a time and under conditions effective to form a beta-halo ketone compound 2-D, wherein PG is defined as in any of Methods 1.151-1.153, and Rx is defined as in Method 1.139 or 1.140; 1.167 Method 1.166, wherein the substituent X is selected from bromo, chloro and iodo; 1.168 Method 1.167, wherein X is bromo; 1.169 Method 1.166, 1.167 or 1.168 wherein the halogenating agent is selected from 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-iodosucciminide, N-iodophthalimide, and iodine; 1.170 Method 1.169, wherein the halogenating agent is selected from N-bromosuccinimide, N- bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, and hypobromous acid; 1.171 Method 1.169, wherein the halogenating agent is N-bromosuccinimide; 1.172 Any of Methods 1.166-1.171, wherein the suitable solvent is a nonpolar solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.174 Method 1.172, wherein the nonpolar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.175 Any of Methods 1.166-1.174, wherein the temperature of the reaction is from <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to 30 °C, e.g., from −5 to 15 °C, or 0 °C to 5 °C; 1.176 Any of Methods 1.166-1.175, wherein the compound 2-C is mixed (e.g., stirred or agitated) in the suitable solvent with the halogenating agent for 0.1 to 3 hours, e.g., 0.2 to 2 hours, or 0.3 to 1 hour, or about 0.5 hours; 1.177 Method 1, or any of Methods 1.1-1.176, wherein the method comprises the step of reacting a compound 2-D with a base in a suitable solvent for a time and under conditions effective to form an alpha, beta-unsaturated ketone compound 2-E, wherein PG is defined as provided in any of Methods 1.151-1.153, and Rx is defined as in Method 1.139 or 1.140, and wherein X is chloro, bromo or iodo; 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 mono-, di-, or tribasic sodium, potassium or lithium phosphate); 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; 1.180 Method 1.179, wherein the base is triethylamine; 1.181 Any of Methods 1.177-1.180, wherein the suitable solvent is a nonpolar solvent; 1.182 Method 1.181, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, or n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.183 Method 1.182, wherein the nonpolar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.184 Any of Methods 1.177-1.183, wherein the temperature of the reaction is from <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to 30 °C, e.g., from -5 to 15 °C, or 0 °C to 5 °C; 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 takes place consecutively in the same vessel without isolation of compound 2-D; 1.186 Method 1, or any of Methods 1.1-1.185, wherein the method comprises the step of reacting a compound 2-E with a promoter in a suitable solvent for a time and under conditions effective to form an epimerized alpha, beta-unsaturated ketone compound 1-E, wherein PG is defined as provided in any of Methods 1.151-1.153, and Rx is defined as in Method 1.139 or 1.140; 1.187 Method 1.186, wherein the promoter 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, or DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, or 1-methylimidazole), inorganic bases (e.g., alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate, or alkali metal phosphates such as mono-, di-, or tribasic sodium, potassium or lithium phosphate), inorganic halides (e.g., lithium chloride, magnesium bromide, magnesium chloride), and acids (e.g., titanium tetraisopropoxide, benzenesulfonic acid, toluenesulfonic acid, or methanesulfonic acid); 1.188 Method 1.187, wherein the promoter is selected from triethylamine, N,N- diisopropylethylamine, N-methylmorpholine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 1.189 Method 1.188, wherein the promoter is DBU; 1.190 Any of Methods 1.186-1.189, wherein the suitable solvent is a nonpolar solvent, polar aprotic solvent or polar protic solvent; 1.191 Method 1.190, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 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); 1.193 Method 1.190, wherein the polar protic solvent is an alcoholic solvent (e.g., methanol, ethanol, propanol, or isopropanol); 1.194 Method 1.190, wherein the nonpolar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.195 Any of Methods 1.186-1.194, wherein the temperature of the reaction is from -10 to 50 °C, e.g., from 0 to 40 °C, or 10 °C to 30 °C, or about 25 °C; 1.196 Method 1, or any of Methods 1.1-1.195, wherein the method comprises the step of thiolating a compound 1-E for a time and under conditions effective to form a compound 3-A by reacting the compound 1-E with a thiol and a base in a suitable solvent, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19; 1.197 Method 1.196, wherein RS is selected from optionally substituted C1-6alkyl (e.g., methyl) and optionally substituted aryl (e.g., phenyl); 1.198 Method 1.197, wherein <semantics>RS<annotation encoding="application / x-tex">R^S< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl optionally substituted with one or more groups selected from C1-6alkoxy, halogen, C1-6alkyl, and aryl (e.g., phenyl), optionally wherein RS is methyl, ethyl or isopropyl; 1.199 Method 1.197, wherein RS is aryl optionally substituted with one or more groups selected from C1-6alkoxy, halogen, C1-6alkyl, and aryl (e.g., phenyl), optionally wherein RS is phenyl or tolyl; 1.200 Method 1.197, wherein RS is 4-tolyl; 1.201 Any of Methods 1.196-1.200, wherein the thiol is RS-SH (e.g., methanethiol, benzenethiol, or 4-methylbenzenethiol); 1.202 Any of Methods 1.196-1.201, 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, or 1,4-diazabicyclo[2.2.2]octane), and aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, imidazole, or 1-methylimidazole); 1.203 Method 1.202, wherein the base is triethylamine or N,N-diisopropylethylamine; 1.204 Any of Methods 1.196-1.203, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 1.205 Method 1.204, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.206 Method 1.204, wherein the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, or isopropyl acetate) and nitriles (e.g., acetonitrile); 1.207 Method 1.204, wherein the nonpolar solvent is a halogenated solvent, optionally wherein the solvent is dichloromethane; 1.208 Any of Methods 1.196-1.207, wherein the temperature of the reaction is from <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to 50 °C, e.g., from 0 to 30 °C, or 10 °C to 20 °C, or about 25 °C; 1.209 Method 1, or any of Methods 1.1-1.208, wherein the method comprises the step of reducing unsaturated thio compound 3-A to thio alcohol compound 3-B, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, Rx is defined as in Method 1.18 or 1.19, and RS is defined as in any of Methods 1.197-1.200; 1.210 Method 1.209, wherein the reduction is carried out by reacting the compound 3-A with a reducing agent and a Lewis acid catalyst, in a suitable solvent; 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 agent (e.g., sodium borohydride, lithium borohydride, or lithium triethylborohydride), an aluminum hydride agent (e.g., lithium aluminum hydride, diisobutylaluminum hydride, or lithium tri-t- butoxyaluminum hydride), a hydrogen source (e.g., isopropanol) with a transfer hydrogenation agent (e.g., <semantics>RuCl[(R,R)<annotation encoding="application / x-tex">RuCl[(R,R)< / annotation>< / semantics>-Tsdpen](p-cymene), <semantics>RuCl[(S,S)<annotation encoding="application / x-tex">RuCl[(S,S)< / annotation>< / semantics>-Tsdpen](p-cymene), an aluminum alkoxide agent in an alcoholic solvent (e.g., aluminum triisopropoxide in ethanol), and a reductase enzyme (e.g., a ketoreductase); 1.212 Method 1.211, wherein the reducing agent is sodium borohydride; 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; 1.214 Method 1.213, wherein the Lewis acid is cerium(III) chloride, e.g., cerium(III) chloride heptahydrate or anhydrous cerium(III) chloride; 1.215 Any of Methods 1.209-1.214, wherein the suitable solvent is a polar protic solvent or nonpolar solvent; 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); 1.217 Method 1.215, wherein the suitable solvent is a nonpolar solvent, such as an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), a hydrocarbon solvent (e.g., toluene, n-hexane, n-heptane), or a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 1.218 Method 1.215, wherein the solvent is ethanol; 1.219 Any of Methods 1.209-1.218, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to 30 °C, e.g., from −20 to 20 °C, or −10 to 10 °C; 1.220 Method 1, or any of Methods 1.1-1.219, wherein the method comprises the step of reacting a compound 3-B with an alkylating agent, and optionally a base, in a suitable solvent for a time and under conditions effective to form an ether compound 3-C, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, Rx is defined as in Method 1.18 or 1.19, RS is defined as in any of Methods 1.197-1.200, and wherein R5 is selected from hydrogen, C1-6alkyl, – (CH2CH2O)pR7, C1-6haloalkyl, or C3-10cycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, or C3- 10cycloalkyl, are optionally substituted with 1-5 R10 groups (R7 and R10 are as defined for the Compound of Formula I); 1.221 Method 1.220, wherein R5 is selected from C1-6alkyl and C1-6haloalkyl, each optionally substituted with 1-3 groups selected from halogen, oxo, C3-6cycloalkyl, and 4-6 membered heterocycloalkyl; 1.222 Method 1.221, wherein R5 is C1-6alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl) optionally substituted with 1-3 halogen (e.g., fluoro); 1.223 Method 1.222, wherein R5 is methyl; 1.224 Any of Methods 1.220-1.223, wherein the alkylating agent is a compound of the formula <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>-X, wherein X is selected from Cl, Br, I, OS(O)2OR5, and OSO2-L wherein L is C1-6alkyl, optionally substituted aryl, or haloC1-6alkyl; 1.225 Method 1.224, wherein the alkylating agent is selected from an alkyl bromide, alkyl chloride, alkyl iodide, alkyl triflate, alkyl tosylate, alkyl mesylate, alkyl nosylate, alkyl benzenesulfonate, and dialkyl sulfate; 1.226 Method 1.224, wherein the alkylating agent is selected from methyl iodide, methyl triflate, methyl tosylate and dimethyl sulfate; 1.227 Any of Methods 1.220-1.226, wherein the reaction further comprises a base selected from inorganic hydrides (e.g., sodium hydride, potassium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t- pentoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), and amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, or potassium diisopropylamide); 1.228 Method 1.227, wherein the base is sodium hydride; 1.229 Any of Methods 1.220-1.228, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, or n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.231 Method 1.229, wherein the polar protic solvent is an alcoholic solvent (e.g., tert-butanol, tert-amyl alcohol), optionally in combination with water; 1.232 Method 1.229, wherein the polar aprotic solvent is selected from N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, optionally in combination with water; 1.233 Method 1.229, wherein the suitable solvent is tetrahydrofuran; 1.234 Any of Methods 1.220-1.233, wherein the temperature of the reaction is from -80 to 50 °C, e.g., from -45 to 10 °C, or -10 °C to 10 °C, or 10 to 20 °C; 1.235 Method 1, or any of Methods 1.1-1.234, wherein the method comprises the step of treating a compound 3-C in a suitable solvent with an S-oxidizing reagent for a time and under conditions effective to form an N-tosylsulfinimidoyl compound 3-D, wherein Rs is defined as in any of Methods 1.197-1.200, wherein PG is defined as in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19, and wherein R5 is defined as in any of Methods 1.220-1.223; 1.236 Method 1.235, wherein <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl, ethyl, isopropyl, propyl, tert-butyl) optionally substituted with 1-3 halogen (e.g., fluoro); 1.237 Method 1.236, wherein R5 is methyl, ethyl, or isopropyl, optionally, wherein R5 is methyl; 1.238 Any of Methods 1.235-1.237, wherein the S-oxidizing agent is selected from N-chloro-4- methylbenzenesulfonamide, or a salt thereof, N-chlorobenzenesulfonamide, or a salt thereof, (tosylimido)iodobenzene, and p-tosylamide / phenyliodine diacetate; 1.239 Method 1.238, wherein the agent is sodium N-chloro-4-methylbenzenesulfonamide (Chloramine-T); 1.240 Any of Methods 1.235-1.239, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 1.241 Method 1.240, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, or n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene); 1.242 Method 1.240, wherein the polar protic solvent is an alcoholic solvent (e.g., methanol, ethanol, isopropanol, n-butanol, tert-butanol, or tert-amyl alcohol); 1.243 Method 1.240, wherein the polar aprotic solvent is selected from N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and a nitrile (e.g., acetonitrile); 1.244 Method 1.240, wherein the suitable solvent is acetonitrile; 1.245 Any of Methods 1.235-1.244, wherein the temperature of the reaction is from 0 to 50 °C, e.g., from 10 to 30 °C, or about 25 °C; 1.246 Method 1, or any of Methods 1.1-1.245, wherein the method comprises the step of thermolyzing a compound 3-D in a suitable solvent to form allylic ether compound 1-G, wherein PG is defined as provided in Method 1.2, 1.3 or 1.4, and Rx is defined as in Method 1.18 or 1.19, and wherein R5 is defined as in any of Methods 1.220-1.223; 1.247 Method 1.246, wherein R5 is C1-6alkyl (e.g., methyl, ethyl, isopropyl, propyl, or tert- butyl) optionally substituted with 1-3 halogen (e.g., fluoro); 1.248 Method 1.247, wherein R5 is methyl, ethyl, or isopropyl, optionally, wherein R5 is methyl; 1.249 Any of Methods 1.246-1.248, wherein heat is applied in the absence of any chemical reagent; 1.250 Any of Methods 1.246-1.249, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent, optionally wherein the solvent has a boiling point of at least 60 °C; 1.251 Method 1.250, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-heptane), and halogenated solvents (e.g., 1,2- dichloroethane, chloroform, chlorobenzene); 1.252 Method 1.250, wherein the polar protic solvent is an alcoholic solvent (e.g., methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, or any mixture thereof); 1.253 Method 1.250, wherein the polar aprotic solvent is selected from N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, or isopropyl acetate); 1.254 Method 1.250, wherein the suitable solvent is isopropyl acetate; 1.255 Any of Methods 1.246-1.254, wherein the temperature of the reaction is from 70 to 150 °C, e.g., from 80 to 100 °C, or about 90 °C; 1.256 Method 1, or any of Methods 1.255, wherein the Method produces a compound according to any one or more of Compounds 1-B, 1-C, 1-D, 1-E, 1-F, 1-G, 1-H, 1-I, 1-J, or 1-K; 1.257 Method 1.256, wherein in one or more of said compounds, R' is methyl, R' is H, X is Cl or Br (e.g., Br), PG is trialkylsilyl or dialkylaryl silyl (e.g., TBDPS), Rz is C1-3 alkyl (e.g., methyl), <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl (e.g., methyl), and / or <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is halogen (e.g., chloro); 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; 1.259 Method 1.258, wherein in one or more of said compounds, Rx is H, PG is trialkylsilyl or dialkylaryl silyl (e.g., TBDPS), and / or X is Cl or Br (e.g., Br); 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; 1.261 Method 1.260, wherein in one or more of said compounds, Rx is H, PG is trialkylsilyl or dialkylaryl silyl (e.g., TBDPS), RS is aryl (e.g., 4-tolyl), and / or R5 is C1-3 alkyl (e.g., methyl); 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; 1.263 Method 1.262, wherein one or more of said compounds 9-A, 9-B, 9-C, 9-D, or 9-E are made according to any one or more of Method 4 or Method 4.1, et seq., or Method 5 or Method 5.1, et seq.; 1.264 Method 1.262 or 1.263, wherein in one or more of said compounds, Rx is H, Ry is H, R2 and R3 are independently H or C1-6alkyl (e.g., methyl), R4 is H, R5 is C1-3 alkyl (e.g., methyl), R6 is halogen (e.g., chloro), and / or R12 is H, or -C(O)-R1, wherein R1 is selected from optionally substituted C1-6 alkyl (e.g., methyl), optionally substituted C1-6alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4- yl); 1.265 Method 1.264, wherein in one or more of said compounds, Rx is H, Ry is H, R2 and R3 are independently H or methyl, R4 is H, R5 is methyl, and R6 is chloro; 1.266 Method 1.265, wherein in one or more of said compounds R2 and R3 are H, or R2 and R3 1.267 are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 1.268 Method 1.266, wherein in one or more of said compounds <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 1.269 Any of Methods 1.262-1.267, wherein in compound 9-C, <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is -C(O)-<semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics> is selected from C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, –ORa, and –NRaRb; wherein <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> and <semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics> is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 1.270 Method 1.268, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 1.271 Method 1.269, wherein in compound 9-C, <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is -C(O)-<semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics> is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy); 1.272 Method 1.269, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy), for example R1 is 3- methoxy-1-methyl-1H-pyrazolyl; 1.273 Method 1, or any of Methods 1.1-1.271, wherein the Method produces a compound according to Compound I; 1.274 Method 1.272, wherein the Compound I is a compound I(a); 1.275 Method 1.272 or 1.273, wherein the Compound I or I(a) is made according to any one or more of Method 4 or Method 4.1, et seq., or Method 5 or Method 5.1, et seq.; 1.276 Any of Methods 1.272-1.274, wherein in Compound I or I(a), R2 and R3 are independently H or C1-6alkyl (e.g., methyl), R4 is H, R5 is C1-3 alkyl (e.g., methyl), R6 is halogen (e.g., chloro), and / or R12 is -C(O)-R1, and R1 is selected from C1-6alkyl, C1-6haloalkyl, C2- 6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6- 10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, and <semantics>−NRaRb<annotation encoding="application / x-tex">-NR^aR^b< / annotation>< / semantics>; wherein <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> and <semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics> is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 1.277 Method 1.275, wherein in Compound I or I(a), R2 and R3 are independently H or methyl, R4 is H, R5 is methyl, and R6 is chloro; 1.278 Method 1.276, wherein in Compound I or I(a), R2 and R3 are H, or R2 and R3 are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 1.279 Method 1.277, wherein in Compound I or <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 1.280 Any of Methods 1.275-1.278, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 1.281 Method 1.279, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy); 1.282 Method 1.280, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy), for example R1 is 3-methoxy-1-methyl-1H-pyrazolyl; 1.283 Any of Methods 1.262-1.281, wherein in one or more of compound 9-E, Compound I or compound <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, === is a double bond; 1.284 Method 1, or any of Methods 1.1-1.282, wherein the Method produces Compound 1; 1.285 Method 1, or any of Methods 1.1-1.283, wherein the method further comprises any steps described in any of Method 2, et seq., Method 3, et seq., Method 4, et seq., and Method 5, et seq..

[0019] In a third aspect, the present disclosure provides a method (Method 2) of making 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), as herein described, wherein the method comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form the product compound. Method 2 generally pertains to formation of the tetracyclic moiety (TC), including advanced intermediates 5-F, and 5-I, as well as the evolution of those intermediates to Compound 1. Without being limited in the order or combination of steps employed, the potential embodiments of Method 2 may include any steps shown in Schemes 4 and 5.

[0020] In particular embodiments, the present disclosure provides Method 2 as follows: 2.1 Method 2, wherein the method comprises the step of reacting a compound 4-A (6- hydroxy-3,4-dihydronaphthalen-1(2H)-one) with a suitable triflating reagent in a suitable solvent, with a suitable base, for a time and under conditions effective to yield a compound 4-B; 2.2 Method 2.1, wherein the triflating reagent is selected from trifluoromethanesulfonyl anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonyl fluoride, trifluoromethanesulfonic acid, N-trifluoromethanesulfonyl imidazole, and N-phenyl trifluoromethanesulfonimide; 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 (monobasic, dibasic or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic or tribasic), potassium fluoride, lithium carbonate, cesium carbonate); [Image disponible dans le document PDF, Image available in the PDF document] - Scheme 5 2.4 Any of Methods 2.1-2.3, wherein the reagent is trifluoromethanesulfonyl anhydride and the base is pyridine; 2.5 Any of Methods 2.1-2.4, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 2.6 Method 2.5, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 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); 2.8 Method 2.5, wherein the nonpolar solvent is dichloromethane; 2.9 Any of Methods 2.1-2.8, wherein the temperature of the reaction is from -80 to 40 °C, e.g., from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to <semantics>20<annotation encoding="application / x-tex">20< / annotation>< / semantics> °C, or <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> °C to <semantics>10<annotation encoding="application / x-tex">10< / annotation>< / semantics> °C, or about <semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics> °C; 2.10 Method 2, or any of Methods 2.1-2.9, wherein the methods comprises the step of reacting a compound 4-B with a halide source for a time and under conditions effective to form a compound 4-C, wherein R6 is fluoro, chloro, bromo or iodo; 2.11 Method 2.10, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is selected from chloro and bromo (e.g., wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro); 2.12 Method 2.10 or 2.11, wherein the halide source is selected from chloride salts (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, bromide salts (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, iodide salts (e.g., potassium iodide, cesium iodide, tetrabutylammonium iodide), copper(II) iodide, copper(I) iodide, fluoride salts (e.g., lithium fluoride, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride), copper(II) fluoride, and copper(I) fluoride; 2.13 Method 2.12, wherein the halide source is a chloride salt, e.g., lithium chloride; 2.14 Any of Methods 2.10-2.13, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 2.15 Method 2.14, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., 1,2- dichloroethane, chloroform, chlorobenzene); 2.16 Method 2.14, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 2.17 Method 2.14, wherein the polar aprotic solvent is N-methyl-2-pyrrolidinone; 2.18 Any of Methods 2.10-2.17, wherein the temperature of the reaction is from 50 to 250 °C, e.g., from 100 to 220 °C, or 130 °C to 150 °C, or about 140 °C; 2.19 Method 2, or any of Methods 2.1-2.18, wherein the methods comprises the step of converting a compound 4-C to a compound 4-D, wherein R6 is defined as provided in Method 2.10 or 2.11; 2.20 Method 2.19, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 2.21 Method 2.19 or 2.20, wherein the reaction comprises treating the compound 4-C with a trimethylsulfonium salt and a base in a polar aprotic solvent; 2.22 Method 2.21, wherein the trimethylsulfonium salt is trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium iodide, trimethylsulfonium tetrafluoroborate or trimethylsulfonium methyl sulfate; 2.23 Method 2.21 or 2.22, wherein the base is an inorganic base (e.g., sodium hydroxide, potassium hydroxide or lithium hydroxide); 2.24 Any of Methods 2.21-2.23, wherein the polar aprotic solvent is selected from N-methyl- 2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, and nitriles (e.g., acetonitrile); 2.25 Any of Methods 2.21-2.24, wherein the temperature of the reaction is from 0 to 50 °C, e.g., from 10 to 40 °C, or 20 °C to 30 °C; 2.26 Any of Methods 2.19-2.25, wherein the stereoisomers of the compound 4-D are not separated prior to the next step of the method; 2.27 Method 2, or any of Methods 2.1-2.26, wherein the method comprises the step of rearranging a compound 4-D for a time and under conditions effective to form a compound 4-E, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is defined as provided in Method 2.10 or 2.11; 2.28 Method 2.27, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 2.29 Method 2.27 or 2.28, wherein the reaction comprises treating the compound 4-D with a Lewis acid in a nonpolar solvent; 2.30 Method 2.29, wherein the Lewis acid is selected from boron trifluoride, boron trichloride reagent, boron tribromide, magnesium dibromide, indium chloride, bismuth triflate, and copper triflate; 2.31 Method 2.30, wherein the boron trifluoride is boron trifluoride diethyl etherate, boron trifluoride dimethyl sulfide, or boron trifluoride tetrahydrofuran complex; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.33 Method 2.32, wherein the nonpolar solvent is tetrahydrofuran; 2.34 Any of Methods 2.27-2.33, wherein the temperature of the reaction is from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> °C to 50 °C, e.g., from 0 to 30 °C, or 0 °C to 10 °C; 2.35 Any of Methods 2.27-2.34, wherein the stereoisomers of the compound 4-E are not separated prior to the next step of the method; 2.36 Method 2, or any of Methods 2.1-2.35, wherein the method comprises the step of converting a compound 4-E to a compound 5-A, wherein R6 is defined as provided in Method 2.10 or 2.11; 2.37 Method 2.36, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 2.38 Method 2.35 or 2.36, wherein the reaction comprises treating the compound 4-E with formaldehyde and a base in a polar protic solvent; 2.39 Method 2.38, wherein the formaldehyde is provided as an aqueous solution; 2.40 Method 2.38 or 2.39, wherein the base is a hydroxide base (e.g., sodium, potassium, lithium, magnesium, barium, calcium, zinc, or aluminum hydroxide); 2.41 Any of Methods 2.38-2.40, wherein the solvent is selected from methanol, ethanol, propanol, isopropanol, t-butyl alcohol, t-amyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, and water, or a combination thereof; 2.42 Method 2.41, wherein the solvent further comprises one or more of tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, and dioxane; 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; 2.44 Any of Methods 2.36-2.43, wherein the temperature of the reaction is from 0 °C to 90 °C, e.g., from 5 to 50 °C, or 10 °C to 40 °C; 2.45 Method 2, or any of Methods 2.1-2.44, wherein the methods comprises the step of acylating a compound 5-A with an acylating agent in a suitable solvent for a time and under conditions effective to form a compound 5-B, wherein R6 is defined as provided in Method 2.10 or 2.11; 2.46 Method 2.45, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 2.47 Method 2.45 or 2.46, wherein Rm is selected from H, C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC1-6alkyl (e.g., trifluoromethyl, trichloromethyl), carboxyC1-6 alkyl (e.g., 3-carboxypropyl), optionally substituted aryl (e.g., phenyl, 4- halophenyl), or optionally substituted heteroaryl (e.g., pyridyl, such as 2-pyridyl); 2.48 Method 2.47, wherein <semantics>Rm<annotation encoding="application / x-tex">R^m< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, optionally wherein <semantics>Rm<annotation encoding="application / x-tex">R^m< / annotation>< / semantics> is methyl; 2.49 Any of Methods 2.45-2.48, wherein the acylation is asymmetric, e.g., the acylation produces a product of greater than 50% e.e. before any purification (e.g., greater than 75% e.e., or greater than 85% e.e., or greater than 90% e.e., or greater than 95% e.e.); 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; 2.51 Method 2.50, wherein the acyl donor is an ester of the formula <semantics>Rm<annotation encoding="application / x-tex">R^m< / annotation>< / semantics>-C(=O)-O-Z or an anhydride of the formula <semantics>Rm<annotation encoding="application / x-tex">R^m< / annotation>< / semantics>-C(=O)-O-C(=O)-<semantics>Rm<annotation encoding="application / x-tex">R^m< / annotation>< / semantics>, wherein Z is selected from C1-6alkyl (e.g., methyl, ethyl, isopropyl), C2-6alkenyl (e.g., vinyl, allyl, methoxyvinyl, isopropenyl), and haloC1- 6alkyl (e.g., trifluoromethyl, 2,2,2-trichloroethyl); 2.52 Method 2.50, wherein the acyl donor is selected from 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, vinyl 4-bromoacetate, vinyl picolinate, glutaric anhydride, and vinyl formate; 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 Candida species (e.g., Lipozyme TL IM or Novozym 435); 2.54 Any of Methods 2.45-2.53, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 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, dioxane), and hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane); 2.56 Method 2.54, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 2.57 Method 2.54, wherein the polar aprotic solvent is ethyl acetate; 2.58 Any of Methods 2.45-2.57, wherein the temperature of the reaction is from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> °C to 110 °C, e.g., from 0 to 80 °C, or 10 °C to 40 °C; or from 20 °C to 30 °C; 2.59 Method 2, or any of Methods 2.1-2.58, wherein the method comprises the step of treating the compound 5-B in a suitable solvent with an oxidizing agent for a time and under conditions effective to form the aldehyde compound 5-C, wherein R6 is defined as provided in Method 2.10 or 2.11, and Rm is defined as in Method 2.47 or 2.48; 2.60 Method 2.59 wherein R6 is chloro and Rm is methyl; 2.61 Method 2.59 or 2.60, wherein the reaction further comprises an additive, a catalyst and / or a base; 2.62 Any of Methods 2.59-2.61, wherein the oxidizing agent is selected from sodium hypochlorite, sulfur trioxide-pyridine, dimethyl sulfoxide with an activating agent (e.g., oxalyl chloride), tetrapropylammonium perruthenate (TPAP) / N-methyl morpholine oxide, Dess-Martin Periodinane, pyridinium chlorochromate, N-chlorosuccinimide / dimethyl sulfide, iodosylbenzene, chromium trioxide, 2-iodoxybenzoic acid, bis(trifluoroacetoxy)iodobenzene, diacetoxyiodobenzene (DAIB), and manganese dioxide; 2.63 Method 2.62, wherein the DMSO activating agent is selected from oxalyl chloride, trifluoroacetic anhydride, cyanuric chloride, N,N'-dicyclohexylcarbodiimide, N,N'- diisopropylcarbodiimide, N-chlorosuccinimide, benzoic anhydride, methanesulfonic anhydride, tosic anhydride, triflic anhydride, methyl chloroglyoxylate, thionyl chloride, diphosgene, triphosgene, methanesulfonyl chloride, tosyl 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; 2.64 Any of Methods 2.61-2.63, wherein the reaction further comprises a catalyst selected from TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl), 4-hydroxy-TEMPO, polymer-supported TEMPO, 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, and 9-azanoradamantane <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>-oxyl; 2.65 Any of Methods 2.61-2.64, wherein the reaction further comprises an additive selected from sodium bromide, lithium bromide and potassium bromide; 2.66 Any of Methods 2.61-2.65, wherein the reaction further comprises a base selected from tertiary amines (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), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine), inorganic bases (e.g., sodium bicarbonate, sodium carbonate, sodium phosphate (monobasic, dibasic or tribasic), sodium acetate, potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic or tribasic), potassium acetate, potassium fluoride, lithium carbonate, lithium acetate, cesium carbonate), and hydroxide bases (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide); 2.67 Any of Methods 2.59-2.66, wherein the oxidizing agent is sulfur trioxide-pyridine; 2.68 Method 2.67, wherein the base is N,N-diisopropylethylamine; 2.69 Any of Methods 2.59-2.68, wherein the suitable solvent is water, a nonpolar solvent, and / or a polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.71 Method 2.69, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), nitriles (e.g., acetonitrile), and ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); 2.72 Method 2.69, wherein the suitable solvent is a mixture of ethyl acetate and dimethylsulfoxide; 2.73 Any of Methods 2.59-2.72, wherein the temperature of the reaction is from -80 to 50 °C, e.g., from <semantics>−40<annotation encoding="application / x-tex">-40< / annotation>< / semantics> to <semantics>40<annotation encoding="application / x-tex">40< / annotation>< / semantics> °C, or <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> °C to <semantics>10<annotation encoding="application / x-tex">10< / annotation>< / semantics> °C; 2.74 Method 2, or any of Methods 2.1-2.73, wherein the method comprises the step of treating a compound 5-C in a suitable solvent with a protecting agent for a time and under conditions effective to form the acetal compound 5-D, wherein R6 is defined as provided in Method 2.10 or 2.11, and Rm is defined as in Method 2.47 or 2.48; 2.75 Method 2.74 wherein R6 is chloro and Rm is methyl; 2.76 Method 2.74 or 2.75, wherein each Rn is independently C1-6alkyl (e.g., methyl, ethyl or isopropyl), or wherein the two <semantics>Rn<annotation encoding="application / x-tex">R^n< / annotation>< / semantics> moieties join together to form a <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> alkyl or <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> alkenyl bridge (i.e., a cyclic acetal), wherein said bridge is optionally substituted by one to four C1- 6alkyl, halogen or aryl; or wherein the two Rn moieties join together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge); 2.77 Method 2.76, wherein each Rn is independently C1-6alkyl, optionally wherein each Rn is methyl; 2.78 Method 2.76, wherein the two Rn moieties join together to form a bridge selected from - 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-, - CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o- <semantics>C6H4<annotation encoding="application / x-tex">C_6H_4< / annotation>< / semantics>)-; 2.79 Method 2.78, wherein the two Rn moieties join together to form a bridge selected from - CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, - CH(CH3) CH2CH(CH3)-, -CH2CH(CH3)CH2-,-CH2C(CH2CH3)2CH2-, -CH(C6H5)CH(C6H5), and <semantics>−CH2CH(C6H5)CH2−;<annotation encoding="application / x-tex">-CH_2CH(C_6H_5)CH_2-;< / annotation>< / semantics> 2.80 Method 2.76, wherein each Rn is the same C1-6alkyl moiety (e.g., methyl, ethyl or isopropyl), and the protecting agent is a <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alcohol or a tri(<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl) orthoformate, e.g., wherein each Rn is methyl and the protecting agent is methanol or trimethyl orthoformate; 2.81 Method 2.76, wherein the two <semantics>Rn<annotation encoding="application / x-tex">R^n< / annotation>< / semantics> moieties form a <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> alkeryl bridge, and the protecting agent is a <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics>alkyl-diol or <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> alkenyl-diol (e.g., ethylene glycol, propylene glycol); 2.82 Method 2.81, wherein the protecting agent is selected from trimethylorthoformate, trimethylorthoacetate, triethylorthoacetate, triethylorthoformate, alcohols (e.g., MeOH) or diols (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, HOCH2CH2CH2OH, HOCH2CBr2CH2OH, HOCH2(C=CH)CH2OH, HOCH2CH(Ph)CH2OH, HOCH(CH3)CH2CH(CH3)OH, HOCH2CH(CH3)CH2OH, HOCH2C(CH3)2CH2OH, HOCH2C(CH2CH3)2CH2OH, HOCH2CH2CH2CH2OH, HOCH2CH2CH2CH2CH2OH)); 2.83 Any of Methods 2.74-2.82, wherein the reaction further comprises an acid, e.g., in a catalytic amount (e.g., from 0.001 to 0.10 equivalents, or 0.01-0.05 equivalents); 2.84 Method 2.83, wherein the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p- toluenesulfonate, 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., AmberlystTM resin); 2.85 Any of Methods 2.74 to 2.84, wherein each Rn is methyl, the protecting agent is trimethyl orthoformate and the acid catalyst is p-toluenesulfonic acid; 2.86 Any of Methods 2.74 to 2.85, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2- dichloroethane, chloroform, chlorobenzene); 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 therefore, optionally wherein the solvent alcohol is the same as the protecting agent; 2.89 Method 2.86, wherein the polar aprotic solvent is selected from N-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 2.90 Method 2.86, wherein the suitable solvent is methanol; 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; 2.92 Any of Methods 2.74-2.91, wherein the temperature of the reaction is from 0 to 150 °C, e.g., from 25 to 120 °C, 0 to 60 °C, or 35 °C to 55 °C; 2.93 Method 2, or any of Methods 2.1-2.92, wherein the method comprises the step of hydrolyzing the compound 5-D in water with a base, optionally with a suitable co-solvent, for a time and under conditions effective to form the acetal compound 5-E, wherein R6 is defined as provided in Method 2.10 or 2.11, Rm is defined as in Method 2.47 or 2.48, and Rn is defined as in any of Methods 2.76-2.79; 2.94 Method 2.93 wherein R6 is chloro, Rm is methyl, and Rn are each methyl; 2.95 Method 2.93 or 2.94, wherein the base is an inorganic base, e.g., a hydroxide, bicarbonate or carbonate base; 2.96 Method 2.95, wherein the base is selected from 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; 2.97 Any of Methods 2.93-2.96, wherein the suitable co-solvent is selected from a nonpolar solvent, polar protic solvent, polar aprotic solvent, or combination thereof; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.99 Method 2.98, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol); 2.100 Method 2.98, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, and nitriles (e.g., acetonitrile); 2.101 Method 2.97, wherein the suitable solvent is a combination of tetrahydrofuran and water; 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, methyltricaprylammonium, methyltributylammonium or methyltrioctylammonium); 2.103 Any of Methods 2.93-2.102, wherein the temperature of the reaction is from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to 70 °C, e.g., from 10 to 30 °C, or 20 °C to 30 °C; 2.104 Any of Methods 2.74-2.103, wherein the compound 5-C is converted in two steps to the compound 5-E without isolation or purification of the intermediate compound 5-D; 2.105 Method 2, or any of Methods 2.1-2.104, wherein the method comprises the step of treating the compound 5-E in a suitable solvent with a transacetalization agent for a time and under conditions effective to form the acetal compound 5-E', wherein R6 is defined as provided in Method 2.10 or 2.11, and wherein each Rn of the compound 5-E is independently C1-6alkyl (e.g., methyl, ethyl or isopropyl), and wherein both Rn of the compound 5-E' are not the same as the Rn of the compound 5-E; 2.106 Method 2.105 wherein R6 is chloro; 2.107 Method 2.105 or 2.106, wherein both Rn of the compound 5-E are methyl; 2.108 Any of Methods 2.105-2.107, wherein each Rn of the compound 5-E' is independently C2-6alkyl (e.g., ethyl or isopropyl), or wherein the two Rn moieties of compound 5-E' join together to form a <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> alkyl or <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> alkenyl bridge (i.e., a cyclic acetal), wherein said bridge is optionally substituted by 1-4 halogen or aryl; or wherein the two Rn moieties join together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge); 2.109 Method 2.108, wherein each Rn of compound 5-E' is independently C2-6alkyl, optionally wherein each <semantics>Rn<annotation encoding="application / x-tex">R^n< / annotation>< / semantics> is ethyl; 2.110 Method 2.108, wherein the two Rn moieties of compound 5-E' join together to form a bridge selected from-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-, - CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o- <semantics>C6H4<annotation encoding="application / x-tex">C_6H_4< / annotation>< / semantics>)-; 2.111 Method 2.110, wherein the two Rn moieties of compound 5-E' join together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-, - CH(CH3)CH(CH3)-, -CH(CH3) CH2CH(CH3)-, -CH2CH(CH3)CH2-,-CH2C(CH2CH3)2CH2-, - <semantics>CH(C6H5)CH(C6H5)<annotation encoding="application / x-tex">CH(C_6H_5)CH(C_6H_5)< / annotation>< / semantics>, and <semantics>−CH2CH(C6H5)CH2<annotation encoding="application / x-tex">-CH_2CH(C_6H_5)CH_2< / annotation>< / semantics>-; 2.112 Method 2.108, wherein each Rn of compound 5-E' is the same C2-6alkyl moiety (e.g., ethyl or isopropyl), and the transacetalization agent is a <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alcohol, e.g., wherein each <semantics>Rn<annotation encoding="application / x-tex">R^n< / annotation>< / semantics> is ethyl and the agent is ethanol; 2.113 Method 2.108, wherein the two Rn moieties of compound 5-E' form a C2-10alkyl or C2-10 alkenyl bridge, and the transacetalization agent is a <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics>alkyl-diol or <semantics>C2−10<annotation encoding="application / x-tex">C_{2-10}< / annotation>< / semantics> alkenyl-diol (e.g., ethylene glycol, propylene glycol); 2.114 Method 2.113, wherein the transacetalization agent is selected from alcohols (e.g. ethanol and propanol), or diols (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); 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 Bronstead acid (e.g., p-toluenesulfonic acid); 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 triflate, copper triflate, 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); 2.117 Method 2.116, wherein the boron trifluoride is boron trifluoride diethyl etherate, boron trifluoride dimethyl sulfide, or boron trifluoride tetrahydrofuran complex; 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-toluenesulfonate, 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); 2.119 Any of Methods 2.105 to 2.118, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent, optionally a nonpolar solvent or polar aprotic solvent combined with a minor volume of polar protic solvent (e.g., less than 10% v / v); 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.121 Method 2.119, wherein the polar protic solvent is selected from alcohols (e.g., ethanol, propanol, isopropanol) and diols (e.g., ethylene glycol, propylene glycol), or combinations therefore, optionally wherein the solvent alcohol is the same as the transacetalization agent; 2.122 Method 2.119, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 2.123 Method 2.119, wherein the suitable solvent is 2-methyltetrahydrofuran; 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; 2.125 Any of Methods 2.105-2.124, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 25 to 120 °C, or 50 °C to 100 °C, or 70 °C to 80 °C; 2.126 Method 2, or any of Methods 2.1-2.125, wherein the method comprises the step of treating a compound 5-E or 5-E' in a suitable solvent with a 4-fluoro-3-nitrobenzoic acid or ester, for a time and under conditions effective to form an ether adduct compound 5-F, wherein R6 is defined as provided in Method 2.10 or 2.11, and wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111; 2.127 Method 2.126, wherein R6 is chloro; 2.128 Method 2.126 or 2.127, wherein both Rn moieties of the compound 5-E or 5-E' are methyl or ethyl, or the two Rn moieties of the compound 5-E or 5-E' join together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 2.129 Any of Methods 2.126-2.128, wherein <semantics>Rz<annotation encoding="application / x-tex">R^z< / annotation>< / semantics> is H, or optionally substituted <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 2.130 Method 2.129, wherein Rz is selected from H, unsubstituted C1-6alkyl (e.g., methyl), C1- 6alkoxy substituted C1-6alkyl (e.g., methoxyethyl, methoxymethyl), C1-6alkoxy substituted C1-1 6alkoxy substituted <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methoxyethoxyethyl, methoxyethoxymethyl), 5-6 membered heterocycloalkyl substituted C1-6alkyl (e.g., 2-N-(morpholino)ethyl, 2-tetrahydropyranyl), aryloxy substituted C1-6alkyl (e.g., benzyloxymethyl), halogen substituted C1-6alkyl (e.g., 2,2,2- trichloroethyl), trialkylsilyl substituted C1-6alkyl (e.g., 2-(trimethylsilyl)ethyl, triisopropylsilylmethyl), trialkylsilyl substituted C1-6alkoxy substituted C1-6alkyl (e.g., 2- (trimethylsilyl)ethoxymethyl), and aryl substituted C1-6alkyl (e.g., benzyl, 4-methylbenzyl, 4- nitrobenzyl); 2.131 Method 2.130, wherein Rz is H or unsubstituted C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl or tert-butyl); 2.132 Any of Methods 2.126-2.131, wherein the compound 5-E or 5-E' is dissolved or suspended in the suitable solvent and treated with a strong base, and optionally with a promoter (e.g., sodium iodide, tetrabutylammonium iodide); 2.133 Method 2.132, wherein the base is selected from inorganic hydrides (e.g., sodium hydride, potassium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t- butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (mono-, di- or tri-basic), sodium phosphate (mono-, di- or tri-basic)); 2.134 Method 2.133, wherein the base is selected from sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t- butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, and potassium diisopropylamide; optionally wherein the base is potassium t-butoxide; 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 after addition of the base, e.g., about 1 to 30 minutes after, or 1 to 20 minutes after, or 1 to 15 minutes after, or 1 to 10 minutes after, or 1 to 5 minutes after; 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-COORz; 2.137 Any of Methods 2.126-2.136, wherein the suitable solvent is a nonpolar solvent; 2.138 Method 2.137, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.139 Method 2.138, wherein the nonpolar solvent is tetrahydrofuran; 2.140 Any of Methods 2.126-2.139, wherein the temperature of the reaction is from -80 to 100 °C, e.g., from −45 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; 2.141 Method 2, or any of Methods 2.1-2.140, wherein the method comprises the step of treating a nitro compound 5-F or 5-G' in a suitable solvent with a reducing agent for a time and under conditions effective to yield an aniline compound 5-G or 5-H, respectively, wherein R6 is defined as provided in Method 2.10 or 2.11, wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, and wherein Rz is defined as in any of Methods 2.129 to 2.131; 2.142 Method 2.141 wherein R6 is chloro; 2.143 Method 2.141 or 2.142, wherein both Rn moieties of the compound 5-F or 5-G' are methyl or ethyl, or the two Rn moieties of the compound 5-F or 5-G' join together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 2.144 Any of Methods 2.141-2.143, wherein Rz is unsubstituted C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl or tert-butyl); 2.145 Any of Methods 2.141-2.144, wherein the reducing agent is selected from zinc, tin or iron, in an acid (e.g., in formic acid or acetic acid or HCl in the suitable solvent); 2.146 Any of Methods 2.141-2.144, wherein the reducing agent is a hydrogenation agent (e.g., hydrogen in combination with a heterogenous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex), or a phase transfer hydrogenation system); 2.147 Method 2.146, wherein the hydrogenation agent is hydrogen gas in combination with 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 ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt / C, PtO2); 2.148 Method 2.147, wherein the hydrogenation agent is hydrogen gas in combination with a Pd, Pd / C, Pd(OAc)2, Pt / C or PtO2 catalyst, optionally at 1-5 bar pressure (e.g., 1-2 bar); 2.149 Method 2.145, wherein the reducing agent is iron in acetic acid; 2.150 Any of Methods 2.141 to 2.149, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.152 Method 2.150, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or acid (e.g., formic acid, acetic acid); 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); 2.154 Method 2.150, wherein the suitable solvent is ethyl acetate or isopropyl acetate or acetic acid; 2.155 Any of Methods 2.141-2.154, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 20 to 50 °C, or 20 °C to 30 °C, or from 50 to 80 °C; 2.156 Method 2, or any of Methods 2.1-2.155, wherein the method comprises the step of treating an acetal compound 5-F or 5-G in a suitable solvent with a deprotection agent for a time and under conditions effective to yield an aldehyde compound 5-G' or 5-H, respectively, wherein R6 is defined as provided in Method 2.10 or 2.11, wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, and wherein Rz is defined as in any of Methods 2.129 to 2.131; 2.157 Method 2.156 wherein R6 is chloro; 2.158 Method 2.156 or 2.157, wherein both Rn are methyl or ethyl, or the two Rn moieties join together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and <semantics>CH2C(CH3)2CH2<annotation encoding="application / x-tex">CH_2C(CH_3)_2CH_2< / annotation>< / semantics>-; 2.159 Any of Methods 2.156-2.158, wherein Rz is unsubstituted C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl or tert-butyl); 2.160 Any of Methods 2.156-2.159, wherein the deprotection agent comprises an acid; 2.161 Method 2.160, wherein the acid is selected from HCl (e.g., aqueous HCl or HCl / methanol, HCl / isopropanol, or HCl / dioxane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium tosylate, trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium triflate), and acidic resin (e.g., Amberlyst); 2.162 Method 2.161, wherein the acid is selected from HCl (e.g., HCl / dioxane), p- toluenesulfonic acid, methanesulfonic acid, and acidic resin (e.g., Amberlyst); 2.163 Any of Methods 2.156 to 2.162, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, polar aprotic solvent, or a combination thereof; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.165 Method 2.163, wherein the polar protic solvent is water and / or an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or acid (e.g., formic acid, acetic acid); 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); 2.167 Method 2.163, wherein the suitable solvent is acetone or dioxane; 2.168 Any of Methods 2.156-2.167, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 20 to 50 °C, or 20 °C to 30 °C; 2.169 Any of Methods 2.141-2.168, as appropriate, where the intended product compound 5-H undergoes spontaneous condensation to form intermediate imine 5-H' either partly or completely, and the mixture of 5-H and 5-H' is carried forward to the next step, or the product isolated is 5-H' which is used in the next step; 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') in a suitable solvent with a reducing agent for a time and under conditions effective to yield the secondary amine compound 5-I, wherein R6 is defined as provided in Method 2.10 or 2.11, and wherein Rz is defined as in any of Methods 2.129 to 2.131; 2.171 Method 2.170 wherein R6 is chloro; 2.172 Method 2.170 or 2.171, wherein Rz is unsubstituted C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl or tert-butyl); 2.173 Any of Methods 2.170-2.172, wherein the reducing agent is selected from a hydride reducing agent, a silane reducing agent, and zinc in acid (e.g., zinc in acetic acid); 2.174 Method 2.173, wherein the reducing agent is a hydride reducing agent; 2.175 Method 2.174, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 2.176 Method 2.175, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 2.177 Any of Methods 2.174-2.176, wherein the hydride reducing agent is combined with a reagent to modulate the hydride reducing activity (e.g., titanium isopropoxide, magnesium perchlorate, or zinc chloride); 2.178 Method 2.173, wherein the silane reducing agent is triethylsilane; 2.179 Any of Methods 2.173 to 2.178, wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoracetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid); 2.180 Any of Methods 2.170-2.179, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 2.182 Method 2.180, wherein the polar aprotic solvent is selected from N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; 2.183 Method 2.180, wherein the suitable solvent is dichloromethane or dichloroethane; 2.184 Any of Methods 2.170-2.183, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to 80 °C, e.g., from 0 to 50 °C, or 20 to 30 °C, or about 20 °C; 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; 2.186 Method 2.185, wherein in any one or more of said compounds, R6 is halogen (e.g., chloro); 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; 2.188 Method 2.187, wherein in one or more of said compounds, <semantics>Rm<annotation encoding="application / x-tex">R^{m}< / annotation>< / semantics> is <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl (e.g., methyl), both Rn are methyl or ethyl, or the two Rn moieties join together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-, Rz is C1-3 alkyl (e.g., methyl), and / or R6 is halogen (e.g., chloro); 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; 2.190 Method 2.189, wherein in one or more of said compounds, <semantics>Rx<annotation encoding="application / x-tex">R^x< / annotation>< / semantics> is H, <semantics>Rz<annotation encoding="application / x-tex">R^z< / annotation>< / semantics> is H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl (e.g., methyl), <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl (e.g., methyl), and / or <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is halogen (e.g., chloro); 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; 2.192 Method 2.191, wherein one or more of said compounds 9-A, 9-B, 9-C, 9-D, or 9-E are made according to any one or more of Method 4 or Method 4.1, et seq., or Method 5 or Method 5.1, et seq.; 2.193 Method 2.191 or 2.192, wherein in one or more of said compounds, Rx is H, Ry is H, R2 and R3 are independently H or C1-6alkyl (e.g., methyl), R4 is H, R5 is C1-3 alkyl (e.g., methyl), R6 is halogen (e.g., chloro), and / or R12 is H, or -C(O)-R1, wherein R1 is selected from optionally substituted C1-6 alkyl (e.g., methyl), optionally substituted C1-6alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4- yl); 2.194 Method 2.193, wherein in one or more of said compounds, Rx is H, Ry is H, R2 and R3 are independently H or methyl, R4 is H, R5 is methyl, and R6 is chloro; 2.195 Method 2.194, wherein in one or more of said compounds R2 and R3 are H, or R2 and R3 are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 2.196 Method 2.195, wherein in one or more of said compounds <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 2.197 Any of Methods 2.191-2.196, wherein in compound 9-C, <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is -C(O)-<semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics> is selected from C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, –ORa, and –NRaRb; wherein <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> and <semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics> is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 2.198 Method 2.197, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 2.199 Method 2.198, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy); 2.200 Method 2.198, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy), for example R1 is 3- methoxy-1-methyl-1H-pyrazolyl; 2.201 Method 2, or any of Methods 2.1-2.200, wherein the Method produces a compound according to Compound I; 2.202 Method 2.201, wherein the Compound I is a compound I(a); 2.203 Method 2.201 or 2.202, wherein the Compound I or I(a) is made according to any one or more of Method 4 or Method 4.1, et seq., or Method 5 or Method 5.1, et seq.; 2.204 Any of Methods 2.201-2.203, wherein in Compound I or <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are independently H or C1-6alkyl (e.g., methyl), R4 is H, R5 is C1-3 alkyl (e.g., methyl), R6 is halogen (e.g., chloro), and / or R12 is -C(O)-R1, and R1 is selected from C1-6alkyl, C1-6haloalkyl, C2- 6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6- 10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> groups; wherein each of said <semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics> group is independently selected from <semantics>C1-6<annotation encoding="application / x-tex">C_{1\text{-}6}< / annotation>< / semantics>alkyl, <semantics>C3-<annotation encoding="application / x-tex">C_{3\text{-}}< / annotation>< / semantics> 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, –ORa, and –NRaRb; wherein Ra and Rb is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 2.205 Method 2.204, wherein in Compound I or I(a), R2 and R3 are independently H or methyl, R4 is H, R5 is methyl, and R6 is chloro; 2.206 Method 2.205, wherein in Compound I or I(a), R2 and R3 are H, or R2 and R3 are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 2.207 Method 2.206, wherein in Compound I or <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 2.208 Any of Methods 2.204-2.207, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 2.209 Method 2.208, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy); 2.210 Method 2.209, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy), for example R1 is 3-methoxy-1-methyl-1H-pyrazolyl; 2.211 Any of Methods 2.191-2.210, wherein in one or more of compound 9-E, Compound I or compound <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, === is a double bond; 2.212 Method 2, or any of Methods 2.1-2.211, wherein the Method produces Compound 1; 2.213 Method 2, or any of Methods 2.1-2.212, wherein the method further comprises any steps described in any of Method 1, et seq., Method 3, et seq., Method 4, et seq., and Method 5, et seq..

[0021] In a fourth aspect, the present disclosure provides a method (Method 3) of making 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 Compound I or I(a), as herein described, wherein the method comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form the product compound. Method 3 generally pertains to formation of the sulfonimidamide moiety (SNO), including advanced intermediates 6-H, 6-L, and 8-B, as well as the evolution of those intermediates to Compound 1. Without being limited in the order or combination of steps employed, the potential embodiments of Method 3 may include any steps shown in Schemes 6, 7 and 8. [Image disponible dans le document PDF, Image available in the PDF document] PCT / US2020 / 061517 [Image disponible dans le document PDF, Image available in the PDF document] Scheme 7 [Image disponible dans le document PDF, Image available in the PDF document] Scheme 8

[0022] In particular embodiments, the present disclosure provides Method 3 as follows: 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, for a time and under conditions effective to yield the activated compound 6-B; 3.2 Method 3.1, wherein Ry is selected from H, C1-6alkyl (e.g., methyl), and optionally substituted aryl (e.g., phenyl); 3.3 Method 3.2, wherein Ry is H; 3.4 Any of Methods 3.1-3.3, wherein R2 is hydrogen, C1-6alkyl, C1-6haloalkyl, C3- 10cycloalkyl, or 3-12 membered heterocycloalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C3- 10cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R10 groups <semantics>(R10<annotation encoding="application / x-tex">(R^{10}< / annotation>< / semantics> are as defined for Compound I); 3.5 Method 3.4, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl); 3.6 Any of Methods 3.1-3.5, wherein R3 is hydrogen, C1-6alkyl, –OR7, C1-6haloalkyl, C3- 10cycloalkyl, 3-12 membered heterocycloalkyl, –C(O)R7, or –CN, wherein said C1-6alkyl, C1- 6haloalkyl, C3-10cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1-5 R10 groups (R7 and R10 are as defined for Compound I); 3.7 Method 3.6, wherein <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl), or <semantics>−OR7<annotation encoding="application / x-tex">-OR^7< / annotation>< / semantics>, wherein <semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> 6alkyl (e.g. methyl); 3.8 Method 3.7, wherein <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl); 3.9 Any of Methods 3.1-3.9, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are both hydrogens, or wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is hydrogen and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl), or wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are both <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl); 3.10 Method 3.9, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is hydrogen and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl); 3.11 Any of Methods 3.1-3.10, wherein the group X of compound 6-B is selected from a halide (e.g., chloride, bromide, iodide), sulfonate (e.g., 4-toluenesulfonate, mesylate, nosylate, benzenesulfonate, triflate), and oxyphosphonium (e.g., oxytriphenylphosphonium), optionally wherein group X is 4-toluenesulfonate; 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, triflic anhydride, N-phenyltriflimide, triphenylphosphine dihalide, triphenylphosphine with tetrahalomethane (e.g. tetrabromomethane), and combinations thereof with metal halide salts (e.g., sodium bromide, potassium iodide); 3.13 Method 3.12, wherein the activating agent is p-toluenesulfonyl chloride; 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, dibasic or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic or tribasic), potassium fluoride, lithium carbonate, cesium carbonate); 3.15 Method 3.14, wherein the base is triethylamine; 3.16 Any of Methods 3.1-3.15, wherein the reaction further comprises a catalyst; 3.17 Method 3.16, wherein the catalyst is selected from 4-dimethylaminopyridine, N- methylimidazole, 4-pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine, optionally wherein the catalyst is 4-dimethylaminopyridine; 3.18 Any of Methods 3.1-3.17, wherein the activation agent is p-toluenesulfonyl chloride, the base is triethylamine and the catalyst is 4-dimethylaminopyridine; 3.19 Any of Methods 3.1-3.18, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 3.20 Method 3.19, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.21 Method 3.19, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 3.22 Method 3.19, wherein the nonpolar solvent is dichloromethane; 3.23 Any of Methods 3.1-3.22, wherein the temperature of the reaction is from <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to 80 °C, e.g., from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to 30 °C, or 0 °C to 20 °C; 3.24 Method 3, or any of 3.1-3.23, wherein the method comprises the step of reacting a compound 6-B with a thiol in a suitable solvent, optionally with a suitable base, for a time and under conditions effective to form a thioether 6-C, wherein Ry is defined as in Method 3.2 or 3.3, and wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and X is as defined in Method 3.11; 3.25 Method 3.24, wherein Re is selected from optionally substituted 5-10 membered heteroaryl (e.g., optionally substituted pyridyl or pyrimidinyl), –C(=NH)NH(C1-6 alkyl), – [Image disponible dans le document PDF, Image available in the PDF document] 3.26 Method 3.25, wherein Re is 5-10 membered heteroaryl, e.g., 6-membered heteroaryl (e.g., 2-pyridyl or 2-pyrimidinyl); 3.27 Any of Methods 3.24-3.26, wherein the thiol is a compound having the formula Re-SH, optionally a salt form thereof (e.g., lithium, sodium or potassium), or a tautomeric equivalent thereof (e.g., a thiourea or thiopyridone); 3.28 Method 3.27, wherein the thiol is selected from 2-mercaptopyrimidine, 2- mercaptopyridine, thiourea, N-methyl thiourea, N,N-dimethylthiourea, each optionally in the form of a salt (e.g., sodium or potassium salt); 3.29 Any of Methods 3.24-3.28, wherein the reaction comprises a base selected from inorganic hydrides (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t- pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, 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 (monobasic, dibasic or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic or tribasic)); 3.30 Method 3.29, wherein the base is an inorganic hydride (e.g., sodium hydride or potassium hydride) or alkoxide base (e.g., sodium ethoxide or sodium methoxide); 3.31 Any of Methods 3.27-3.29 wherein the thiol is 2-mercaptopyrimidine and the base is sodium ethoxide; 3.32 Any of Methods 3.24-3.31, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.34 Method 3.32, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol); 3.35 Method 3.32, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.36 Method 3.32, wherein the suitable solvent is methanol or ethanol, optionally wherein the suitable solvent is ethanol; 3.37 Any of Methods 3.24-3.36, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 20 to 80 °C, or 55 °C to 75 °C, or about 65 °C; 3.38 Method 3, or any of Methods 3.1-3.37, wherein the method comprises the step of oxidizing a thioether compound 6-C to with an oxidizing agent in a suitable solvent for a time and under conditions effective to form a sulfone compound 6-D, wherein Ry is as defined in Method 3.2 or 3.3, and wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and Re is as defined in Method 3.25 or 3.26; 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, meta-chloroperoxybenzoic acid, magnesium monoperoxyphthalate), hypochlorite salts (e.g., sodium hypochlorite, potassium hypochlorite, calcium hypochlorite), periodate salts (e.g., sodium periodate, potassium periodate), perborate salts (e.g., sodium perborate), peroxymonosulfate salts (e.g., potassium peroxymonosulfate, Oxone), permanganate salts (e.g., potassium permanganate), tetramethylperruthenate (TPAP), and any combination thereof; 3.40 Method 3.39, wherein the oxidizing agent is a peroxide (e.g., hydrogen peroxide); 3.41 Any of Methods 3.38-3.40, wherein the reaction further comprises a catalyst, e.g., selected from sodium tungstate, tungsten oxytetrachloride, tetrabutylammonium hexapolytungstate, ammonium molybdate, vanadyl acetylacetonate, manganese sulfate, phosphotungstic acid, cerium ammonium nitrate, ruthenium trichloride, methyltrioxorhenium, scandium triflate, iron, and any combination thereof; 3.42 Any of Methods 3.38-3.41 wherein the oxidizing agent is hydrogen peroxide and the catalyst is sodium tungstate; 3.43 Any of Methods 3.38-3.42, wherein the reaction further comprises an acid, e.g., a phosphorus acid, optionally in a catalytic amount (e.g., 0.01-0.1 equivalents); 3.44 Method 3.43, wherein the phosphorus 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 a phase transfer reagent, e.g., a tetraalkylammonium salt (e.g., a tetraethylammonium or tetrabutylammonium salt), optionally in a catalytic amount (e.g., 0.01-0.1 equivalents); 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; 3.47 Any of Methods 3.42-3.46, wherein the reaction further comprises phenylphosphonic acid and tetrabutylammonium hydrogen sulfate, each optionally in a catalytic amount (e.g., 0.01- 0.1 equivalents); 3.48 Any of Methods 3.38-3.47, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.50 Method 3.48, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol), water, or a combination thereof; 3.51 Method 3.48, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.52 Method 3.48, wherein the suitable solvent is toluene; 3.53 Any of Methods 3.38-3.52, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 0 to 60 °C, or 10 °C to 30 °C; 3.54 Method 3, or any of Methods 3.1-3.53, wherein the method comprises the step of reacting a compound 6-D with a base in a suitable solvent for a time and under conditions effective to form a compound 6-E, wherein Ry is as defined in Method 3.2 or 3.3, and wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and Re is as defined in Method 3.25 or 3.26; 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; 3.56 Method 3.54 or 3.55, wherein the base is selected from inorganic hydrides (e.g., sodium hydride, potassium hydride, lithium hydride, calcium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t- pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organolithium bases (e.g., methyllithium, ethyllithium, propyllithium, n-butyllithium, s- butyllithium, t-butyllithium), and inorganic carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate); 3.57 Method 3.56, wherein the base is selected from inorganic hydrides, alkoxides and and inorganic hydroxides; 3.58 Method 3.57, wherein the base is selected from sodium methoxide and potassium methoxide; 3.59 Any of Methods 3.54-3.58, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 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 the alkoxide corresponding to the alcohol (e.g., a methoxide base and methanol solvent), or the base is a hydroxide base and the solvent is water; 3.62 Method 3.59, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.63 Any of Methods 3.58 to 3.61, wherein the base is sodium methoxide or potassium methoxide and the solvent is methanol; 3.64 Any of Methods 3.54-3.63, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 0 to 60 °C, or 10 °C to 30 °C; 3.65 Any of Methods 3.54-3.64, wherein the solvents are removed from the reaction and the crude compound 6-E is washed with water and / or with organic solvents, then carried onto the next step without further purification 3.66 Method 3, or any of 3.1-3.65, wherein the method comprises the step of oxidizing a compound 6-E with a suitable oxidizing agent and a base in a suitable solvent to from a sulfonamide compound 6-F, wherein Ry is defined as in Method 3.2 or 3.3, and wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and M is as defined in Method 3.55; 3.67 Method 3.66, wherein the oxidizing agent is hydroxylamine-O-sulfonic acid, or the oxidizing agent is a combination of ammonia with an oxidant selected from iodine, N- chlorosuccinimide, N-bromosuccinimide, tert-butyl hydroperoxide, and m-chloroperoxybenzoic acid; 3.68 Method 3.67, wherein the oxidizing agent is hydroxylamine-O-sulfonic acid; 3.69 Any of Methods 3.66-3.68, wherein the base is selected from alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t- pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide), 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, dibasic or tribasic), potassium bicarbonate, potassium carbonate, potassium phosphate (monobasic, dibasic or tribasic), lithium carbonate, cesium carbonate), other alkali metal carboxylates (e.g., potassium propionate), and combinations thereof; 3.70 Method 3.69, wherein the base is sodium acetate or potassium acetate; 3.71 Any of Methods 3.66-3.70, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 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; 3.74 Method 3.71, wherein the polar aprotic solvent is selected from N-methyl-2- pyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.75 Method 3.71, wherein the suitable solvent is water; 3.76 Any of Methods 3.66-3.71, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 20 to 80 °C, or 35 °C to 55 °C, or about 45 °C; 3.77 Method 3, or any of Methods 3.1-3.76, wherein the method comprises the step of reacting a compound 6-F with a protecting agent in a suitable solvent for a time and under conditions effective to form an N-protected compound 6-G, wherein Ry is as defined in Method 3.2 or 3.3, and wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are as defined in any of Methods 3.4-3.10; 3.78 Method 3.77, wherein the protecting group <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is selected from a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C1-6alkyl, such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C1-6 6alkyl(aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), an arylcarbonyl group (e.g. benzoyl), an alkoxycarbonyl group (e.g., <semantics>−C(=O)−O−C1−6<annotation encoding="application / x-tex">-C(=O)-O-C_{1-6}< / annotation>< / semantics>alkyl, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or <semantics>−C(=O)−O−C1−6<annotation encoding="application / x-tex">-C(=O)-O-C_{1-6}< / annotation>< / semantics>alkyl(aryl), such as 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), an aryloxycarbonyl group (e.g., phenoxycarbonyl), a tertiary alkyl group (e.g., t-butyl or trityl), an C1-6alkoxy C1-6alkyl group (e.g., C1-6alkoxymethyl, such as methoxymethyl or ethoxymethyl), a C1-6alkylaryl group (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), a diarylalkyl group (e.g., C1-6alkyl(aryl)(aryl), such as diphenylmethyl), an alkylsulfonyl group (e.g., SO2C1-6alkyl, such as methanesulfonyl or isopropylsulfonyl), and an arylsulfonyl group (e.g., SO2-aryl, such as benzenesulfonyl, toluenesulfonyl); 3.79 Method 3.78, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is selected from a trialkyl silyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), a dialkylaryl silyl group (e.g., dimethylphenylsilyl), an alkyldiaryl silyl group (e.g., t-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl); 3.80 Method 3.79, wherein Rk is selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl; 3.81 Method 3.80, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is tert-butyldimethylsilyl; 3.82 Any of Methods 3.77-3.81, wherein the protecting reagent is selected from silyl chlorides (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, bromotriphenylsilane), 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), anhydrides (e.g., di- tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethylchloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane), and alkoxymethyl halides (e.g., methoxymethyl chloride); 3.83 Any of Methods 3.77-3.82, wherein the reaction further comprises a base; 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), organolithium bases (e.g., n-butyllithium, s-butyllithium, t-butyllithium), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic or tribasic), sodium phosphate (monobasic, dibasic or tribasic)); 3.85 Method 3.84, wherein the protecting agent is tert-butyldimethylsilyl chloride and the base is triethylamine; 3.86 Any of Methods 3.77-3.85, wherein the reaction further comprises a catalyst selected from 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, N-methylimidazole, imidazole, 4- pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 3.87 Any of Methods 3.77-3.86, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.89 Method 3.87, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.90 Method 3.87, wherein the nonpolar solvent is an ether, optionally, wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran; 3.91 Any of Methods <semantics>3.77−3.90<annotation encoding="application / x-tex">3.77-3.90< / annotation>< / semantics>, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to 100 °C, e.g., from −10 to 30 °C, from 0 °C to 25 °C, from 0 to 100 °C, e.g., from 20 to 80 °C, or 35 °C to 55 °C, or about 45 °C; 3.92 Method 3, or any of Methods 3.1-3.91, wherein the method comprises the step of treating a protected sulfonamide 6-G with (1) a chlorinating agent and a base in a suitable solvent, followed by (2) an ammonia source in a suitable solvent, for a time and under conditions effective to form a compound 6-H, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are as defined in any of Methods 3.4-3.10, and wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is as defined in any of Methods 3.78-3.81; 3.93 Method 3.92, wherein the chlorinating agent is a 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, e.g., sodium chloride, potassium chloride or tetrabutylammonium chloride), phenyldichlorophosphate, triphenyldichlorophosphorane, phenylphosphonic 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; 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; 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); 3.96 Method 3.95 wherein the base is N,N-diisopropylethylamine; 3.97 Any of Methods 3.92-3.96, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.99 Method 3.97, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.100 Method 3.97, wherein the nonpolar solvent is dichloromethane; 3.101 Any of Methods 3.92-3.100, wherein the ammonia source is selected from ammonia gas dissolved in any of the solvents provided in Methods 3.97-3.100, 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., tert-butyl carbamate); 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); 3.103 Any of Methods 3.92-3.102, wherein the temperature of the reaction for step (1) and step (2) is independently selected from <semantics>−40<annotation encoding="application / x-tex">-40< / annotation>< / semantics> to <semantics>60<annotation encoding="application / x-tex">60< / annotation>< / semantics> °C, <semantics>−25<annotation encoding="application / x-tex">-25< / annotation>< / semantics> to <semantics>30<annotation encoding="application / x-tex">30< / annotation>< / semantics> °C, <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to <semantics>30<annotation encoding="application / x-tex">30< / annotation>< / semantics> °C, <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to <semantics>10<annotation encoding="application / x-tex">10< / annotation>< / semantics> °C, <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to 30 °C, -10 to 10 °C, -20 to 0 °C, -10 to 0 °C, and 0 to 30 °C; 3.104 Any of Methods 3.92-3.103, wherein step (1) comprises combining the compound 6-G with the base and the suitable solvent at a temperature of -20 to 0 °C followed by addition of the chlorinating agent (or formation of the chlorinating agent in situ), stirring the reaction for a period of time from 0.5 hours to 10 hours (e.g., 1 to 5 hours), followed by step (2) which comprises cooling the reaction to <semantics>−40<annotation encoding="application / x-tex">-40< / annotation>< / semantics> to <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> °C, adding the ammonia source and stirring the reaction for a period of time from 0.1 to 5 hours (e.g., 0.1 to 2 hours) at a temperature ranging from <semantics>−10<annotation encoding="application / x-tex">-10< / annotation>< / semantics> to <semantics>10<annotation encoding="application / x-tex">10< / annotation>< / semantics> °C; 3.105 Method 3, or any of Methods 3.1-3.104, wherein the method comprises the step of reacting a monoprotected sulfonimidamide compound 6-H with a protecting agent in a suitable solvent for a time and under conditions effective to yield diprotected sulfonimidamide compound 6-I, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is as defined in any of Methods 3.78-3.81, provided that <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is not the same as <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>; 3.106 Method 3.105 wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is selected from a trialkyl silyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), a dialkylaryl silyl group (e.g., dimethylphenylsilyl), an alkyldiaryl silyl group (e.g., t-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl); 3.107 Method 3.106, wherein Rk is selected from tert-butyldimethylsilyl, tert- butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl; 3.108 Method 3.107, wherein Rk is tert-butyldimethylsilyl; 3.109 Any of Methods 3.105-3.108, wherein the protecting group Rp is selected from a silyl group, an alkylcarbonyl group (e.g., <semantics>−C(=O)−C1−6<annotation encoding="application / x-tex">-C(=O)-C_{1-6}< / annotation>< / semantics>alkyl, such as acetyl, isobutyryl, pivaloyl, or - C(=O)-C1-6alkyl(aryl), such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), an arylcarbonyl group (e.g. benzoyl), an alkoxycarbonyl group (e.g., -C(=O)-O-C1-6alkyl, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, or <semantics>−C(=O)−O−C1−<annotation encoding="application / x-tex">-C(=O)-O-C_{1-}< / annotation>< / semantics> 6alkyl(aryl), such as 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl, an aryloxycarbonyl group (e.g., phenoxycarbonyl), a tertiary alkyl group (e.g., t-butyl or trityl), an C1-6alkoxy C1- 6alkyl group (e.g., C1-6alkoxymethyl, such as methoxymethyl or ethoxymethyl), a C1-6alkylaryl group (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), a diarylalkyl group (e.g., C1- 6alkyl(aryl)(aryl), such as diphenylmethyl), an alkylsulfonyl group (e.g., SO2C1-6alkyl, such as methanesulfonyl or isopropylsulfonyl), and an arylsulfonyl group (e.g., SO2-aryl, such as benzenesulfonyl, toluenesulfonyl); 3.110 Method 3.109, wherein Rp is selected from -C(=O)-C1-6alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g. benzoyl), -C(=O)-O-C1-6alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-O-C1-6alkyl(aryl) (e.g., 2- phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and <semantics>−C(=O)<annotation encoding="application / x-tex">-C(=O)< / annotation>< / semantics>-O-aryl (e.g., phenoxycarbonyl); 3.111 Method 3.110, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 3.112 Method 3.111, wherein Rp is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 3.113 Any of Methods 3.105-3.112, wherein the protecting reagent is selected from silyl chlorides (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide, tert-butyldimethylsilyl bromide, bromodimethylphenylsilane, bromotriphenylsilane), 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), anhydrides (e.g., di- tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethylchloroformate), alkyl halides (e.g., trityl chloride, tert-butyl chloride, benzyl bromide, benzyl chloride, 2-chloro-2-phenylpropane), and alkoxymethyl halides (e.g., methoxymethyl chloride); 3.114 Any of Methods 3.105-3.112, wherein the protecting agent is a C1-6alkyl or C1- 6alkyl(aryl) 1H-imidazole-1-carboxylate, optionally made in situ by reacting the corresponding C1-6alkyl alcohol or C1-6alkyl(aryl) alcohol with carbonyldiimidazole (CDI), in a suitable solvent, followed by addition of the compound 6-H; 3.115 Method 3.113 or 3.114, wherein the protecting agent is selected from a symmetrical or unsymmetrical carbonate (e.g., di-tert-butyldicarbonate or 4-nitrophenyl (1-phenylethyl) carbonate), a C1-6alkyl or C1-6alkyl(aryl) chloroformate (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate, 1-phenylethylchloroformate) or a <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl(aryl) 1H-imidazole-1-carboxylate; 3.116 Method 3.115, wherein the protecting agent is selected from 1-phenylethyl-1H- imidazole-1-carboxylate (optionally made in situ from 1-phenylethanol and CDI), 4-nitrophenyl- (1-phenylethyl) carbonate, and 1-phenylethyl chloroformate, wherein each of said reagents is optionally in (R) or (S) form; 3.117 Any of Methods 3.105-3.116, wherein the reaction further comprises a base; 3.118 Method 3.117, 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), organolithium bases (e.g., n-butyllithium, s-butyllithium, t-butyllithium), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic or tribasic), sodium phosphate (monobasic, dibasic or tribasic)); 3.119 Method 3.118, wherein the base is an inorganic hydride (e.g., sodium hydride, potassium hydride, lithium hydride), amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), or organolithium base (e.g., n-butyllithium, s- butyllithium, t-butyllithium); 3.120 Method 3.119, wherein the protecting agent is (S)-1-phenylethyl 1H-imidazole-1- carboxylate (optionally made in situ from (S)-1-phenylethanol and CDI), and the base is lithium hexamethyldisilazide; 3.121 Any of Methods 3.105-3.120, wherein the reaction further comprises a catalyst selected from 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, N-methylimidazole, imidazole, 4- pyrrolidinopyridine, 4-piperidinopyridine, and 9-azajulolidine; 3.122 Any of Methods 3.105-3.121, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.124 Method 3.122, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.125 Method 3.122, wherein the nonpolar solvent is an ether, optionally, wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran; 3.126 Any of Methods 3.105-3.125, wherein the temperature of the reaction is from -30 to 100 °C, e.g., from –20 to 60 °C, from –20 to 10 °C, from 0 °C to 25 °C, from 0 to 100 °C, e.g., from 20 to 80 °C, or 35 °C to 55 °C; 3.127 Method 3, or any of Methods 3.1-3.126, wherein the method comprises the step of reacting a compound 6-I with a deprotecting agent in a suitable solvent for a time and under conditions effective to form a compound 6-J, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, wherein Rk is as defined in any of Methods 3.78-3.81, and wherein Rp is as defined in any of Methods 3.109-3.112, provided that <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is not the same as <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics>; 3.128 Method 3.127 wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is selected from a trialkyl silyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), a dialkylaryl silyl group (e.g., dimethylphenylsilyl), an alkyldiaryl silyl group (e.g., t-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl); 3.129 Method 3.128, wherein Rk is selected from tert-butyldimethylsilyl, tert- butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl; 3.130 Method 3.129, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is tert-butyldimethylsilyl; 3.131 Any of Methods 3.127-3.130, Rp is selected from -C(=O)-C1-6alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g. benzoyl), -C(=O)-O-C1-6alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-O-C1-6alkyl(aryl) (e.g., 2- phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and <semantics>−C(=O)<annotation encoding="application / x-tex">-C(=O)< / annotation>< / semantics>-O-aryl (e.g., phenoxycarbonyl); 3.132 Method 3.131, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 3.133 Method 3.132, wherein Rp is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 3.134 Method 3.133, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is tert-butyldimethylsilyl and <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 3.135 Any of Methods 3.127-3.134, wherein the deprotection reagent 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 hydrogenation agent (e.g., hydrogen in combination with a heterogenous 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; 3.136 Method 3.135, wherein the deprotection reagent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, sodium phosphate (mono-, di- or tri-basic), potassium phosphate (mono-, di- or tri-basic), hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), sulfuric acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, 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); 3.137 Any of Methods 3.127-3.136, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is a silyl group, and the deprotection agent is fluoride agent or an inorganic base; 3.138 Method 3.137, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is a trialkyl silyl group (e.g., tripropylsilyl, triisopropylsilyl, t- butyldiethylsilyl, t-butyldimethylsilyl), and the deprotection reagent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium bicarbonate, potassium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, lithium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine trihydrofluoride, tetrabutylammonium fluoride, tetrabutylammonium difluorotriphenylsilicate, and tetrabutylammonium difluorotriphenylsilicate; 3.139 Method 3.138, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is t-butyldimethylsilyl and the deprotection agent is selected from sodium carbonate, potassium carbonate and cesium carbonate; 3.140 Any of Methods 3.127-3.139, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent, or a combination thereof; 3.141 Method 3.140, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.142 Method 3.140, wherein the polar protic solvent is an alcoholic 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; 3.143 Method 3.140, wherein the polar aprotic solvent is selected from N,N- dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile), optionally in combination with water; 3.144 Method 3.140, wherein the suitable solvent is tetrahydrofuran or 2- methyltetrayhydrofuran, optionally in combination with water; 3.145 Any of Methods 3.127-3.144, wherein the temperature of the reaction is from -15 to 70 °C, e.g., from –5 to 40 °C, or 0 °C to 30 °C, or from 10 °C to 30 °C, or from 20 °C to 70 °C, 40 °C to 60 °C, or about 50 °C; 3.146 Method 3, or any of Methods 3.1-3.145, wherein the method comprises the step of acylating a compound 6-J with an acylating agent and a base for a time and under conditions effective to form a compound 6-K, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined in any of Methods 3.109-3.112; 3.147 Method 3.146, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 3.148 Method 3.147, wherein Rp is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 3.149 Any of Methods 3.146-3.148, wherein R'' is selected from H, C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC1-6alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl); 3.150 Method 3.149, wherein R'' is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 3.151 Method 3.150, wherein R'' is methyl; 3.152 Any of methods 3.146-3.151, wherein 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''), or a combination of a carboxylic acid (e.g., R''-COOH) with an activator or coupling reagent (e.g., oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling reagent (e.g., HATU, T3P, isobutyl chloroformate); 3.153 Method 3.152, wherein R'' is C1-6alkyl (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''); 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); 3.155 Method 3.154 wherein the base is pyridine; 3.156 Any of Methods 3.146-3.155, wherein the reaction further comprises a catalyst, e.g., selected from 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, and N,N-dimethylformamide; 3.157 Any of Methods 3.146-3.156, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.159 Method 3.157, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 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); 3.160 Method 3.157, wherein the nonpolar solvent is dichloromethane; 3.161 Any of Methods 3.146-3.160, wherein the temperature of the reaction is from -20 to 60 °C, e.g., from –5 to 40 °C, or 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 a compound 6-K in a suitable solvent for a time and under conditions effective to yield a mixture of hydrolyzed stereoisomer 6-L and unreacted stereoisomer 6-L', wherein Ry is defined as in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is defined as in any of Methods 3.109-3.112; 3.163 Method 3.162, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 3.164 Method 3.163, wherein Rp is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 3.165 Method 3.164, wherein R'' is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 3.166 Method 3.165, wherein R'' is methyl; 3.167 Any of Methods 3.162-3.166, wherein the reaction comprises treating the compound 6-K with an enzyme, such as a lipase or protease, e.g., a bacterial or fungal lipase or protease; 3.168 Method 3.167, wherein the lipase or protease is derived from Candida species (e.g., Candida rugosa), Pseudomonas species (e.g., Pseudomonas stutzeri), or Rhizomucor species (e.g., Rhizomucor miehei); 3.169 Any of Methods 3.162-3.168, wherein the reaction further comprises an aqueous buffer, e.g., sodium phosphate buffer or potassium phosphate buffer, optionally having a pH of 5-8 (e.g., about pH 7); 3.170 Any of Methods 3.162-3.169, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent, water or a combination thereof; 3.171 Method 3.170, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.172 Method 3.170, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and nitriles (e.g., acetonitrile); 3.173 Method 3.170, wherein the nonpolar solvent is methyl isobutyl ketone, in combination with aqueous sodium phosphate buffer (pH about 7); 3.174 Any of Methods 3.162-3.173, wherein the temperature of the reaction is from 0 to 50 °C, e.g., from 10 to 40 °C, or 10 °C to 30 °C, or about 20 °C; 3.175 Any of Methods 3.162-3.174, wherein the compound 6-L and the compound 6-L' are purified and separately isolated; 3.176 Method 3, or any of Methods 3.1-3.175, wherein the method comprises the step of converting a compound 6-B to a compound 6-B' by substituting the group X with a different group X, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are 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, mesylate, nosylate, benzenesulfonate, triflate); 3.177 Method 3.176, wherein group X of compound 6-B' is a halide (e.g., chloride, bromide or iodide); 3.178 Method 3.177, wherein group X of compound 6-B is 4-toluenesulfonate and group X of compound 6-B' is bromide; 3.179 Method 3.176, 3.177 or 3.178, wherein the method comprises treating the compound 6-B with an inorganic halide salt (e.g., the lithium, sodium, potassium or cesium salt of chloride, bromide or iodide) in a suitable solvent; 3.180 Method 3.179, wherein the inorganic halide is lithium bromide; 3.181 Any of Methods 3.176-3.180, wherein the suitable solvent is a nonpolar solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.183 Method 3.181, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 3.184 Method 3.181, wherein the polar aprotic solvent is N-methyl-2-pyrrolidinone; 3.185 Any of Methods 3.176-3.184, wherein the temperature of the reaction is from 20 to 120 °C, e.g., from 20 to 100 °C, or 40 °C to 60 °C; 3.186 Method 3, or any of 3.1 to 3.185, wherein the method comprises the step of treating a compound 6-B or 6-B' with a sulfite source for a time and under conditions effective to yield sulfonic acid 7-A, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any 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, mesylate, nosylate, benzenesulfonate, triflate), and oxyphosphonium (e.g., oxytriphenylphosphonium), or the group X of compound 6-B' is halide (e.g., bromide, chloride or iodide); 3.187 Method 3.186, wherein the group X of compound 6-B or 6-B' is halide, optionally wherein the halide is bromide or iodide; 3.188 Method 3.186 or 3.187 wherein the sulfite source is an inorganic sulfite or bisulfite salt, e.g., the lithium, sodium, potassium or cesium salt of sulfite or bisulfite; 3.189 Method 3.188 wherein the sulfite source is sodium sulfite; 3.190 Any of Methods 3.186-3.189, wherein the suitable solvent is a nonpolar solvent, polar aprotic solvent, water, or a combination thereof; 3.191 Method 3.190, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.192 Method 3.190, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, nitriles (e.g., acetonitrile), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate); 3.193 Method 3.190, wherein the solvent is a mixture of acetone and water; 3.194 Any of Methods 3.186-3.193, wherein the temperature of the reaction is from 20 to 120 °C, e.g., from 40 to 100 °C, or 50 °C to 70 °C; 3.195 Method 3, or any of Methods 3.1-3.194, wherein the method comprises the step of treating a sulfonic acid 7-A with (1) a chlorinating agent and optionally a catalyst in a suitable solvent, followed by (2) an ammonia source in a suitable solvent, for a time and under conditions effective to form a sulfonamide compound 6-F, wherein Ry is as defined in Method 3.2 or 3.3, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are as defined in any of Methods 3.4-3.10; 3.196 Method 3.195, wherein the chlorinating agent is selected from oxalyl chloride, thionyl chloride, sulfuryl chloride, phosphorus (V) oxychloride, phosphorus trichloride, and phosphorus pentachloride; 3.197 Method 3.196, wherein the chlorinating agent is oxalyl chloride; 3.198 Any of Methods 3.195-3.197, wherein the reaction step (1) further comprises a catalyst, e.g., 4-dimethylaminopyridine or N,N-dimethylformamide; 3.199 Any of Methods 3.195-3.198, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent, or wherein the solvent is the neat chlorinating agent (e.g., thionyl chloride); 3.200 Method 3.199, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.201 Method 3.199, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 3.202 Method 3.199, wherein solvent is tetrahydrofuran; 3.203 Any of Methods 3.195-3.302, wherein the ammonia source is selected from ammonia gas dissolved in any of the solvents provided in Methods 3.199-3.202, gaseous ammonia, aqueous ammonia, and ammonia surrogates (e.g., hexamethyldisilazane); 3.204 Method 3.203, wherein the ammonia source is aqueous ammonia; 3.205 Any of Methods 3.195-3.204, wherein the temperature of the reaction for step (1) and step (2) is independently selected from -10 to 100 °C, 0 to 50 °C, 0 to 30 °C, and 20 to 30 °C; 3.206 Any of Methods 3.195-3.205, wherein step (1) comprises combining the compound 7-A with the catalyst and the suitable solvent at a temperature of 0 to 30 °C followed by addition of the chlorinating agent, stirring the reaction for a period of time from 0.1 hours to 2 hours (e.g., 0.5 to 1 hour), followed by step (2) which comprises adding the reaction mixture from step (1) into a reactor containing the ammonia source and stirring the reaction for a period of time from 0.1 to 2 hours (e.g., 0.1 to 0.5 hours) at a temperature ranging from 10 to 30 °C; 3.207 Method 3, or any of Methods 3.1-3.206, wherein the method comprises the step of acylating a compound 6-H with an acylating agent and a base in a suitable solvent for a time and under conditions effective to form the di-acyl compound 8-A, wherein Ry is defined as in Method 3.2 or 3.3, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are as defined in any of Methods 3.4-3.10, and wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is a silyl group; 3.208 Method 3.207 wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is selected from a trialkyl silyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), a dialkylaryl silyl group (e.g., dimethylphenylsilyl), an alkyldiaryl silyl group (e.g., t-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl); 3.209 Method 3.208, wherein Rk is selected from tert-butyldimethylsilyl, tert- butyldiphenylsilyl, dimethylphenylsilyl, trimethylsilyl, triethylsilyl and triisopropylsilyl; 3.210 Method 3.209, wherein <semantics>Rk<annotation encoding="application / x-tex">R^k< / annotation>< / semantics> is tert-butyldimethylsilyl; 3.211 Any of Methods 3.207-3.210, wherein R'' is selected from H, C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl), haloC1-6alkyl (e.g., trifluoromethyl, trichloromethyl), optionally substituted aryl (e.g., phenyl, 4-bromophenyl), and optionally substituted heteroaryl (e.g., 2-pyridyl), 3.212 Method 3.211, wherein R'' is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 3.213 Method 3.212, wherein R" is methyl; 3.214 Any of methods 3.207-3.213, wherein 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''), or a combination of a carboxylic acid (e.g., R''-COOH) with an activator or coupling reagent (e.g., oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling reagent (e.g., HATU, T3P, isobutyl chloroformate); 3.215 Method 3.214, wherein R'' is C1-6alkyl (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''); 3.216 Method 3.215, wherein R'' is methyl and the acylating agent is acetyl chloride; 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, collidine, 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 t-butoxide, potassium methoxide, potassium ethoxide, potassium t- butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, lithium isopropoxide); 3.218 Method 3.217 wherein the base is an aromatic amine selected from pyridine, pyrimidine, pyridazine, and pyrazine; 3.219 Any of Methods 3.207-3.218, wherein the reaction further comprises a catalyst, e.g., selected from 4-dimethylaminopyridine, imidazole, N-methylimidazole, triphenylphosphine oxide, 1-hydroxy-7-azabenzotriazole, and N,N-dimethylformamide; 3.220 Any of Methods 3.207-3.219, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.222 Method 3.220, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 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); 3.223 Method 3.220, wherein the solvent is acetonitrile; 3.224 Any of Methods 3.207-3.223, wherein the temperature of the reaction is from <semantics>−20<annotation encoding="application / x-tex">-20< / annotation>< / semantics> to 50 °C, e.g., from -5 to 40 °C, or 0 °C to 30 °C, or from 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 a compound 8-A in a suitable solvent for a time and under conditions effective to yield a hydrolyzed stereoisomer 8-B, wherein Ry is defined as in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein R'' is as defined in any of Methods 3.211-3.213; 3.226 Method 3.225, wherein R" is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 3.227 Method 3.226, wherein R" is methyl; 3.228 Any of Methods 3.225-3.227, wherein the reaction comprises treating the compound 8-B with an enzyme, such as a lipase or protease, e.g., a bacterial or fungal lipase or protease; 3.229 Method 3.228, wherein the lipase or protease is derived from Carica species (e.g., Carica papaya); 3.230 Any of Methods 3.225-3.229, wherein the reaction further comprises an aqueous buffer, e.g., sodium phosphate buffer or potassium phosphate buffer, optionally having a pH of 5-8 (e.g., about pH 7); 3.231 Any of Methods 3.225-3.230, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent, water or a combination thereof; 3.232 Method 3.231, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 3.233 Method 3.231, wherein the polar aprotic solvent is selected from N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and nitriles (e.g., acetonitrile); 3.234 Method 3.231, wherein the nonpolar solvent is methyl isobutyl ketone, in combination with aqueous sodium phosphate buffer (pH about 7); 3.235 Any of Methods 3.225-3.234, wherein the temperature of the reaction is from 0 to 50 °C, e.g., from 10 to 40 °C, or 20 °C to 40 °C, or about 30 °C; 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; 3.237 Method 3.236 wherein in any one or more of said compounds, Ry is H, R2 is H or C1- 3alkyl (e.g., methyl), R3 is H or C1-3alkyl (e.g., methyl), X is 4-toluenesulfonyl or bromo, Re is 2- pyrimidyl, M is Na, Rk is trialkylsilyl (e.g., tert-butyldimethylsilyl), Rp is -C(=O)-O-C1- 6alkyl(aryl) (e.g., 1-phenylethoxycarbonyl, optionally in (R) or (S) form), and R'' is C1-3alkyl (e.g., methyl); 3.238 Method 3.237, wherein in one or more of said compounds R2 and R3 are H, or R2 and R3 are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 3.239 Method 3.238, wherein in one or more of said compounds <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 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; 3.241 Method 3.240, wherein one or more of said compounds 9-A, 9-B, 9-C, 9-D, or 9-E are made according to any one or more of Method 4 or Method 4.1, et seq., or Method 5 or Method 5.1, et seq.; 3.242 Method 3.240 or 3.241, wherein in one or more of said compounds, Rx is H, Ry is H, R2 and R3 are independently H or C1-6alkyl (e.g., methyl), R4 is H, R5 is C1-3 alkyl (e.g., methyl), R6 is halogen (e.g., chloro), and / or R12 is H, or -C(O)-R1, wherein R1 is selected from optionally substituted C1-6 alkyl (e.g., methyl), optionally substituted C1-6alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl-3-methoxy-1H-pyrazol-4- yl); 3.243 Method 3.242, wherein in one or more of said compounds, Rx is H, Ry is H, R2 and R3 are independently H or methyl, R4 is H, R5 is methyl, and R6 is chloro; 3.244 Method 3.243, wherein in one or more of said compounds <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are H, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 3.245 Method 3.244, wherein in one or more of said compounds <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 3.246 Any of Methods 3.240-3.245, wherein in compound 9-C, <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is -C(O)-<semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics> is selected from C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, –ORa, and –NRaRb; wherein <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> and <semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics> is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 3.247 Method 3.246, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 3.248 Method 3.247, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy); 3.249 Method 3.247, wherein in compound 9-C, R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy), for example R1 is 3- methoxy-1-methyl-1H-pyrazolyl; 3.250 Method 3, or any of Methods 3.1-3.249, wherein the Method produces a compound according to Compound I; 3.251 Method 3.250, wherein the Compound I is a compound I(a); 3.252 Method 3.251 or 3.251, wherein the Compound I or I(a) is made according to any one or more of Method 4 or Method 4.1, et seq., or Method 5 or Method 5.1, et seq.; 3.253 Any of Methods 3.250-3.252, wherein in Compound I or <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are independently H or C1-6alkyl (e.g., methyl), R4 is H, R5 is C1-3 alkyl (e.g., methyl), R6 is halogen (e.g., chloro), and / or R12 is -C(O)-R1, and R1 is selected from C1-6alkyl, C1-6haloalkyl, C2- 6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6- 10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, –ORa, and –NRaRb; wherein Ra and Rb is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 3.254 Method 3.253, wherein in Compound I or I(a), R2 and R3 are independently H or methyl, R4 is H, R5 is methyl, and R6 is chloro; 3.255 Method 3.254, wherein in Compound I or I(a), R2 and R3 are H, or R2 and R3 are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 3.256 Method 3.255, wherein in Compound I or I(a), R2 is H and R3 is methyl; 3.257 Any of Methods 3.253-3.256, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 3.258 Method 3.257, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy); 3.259 Method 3.258, wherein in Compound I or I(a), R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 C1-6alkyl (e.g., methyl) or C1-6alkoxy (e.g., methoxy), for example <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is 3-methoxy-1-methyl-1H-pyrazolyl; 3.260 Any of Methods 3.240-3.259, wherein in one or more of compound 9-E, Compound I or compound <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, === is a double bond; 3.261 Method 3, or any of Methods 3.1-3.260, wherein the Method produces Compound 1; 3.262 Method 3, or any of Methods 3.1-3.261, wherein the method further comprises any steps described in any of Method 1, et seq., Method 2, et seq., Method 4, et seq., and Method 5, et seq..

[0023] In a fifth aspect, the present disclosure provides a method (Method 4) of making a compound selected from one or more of Compounds 9-A, 9-B, 9-C, 9-D, 9-E, and Compound I or I(a), as herein described, wherein the method comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form the product compound. Method 4 generally pertains to formation of the SNO- CB-TC cyclic fragment (including the ring closing metathesis step) and attachment of the side chain fragment (SC), including advanced intermediates 9-B, 9-C, and 9-E, as well as the evolution of those intermediates to Compound 1. Without being limited in the order or combination of steps employed, the potential embodiments of Method 4 may include any steps shown in Scheme 9. [Image disponible dans le document PDF, Image available in the PDF document] Scheme 9

[0024] In particular embodiments, the present disclosure provides Method 4 as follows: 4.1 Method 4, wherein the method comprises the step of deprotecting a compound 6-L' with a deprotection agent in a suitable solvent for a time and under conditions effective to yield the inverted stereoisomer 8-B, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined in any of Methods 3.109- 3.112, and wherein R" is as defined in any of Methods 3.211-3.213; 4.2 Method 4.1, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 4.3 Method 4.2, wherein Rp is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 4.4 Any of Methods 4.1-4.3, wherein R'' is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 4.5 Method 4.4, wherein R'' is methyl; 4.6 Any of Methods 4.1-4.5, wherein the deprotection reagent 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 (mono-, di- or tri-basic), potassium phosphate (mono-, di- or tri-basic), optionally as 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., hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, triethylamine trihydrofluoride, tetrabutylammonium difluorotriphenylsilicate, optionally in an organic solvent), a hydrogenation agent (e.g., hydrogen in combination with a heterogenous 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, Ru complexes, Rh complexes, PtO2, Pt complexes, Pd complexes, Ir complexes, 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; 4.7 Method 4.6, wherein the deprotection agent is an acid, e.g., selected from trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid (e.g., aqueous HCl, HCl in 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; 4.8 Any of Methods 4.1-4.7, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 4.9 Method 4.8, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 4.10 Method 4.8, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 4.11 Method 4.8, wherein the solvent is dichloromethane; 4.12 Any of Methods 4.1-4.11, wherein the temperature of the reaction is from <semantics>−50<annotation encoding="application / x-tex">-50< / annotation>< / semantics> to <semantics>50<annotation encoding="application / x-tex">50< / annotation>< / semantics> °C, e.g., from 0 to 40 °C, or 10 °C to 30 °C, or about 20 °C; 4.13 Method 4, or any of 4.1-4.12, wherein the method comprises the step of condensing a sulfonimidamide compound 8-B or a sulfonimidamide compound 6-L with carboxylic acid 1-K using an acid activator, a base, and optionally a promoter, in a suitable solvent for a time and under conditions effective to form the N-acyl sulfonimidamide compound 9-A, wherein Ry is defined as in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp of compound 6-L is defined as in any of Methods 3.109-3.112, wherein R'' of compound 8-B is as defined in any of Methods 3.211-3.213, wherein Rx is defined as in Method 1.18 or 1.19, wherein R5 is defined as in any of Methods 1.75-1.78, and wherein R6 is hydrogen or halogen; 4.14 Method 4.13, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 4.15 Method 4.14, wherein <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is 1-phenylethoxycarbonyl, optionally in <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics> or <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics> form; 4.16 Any of Methods 4.13-4.15, wherein R'' is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 4.17 Method 4.16, wherein R'' is methyl; 4.18 Any of Methods 4.13-4.17, wherein the acid activator is selected from <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl), carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N'N'- tetramethylchloroformamidinium 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); 4.19 Method 4.18, wherein the acid activator is <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>-(3-dimethylaminopropyl)-<semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>'- ethylcarbodiimide hydrochloride (EDC HCl); 4.20 Any of Methods 4.13-4.19, wherein the base is selected from tertiary amines (e.g., N- methylmorpholine, triethyl amine, 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, mono, di and tri basic potassium and sodium phosphate; 4.21 Method 4.20, wherein the base is imidazole; or in one embodiment, the base is 1- methylimidazole; 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); 4.23 Any of Methods 4.13-4.22, wherein the acid activator is EDC-HCl, the base is 1- methylimidazole and the promoter is DMAP; 4.24 Any of Methods 4.13-4.23, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent, or a combination with water thereof; 4.25 Method 4.24, wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 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- pyrrolidinone, 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- pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 4.27 Method 4.24, wherein the solvent is N,N-dimethylformamide. In one embodiment, the solvent is acetonitrile; 4.28 Any of Methods 4.13-4.27, wherein the temperature of the reaction is from −50 to 50 °C, e.g., from 0 to 40 °C, or 10 °C to 30 °C, or 0 °C to 80 °C, or about 20 °C; 4.29 Method 4, or any of Methods 4.1-4.28, wherein the method comprises the step of deprotecting a compound 9-A for a time and under conditions effective to form a compound 9- B, or of deprotecting a compound 9-D for a time and under conditions effective to form a compound 9-E, using a deprotection agent in a suitable solvent, wherein Ry is defined as in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined either as 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 Rx is defined as in Method 1.18 or 1.19, wherein R5 is defined as in any of Methods 1.75-1.78, and wherein R6 is hydrogen or halogen; 4.30 Method 4.29, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 4.31 Method 4.30, wherein <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is 1-phenylethoxycarbonyl, optionally in <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics> or <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics> form; 4.32 Any of Methods 4.31, wherein <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is <semantics>−C(=O)−R″<annotation encoding="application / x-tex">-C(=O)-R''< / annotation>< / semantics>, and <semantics>R″<annotation encoding="application / x-tex">R''< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl); 4.33 Method 4.32, wherein R" is methyl; 4.34 Any of Methods 4.29-4.33, wherein the deprotection reagent 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 hydrogenation agent (e.g., hydrogen in combination with a heterogenous 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; 4.35 Method 4.34, wherein the deprotection reagent 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 (mono-, di- or tri-basic), potassium phosphate (mono-, di- or tri-basic), methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-touenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, formic acid, phosphoric acid, oxalic acid, citric acid, hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), methanesulfonic acid, hydrofluoric acid, hydrogen fluoride pyridine, hydrogen fluoride triethylamine, 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 deprotection reagent is sodium isopropoxide; in one embodiment, the deprotection reagents is trifluoroacetic acid; 4.36 Method 4.34, wherein the deprotection agent is an enzyme, such as a lipase or protease, e.g., a bacterial or fungal lipase or protease; 4.37 Method 4.36, wherein the lipase or protease is derived from Candida species (e.g., Candida rugosa), Pseudomonas species (e.g., Pseudomonas stutzeri), or Rhizomucor species (e.g., Rhizomucor miehei); 4.38 Method 4.37 wherein the enzyme is lipase from Pseudomonas stutzeri; 4.39 Method 4.36-4.38, wherein the reaction further comprises an aqueous buffer, e.g., sodium phosphate buffer or potassium phosphate buffer, optionally having a pH of 5-8 (e.g., about pH 7); 4.40 Any of Methods 4.29-4.39, wherein the suitable solvent is a nonpolar solvent, polar aprotic solvent, polar protic solvent, water or a combination thereof; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); in one embodiment, the nonpolar solvent is tolunene; 4.42 Method 4.40, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), and nitriles (e.g., acetonitrile); 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; 4.44 Method 4.40, wherein the nonpolar solvent is methyl tert-butyl ether, in combination with aqueous sodium phosphate buffer (pH about 7). In one embodiment, the solvent is a combination of tetrahydrofuran (THF) and 2-propanol (IPA); 4.45 Any of Methods 4.29-4.44, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 10 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 the temperature of the reaction is from 10 - 30 °C. In one embodiment, the temperature of the reaction is from 60 - 80 °C; 4.46 Method 4, or any of 4.1-4.45, wherein the method comprises the step of acylating a compound 9-B for a time and under conditions effective to form a compound 9-C, or acylating a compound 9-E for a time and under conditions effective to form a Compound I, the step comprising treating the starting material compound with a suitable acylating agent and a base, in a suitable solvent, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, wherein Rx is defined as in Method 1.18 or 1.19, wherein R5 is defined as in any of Methods 1.75-1.78, and wherein R6 is hydrogen or halogen; 4.47 Method 4.46, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is as defined in Compound I or I(a); 4.48 Method 4.46, R12 is -C(O)-R1, and R1 is selected from C1-6alkyl, C1-6haloalkyl, C2- 6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6- 10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, -ORa, and -NRaRb; wherein Ra and Rb is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 4.49 Method 4.48, wherein R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 4.50 Method 4.49, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkoxy (e.g., methoxy); 4.51 Method 4.50, wherein R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl) or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkoxy (e.g., methoxy); 4.52 Method 4.51, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is 3-methoxy-1-methyl-1H-pyrazolyl; 4.53 Any of Methods 4.46-4.52, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is any optionally substituted <semantics>C1-6<annotation encoding="application / x-tex">C_{1\text{-}6}< / annotation>< / semantics>alkyl, <semantics>C1-6<annotation encoding="application / x-tex">C_{1\text{-}6}< / annotation>< / semantics>haloalkyl, <semantics>C2-6<annotation encoding="application / x-tex">C_{2\text{-}6}< / annotation>< / semantics>alkenyl, <semantics>C2-6<annotation encoding="application / x-tex">C_{2\text{-}6}< / annotation>< / semantics>alkynyl, <semantics>C3-10<annotation encoding="application / x-tex">C_{3\text{-}10}< / annotation>< / semantics>cycloalkyl, <semantics>C6-10<annotation encoding="application / x-tex">C_{6\text{-}10}< / annotation>< / semantics>aryl, <semantics>3-12<annotation encoding="application / x-tex">3\text{-}12< / annotation>< / semantics> membered heterocycloalkyl, or 5-10 membered heteroaryl, and the acylating agent is an acid chloride (e.g., <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>-C(=O)-Cl), an acid anhydride (e.g., <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>-C(=O)-O-(C=O)-<semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>), or a combination of a carboxylic acid (e.g., R1-COOH) with an activator or coupling reagent (e.g., oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, a carbodiimide reagent (e.g., DCC or EDC), or any other peptide coupling reagent (e.g., HATU, T3P, isobutyl chloroformate); 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]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N'N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT); 4.55 Method 4.54, wherein the activating agent is <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>-(3-dimethylaminopropyl)-<semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>'- ethylcarbodiimide hydrochloride (EDC HCl); 4.56 Any of Methods 4.46-4.52, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is any optionally substituted -OR7, and the acylating agent is a chloroformate (e.g., R7-O-C(=O)-Cl), or a carbonate (e.g., R7- <semantics>O−C(=O)−O−R7<annotation encoding="application / x-tex">O-C(=O)-O-R^7< / annotation>< / semantics>). 4.57 Any of Methods 4.46-4.52, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is any optionally substituted <semantics>−NR8R9<annotation encoding="application / x-tex">-NR^8R^9< / annotation>< / semantics>, and the acylating agent is an isocyanate (e.g., <semantics>R8R9<annotation encoding="application / x-tex">R^8R^9< / annotation>< / semantics>-N-C(=O)); 4.58 Any of Methods 4.46-4.57, wherein the base is selected from tertiary amines (e.g N- methylmorpholine, triethyl amine, 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, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate (monobasic, dibasic or tribasic), sodium phosphate (monobasic, dibasic or tribasic)), 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 t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t- pentoxide, lithium t-pentoxide, sodium isopropoxide, potassium isopropoxide, and lithium isopropoxide). In one embodiment, the base is 1-methylimidazole; 4.59 Any of Methods 4.46-4.58, wherein the reaction further comprises a catalyst / promoter, e.g., selected from 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; 4.60 Any of Methods 4.46-4.59, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent, optionally further comprising water; 4.61 Method 4.60, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, and chlorobenzene); 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, dimethylsulfoxide, N-methyl-2-pyrrolidone), and nitriles (e.g., propionitrile); 4.63 Method 4.60, wherein the solvent is acetonitrile; 4.64 Any of Methods 4.46-4.63, wherein the temperature of the reaction is from −20 to 60 °C, e.g., from -5 to 40 °C, or 0 °C to 30 °C, or from 10 °C to 30 °C, or about 20 °C; 4.65 Method 4, or any of Methods 4.1-4.64, wherein the reaction comprises the step of performing a ring-closing metathesis on a compound 9-A for a time and under conditions effective to form a compound 9-D, or on a compound 9-B for a time and under conditions effective to form a compound 9-E, or on a compound 9-C for a time and under conditions effective to form a Compound I, using a suitable catalyst in a suitable solvent, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, wherein Rx is defined as in Method 1.18 or 1.19, wherein R5 is defined as in any of Methods 1.75-1.78, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is hydrogen or halogen, and wherein <semantics>==<annotation encoding="application / x-tex">==< / annotation>< / semantics> is a double bond; 4.66 Method 4.65, wherein Rx and Ry are both hydrogen; 4.67 Method 4.65 or 4.66, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is as defined in Compound I or <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>; 4.68 Method 4.67, R12 is -C(O)-R1, and R1 is selected from C1-6alkyl, C1-6haloalkyl, C2- 6alkynyl, C3-10cycloalkyl, C6-10aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl, and –NR8R9, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkynyl, C3-10cycloalkyl, C6- 10aryl, 3-12 membered heterocycloalkyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein each R8 and R9 are independently hydrogen, C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl, or R8 and R9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein said C1-6alkyl, C3-10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, 3-12 membered heterocycloalkyl, C6-10aryl, 5-10 membered heteroaryl, halogen, oxo, –ORa, and –NRaRb; wherein Ra and Rb is independently hydrogen or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; 4.69 Method 4.68, wherein R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3- 10cycloalkyl, C1-6haloalkyl, C1-6alkoxy and halogen; 4.70 Method 4.69, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkoxy (e.g., methoxy); 4.71 Method 4.70, R12 is -C(O)-R1, and R1 is pyrazolyl optionally substituted by 1-3 C1-6alkyl (e.g., methyl) or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkoxy (e.g., methoxy); 4.72 Method 4.71, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is 3-methoxy-1-methyl-1H-pyrazolyl; 4.73 Any of Methods 4.65-4.72, wherein the catalyst is a ruthenium catalyst or a molybdenum catalyst; 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-imidazolidinylidene] (benzylidene) (tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), [1,3-dimesityl-2- imidazolidinylidene]dichloro(phenylmethylene)bis(3-bromopyridine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-methyl-2-butenylidene) (tricyclohexylphosphine) ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2- imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), [1,3-dimesityl-2- imidazolidinylidene]dichloro[3-(2-pyridinyl)propylidene]-ruthenium(II), (1,3- dimesitylimidazolidin-2-ylidene)dichloro(2-isopropoxy-5-nitrobenzylidene) ruthenium(II), tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl) imidazol-2-ylidene][2- thienylmethylene] ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6- trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2- thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6- trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2- isopropoxyphenylmethylene)ruthenium(II), and bis(tricyclohexylphosphine)-3-phenyl-1H- inden-1-ylideneruthenium(II) dichloride; 4.75 Method 4.73, wherein the catalyst is selected from 2,6-diisopropyl-phenylimido- neophylidene[(S)-(-)-BIPHEN]molybdenum(VI), dichlorobis[(2,6- diisopropylphenyl)imido](1,2-dimethoxyethane)molybdenum(VI), and (T-4)-chloro(2,2- dimethylpropylidene)[2,2",4,4',6,6'-hexakis(1-methylethyl)[1,1':3',1-terphenyl]-2'-olato][2- methyl-2-propanaminoato(2-)|molybdenum(VI); 4.76 Method 4.73, wherein the suitable catalyst is the Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2- isopropoxyphenylmethylene)ruthenium(II)); 4.77 Any of Methods 4.65-4.76, wherein the solvent is a nonpolar solvent or polar aprotic solvent; 4.78 Method 4.77, wherein the solvent is selected from ethers (e.g., tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), 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; 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); 4.80 Any of Methods 4.65-4.79, wherein the temperature of the reaction is from 0 to 150 °C, e.g., from 20 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 temperature of the reaction is from 70 °C to 90 °C; 4.81 Method 4, or any of Methods 4.1-4.80, wherein the method further comprises a step of reducing the double bond of a compound 9-D, 9-E, I or I(a), wherein === is a double bond, for a time and under conditions effective to form a compound 9-D, 9-E, I or I(a), respectively, wherein === is a double bond, the step comprising treating said compound with hydrogen gas over a suitable catalyst (e.g., Pd / C, Pt, PtO2, Raney nickel, nickel boride, RhCl(Ph3P)3), in a suitable solvent (e.g., acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene); 4.82 Method 4, or any of Methods 4.1-4.81, wherein the Method produces a compound according to one or more of Compounds 8-B, 9-A, 9-B, 9-C, 9-D, 9-E or Compound I or I(a); 4.83 Method 4.82, wherein in any one or more of said compounds, Rx is H, Ry is H, R2 and R3 are independently H or C1-6alkyl (e.g., methyl), R4 is H, R5 is C1-3 alkyl (e.g., methyl), R6 is halogen (e.g., chloro), Rp is -C(=O)-O-C1-6alkyl(aryl) (e.g., 1-phenylethoxycarbonyl, optionally in (R) or (S) form), R'' is C1-3alkyl (e.g., methyl), and / or R12 is H, or -C(O)-R1, wherein R1 is selected from optionally substituted <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl (e.g., methyl), optionally substituted <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkoxy (e.g., (S)-1-phenylethoxy), or optionally substituted 5-10 membered heteroaryl (e.g., 1-methyl- 3-methoxy-1H-pyrazol-4-yl); 4.84 Method 4.83, wherein in one or more of said compounds R2 and R3 are H, or R2 and R3 are methyl, or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 4.85 Method 4.84, wherein in one or more of said compounds <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is H and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is methyl; 4.86 Any of Methods 4.82-4.85, wherein in one or more of compound 9-C, Compound I and Compound I(a), R12 is -C(O)-R1, and R1 is 5-10 membered heteroaryl (e.g., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl), optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently selected from C1-6alkyl, C3-10cycloalkyl, C1- 6haloalkyl, C1-6alkoxy and halogen; 4.87 Method 4.86, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is pyrazolyl or imidazolyl, optionally substituted with 1-5 R10 groups; wherein each of said R10 group is independently C1-6alkyl (e.g., methyl) or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkoxy (e.g., methoxy); 4.88 Method 4.87, wherein <semantics>R12<annotation encoding="application / x-tex">R^{12}< / annotation>< / semantics> is <semantics>−C(O)−R1<annotation encoding="application / x-tex">-C(O)-R^1< / annotation>< / semantics>, and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is pyrazolyl optionally substituted by 1-3 <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl (e.g., methyl) or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkoxy (e.g., methoxy), for example <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is 3-methoxy-1-methyl- 1H-pyrazolyl; 4.89 Any of Methods 4.82-4.88, wherein in one or more of compound 9-D, 9-E, Compound I or compound <semantics>I(a)<annotation encoding="application / x-tex">I(a)< / annotation>< / semantics>, <semantics>==<annotation encoding="application / x-tex">==< / annotation>< / semantics> is a double bond; 4.90 Method 4, or any of Methods 4.1-4.89, wherein the product of the method is the Compound 1; 4.91 Method 4, or any of Methods 4.1-4.90, wherein the method further comprises any steps described in any of Method 1, et seq., Method 2, et seq., Method 3, et seq., and Method 5, et seq..

[0025] In a sixth aspect, the present disclosure provides a method (Method 5) of making 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, as herein described, wherein the method comprises the step of reacting a precursor compound with one or more reagents in a suitable solvent for a time and under conditions effective to form the product compound. Method 5 generally pertains to alternative routes for formation of the SNO-CB-TC cyclic fragment (including the ring closing metathesis step) and attachment of the side chain fragment, including advanced intermediates 10-C, 10-C', and 10-E, as well as the evolution of those intermediates to Compound 1. Without being limited in the order or combination of steps employed, the potential embodiments of Method 5 may include any steps shown in Scheme 10. [Image disponible dans le document PDF, Image available in the PDF document] 3 Scheme 10

[0026] In particular embodiments, the present disclosure provides Method 5 as follows: 5.1 Method 5, wherein the method comprises any of the steps described in any of Method 1, et seq., Method 2, et seq., Method 3, et seq., and Method 4, et seq.; 5.2 Method 5 or 5.1, wherein the method comprises the step of (1) reacting a compound 5-E or 5-E' with a 4-fluoro-3-nitrobenzoic acid or ester for a time and under conditions effective to form a compound 5-F, as described in any of Methods 2.126-2.2.140, wherein R6, Rn and Rz are defined as in any of Methods 2.126-2.131, and optionally (2) hydrolyzing a compound 5-F wherein Rz is not H to the corresponding compound 5-F' wherein Rz is H by treating with compound 5-F as provided in any of Methods 1.134-1.138, for a time and under conditions effective to form the compound 5-F'; in one embodiment, Rn is each independently CH3, or wherein the two Rn moieties join together to form a bridge selected from -CH2CH2-, [Image disponible dans le document PDF, Image available in the PDF document] 5.3 Method 5.2, wherein Rz of compound 5-F is unsubstituted C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl or tert-butyl); 5.4 Method 5.3, wherein Rz of compound 5-F or 5-F' is H; 5.5 Method 5, or any of Methods 5.1 or 5.2, wherein the method comprises the step of acylating a compound 6-L with 4-fluoro-3-nitrobenzoic acid for a time and under conditions effective to form a compound 10-A, or acylating a compound 6-L with a benzoic acid compound 5-F / 5-F' for a time and under conditions effective to form a compound 10-B, using an acid activator and a base in a suitable solvent, wherein R6 is defined as provided in Method 2.10 or 2.11, wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, wherein Rz of compound 5-F or 5-F' is H, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined in any of Methods 3.109-3.112; 5.6 Method 5.5, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 5.7 Method 5.5 or 5.6 wherein both Rn are methyl or ethyl, or the two Rn moieties join together to form a bridge selected from -CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH(CH3) CH2CH(CH3)-, -CH2CH(CH3)CH2-,- [Image disponible dans le document PDF, Image available in the PDF document] 5.8 Any of Methods 5.5-5.7, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.9 Method 5.8, wherein <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is 1-phenylethoxycarbonyl, optionally in <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics> or <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics> form; 5.10 Any of Methods 5.5-5.9, wherein the acid activator is selected from <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>-(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]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, and sulfuryl chloride; 5.11 Method 5.10, wherein the acid activator is <semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>-(3-dimethylaminopropyl)-<semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>'- ethylcarbodiimide hydrochloride (EDC HCl); 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 (monobasic, dibasic or tribasic), sodium phosphate (monobasic, dibasic or tribasic)); 5.13 Method 5.12, wherein the base is imidazole or 1-methylimidazole; 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); 5.15 Any of Methods 5.5-5.14, wherein the acid activator is EDC-HCl, the base is 1- methylimidazole and the promoter is DMAP; 5.16 Any of Methods 5.5-5.15, wherein the suitable solvent is a nonpolar solvent or polar aprotic solvent; 5.17 Method 5.16, wherein the nonpolar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.18 Method 5.16, wherein the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 5.19 Method 5.16, wherein the solvent is acetonitrile; 5.20 Any of Methods 5.5-5.19, wherein the temperature of the reaction is from <semantics>−50<annotation encoding="application / x-tex">-50< / annotation>< / semantics> to <semantics>50<annotation encoding="application / x-tex">50< / annotation>< / semantics> °C, e.g., from 0 to 40 °C, or 10 °C to 30 °C, or about 20 °C; 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 in a suitable solvent with an alcohol compound 5-E or 5-E', for a time and under conditions effective to form the ether adduct compound 10-B, wherein R6 is defined as provided in Method 2.10 or 2.11, wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, wherein Ry is defined as in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined in any of Methods 3.109-3.112; 5.22 Method 5.21, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 5.23 Method 5.21 or 5.22, wherein both Rn of the compound 5-E are methyl or ethyl, or the two Rn moieties of the compound 5-E or 5-E' join together to form a bridge selected from [Image disponible dans le document PDF, Image available in the PDF document] 5.24 Any of Methods 5.21-5.23, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.25 Method 5.24, wherein <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is 1-phenylethoxycarbonyl, optionally in <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics> or <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics> form; 5.26 Any of Methods 5.21-5.25, wherein the compound 5-E or 5-E' is dissolved or suspended in the suitable solvent and treated with a strong base, and optionally with a promoter (e.g., sodium iodide, tetrabutylammonium iodide); 5.27 Method 5.26, wherein the base is selected from inorganic hydrides (e.g., sodium hydride, potassium hydride), alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide), inorganic hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), amide bases (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (mono-, di- or tri-basic), sodium phosphate (mono-, di- or tri-basic)); 5.28 Method 5.27, wherein the base is selected from sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t- butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, and potassium diisopropylamide; optionally wherein the base is potassium t-butoxide; 5.29 Any of Methods 5.21-5.28, wherein the compound 10-A is added to the reaction about 1 to 60 minutes after addition of the base, e.g., about 1 to 30 minutes after, or 1 to 20 minutes after, or 1 to 15 minutes after, or 1 to 10 minutes after, or 1 to 5 minutes after; 5.30 Any of Methods 5.21-5.29, wherein the suitable solvent is a nonpolar solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.32 Method 5.30, wherein the nonpolar solvent is tetrahydrofuran; 5.33 Any of Methods <semantics>5.21−5.32<annotation encoding="application / x-tex">5.21-5.32< / annotation>< / semantics>, wherein the temperature of the reaction is from <semantics>−80<annotation encoding="application / x-tex">-80< / annotation>< / semantics> to 100 °C, e.g., from −45 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; 5.34 Method 5, or any of 5.1-5.33, wherein the method comprises the step of treating the acetal compound 10-B or 10-C' with a deprotecting agent in a suitable solvent for a time and under conditions effective to form an aldehyde compound 10-C or 10-D, respectively, wherein R6 is defined as in Method 2.10 or 2.11, wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined in any of Methods 3.109-3.112; 5.35 Method 5.34, wherein R6 is chloro; 5.36 Method 5.34 or 5.35, wherein both Rn of the compound 5-E are methyl or ethyl, or the two Rn moieties of the compound 5-E or 5-E' join together to form a bridge selected from - CH2CH2-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, and CH2C(CH3)2CH2-; 5.37 Any of Methods 5.34-5.36, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.38 Method 5.37, wherein <semantics>ℝp<annotation encoding="application / x-tex">\mathbb{R}^p< / annotation>< / semantics> is 1-phenylethoxycarbonyl, optionally in <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics> or <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics> form; 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 / dioxane), HBr (e.g., aqueous HBr or HBr / acetic acid), sulfuric acid, phosphoric acid, p-toluenesulfonic acid, pyridinium tosylate, trifluoroacetic acid, methanesulfonic acid, trichloroacetic acid, Lewis acids (e.g., erbium triflate), and acidic resin (e.g., Amberlyst); 5.40 Method 5.39, wherein the acid is methanesulfonic acid; 5.41 Any of Methods 5.34-5.40, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, polar aprotic solvent, or a combination thereof; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.43 Method 5.41, wherein the polar protic solvent is water and / or an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or acid (e.g., formic acid, acetic acid); 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); 5.45 Method 5.41, wherein the suitable solvent is tetrahydrofuran and water; 5.46 Any of Methods 5.34-5.45, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 20 to 50 °C, or 20 °C to 30 °C, or from 60 to 70 °C; 5.47 Any of Methods 5.34-5.46, wherein the method results in the cleavage of the Rp protecting group, such that in the product compound 10-C or 10-D of the reaction Rp is hydrogen; 5.48 Method 5, or any of 5.1-5.47, wherein the method comprises the step of reducing a nitro / aldehyde compound 10-C to a aniline / aldehyde compound 10-D, or of reducing nitro / acetal 10-B to aniline / acetal 10-C', wherein R6 is defined as provided in Method 2.10 or 2.11, wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111, wherein Ry is defined as in Method 3.2 or 3.3, wherein <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined in any of Methods 3.109-3.112 or Rp is hydrogen; and wherein each Rn is defined as provided in any of Methods 2.76-2.79 or 2.108-2.111; 5.49 Method 5.48, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 5.50 Method 5.48 or 5.49, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.51 Method 5.50, wherein Rp is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 5.52 Method 5.48 or 5.49, wherein Rp is hydrogen; 5.53 Any of Methods 5.48-5.52, wherein the reducing agent is selected from zinc, tin or iron in an acid (e.g., in formic acid or acetic acid or HCl in the suitable solvent, or ammonium chloride); 5.54 Method 5.53, wherein the reducing agent is iron (e.g., powder) in acetic acid; 5.55 Any of Methods 5.48-5.52, wherein the reducing agent is a hydrogenation agent (e.g., hydrogen in combination with a heterogenous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex), or a phase transfer hydrogenation system); 5.56 Method 5.55, wherein the hydrogenation agent is hydrogen gas in combination with 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 ammonium formate in combination with a palladium or platinum catalyst (e.g., Pd, Pd / C, Pt / C, PtO2); 5.57 Method 5.56, wherein the hydrogenation agent is hydrogen gas in combination with a Pd, Pd / C, Pd(OAc)2, Pt / C or PtO2 catalyst, optionally at 1-5 bar pressure (e.g., 1-2 bar); 5.58 Any of Methods 5.48-5.57, wherein the suitable solvent is a nonpolar solvent, polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 5.60 Method 5.58, wherein the polar protic solvent is an alcohol (e.g., methanol, ethanol, propanol, isopropanol) or acid (e.g., formic acid, acetic acid) or an aqueous acid (e.g., aqueous HCl); 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); 5.62 Method 5.58, wherein the suitable solvent is acetic acid; 5.63 Any of Methods 5.48-5.62, wherein the temperature of the reaction is from 0 to 100 °C, e.g., from 20 to 50 °C, or 20 °C to 30 °C, or from 50 to 90 °C, or from 65 to 85 °C; 5.64 Any of Methods 5.34-5.63, where the intended product compound 10-D of the step undergoes spontaneous condensation to form intermediate imine 10-D' either partly or completely, and the mixture of 10-D and 10-D' is carried forward to the next step, or the product isolated is 10-D' which is used in the next step; 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') in a suitable solvent with a reducing agent for a time and under conditions effective to yield the secondary amine compound 10-E, wherein R6 is defined as provided in Method 2.10 or 2.11, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, and wherein Rp is as defined in any of Methods 3.109-3.112 or Rp is hydrogen; 5.66 Method 5.65, wherein R6 is chloro; 5.67 Method 5.65 or 5.66, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.68 Method 5.67, wherein <semantics>Rp<annotation encoding="application / x-tex">R^p< / annotation>< / semantics> is 1-phenylethoxycarbonyl, optionally in <semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics> or <semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics> form; 5.69 Method 5.65 or 5.66, wherein Rp is hydrogen; 5.70 Any of Methods 5.65-5.69, wherein the reducing agent is selected from a hydride reducing agent, a silane reducing agent, hydrogenation, iron powder (Fe) in combination, sodium triacetoxyborohydride (NaBH(OAc)3), tin or zinc in combination with acids (e.g. hydrochloric acid, acetic acid, ammonium chloride), transition metal (e.g. Pd, Pt or Rh) in combination with H2 or a formate salt, poisoned heterogeneous catalysts (e.g. Pt / S / C), silanes (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 iron powder (Fe) in combination with sodium triacetoxyborohydride <semantics>(NaBH(OAc)3);<annotation encoding="application / x-tex">(NaBH(OAc)_3);< / annotation>< / semantics> 5.71 Method 5.70, wherein the reducing agent is a hydride reducing agent; 5.72 Method 5.71, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 5.73 Method 5.72, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 5.74 Any of Methods 5.71-5.73, wherein the hydride reducing agent is combined with a reagent to modulate the hydride reducing activity (e.g., titanium isopropoxide, titanium ethoxide, borate salts, magnesium perchlorate, or zinc chloride); 5.75 Method 5.70, wherein the silane reducing agent is triethylsilane; 5.76 Any of Methods 5.70-5.75, wherein the reaction further comprises an acid (e.g., selected from formic acid, acetic acid, trifluoracetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid); 5.77 Any of Methods 5.65-5.76, wherein the suitable solvent is a nonpolar solvent, a polar protic solvent, or polar aprotic solvent; 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, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene); 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, trifluoracetic acid); 5.80 Method 5.77, wherein the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile); 5.81 Method 5.77, wherein the suitable solvent is acetic acid; 5.82 Any of Methods 5.65-5.81, wherein the temperature of the reaction is from <semantics>−30<annotation encoding="application / x-tex">-30< / annotation>< / semantics> to 100 °C, e.g., from 0 to 80 °C, or 20 to 30 °C, 20 to 50 °C, from 50 to 90 °C, or 60 to 80 °C; 5.83 Method 5, or any of Methods 5.1-5.82, wherein the method comprises the step of treating the compound 10-E in a suitable solvent with a reducing agent and the compound 1-I, for a time and under conditions effective to form a tertiary amine compound 9-A, wherein R6 is defined as provided in Method 2.10 or 2.11, wherein Ry is as defined in Method 3.2 or 3.3, wherein R2 and R3 are as defined in any of Methods 3.4-3.10, wherein Rp is as defined in any of Methods 3.109- 3.112 or Rp is hydrogen, wherein Rx is defined as in Method 1.18 or 1.19, and wherein R5 is WO 2021 / 108254 defined as in any of Methods 1.75-1.78; 5.84 Method 5.83, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is chloro; 5.85 Method 5.83 or 5.84, wherein Rp is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4- methoxyphenoxycarbonyl, and benzyloxycarbonyl; 5.86 Method 5.85, wherein Rp is 1-phenylethoxycarbonyl, optionally in (R) or (S) form; 5.87 Method 5.83 or 5.84, wherein Rp is hydrogen; 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 hydrogenation; 5.89 Method 5.88, wherein the reducing agent is a hydride reducing agent; 5.90 Method 5.89, wherein the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride; 5.91 Method 5.90, wherein the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride; 5.92 Any of Methods 5.89-5.91, wherein the hydride reducing agent is combined with a reagent to modulate the hydride reducing activity (e.g., titanium isopropoxide, titanium ethoxide, borate salts, magnesium perchlorate, or zinc chloride); 5.93 Method 5.88, wherein the silane reducing agent is triethylsilane; 5.94 Any of Methods 5.83-5.93, wherein the reaction further comprises an acid (e.g., selected from acetic acid, trifluoracetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid); 5.95 Any of Meth...

Claims

<pat:ClaimStatement>CLAIMS:< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound selected from: [Image disponible dans le document PDF, Image available in the PDF document] or a salt thereof; wherein <semantics>Ry<annotation encoding="application / x-tex">R^y< / annotation>< / semantics> is H or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> are independently H or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; R6 is halogen; each Rn is independently C1-6alkyl, or the two Rn moieties join together to form a C2- 4alkyl bridge, wherein the bridge is optionally substituted by one to four groups independently selected from C1-3alkyl and phenyl; and Rp is selected from H, -C(=O)-C1-6alkyl, -C(=O)-heteroaryl, -C(=O)-O-C1-6alkyl, and - C(=O)-O-C1-6alkyl-phenyl, wherein each phenyl or heteroaryl is optionally substituted with one to four groups independently selected from C1-3alkyl and - OC1-3alkyl; wherein each heteroaryl has one to four heteroatoms, and each heteroatom is independently selected from N, O, and S; and wherein each heteroaryl has 5 to 10 ring members. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. The compound of claim 1 selected from: [Image disponible dans le document PDF, Image available in the PDF document] or a salt thereof. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>