Intermediates of elacestrant and methods of making and using the same

Abstract

The present disclosure relates to novel intermediates in the synthesis of elacestrant and methods of making the same. The chiral compound N-(2-((1R,2S)-6-(benzyloxy)-1-hydroxy-1,2,3,4- tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (I-1)), is prepared in two steps: (1) a Pd-catalyzed α-arylation of a ketone precursor, 6-(benzyloxy)-3,4-dihydronaphthalen- 1(2H)-one, (Compound (a-1)), with N-(2-bromo-5-methoxyphenyl)acetamide (Compound (b- 1)); and (2) the asymmetric transfer hydrogenation of the product from Step 1, N-(2-(6- (benzyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)), to produce N-(2-((1R,2S)-6-(benzyloxy)-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5- methoxyphenyl)acetamide (Compound (I-1)). The chiral compound (R)-6-(2-amino-4- methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) is produced from Compound (I-1) by two additional steps: 3) dehydroxylation and debenzylation of N-(2-((1R,2S)-6- (benzyloxy)-1-hydroxy-1,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (I-1)) to produce N-(2-(6-hydroxy)-1,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (III-1)); and 4) hydrolysis of N-(2-(6-hydroxy)-1,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (III-1)) to produce (R)-6-(2- amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)).

Description

Atty. Dkt. No.: 111346-2359INTERMEDIATES OF ELACESTRANT AND METHODS OF MAKING AND USING THF SAMECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of Italian Application No.102024000029406, filed December 20, 2024. The contents of this application is incorporated herein by reference in its entirety.BACKGROUND

[0002] Breast cancer is the second leading cause of cancer-related death in women, with an estimated 246,660 newly diagnosed cases and 40,450 deaths in the United States alone in 2016. Breast cancer is a heterogeneous disease divided into three subtypes based on expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Overexpression of ERs is found in many breast cancer patients. ER-positive (ER+) breast cancers comprise two-thirds of all breast cancers. Other than breast cancer, estrogen and ERs are associated with ovarian cancer, colon cancer, prostate cancer, and endometrial cancer, among others.10003] Elacestrant ((R)-6 -(2-(ethylamino)ethyl)benzyl)amino)-4- methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol) is an oral nonsteroidal small molecule that acts as a selective estrogen receptor (ER) degrader (SERD). Elacestrant has been approved by the Food and Drug Administration (FDA) for treating postmenopausal women or adult men with ERpositive, HER2-negative, estrogen receptor gene a (ESRl)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

[0004] Thus, improved commercial-scale methods of synthesizing elacestrant, and intermediates thereof, would be highly advantageous.SUMMARY

[0005] In one aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a compound of Formula (I):-1- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359(I),wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl.

[0006] In some embodiments, Pi is (C=O)-Ci alkyl. In some embodiments, P2is CH2-aryl.

[0007] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of making a compound according to Formula (I), the method comprising:stereoselective reduction of a compound of Formula (c) in the presence of a chiral catalyst and a hydrogen source to produce the compound of Formula (I):wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; and-2- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-C5 alkyl) and CEb-aryl.

[0008] In some embodiments: the compound of Formula (c) is prepared by a method comprising performing an a-arylation of a compound of Formula (a) with a compound of Formula (b) in the presence of a Pd compound, a ligand, and an additive,wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3;wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-C5 alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CEb-aryl; and wherein X is Cl, Br, I or OTf.

[0009] In some embodiments, X is Cl or Br. In some embodiments, P2 is CEE-aryl. In some embodiments, Pi is (C=O)-Ci alkyl. In some embodiments, P2 is CEE-aryl and Pi is (C=O)-Ci alkyl.

[0010] In some embodiments, the chiral catalyst is a ruthenium-based catalyst. In some embodiments, the chiral catalyst comprises RuCl[(R, R)-TsDpen(mesitylene)], RuCl(p- cymene)[(S,S)-Ts- DPEN], or RuCl(R, R)-Teth-Tsdpen RuCl. In some embodiments, the ruthenium catalyst comprises RuCl[(R, R)-TsDpen(mesitylene)].

[0011] In some embodiments, the hydrogen source comprises formic acid / triethylamine or borane / morpholine.4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0012] In some embodiments, the stereoselective hydrogenation is performed in tetrahydrofuran (THF), 2-methyl-THF, dimethyl ether (DME), dioxane, 1,2-dichloroethane (DCE), or dichloromethane (DCM). In some embodiments, the stereoselective hydrogenation is performed in THF or DCM. In some embodiments, the stereoselective hydrogenation is performed at 40°C to 70°C. In some embodiments, the stereoselective hydrogenation is performed at about 50°C.

[0013] In some embodiments, the obtained compound of Formula (I) has an enantiomeric excess (e.e.) of greater than or equal to 95%. In some embodiments, the obtained compound of Formula (I) has an enantiomeric excess (e.e.) of greater than or equal to 98%.

[0014] In some embodiments, the Pd compound comprises Pd₂(dba)₃. In some embodiments, the ligand comprises BuPAd₂. In some embodiments, the additive comprises phenol.

[0015] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of making a compound of Formula (II), the method comprising performing a dehydroxylation reaction on a compound of Formula (I) in the presence of a hydride reagentwherein the compound of Formula (I) is obtained by any of the methods disclosed herein.

[0016] In some embodiments, the hydride reagent comprises NaBHi.

[0017] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a compound of Formula (c)-4- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl.

[0018] In some embodiments, P2is CH2-aryl. In some embodiments, P1is (C=O)-C1alkyl. In some embodiments, P2is CH2-aryl and P1is (C=O)-C1alkyl.

[0019] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of making a compound of Formula (c), the method comprising reacting a compound of Formula (a) with a compound of Formula (b) in the presence of a Pd compound, a ligand, and an additive4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3;wherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl; and wherein X is Cl, Br, I, or OTf.

[0020] In some embodiments, X is Cl or Br. In some embodiments, P2is CH2-aryl. In some embodiments, P1is (C=O)-C1alkyl. In some embodiments, P2is CH2-aryl and P1is (C=O)-C1alkyl.

[0021] In some embodiments, the Pd compound comprises Pd2(dba)3. In some embodiments, the ligand comprises BuPAd2. In some embodiments, the additive comprises phenol.

[0022] A method of making a compound of Formula (d), the method comprising deprotection, followed by acid hydrolysis, of a compound according to Formula (II)wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl.

[0023] In some embodiments, Pi is (C=O)-Ci alkyl. In some embodiments, P2is CH2-aryl. In some embodiments, Pi is (C=O)-Ci alkyl and P2is CH2-aryl.-6- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0024] In some embodiments, the deprotection is a debenzylation performed in the presence of HBr and acetic acid.

[0025] In some embodiments, the compound of Formula (II) is

[0026] In some embodiments, the compound of Formula (II) is obtained by any of the methods disclosed herein.

[0027] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of making a compound of Formula (d), the method comprising deprotecting a compound of Formula (III) by acid hydrolysis to obtain the compound of Formula (d)(HI)wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein the compound of Formula (III) is obtained starting from a compound of Formula (I)-7- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0028] In some embodiments, the compound of Formula (III) is obtained by deprotection of the compound of Formula (I)(I),wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)-, wherein n is 2 or 3; andwherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl.

[0029] In some embodiments, the deprotection is performed using Pd / C.

[0030] In some embodiments, Pi is (C=O)-Ci alkyl and P2is CH2-aryl. In some embodiments, P2is CH2-benzyl, and the deprotection is a debenzylation.

[0031] In some embodiments, the compound of Formula (III) is obtained by deprotection of a compound of Formula (II)wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)-, wherein n is 2 or 3; and-8- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-C5 alkyl) and CHz-aryl.

[0032] In some embodiments, the compound of Formula (II) is obtained by a method according to any of the embodiments disclosed herein.

[0033] In some embodiments, the compound of Formula (II) isX > NHAcBnO; andthe deprotection is a debenzylation performed in the presence of a Pd catalyst and hydrogen.

[0034] In some embodiments, the compound of Formula (d) is obtained in at least 20% overall yield.

[0035] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a method of synthesizing elacestrant, wherein the method comprises making or providing a compound according to Formula (I) or Formula (c).

[0036] Both the foregoing summary and the following detailed description are exemplary and explanatory. They are intended to provide further details of the disclosure but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the disclosure.DETAILED DESCRIPTION10037] The present disclosure relates to novel intermediates in the synthesis of elacestrant and methods of making the same. The chiral compound N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)), is prepared in two steps: (1) a Pd-catalyzed a-arylation of a ketone precursor, 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one, (Compound (a-1)), with N-(2-bromo-5-methoxyphenyl)acetamide (Compound (b-1)), to produce N-(2-(6-(benzyloxy)-l-oxo-4902-2817-2415.2Atty. Dkt. No.: 111346-2359l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)); and (2) the asymmetric transfer hydrogenation (or Dynamic Kinetic Resolution, DKR), catalyzed by ruthenium organic complexes, of Compound (c-1), to produce N-(2-((lR,2S)-6-(benzyloxy)- 1-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (I-1)). Further, the asymmetric transfer hydrogenation of Step 2 introduces two stereocenters with very high stereoselectivity.

[0038] Then, N-(2-((lR, 2S)-6-(benzyloxy)-l -hydroxy- 1,2,3, 4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) can be converted using three alternative synthetic routes (see Scheme 1) to (R)-6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) a known intermediate of the elacestrant synthesis. The methods of the present disclosure allow production of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) with a high yield (about 75% in two steps) and high purity (chemical purity ~ 97% and e.e. > 99%) from N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)).

[0039] The methods of the present disclosure allow production of N-(2-((lR,2S)-6-(benzyloxy)- 1 -hydroxy- 1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) from 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one, (Compound (a-1)) with a high yield (> 75% in two steps) and high purity (chemical purity > 97% and e.e. > 99%).

[0040] Further, the known intermediate (R)-6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) can be obtained from N-(2-((lR,2S)-6-(benzyloxy)- 1 -hydroxy- 1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) with a yield of > 41% (two steps), a chemical purity of > 99.7%, and enantiomeric excess (e.e.) of > 97%.

[0041] The overall yield of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen- 2-ol (Compound (d)), starting from 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one, (Compound (a-1)), is > about 31%.-10- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0042] This marks a significant improvement over the known processes for producing (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)). PCT International Application No. PCT / US2020 / 017777, published as published as WO 2020 / 167855A1, discloses a six-step synthesis of Compound (d) starting from the vinyl bromide: (1) a palladium-catalyzed borylation; (2) a palladium-catalyzed coupling with the bromoaryl derivative; (3) a palladium-catalyzed hydrogenation; (4) an acid hydrolysis; (5) formation and crystallization of a mixture of diastereomeric salts; and (6) displacement of the chiral auxiliary used to form the diastereomeric salts, to obtain the desired optically pure (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)). The overall yield of this six-step process is very low – about 15% – almost exclusively due to the diastereoselective salt resolution step.

[0043] The methods of the present disclosure are stereoselective, thereby eliminating the diastereoselective salt resolution of a racemic mixture. Moreover, the vinyl bromide starting material of the process described in PCT International Application No. PCT / US2020 / 017777 is prepared with an overall yield of about 13% using a three-step process from 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one (Compound (a-1)), which is the same starting material used in the methods of the present disclosure. Thus, the process described in PCT International Application No. PCT / US2020 / 017777 requires 9 total steps to produce (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) with an overall yield of less than 2%, while the methods of the present disclosure produce (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) from 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one (Compound (a-1)) in 4 steps with an overall yield of > 31%.

[0044] Thus, the methods of the present disclosure afford higher yield, require less time, and produce less chemical waste, compared to known methods of synthesizing the key intermediate (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)).

[0045] Accordingly, in one aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to improved syntheses of intermediates of-11- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359elacestrant, in particular (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)). The improved syntheses are summarized in Scheme 1.(R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d))

[0046] In some embodiments, the improved synthesis includes multiple steps, comprising:• Step 1 - synthesis of a compound according to Formula (c) by a-arylation of a compound of Formula (a) using a compound of Formula (b);• Step 2 - stereoselective reduction of the compound of Formula (c) to obtain a compound according to Formula (I);• Step 3 - dehydroxylation and deprotection of the compound of Formula (I) to produce a compound of Formula (III); and• Step 4 - hydrolysis of the compound of Formula (III) to produce the Compound (d).Scheme 1. General Synthesis of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d))stereoselective a-arylation reduction Step 1 Step 2dehydroxylation deprotection Step 3dehydroxylation hydrolysis Step 3a Step 4 OMe deprotection hydrolysis Step 4a(II)-12- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0047] As a first alternative route, the improved synthesis comprises:• Step 1 - synthesis of a compound according to Formula (c) by a-arylation of a compound of Formula (a) using a compound of Formula (b);• Step 2 - stereoselective reduction of the compound of Formula (c) to obtain a compound according to Formula (I);• Step 3a - dehydroxylation of the compound of Formula (I) to produce a compound of Formula (II); and• Step 4a - deprotection and hydrolysis of the compound of Formula (II) to produce the Compound (d).

[0048] As a second alternative route, the improved synthesis comprises:• Step 1 - synthesis of a compound according to Formula (c) by a-arylation of a compound of Formula (a) using a compound of Formula (b);• Step 2 - stereoselective reduction of the compound of Formula (c) to obtain a compound according to Formula (I);• Step 3a - dehydroxylation of the compound of Formula (I) to produce a compound of Formula (II);• Step 3b - deprotection of the compound of Formula (II) to obtain a compound of Formula (III); and• Step 4 - hydrolysis of the compound of Formula (III) to produce the Compound (d).

[0049] In some embodiments, the improved synthesis is the synthesis shown in Scheme 2.Scheme 2. Embodiment of an Improved Synthesis of Compound (d)-13- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359stereoselective a-arylation reduction Step 2dehydroxyiation debenzylation Step 3dehydroxylation hydrolysis Step 3a X" Step 4 / ^. OMe debenzylation ii i hydrolysis if A"" Step 4a A xA J NHAC HO"BnO ■■■•(11-1)

[0050] In some embodiments, the improved synthesis includes multiple steps, comprising:• Step 1 - synthesis N-(2-6-(benzyloxy)-l-oxo-l, 2,3, 4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (c-1)) via a-arylation of 6-(benzyloxy)-3,4- dihydronaphthalen-l(2H)-one (Compound (a-1)) using N-(2-bromo-5- methoxyphenyl)acetamide (Compound (b-1));• Step 2 - stereoselective reduction of N-(2-6-(benzyloxy)-l-oxo-l,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) to obtain N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1));• Step 3 - dehydroxylation and debenzylation of N-(2-((lR,2S)-6-(benzyloxy)-l- hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) to produce N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (III-l)); and• Step 4 - hydrolysis of N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (III-l)) to produce (R)-6-(2-amino-4- methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)).100511 As a first alternative route, the improved synthesis comprises:• Step 1 - synthesis N-(2-6-(benzyloxy)-l-oxo-l, 2,3, 4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (c-1)) via a-arylation of 6-(benzyloxy)-3,4--14- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359dihydronaphthalen-l(2H)-one (Compound (a-1)) using N-(2-bromo-5- methoxyphenyl)acetamide (Compound (b-1));• Step 2 - stereoselective reduction of N-(2-6-(benzyloxy)-l-oxo-l,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) to obtain N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1));• Step 3a - dehydroxylation of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) to produce (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (II-l));• Step 4a - debenzylation and hydrolysis of (R)-N-(2-(6-(benzyloxy)-l, 2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l)) to produce (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)).

[0052] As a second alternative route, the improved synthesis comprises:• Step 1 - synthesis N-(2-6-(benzyloxy)-l-oxo-l, 2,3, 4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (c-1)) via a-arylation of 6-(benzyloxy)-3,4- dihydronaphthalen-l(2H)-one (Compound (a-1)) using N-(2-bromo-5- methoxyphenyl)acetamide (Compound (b-1));• Step 2 - stereoselective reduction of N-(2-6-(benzyloxy)-l-oxo-l,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) to obtain N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1));• Step 3a - dehydroxylation of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l, 2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) to produce (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (II-l));• Step 3b - debenzylation of (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2- yl)-5-methoxyphenyl)acetamide (Compound (II-l)) to obtain N-(2-(6-hydroxy)- l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (III-l)); and• Step 4 - hydrolysis of N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (III-l)) to produce (R)-6-(2-amino-4- methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)).Step 1. a-Arylation

[0053] In one aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a compound according to Formula (c):-15- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C1-C5alkyl)3, Si(aryl)2(C1-C5alkyl), and CH2-aryl.

[0054] In some embodiments, P2is CH2-aryl. In some embodiments, P1is (C=O)-C1alkyl. In some embodiments, P2is CH2-aryl and P1is (C=O)-C1alkyl. In some embodiments, the compound of Formula (c) is N-(2-6-(benzyloxy)-l-oxo-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)).N-(2-6-(benzyloxy)-l-oxo-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1))

[0055] In some embodiments, the compound of Formula (c) is synthesized by a-arylation of a compound according to Formula (a) using a compound according to Formula (b), as shown in Scheme 3.Scheme 3. General Synthesis of a Compound of Formula (c)4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3;wherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C1-C5alkyl)3, Si(aryl)2(C1-C5alkyl), and CH2-aryl; and wherein X is Cl, Br, I, or OTf.

[0056] In some embodiments, P2is CH2-aryl. In some embodiments, P1is (C=O)-C1alkyl. In some embodiments, P2is CH2-aryl and P1is (C=O)-C1alkyl. In some embodiments, X is Cl or Br. In some embodiments, X is Br.

[0057] In some embodiments, the compound of Formula (a) is 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one (Compound (a-1)). In some embodiments, the compound of Formula (b) is N-(2-bromo-5-methoxyphenyl)acetamide (Compound (b-1)).OCompound (a-1) Compound (b-1)(0058] In some embodiments, the compound of Formula (c) is N-(2-6-(benzyloxy)-l-oxo-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)).N-(2-6-(benzyloxy)-l-oxo-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1))

[0059] In some embodiments, the compound of Formula (b) is used at a concentration, relative to the concentration of the compound of Formula (a), of at least about 0.5 eq, at least about 0.6 eq., at least about 0.7 eq, at least about 0.8 eq, at least about 0.9 eq, at least about 1.0 eq, at least about 1.2 eq, at least about 1.4 eq, at least about 1.6 eq, at least about 1.8 eq, at-17- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359least about 2.0 eq, at least about 2.2 eq, at least about 2.4 eq, at least about 2.6 eq, at least about 2.8 eq, at least about 3.0 eq, at least about 3.2 eq, at least about 3.4 eq, at least about 3.6 eq, at least about 3.8 eq, at least about 4.0 eq, at least about 4.2 eq, at least about 4.4 eq, at least about 4.6 eq, at least about 5.0 eq, or any range or value including and / or in between any two of these values.

[0060] In some embodiments, the compound of Formula (b) is used at a concentration, relative to the concentration of the compound of Formula (a), of less than or equal to about 5.0 eq, less than or equal to about 4.8 eq, less than or equal to about 4.6 eq, less than or equal to about 4.4 eq, less than or equal to about 4.2 eq, less than or equal to about 4.0 eq, less than or equal to about 3.8 eq, less than or equal to about 3.6 eq, less than or equal to about 3.4 eq, less than or equal to about 3.2 eq, less than or equal to about 3.0 eq, less than or equal to about 2.8 eq, less than or equal to about 2.6 eq, less than or equal to about 2.4 eq, less than or equal to about 2.2 eq, less than or equal to about 2.0 eq, less than or equal to about 1.8 eq, less than or equal to about 1.6 eq, less than or equal to about 1.4 eq, less than or equal to about 1.2 eq, less than or equal to about 1.0 eq, less than or equal to about 0.9 eq, less than or equal to about 0.8 eq, less than or equal to about 0.7 eq, less than or equal to about 0.6 eq, less than or equal to 0.5 eq, or any range or value including and / or in between any two of these values.Catalyst

[0061] In some embodiments, the a-arylation is performed using a catalyst in the presence of a ligand. In some embodiments, the catalyst is a palladium, platinum, or ruthenium catalyst. In some embodiments, the catalyst is a Pd catalyst. In some embodiments, the catalyst is Pd / C, PdCh(DtBPF), Pd₂(dba)₃, or any combination thereof. In some embodiments, the catalyst is Pd₂(dba)₃.

[0062] In some embodiments, the catalyst is present at a concentration, relative to the compound of Formula (a), of at least about 0.01 eq, at least about 0.02 eq, at least about 0.03 eq, at least about 0.04 eq, at least about 0.05 eq, at least about 0.06 eq, at least about 0.07 eq, at least about 0.08 eq, at least about 0.09 eq, at least about 0.1 eq, at least about 0.15 eq, at least about 0.2 eq, at least about 0.25 eq, at least about 0.3 eq, at least about 0.35 eq, at least -18- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359about 0.4 eq, at least about 0.45 eq, at least about 0.5 eq, or any range or value including and / or in between any two of these values.

[0063] In some embodiments, the catalyst is present at a concentration, relative to the compound of Formula (a), of less than or equal to about 0.5 eq, less than or equal to about 0.45 eq, less than or equal to about 0.4 eq, less than or equal to about 0.35 eq, less than or equal to about 0.3 eq, less than or equal to about 0.25 eq, less than or equal to about 0.2 eq, less than or equal to about 0.15 eq, less than or equal to about 0.1 eq, less than or equal to about 0.09 eq, less than or equal to about 0.08 eq, less than or equal to about 0.07 eq, less than or equal to about 0.06 eq, less than or equal to about 0.05 eq, less than or equal to about 0.04 eq, less than or equal to about 0.03 eq, less than or equal to about 0.02 eq, less than or equal to about 0.01 eq, or any range or value including and / or in between any two of these values.Ligand

[0064] In some embodiments, the ligand is selected from the ligands shown in Scheme 4.Scheme 4. Ligands for a-ArylationPPh3P(o-Tol)3PCy3P'BU3Aphos Xphos4902-2817-2415.2Atty. Dkt. No.: 111346-2359Davephos Johnphos DPPP DPPFDPEphos

[0065] In some embodiments, the ligand is BuPAd₂.

[0066] In some embodiments, the ligand is present at a concentration, relative to the compound of Formula (a), of at least about 0.01 eq, at least about 0.02 eq, at least about 0.03 eq, at least about 0.04 eq, at least about 0.05 eq, at least about 0.06 eq, at least about 0.07 eq, at least about 0.08 eq, at least about 0.09 eq, at least about 0.1 eq, at least about 0.15 eq, at least about 0.2 eq, at least about 0.25 eq, at least about 0.3 eq, at least about 0.35 eq, at least about 0.4 eq, at least about 0.45 eq, at least about 0.5 eq, or any range or value including and / or in between any two of these values.

[0067] In some embodiments, the ligand is present at a concentration, relative to the compound of Formula (a), of less than or equal to about 0.5 eq, less than or equal to about 0.45 eq, less than or equal to about 0.4 eq, less than or equal to about 0.35 eq, less than or equal to about 0.3 eq, less than or equal to about 0.25 eq, less than or equal to about 0.2 eq, less than or equal to about 0.15 eq, less than or equal to about 0.1 eq, less than or equal to about 0.09 eq, less than or equal to about 0.08 eq, less than or equal to about 0.07 eq, less than or equal to about 0.06 eq, less than or equal to about 0.05 eq, less than or equal to about 0.04 eq, less than or equal to about 0.03 eq, less than or equal to about 0.02 eq, less than or equal to about 0.01 eq, or any range or value including and / or in between any two of these values.Additive4902-2817-2415.2Atty. Dkt. No.: 111346-2359(0068] In some embodiments, the a-arylation is performed in the presence of an additive. In some embodiments, the additive is phenol.(0069] In some embodiments, the additive is present at a concentration, relative to the compound of Formula (a), of at least about 0.01 eq, at least about 0.02 eq, at least about 0.03 eq, at least about 0.04 eq, at least about 0.05 eq, at least about 0.06 eq, at least about 0.07 eq, at least about 0.08 eq, at least about 0.09 eq, at least about 0.1 eq, at least about 0.15 eq, at least about 0.2 eq, at least about 0.25 eq, at least about 0.3 eq, at least about 0.35 eq, at least about 0.4 eq, at least about 0.45 eq, at least about 0.5 eq, or any range or value including and / or in between any two of these values.

[0070] In some embodiments, the additive is present at a concentration, relative to the compound of Formula (a), of less than or equal to about 0.5 eq, less than or equal to about 0.45 eq, less than or equal to about 0.4 eq, less than or equal to about 0.35 eq, less than or equal to about 0.3 eq, less than or equal to about 0.25 eq, less than or equal to about 0.2 eq, less than or equal to about 0.15 eq, less than or equal to about 0.1 eq, less than or equal to about 0.09 eq, less than or equal to about 0.08 eq, less than or equal to about 0.07 eq, less than or equal to about 0.06 eq, less than or equal to about 0.05 eq, less than or equal to about 0.04 eq, less than or equal to about 0.03 eq, less than or equal to about 0.02 eq, less than or equal to about 0.01 eq, or any range or value including and / or in between any two of these values.Base[00711 In some embodiments, the a-arylation is performed in the presence of base, including but not limited to K3PO4. NaOH, KOH, K2CO3, KO'Bu, CsCO3, Na2CO3or any combination thereof. In some embodiments, the base is K3PO4, present at a concentration of 0.5 to 5.0 equivalents, relative to the compound of Formula (a).Reaction Conditions(0072] The a-arylation may be performed at any suitable temperature for achieving high yield and purity (e.g., chemical purity and e.e.) of the compound of Formula (c). In some embodiments, the a-arylation is performed at a temperature of at least about 40°C, at least -21- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359about 45°C, at least about 50°C, at least about 55°C, at least about 60°C, at least about 65°C, at least about 70°C, at least about 75°C, at least about 80°C, at least about 85°C, at least about 90°C, at least about 95°C, at least about 100°C, at least about 105°C, at least about 110°C, at least about 115°C, at least about 120°C, or any range or value including and / or in between any two of these values.

[0073] In some embodiments, the a-arylation is performed at a temperature of less than or equal to about 120°C, less than or equal to about 115°C, less than or equal to about 110°C, less than or equal to about 105°C, less than or equal to about 100°C, less than or equal to about 95°C, less than or equal to about 90°C, less than or equal to about 85°C, less than or equal to about 80°C, less than or equal to about 75°C, less than or equal to about 70°C, less than or equal to about 65°C, less than or equal to about 60°C, less than or equal to about 55°C, less than or equal to about 50°C, less than or equal to about 45°C, less than or equal to about 40°C, or any range or value including and / or in between any two of these values.

[0074] The a-arylation may be performed in any suitable solvent for achieving high yield and purity of the compound of Formula (c). In some embodiments, the a-arylation is performed in toluene, 2-methyl-tetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), dioxane, tert-amyl alcohol (tamylOH), acetonitrile (MeCN), dimethylformamide (DMF), N-methyl pyrrolidinone (NMP) methanol, ethanol, tert-butyl alcohol (tBuOH), or any other suitable solvent. In some embodiments, the solvent is toluene.

[0075] The a-arylation may be performed for any suitable amount of time for achieving high yield and purity of the compound of Formula (c). In some embodiments, the a-arylation is performed for at least about 8 hr, at least about 10 hr, at least about 12 hr, at least about 14 hr, at least about 16 hr, at least about 18 hr, at least about 20 hr, at least about 22 hr, at least about 24 hr, at least about 26 hr, at least about 28 hr, at least about 30 hr, or any range or value including and / or in between any two of these values.

[0076] In some embodiments, the a-arylation is performed for less than or equal to about 30 hr, less than or equal to about 28 hr, less than or equal to about 26 hr, less than or equal to about 24 hr, less than or equal to about 22 hr, less than or equal to about 20 hr, less than or equal to about 18 hr, less than or equal to about 16 hr, less than or equal to about 14 hr, less -22- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359than or equal to about 12 hr, less than or equal to about 10 hr, less than or equal to about 8 hr, or any range or value including and / or in between any two of these values. In some embodiments, the the a-arylation is performed for about 10 hr to about 20 hr, about 12 hr to about 18 hr, or about 16 hr.Yield / Purity

[0077] The a-arylation may produce the compound of Formula (c) in high yield, relative to the compound of Formula (a). In some embodiments, the yield is at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, or any range or value including and / or in between any two of these values.

[0078] In some embodiments, the yield is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, or any range or value including and / or in between any two of these values.

[0079] The a-arylation may produce the compound of Formula (c) in high purity, as determined by any suitable method (HPLC, IPC, etc.). In some embodiments, the purity is at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, or any range or value including and / or in between any two of these values.-23- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359(0080] In some embodiments, the purity is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, or any range or value including and / or in between any two of these values.Step 2 - Stereoselective Reduction

[0081] In one aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to compound of Formula (I):wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein P2is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C1-C5alkyl)3, Si(aryl)2(C1-C5alkyl), and CH2-aryl.

[0082] In some embodiments, P2is CH2-aryl. In some embodiments, P1is (C=O)-C1alkyl. In some embodiments, P2is CH2-aryl and P1is (C=O)-C1alkyl. In some embodiments, the compound of Formula (I) is N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l, 2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)).4902-2817-2415.2Atty. Dkt. No.: 111346-2359N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1))

[0083] In some embodiments, the compound of Formula (I) is synthesized by stereoselective reduction of a compound according to Formula (c) using a catalyst, as shown in Scheme 5.Scheme 5. General Synthesis of a Compound of Formula (I) by Stereoselective Reduction of a Compound of Formula (c)Formula (c) Formula (I)Catalyst100841 The stereoselective reduction is performed using a stereoselective catalyst. In some embodiments, the stereoselective catalyst is a ruthenium, platinum, palladium, or nickel catalyst. In some embodiments, the stereoselective catalyst is a ruthenium catalyst. In some embodiments, the stereoselective catalyst is selected from the ruthenium catalysts shown in Scheme 6. In some embodiments, the stereoselective catalyst is selected from Ru(OAc)2[(S)-binap], (S-BINAP)RuCl2, [RuCl(p-cymene)((S)-binap)]Cl, RuCl2[(R)-binap][(R, R)-dpen], (R)-Ru(OAc)2(segphos), RuCl(p- cymene)[(S,S)-Ts- DPEN], Ru(OAc)2[(S)-OMe-BIPHEP], RuCl[(R, R)-Tsdpen(mesitylene), RuCl[(S, S)-FsDPEN](p-cymene), RuCl(R, R)-Teth-TsDpen RuCl, or any combination thereof. In some embodiments, the stereoselective catalyst is RuCl[(R, R)-TsDpen(mesitylene)] or RuCl (R, R)-Teth-TsDpen RuCl. In some embodiments, the stereoselective catalyst is RuCl[(R, R)-TsDpen(mesitylene)]. In some embodiments, the stereoselective catalyst is RuCl (R, R)-Teth-TsDpen RuCl.Scheme 6. Stereoselective Ru Catalysts-25- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Ru(OAc)2[(S)-OMe-BIPHEP] (R)-Ru(OAc)2(segphos) RuCl(p- cymene)[(S,S)-Ts- DPEN]Ru(OAc)2[(S)-binap] RuCl(p-cymene)((S)-binap]ClRuCl2[(R)-binap][(R, R)-dpen]

[0085] The catalyst may be added at any concentration, relative to the compound of Formula (c) to achieve high yield and purity of the product compound of Formula (I). In some embodiments, the stereoselective catalyst is present at a concentration, relative to the compound of Formula (c), of at least about 0.1 mol%, at least about 0.2 mol%, at least about 0.3 mol%, at least about 0.4 mol%, at least about 0.5 mol%, at least about 0.6 mol%, at least about 0.7 mol%, at least about 0.8 mol%, at least about 0.9 mol%, at least about 1.0 mol%, at least about 1.5 mol%, at least about 2.0 mol%, at least about 2.5 mol%, at least about 3.0 mol%, at least about 3.5 mol%, at least about 4.0 mol%, at least about 4.5 mol%, at least about 5.0 mol%, or any range or value including and / or in between any two of these values.4902-2817-2415.2Atty. Dkt. No.: 111346-2359(0086] In some embodiments, the stereoselective catalyst is present at a concentration, relative to the compound of Formula (c), of less than or equal to about 5.0 mol%, less than or equal to about 4.5 mol%, less than or equal to about 4.0 mol%, less than or equal to about 3.5 mol%, less than or equal to about 3.0 mol%, less than or equal to about 2.5 mol%, less than or equal to about 2.0 mol%, less than or equal to about 1.5 mol%, less than or equal to about 1.0 mol%, less than or equal to about 0.9 mol%, less than or equal to about 0.8 mol%, less than or equal to about 0.7 mol%, less than or equal to about 0.6 mol%, less than or equal to about 0.5 mol%, less than or equal to about 0.4 mol%, less than or equal to about 0.3 mol%, less than or equal to about 0.2 mol%, less than or equal to about 0.1 mol%, or any range or value including and / or in between any two of these values.

[0087] In some embodiments, the stereoselective catalyst is present at a concentration, relative to the compound of Formula (c), of about 1 mol% to about 3 mol%, about 1.5 mol% to about 2.5 mol%, or about 2 mol%.Hydrogen Source

[0088] The stereoselective reduction is performed using a hydrogen source. In some embodiments, the hydrogen source comprises ammonium formate (NH4HCO2), formic acid (HCOOH), and / or triethylamine (NEt3). In some embodiments, the hydrogen source comprises borane and / or morpholine.

[0089] The hydrogen source may be used at any suitable concentration, relative to the compound of Formula (c), to provide high yield and high purity of the compound of Formula (I). In some embodiments, any component of the hydrogen source (e.g., formic acid, triethylamine, borane, or morpholine) is present at a concentration, relative to the compound of Formula (c), of at least about 1 eq, at least about 1.5 eq, at least about 2 eq, at least about 2.5 eq, at least about 3 eq, at least about 3.5 eq, at least about 4 eq, at least about 4.5 eq, at least about 5 eq, at least about 5.5 eq, at least about 6 eq, at least about 6.5 eq, at least about 7 eq, at least about 7.5 eq, at least about 8 eq, at least about 8.5 eq, at least about 9 eq, at least about 9.5 eq, at least about 10 eq, or any range or value including and / or in between any two of these values.-27- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0090] In some embodiments, any component of the hydrogen source (e.g., formic acid, triethylamine, borane, or morpholine) is present at a concentration, relative to the compound of Formula (c), of less than or equal to about 10 eq, less than or equal to about 9.5 eq, less than or equal to about 9 eq, less than or equal to about 8.5 eq, less than or equal to about 8 eq, less than or equal to about 7.5 eq, less than or equal to about 7 eq, less than or equal to about 6.5 eq, less than or equal to about 6 eq, less than or equal to about 5.5 eq, less than or equal to about 5 eq, less than or equal to about 4.5 eq, less than or equal to about 4 eq, less than or equal to about 3.5 eq, less than or equal to about 3 eq, less than or equal to about 2.5 eq, less than or equal to about 2 eq, less than or equal to about 1.5 eq, less than or equal to about 1 eq, or any range or value including and / or in between any two of these values.

[0091] In some embodiments, the hydrogen source comprises formic acid at about 3 eq to 7 eq, about 4 eq to about 6 eq, or about 5 eq, relative to the compound of Formula (c). In some embodiments, the hydrogen source comprises triethylamine at about 1 eq to 6 eq, about 2 eq to about 5 eq, about 3 eq to about 4 eq, or about 3 eq, relative to the compound of Formula (c)Reaction Conditions

[0092] The stereoselective reduction may be performed at any suitable temperature for achieving high yield and purity of the compound of Formula (I). In some embodiments, the stereoselective reduction is performed at a temperature of at least about 35°C, at least about 40°C, at least about 45°C, at least about 50°C, at least about 55°C, at least about 60°C, at least about 65°C, at least about 70°C, at least about 75°C, at least about 80°C, at least about 85°C, at least about 90°C, at least about 95°C, at least about 100°C, at least about 105°C, at least about 110°C, at least about 115°C, at least about 120°C, or any range or value including and / or in between any two of these values.

[0093] In some embodiments, the stereoselective reduction is performed at a temperature of less than or equal to about 120°C, less than or equal to about 115°C, less than or equal to about 110°C, less than or equal to about 105°C, less than or equal to about 100°C, less than or equal to about 95°C, less than or equal to about 90°C, less than or equal to about 85°C, less than or equal to about 80°C, less than or equal to about 75°C, less than or equal to about -28- 4902-2817-2415.2Atty. Dkt. No.: 111346-235970°C, less than or equal to about 65°C, less than or equal to about 60°C, less than or equal to about 55°C, less than or equal to about 50°C, less than or equal to about 45°C, less than or equal to about 40°C, less than or equal to about 35°C, or any range or value including and / or in between any two of these values.

[0094] In some embodiments, the stereoselective reduction is performed at about 40°C to about 70°C. In some embodiments, the stereoselective reduction is performed at about 50°C.

[0095] The stereoselective reduction may be performed in any suitable solvent for achieving high yield and purity of the compound of Formula (I). In some embodiments, the stereoselective reduction is performed in toluene, 2-methyl-tetrahydrofuran (2-MeTHF), tetrahydrofuran (THF) tert-amyl alcohol (tamylOH), acetonitrile (MeCN), dimethylformamide (DMF), N-methyl pyrrolidinone (NMP), methanol, ethanol, tert-butyl alcohol (tBuOH), isopropyl alcohol (IP A), ethyl acetate (EA), dichloromethane (DCM), di chloroethane (DCE), dimethoxyethane (DME), dioxane, or any other suitable solvent. In some embodiments, the solvent is THF. In some embodiments, the solvent is DCM.

[0096] The stereoselective reduction may be performed for any suitable amount of time for achieving high yield and purity of the compound of Formula (I). In some embodiments, the stereoselective reduction is performed for at least about 8 hr, at least about 10 hr, at least about 12 hr, at least about 14 hr, at least about 16 hr, at least about 18 hr, at least about 20 hr, at least about 22 hr, at least about 24 hr, at least about 26 hr, at least about 28 hr, at least about 30 hr, or any range or value including and / or in between any two of these values.

[0097] In some embodiments, the stereoselective reduction is performed for less than or equal to about 30 hr, less than or equal to about 28 hr, less than or equal to about 26 hr, less than or equal to about 24 hr, less than or equal to about 22 hr, less than or equal to about 20 hr, less than or equal to about 18 hr, less than or equal to about 16 hr, less than or equal to about 14 hr, less than or equal to about 12 hr, less than or equal to about 10 hr, less than or equal to about 8 hr, or any range or value including and / or in between any two of these values.-29- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0098] In some embodiments, the stereoselective reduction is performed for about 10 hr to about 20 hr, about 12 hr to about 18 hr, or for about 16 hr.Yield / Purity

[0099] The stereoselective reduction may produce the compound of Formula (I) in high yield, relative to the compound of Formula (c). In some embodiments, the yield is at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, or any range or value including and / or in between any two of these values.

[0100] In some embodiments, the yield is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, less than or equal to about 75%, less than or equal to about 70%, or any range or value including and / or in between any two of these values.

[0101] The stereoselective reduction may produce the compound of Formula (I) in high purity, as determined by any suitable method (HPLC, IPC, etc.). In some embodiments, the purity is at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, or any range or value including and / or in between any two of these values.

[0102] In some embodiments, the purity is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less-30- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, or any range or value including and / or in between any two of these values.

[0103] The stereoselective reduction may produce the compound of Formula (I) at a high optical purity (enantiomeric excess, or “e.e ”). In some embodiments, the enantiomeric excess is at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, or any range or value including and / or in between any two of these values.

[0104] In some embodiments, the enantiomeric excess is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, or any range or value including and / or in between any two of these values.Step 3 – Dehydroxylation and Deprotection

[0105] In some embodiments, the present disclosure relates to a synthesis of elacestrant intermediates in which a compound of Formula (III) is synthesized by deprotecting and dehydroxylating (simultaneously) a compound of Formula (I), as shown in Scheme 7.Scheme 7. Deprotection and Dehydroxylation of Compound of Formula (I)-31- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359dehydroxylation deprotection Step 3(0

[0106] In some embodiments, Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-C8alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3. In some embodiments, P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(C1-C5alkyl)3, Si(aryl)2(C1-C5alkyl), and CH2-aryl. In some embodiments, P2is CH2-aryl. In some embodiments, P1is (C=O)-C1alkyl. In some embodiments, P2is CH2-aryl and P1is (C=O)-C1alkyl.

[0107] In some embodiments, the compound of Formula (I) is N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (I-1)). In some embodiments, the compound of Formula (III) is N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (III-l)). In some embodiments, the compound of Formula (I) is Compound (1-1), and the compound of Formula (III) is Compound (III-l), as shown in Scheme 8.Scheme 8. Deprotection and Dehydroxylation of Compound (1-1) to Obtain Compound (III-l)

[0108] In some embodiments, the deprotection and dehydroxylation is performed in the presence of a catalyst and hydrogen source.Catalyst

[0109] The dehydroxylation / deprotection may be performed using any suitable catalyst to ensure high yield, high purity, and high enantiomeric excess of the compound of Formula (III) In some embodiments, the catalyst is a platinum-, palladium-, ruthenium-, or nickel-based catalyst. In some embodiments, the catalyst is a palladium-based catalyst. In some -32- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359embodiments, the catalyst comprises Pd / C, Pt / C, Pd(OAc)2, NiCh, Raney Ni, FeCh C0CI2, PdCh, or any combination thereof. In some embodiments, the catalyst is Pd / C.

[0110] The catalyst may be added in any suitable amount to facilitate dehydroxylation and deprotection, enabling a high yield and high enantiomeric excess of the compound of Formula (III). In some embodiments, the catalyst is added in an amount, relative to the mass of the compound of Formula (I), on a wet basis, of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 180%, at least about 200%, or any range or value including and / or in between any two of these values.

[0111] In some embodiments, the catalyst is added in an amount, relative to the mass of the compound of Formula (I), on a wet basis, of less than or equal to about 200%, less than or equal to about 180%, less than or equal to about 160%, less than or equal to about 140%, less than or equal to about 120%, less than or equal to about 100%, less than or equal to about 90%, less than or equal to about 80%, less than or equal to about 70%, less than or equal to about 60%, less than or equal to about 50%, less than or equal to about 45%, less than or equal to about 40%, less than or equal to about 35%, or any range or value including and / or in between any two of these values.

[0112] In some embodiments, the catalyst is added in an amount, relative to the mass of the compound of Formula (I), on a wet basis, of about 35%, about 50%, about 100% or about 200%.Hydrogen Source

[0113] The dehydroxlyation / deprotection may be performed using a hydrogen source. In some embodiments, the hydrogen source comprises formic acid (HCOOH) and / or triethylamine (NEts). In some embodiments, the hydrogen source comprises borane and / or morpholine. In some embodiments, the hydrogen source comprises hydrogen, NH4HCO2, NaBH4, LiBH4, LiAlH4, BH3, formic acid (HCOOH), oxalic acid ((COOH)2), triethylamine (NEts), triethylsilane (EtsSiH), phenylsilane (PhSiH3), or any combination thereof.-33- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0114] The hydrogen source may be used at any suitable concentration, relative to the compound of Formula (I), to provide high yield and high purity of the compound of Formula (III). In some embodiments, any component of the hydrogen source (e.g., formic acid, triethylamine, borane, or morpholine) is present at a concentration, relative to the compound of Formula (I), of at least about 1 eq, at least about 1.5 eq, at least about 2 eq, at least about 2.5 eq, at least about 3 eq, at least about 3.5 eq, at least about 4 eq, at least about 4.5 eq, at least about 5 eq, at least about 5.5 eq, at least about 6 eq, at least about 6.5 eq, at least about 7 eq, at least about 7.5 eq, at least about 8 eq, at least about 8.5 eq, at least about 9 eq, at least about 9.5 eq, at least about 10 eq, or any range or value including and / or in between any two of these values.

[0115] In some embodiments, any component of the hydrogen source e.g., formic acid, triethylamine, borane, or morpholine) is present at a concentration, relative to the compound of Formula (I), of less than or equal to about 10 eq, less than or equal to about 9.5 eq, less than or equal to about 9 eq, less than or equal to about 8.5 eq, less than or equal to about 8 eq, less than or equal to about 7.5 eq, less than or equal to about 7 eq, less than or equal to about 6.5 eq, less than or equal to about 6 eq, less than or equal to about 5.5 eq, less than or equal to about 5 eq, less than or equal to about 4.5 eq, less than or equal to about 4 eq, less than or equal to about 3.5 eq, less than or equal to about 3 eq, less than or equal to about 2.5 eq, less than or equal to about 2 eq, less than or equal to about 1.5 eq, less than or equal to about 1 eq, or any range or value including and / or in between any two of these values.

[0116] In some embodiments, the hydrogen source comprises formic acid at about 3 eq to 7 eq, about 4 eq to about 6 eq, or about 5 eq, relative to the compound of Formula (I). In some embodiments, the hydrogen source comprises triethylamine at about 1 eq to 6 eq, about 2 eq to about 5 eq, about 3 eq to about 4 eq, or about 3 eq, relative to the compound of Formula (I)

[0117] In some embodiments, the hydrogen source is hydrogen gas. In some embodiments, the hydrogen gas is present at a pressure of at least about 0.1 MPa, at least about 0.5 MPa, at least about 1 MPa, at least about 2 MPa, at least about 3 MPa, at least about 4 MPa, at least about 5 MPa, at least about 6 MPa, at least about 7 MPa, at least about 8 MPa, at least about-34- 4902-2817-2415.2Atty. Dkt. No.: 111346-23599 MPa, at least about 10 MPa, or any range or value including and / or in between any two of these values. In some embodiments, the hydrogen gas is present at a pressure of less than or equal to about 10 MPa, less than or equal to about 9 MPa, less than or equal to about 8 MPa, less than or equal to about 7 MPa, less than or equal to about 6 MPa, less than or equal to about 5 MPa, less than or equal to about 4 MPa, less than or equal to about 3 MPa, less than or equal to about 2 MPa, less than or equal to about 1 MPa, less than or equal to about 0.5 MPa, less than or equal to about 0.1 MPa.Reaction Conditions

[0118] The dehydroxlyation / deprotection may be performed at any suitable temperature for achieving high yield and purity of the compound of Formula (III). In some embodiments, the dehydroxlyation / deprotection is performed at a temperature of at least about 20°C, at least about 30°C, at least about 35°C, at least about 40°C, at least about 45°C, at least about 50°C, at least about 55°C, at least about 60°C, at least about 65°C, at least about 70°C, at least about 75°C, at least about 80°C, at least about 85°C, at least about 90°C, at least about 95°C, at least about 100°C, at least about 105°C, at least about 110°C, at least about 115°C, at least about 120°C, or any range or value including and / or in between any two of these values.

[0119] In some embodiments, the dehydroxlyation / deprotection is performed at a temperature of less than or equal to about 120°C, less than or equal to about 115°C, less than or equal to about 110°C, less than or equal to about 105°C, less than or equal to about 100°C, less than or equal to about 95°C, less than or equal to about 90°C, less than or equal to about 85°C, less than or equal to about 80°C, less than or equal to about 75°C, less than or equal to about 70°C, less than or equal to about 65°C, less than or equal to about 60°C, less than or equal to about 55°C, less than or equal to about 50°C, less than or equal to about 45°C, less than or equal to about 40°C, less than or equal to about 35°C, less than or equal to about 30°C, less than or equal to about 25°C, or any range or value including and / or in between any two of these values.

[0120] In some embodiments, the dehydroxlyation / deprotection is performed at about 20°C to about 70°C, about 25°C to about 65°C, about 30°C to about 60°C, about 35°C to about 55°C, or about 40°C to about 60°C. In some embodiments, the dehydroxlyation / deprotection-35- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359is performed at about 25°C. In some embodiments, the dehydroxlyation / deprotection is performed at about 65°C.

[0121] The dehydroxlyation / deprotection may be performed in any suitable solvent for achieving high yield and purity of the compound of Formula (III). In some embodiments, the dehydroxlyation / deprotection is performed in toluene, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-MeTHF), tert-amyl alcohol (tamylOH), acetonitrile (MeCN), dimethylformamide (DMF), methanol, ethanol, tert-butyl alcohol (tBuOH), isopropyl alcohol (IP A), ethyl acetate (EA), dichloromethane (DCM), dichloroethane (DCE), dioxane, dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), or any other suitable solvent. In some embodiments, the solvent is DMAc.

[0122] The dehydroxlyation / deprotection may be performed for any suitable amount of time for achieving high yield and purity of the compound of Formula (III). In some embodiments, the dehydroxlyation / deprotection is performed for at least about 8 hr, at least about 10 hr, at least about 12 hr, at least about 14 hr, at least about 16 hr, at least about 18 hr, at least about 20 hr, at least about 22 hr, at least about 24 hr, at least about 26 hr, at least about 28 hr, at least about 30 hr, or any range or value including and / or in between any two of these values.

[0123] In some embodiments, the dehydroxlyation / deprotection is performed for less than or equal to about 30 hr, less than or equal to about 28 hr, less than or equal to about 26 hr, less than or equal to about 24 hr, less than or equal to about 22 hr, less than or equal to about 20 hr, less than or equal to about 18 hr, less than or equal to about 16 hr, less than or equal to about 14 hr, less than or equal to about 12 hr, less than or equal to about 10 hr, less than or equal to about 8 hr, or any range or value including and / or in between any two of these values. In some embodiments, the dehydroxlyation / deprotection is performed for about 10 hr to about 20 hr, about 12 hr to about 18 hr, or about 16 hr.Yield / Purity

[0124] The dehydroxlyation / deprotection may produce the compound of Formula (III) in high yield, relative to the amount of starting material compound of Formula (I). In some-36- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359embodiments, the yield is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, or any range or value including and / or in between any two of these values.

[0125] In some embodiments, the yield is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, less than or equal to about 75%, less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, or any range or value including and / or in between any two of these values.

[0126] The dehydroxlyation / deprotection may produce the compound of Formula (III) in high purity, as determined by any suitable method (HPLC, IPC, etc.). In some embodiments, the purity is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, about 100%, or any range or value including and / or in between any two of these values.[01271 In some embodiments, the purity is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to-37- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, less than or equal to about 75%, less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, less than or equal to about 50%, or any range or value including and / or in between any two of these values.

[0128] The dehydroxlyation / deprotection may produce the compound of Formula (III) at a high optical purity (enantiomeric excess, or “e.e ”). In some embodiments, the enantiomeric excess is at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, about 100%, or any range or value including and / or in between any two of these values.

[0129] In some embodiments, the enantiomeric excess is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, less than or equal to about 75%, less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, or any range or value including and / or in between any two of these values.Step 3A – Dehydroxylation

[0130] In some embodiments, the present disclosure relates to a synthesis of elacestrant intermediates in which a compound of Formula (II) is synthesized by dehydroxylating a compound of Formula (I), as shown in Scheme 9.Scheme 9. Dehydroxylation of Compound of Formula (I)-38- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359OMeOHdehydroxytationStep 3A(I) (H)[01311 In some embodiments, Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-C8alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3. In some embodiments, P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-C5 alkyl)3, Si(aryl)2(Ci-Cs alkyl), and CFb-aryl. In some embodiments, P2 is CH2-aryl. In some embodiments, Pi is (C=O)-Ci alkyl. In some embodiments, P2 is CFb-aryl, and Pi is (C=O)-Ci alkyl.

[0132] In some embodiments, the compound of Formula (I) is N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (I-1)). In some embodiments, the compound of Formula (II) is (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l)). In some embodiments, the compound of Formula (I) is Compound (1-1), and the compound of Formula (II) is Compound (II-l), as shown in Scheme 10.Scheme 10. Dehydroxylation of Compound (1-1) to Obtain Compound (II-l)0-1) 01-1}

[0133] In some embodiments, the dehydroxylation is performed in the presence of an acid and a hydrogen source.Hydrogen Source[01341 The dehydroxlyation of Step 3 A may be performed using a hydrogen source. In some embodiments, the hydrogen source comprises formic acid (HCOOH) and triethylamine (NEt3). In some embodiments, the hydrogen source comprises borane and morpholine. In some embodiments, the hydrogen source comprises NaBF, NH4HCO2, LiBH4, Li AIH4, BH3,-39- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359oxalic acid ((COOH)2), LiAlH4, BH3, formic acid (HCOOH), triethylamine (NEts), triethylsilane (EtsSiH), phenylsilane (PhSiH3), or any combination thereof. In some embodiments, the hydrogen source is NaBH4, LiAlH4, or a combination thereof.

[0135] The hydrogen source may be used at any suitable concentration, relative to the compound of Formula (I), to provide high yield and high purity of the compound of Formula (II). In some embodiments, any component of the hydrogen source (e.g., formic acid, triethylamine, borane, or morpholine) is present at a concentration, relative to the compound of Formula (I), of at least about 1 eq, at least about 1.5 eq, at least about 2 eq, at least about 2.5 eq, at least about 3 eq, at least about 3.5 eq, at least about 4 eq, at least about 4.5 eq, at least about 5 eq, at least about 5.5 eq, at least about 6 eq, at least about 6.5 eq, at least about 7 eq, at least about 7.5 eq, at least about 8 eq, at least about 8.5 eq, at least about 9 eq, at least about 9.5 eq, at least about 10 eq, or any range or value including and / or in between any two of these values.

[0136] In some embodiments, any component of the hydrogen source (e.g., formic acid, triethylamine, borane, or morpholine) is present at a concentration, relative to the compound of Formula (I), of less than or equal to about 10 eq, less than or equal to about 9.5 eq, less than or equal to about 9 eq, less than or equal to about 8.5 eq, less than or equal to about 8 eq, less than or equal to about 7.5 eq, less than or equal to about 7 eq, less than or equal to about 6.5 eq, less than or equal to about 6 eq, less than or equal to about 5.5 eq, less than or equal to about 5 eq, less than or equal to about 4.5 eq, less than or equal to about 4 eq, less than or equal to about 3.5 eq, less than or equal to about 3 eq, less than or equal to about 2.5 eq, less than or equal to about 2 eq, less than or equal to about 1.5 eq, less than or equal to about 1 eq, or any range or value including and / or in between any two of these values.

[0137] In some embodiments, the dehydroxylation is performed in the presence of an acid. In some embodiments, the acid comprises oxalic acid, formic acid, trifluoroacetic acid, p-toluenesulfonic acid, or any combination thereof. In some embodiments, the acid comprises oxalic acid or formic acid. In some embodiments, the acid comprises or trifluoracetic acid or p-toluenesulfonic acid. In some embodiments, the acid is present, at a concentration relative to the molar amount of the compound of Formula (I), of at least about 1 eq, at least about 2-40- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359eq, at least about 3 eq, at least about 4 eq, at least about 5 eq, at least about 10 eq, at least about 15 eq, at least about 20 eq, at least about 25 eq, at least about 30 eq, at least about 35 eq, at least about 40 eq, at least about 45 eq, at least about 50 eq, or any range or value including and / or in between any two of these values.

[0138] In some embodiments, the acid is present, at a concentration relative to the molar amount of the compound of Formula (I), of less than or equal to about 50 eq, less than or equal to about 45 eq, less than or equal to about 40 eq, less than or equal to about 35 eq, less than or equal to about 30 eq, less than or equal to about 25 eq, less than or equal to about 20 eq, less than or equal to about 15 eq, less than or equal to about 10 eq, less than or equal to about 5 eq, less than or equal to about 4 eq, less than or equal to about 3 eq, less than or equal to about 2 eq, less than or equal to about 1 eq, or any range or value including and / or in between any two of these values.Reaction Conditions10139] The dehydroxlyation may be performed at any suitable temperature for achieving high yield and purity of the compound of Formula (II). In some embodiments, the dehydroxlyation is performed at a temperature of at least about -30°C, at least about -10°C, at least about -10°C, at least about 0°C, at least about 10°C, at least about 20°C, at least about 30°C, at least about 35°C, at least about 40°C, at least about 45°C, at least about 50°C, at least about 55°C, at least about 60°C, at least about 65°C, at least about 70°C, at least about 75°C, at least about 80°C, at least about 85°C, at least about 90°C, at least about 95°C, at least about 100°C, at least about 105°C, at least about 110°C, at least about 115°C, at least about 120°C, or any range or value including and / or in between any two of these values.

[0140] In some embodiments, the dehydroxlyation is performed at a temperature of less than or equal to about 120°C, less than or equal to about 115°C, less than or equal to about 110°C, less than or equal to about 105°C, less than or equal to about 100°C, less than or equal to about 95°C, less than or equal to about 90°C, less than or equal to about 85°C, less than or equal to about 80°C, less than or equal to about 75°C, less than or equal to about 70°C, less than or equal to about 65°C, less than or equal to about 60°C, less than or equal to about 55°C, less than or equal to about 50°C, less than or equal to about 45°C, less than or equal to about 40°C, less than or equal to about 35°C, less than or equal to about 30°C, less than or -41- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359equal to about 25°C, less than or equal to about 20°C, less than or equal to about 10°C, less than or equal to about 0°C, less than or equal to about -10°C, less than or equal to about -20°C, less than or equal to about -30°C, or any range or value including and / or in between any two of these values.101411 In some embodiments, the dehydroxlyation is performed at about 40°C to 70°C or at about -10 C° to 30 °C or about -20°C to about -10°C.

[0142] The dehydroxlyation may be performed in any suitable solvent for achieving high yield and purity of the compound of Formula (II). In some embodiments, the dehydroxlyation is performed in toluene, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-MeTHF), tert-amyl alcohol (tamylOH), acetonitrile (MeCN), dimethylformamide (DMF), methanol, ethanol, tert-butyl alcohol (tBuOH), isopropyl alcohol (IP A), ethyl acetate (EA), dichloromethane (DCM), di chloroethane (DCE), dioxane, dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), or any other suitable solvent. In some embodiments, the solvent is THF.

[0143] The dehydroxlyation may be performed for any suitable amount of time for achieving high yield and purity of the compound of Formula (II). In some embodiments, the dehydroxlyation is performed for at least about 1 hr, at least about 2 hr, at least about 3 hr, at least about 4 hr, at least about 6 hr, at least about 8 hr, at least about 10 hr, at least about 12 hr, at least about 14 hr, at least about 16 hr, at least about 18 hr, at least about 20 hr, at least about 22 hr, at least about 24 hr, at least about 26 hr, at least about 28 hr, at least about 30 hr, or any range or value including and / or in between any two of these values.

[0144] In some embodiments, the dehydroxlyation is performed for less than or equal to about 30 hr, less than or equal to about 28 hr, less than or equal to about 26 hr, less than or equal to about 24 hr, less than or equal to about 22 hr, less than or equal to about 20 hr, less than or equal to about 18 hr, less than or equal to about 16 hr, less than or equal to about 14 hr, less than or equal to about 12 hr, less than or equal to about 10 hr, less than or equal to about 8 hr, less than or equal to about 6 hr, less than or equal to about 4 hr, less than or equal to about 3 hr, less than or equal to about 2 hr, less than or equal to about 1 hr, or any range or value including and / or in between any two of these values.-42- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0145] In some embodiments, the dehydroxlyation is performed for about 1 hr to about 3 hr. In some embodiments, the dehydroxylation is performed for about 1 hr.Yield / Purity

[0146] The dehydroxlyation may produce the compound of Formula (II) in high yield, relative to the amount of starting material compound of Formula (I). In some embodiments, the yield is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, or any range or value including and / or in between any two of these values.[01471 In some embodiments, the yield is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, less than or equal to about 75%, less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, or any range or value including and / or in between any two of these values.

[0148] The dehydroxlyation / deprotection may produce the compound of Formula (II) in high purity, as determined by any suitable method (HPLC, IPC, etc.). In some embodiments, the purity is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, about 100%, or any range or value including and / or in between any two of these values.-43- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0149] In some embodiments, the purity is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, less than or equal to about 75%, less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, less than or equal to about 50%, or any range or value including and / or in between any two of these values.

[0150] The dehydroxlyation may produce the compound of Formula (II) at a high optical purity (enantiomeric excess, or “e.e ”). In some embodiments, the enantiomeric excess is at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, about 100%, or any range or value including and / or in between any two of these values.

[0151] In some embodiments, the enantiomeric excess is less than or equal to about 100%, less than or equal to about 99%, less than or equal to about 98%, less than or equal to about 97%, less than or equal to about 96%, less than or equal to about 95%, less than or equal to about 94%, less than or equal to about 93%, less than or equal to about 92%, less than or equal to about 91%, less than or equal to about 90%, less than or equal to about 89%, less than or equal to about 88%, less than or equal to about 87%, less than or equal to about 86%, less than or equal to about 85%, less than or equal to about 80%, less than or equal to about 75%, less than or equal to about 70%, less than or equal to about 65%, less than or equal to about 60%, less than or equal to about 55%, or any range or value including and / or in between any two of these values.Step 3B - Deprotection-44- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0152] In some embodiments, the present disclosure relates to a synthesis of elacestrant intermediates in which a compound of Formula (III) is synthesized by deprotecting a compound of Formula (II), as shown in Scheme 1.

[0153] In some embodiments, the deprotection of Step 3B is a debenzylation of (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-1)) to obtain N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (III-l)), as shown in Scheme 2.

[0154] Such deprotection reactions are described in Italian Patent Application No.IT 102023000021471, filed October 16, 2023; PCT International Application No.PCT / EP2024 / 079146, filed October 16, 2024; and in PCT International Application No. PCT / US2020 / 017777 (published as WO 2020 / 167855A1). Suitable experimental conditions are presented herein as Example 13.Step 4 - Hydrolysis

[0155] In some embodiments, the present disclosure relates to a synthesis of elacestrant intermediates in which Compound (d) is synthesized by hydrolyzing a compound of Formula (III), as shown in Scheme 1.

[0156] In some embodiments, Step 4 is hydrolysis of N-(2-(6-hydroxy)-l, 2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (III-l)) to produce (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)), as shown in Scheme 2.

[0157] Such deprotection reactions are described in Italian Patent Application No.IT 102023000021471, filed October 16, 2023; PCT International Application No.PCT / EP2024 / 079146, filed October 16, 2024; and in PCT International Application No. PCT / US2020 / 017777 (published as WO 2020 / 167855A1). Suitable experimental conditions are presented herein as Example 14.Step 4A - Deprotection / Hydrolysis-45- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0158] In some embodiments, the present disclosure relates to a synthesis of elacestrant intermediates in which Compound (d) is synthesized by deprotecting and hydrolyzing a compound of Formula (II), as shown in Scheme 1.

[0159] In some embodiments, Step 4A is debenzylation and hydrolysis of (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-1)) to produce (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)), as shown in Scheme 2.[0160[ Such deprotection reactions are described in Italian Patent Application No.IT 102023000021471, filed October 16, 2023; PCT International Application No.PCT / EP2024 / 079146, filed October 16, 2024; and in PCT International Application No. PCT / US2020 / 017777 (published as WO 2020 / 167855A1). Suitable experimental conditions are presented herein as Example 15.

[0161] The removal of the protecting groups P1 and P2 is performed in two separate steps without isolation of the intermediate. The deprotection (e.g., debenzylation) may be performed using 48% HBr in water, 33% HBr in acetic acid, BCl3, TiCl4, TFA, or AlCl3. Acid hydrolysis of the P1 protecting group may be performed using an aqueous acid (e.g., HCl).Synthesis of Elacestrant

[0162] In another aspect, which may be combined with any other aspect or embodiment, the present disclosure relates to a synthesis of elacestrant, wherein the method comprises making or providing a compound according to Formula (I) or Formula (c). In some embodiments, the compound of Formula (I) is N-(2-((lR,2S)-6-(benzyloxy)-l -hydroxy- 1, 2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)). In some embodiments, the compound of Formula (c) is N-(2-6-(benzyloxy)-l-oxo-l, 2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide. Synthesis of the (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) may proceed from the compound of Formula (I) by at least three alternative routes, as described below.

[0163] Referring to Scheme 11 A, in some embodiments, the improved synthesis comprises:-46- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359• Step 1 - synthesis of a compound according to Formula (c) by a-arylation of a compound of Formula (a) using a compound of Formula (b);• Step 2 - stereoselective reduction of the compound of Formula (c) to obtain a compound according to Formula (I);• Step 3 - dehydroxylation and deprotection of the compound of Formula (I) to produce a compound of Formula (III);• Step 4 - hydrolysis of the compound of Formula (III) to produce the Compound (d); and• synthesizing elacestrant from the Compound (d).Scheme 11 A. Synthesis of Elacestrant Using Novel Intermediates of the Present DisclosurePd cat, ligand Step 1Formula a Formula b Formula cFormula I Formula IIIElacestrantFormula d

[0164] In some embodiments, the improved synthesis comprises:• Step 1 - synthesis N-(2-6-(benzyloxy)-l-oxo-l, 2,3, 4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (c-1)) via a-arylation of 6-(benzyloxy)-3,4- dihydronaphthalen-l(2H)-one (Compound (a-1)) using N-(2-bromo-5- methoxyphenyl)acetamide (Compound (b-1));• Step 2 - stereoselective reduction of N-(2-6-(benzyloxy)-l-oxo-l,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) to obtain N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1));-47- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359• Step 3 - dehydroxylation and debenzylation of N-(2-((lR,2S)-6-(benzyloxy)-l- hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) to produce N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (III-l));• Step 4 - hydrolysis of N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (III-l)) to produce (R)-6-(2-amino-4- methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)); and• synthesis of elacestrant from the Compound (d).

[0165] Referring to Scheme 11B, in some embodiments, the improved synthesis comprises:• Step 1 - synthesis of a compound according to Formula (c) by a-arylation of a compound of Formula (a) using a compound of Formula (b);• Step 2 - stereoselective reduction of the compound of Formula (c) to obtain a compound according to Formula (I);• Step 3a (“Step 3” in Scheme 11B) - dehydroxylation of the compound of Formula (I) to produce a compound of Formula (II);• Step 4a (“Step 4” in Scheme 11B) - deprotection and hydrolysis of the compound of Formula (II) to produce the Compound (d); and• synthesis of elacestrant from the Compound (d).Scheme 11B. Synthesis of Elacestrant Using Novel Intermediates of the Present DisclosurePd cat, ligand Step 1 Formula b Formula cFormula I Formula IIElacestrantFormula d4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0166] In some embodiments, the improved synthesis comprises:• Step 1 - synthesis N-(2-6-(benzyloxy)-l-oxo-l, 2,3, 4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (c-1)) via a-arylation of 6-(benzyloxy)-3,4- dihydronaphthalen-l(2H)-one (Compound (a-1)) using N-(2-bromo-5- methoxyphenyl)acetamide (Compound (b-1));• Step 2 - stereoselective reduction of N-(2-6-(benzyloxy)-l-oxo-l,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) to obtain N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1));• Step 3a (corresponding to “Step 3” in Scheme 11B) - dehydroxylation of N-(2- ((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1)) to produce (R)-N-(2-(6-(benzyloxy)- l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l));• Step 4a (corresponding to “Step 4” in Scheme 11B) - debenzylation and hydrolysis of (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (II-l)) to produce (R)-6-(2-amino-4- methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)); and• synthesis of elacestrant from the Compound (d).

[0167] Referring to Scheme 11C, in some embodiments, the improved synthesis comprises:• Step 1 - synthesis of a compound according to Formula (c) by a-arylation of a compound of Formula (a) using a compound of Formula (b);• Step 2 - stereoselective reduction of the compound of Formula (c) to obtain a compound according to Formula (I);• Step 3a (“Step 3” in Scheme 11C) - dehydroxylation of the compound of Formula (I) to produce a compound of Formula (II);• Step 3b (“Step 4” in Scheme 11C) - deprotection of the compound of Formula (II) to obtain a compound of Formula (III);• Step 4 (“Step 5” in Scheme 11C) - hydrolysis of the compound of Formula (III) to produce the Compound (d); and• synthesis of elacestrant from the Compound (d).-49- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Scheme 11C. Synthesis of Elacestrant Using Novel Intermediates of the Present DisclosureFormula a Formula b Formula cFormula I Formula II Formula III HCI aqElacestrantStep 5Formula d

[0168] In some embodiments, the improved synthesis comprises:• Step 1 - synthesis N-(2-6-(benzyloxy)-l-oxo-l, 2,3, 4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (c-1)) via a-arylation of 6-(benzyloxy)-3,4- dihydronaphthalen-l(2H)-one (Compound (a-1)) using N-(2-bromo-5- methoxyphenyl)acetamide (Compound (b-1));• Step 2 - stereoselective reduction of N-(2-6-(benzyloxy)-l-oxo-l,2,3,4- tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) to obtain N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1));• Step 3a (corresponding to “Step 3” in Scheme 11C) - dehydroxylation of N-(2- ((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (1-1)) to produce (R)-N-(2-(6-(benzyloxy)- l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l));• Step 3b (corresponding to “Step 4” in Scheme 11C) - debenzylation of (R)-N-(2-(6- (benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l)) to obtain N-(2-(6-hydroxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5- methoxyphenyl)acetamide (Compound (III-l));• Step 4 (corresponding to “Step 5” in Scheme 11C) - hydrolysis of N-(2-(6-hydroxy)- l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (III-l)) to produce (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d));• synthesis of elacestrant from the Compound (d).-50- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0169] In any of the embodiments disclosed herein, synthesis of elacestrant from the Compound (d) may proceed as described in PCT International Application No.PCT / US2020 / 017777, filed February 11, 2020, and published as WO 2020 / 167855A1. In particular, elacestrant may be produced from the enantiomerically pure Compound (d) by the methods disclosed at paragraphs

[0112] -

[0115] , reproduced below, with reference to Scheme 1 (paragraph

[0102] ) of WO 2020 / 167855A1, the relevant portion of which is reproduced as Scheme 12 herein. Compound (d) of the present application corresponds to (e) of PCT / US2020 / 017777.Scheme 12. Synthesis of Elacestrant (((R)-6 -(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol)) from (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d))i. THF, (+)-DBTA, heptane ii. NaBH(OAc)3, THF iii. NaOH, EtOAc, heptane, THFi. NaBH4, l2, THF ii. HCI, MeOH, EtOAc, Na2S2O3iii. HCI, EtOH, MeOH, EtOAcCompound 1Preparation of (R)-N-ethyl-3-(4-((ethyl(2-(6-hydroxy-l,2,3,4- tetrahydronapthalen-2-yl)-5-methoxyphenyl)amino)methyl)propanamide (g)

[0170] A mixture containing 1 equivalent of Compound (d) together with 1 wt equivalent of activated molecular sieves and anhydrous sTHF was agitated at ambient temperature for > 2 hours. The mixture was filtered through THF-compacted celite and rinsed with 10 volumes of THF. The solution was charged with N-ethyl-2-(4-formylphenyl)acetamide (f) (1.2 eq.) and 7.5 volumes of heptane and DBTA (0.1%) and heated to reflux (approximately 65°C). The mixture was atmospherically distilled to 10 volumes at reflux. The reaction was monitored-51- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359for completion via TLC. 2.9 volumes of heptane and 7.1 volumes of THF were added, and the reaction was atmospherically distilled to 10 volumes at reflux and monitored for completion by TLC. The solution was cooled to 20°C and agitated for > 5 hours to ensure that crystallization had occurred. The solid product was collected by filtration, rinsed with 2 volumes of heptane and dissolved in 40 volumes of anhydrous THF and treated with 4.5 equivalents of NaBH(OAc)3. The mixture was heated to 50°C for > 16 hours and monitored by TLC. An additional 4.5 equivalents of NaBH(OAc)3 was added (additional N-ethyl-2-(4-formylphenyl)acetamide (f) could be added at this point if the reaction was not complete).[0171 | The reaction was cooled to 20° C and quenched with 15 volumes of 3 M NaOH. The solution / mixture was agitated for > 30 minutes and the pH adjusted to 8-9 with 9% aqueous NaHCCh (approximately 14 volumes) if necessary. The aqueous layer was separated out and the organic layer concentrated to 5 volumes under vacuum at < 45°C. The resulting solution was diluted with 10 volumes of EtOAc and concentrated to 5 volumes under vacuum at < 45°C. The solution was treated with 10 volumes of EtOAc and 5 volumes of 5.6% NaCl solution, stirred, and then allowed to settle and the aqueous layer removed. The mixture was dried with Na2SO4 (4 wt) and filtered and concentrated to 5 volumes under vacuum at < 45°C, treated with 10 volumes of heptane and concentrated to 5 volumes under vacuum at < 45°C, treated with 10 volumes of heptane and concentrated to 5 volumes under vacuum at < 45°C and treated with 10 volumes of heptane and concentrated to 5 volumes under vacuum at < 45°C. The solution was then treated with 10 volumes of THF and dried under vacuum at < 45°C and treated again with 10 volumes of THF and dried to 5 volumes under vacuum at < 45°C and treated with 5 volumes of THF and residual heptane evaluated by GC (<4%), and the THF solution carried forward to the next reaction. The yield of the final product was determined to be >90%.Preparation of (R)-6 -(2-(ethylamino)ethyl)benzyl)amino)-4- methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol

[0172] A reactor was charged with 7 volumes of THF and 2.5 equivalents of NaBHi and cooled to from -10°C to 0°C. The solution was charged with the THF solution carried over from the previous step (1 equivalent of intermediate (g)) while maintaining the reactor temperature at < 5°C. The solution was stirred with an internal temperature adjusted to -25°C.-52- 4902-2817-2415.2Atty. Dkt. No.: 111346-23591 Equivalent of (h) in 1 volume of THF was added to the solution while maintaining the temperature at < -10°C. The mixture was agitated for > 30 minutes at < -10°C, then heated to reflux and stirred at reflux (approximately 66°C) for at 4 hours and monitored by HPLC for completion. The reaction mixture was cooled to <5°C and quenched with 0.5 volumes of concentrated HC1 while maintaining the reaction mixture temperature of < -10°C, and then treated with 15 volumes of water. The pH was checked and adjusted to less than 1.5 as needed. The solution was then heated to reflux and atmospherically distilled until the internal temperature reached 80°C. The reaction mixture was cooled to 15-25°C, stirred for 6 hours, and the solid isolated by filtration. The solid was charged back into the reactor along with 10 volumes of EtOAc and 5 volumes of 1 M NaOH and the mixture agitated for up to 30 minutes at 10-20°C. The pH was checked and adjusted to 8-9 as needed. The organic and aqueous layers were allowed to separate and the aqueous layer removed and washed with 10 volumes of EtOAc. The aqueous layer was removed and the combined organic layers were washed with 2 ^ 5 volumes of 5% sodium thiosulfate solution. The organic layer was washed with 4 x 10 volumes of 1% NaCl solution. The aqueous layer was removed and the organic layer concentrated to 3 volumes at an external temperature of up to 45°C. Three times, the residue was dissolved in 10 volumes of EtOH and concentrated to 3 volumes at < 45°C. The solution was dried with Na2SC>4 and filtered and the filtrate charged to a reactor where it was treated with 1 volume of EtOAc and stirred and charged with 3.3 M HC1 in EtOH (1.4 volumes) and the mixture agitated at 15-25°C for > 2 hours and then concentrated to 4.6 volumes at < 45°C. The solution was treated with 12.4 volumes of EtOAc and agitated at 15-25°C for > 2 hours to ensure that crystallization had occurred. The solids were collected by filtration and rinsed with 3.1 volumes of EtOAc. The filter cake was dried at < 50° C. The material can be assayed for purity and recrystallized from MeOHZEtOAc if desired. The yield of the final product was >50% and the purity >90%. If desired, the product can be recrystallized from EtOH / EtOAc to generate a polymorphic form having good stability.[01731 As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.-53- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0174] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.101751 Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s).10.176 j The present disclosure, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present disclosure.EXAMPLESExample 1. Synthesis of N-(2-6-(benzyloxy)-l-oxo-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) Via a-Arylation of 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one (Compound (a-1)) Using N-(2-bromo-5-methoxyphenyl)acetamide (Compound (b-1))

[0017] To assess the a-arylation of Compound (a-1) using Compound (b-1) and identify reaction conditions for producing Compound (c-1), a-arylation was carried out according to Scheme 2 and Scheme 3 above using the reaction conditions shown in Table 1.Table 1. Coupling Reactions Between 6-(benzyloxy)-3,4-dihydronaphthalen-l(2H)-one (Compound (a-1)) and N-(2-bromo-5-methoxyphenyl)acetamide (Compound (b-1))-54- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Entry Catalyst (% Base T (°C) / a-1 b-1 Solvent Result mole) (eq) TimePdCl2(DtBPF) One unidentified 1 1.0 eq 1.0 eq KOtBu THF Reflux / 16h product and trace of (2%) (1.1 eq)the desired product Complex mixture of PdCl2(DtBPF) KOtBu products with only 2 1.0 eq 1.0 eq. THF Reflux / 16h(2.2 eq) trace of the desired (2%)product Complex mixture of PdCl2(DtBPF) KOtBu products with only 3 1.0 eq 1.0 eq THF Reflux / 16h(20%) (2.2 eq) trace of the desired product Pd(dba) Complex mixture of (2.5%) + Dioxan KOtBu products with only 4 1.0 eq 1.2 eq Reflux / 16h(2.2 eq) e / water trace of the desired P(tBu)3-HBF4(10%) product... OMeJi J Sf - 'y"'a_ | BnQ"v<>"; b-1: NHAc

[0178] The reaction conditions used in this screening produced complex mixtures of products in which the desired product, N-(2-6-(benzyloxy)-l-oxo-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (c-1)) was present as a minor product.1017 1 To further investigate reaction conditions that might produce a higher yield of Compound (c-1), ligand / solvent screening was performed using Pd₂(dba)₃ as the Pd compound, phenol as the additive, and a selection of 15 different ligands and 6 different solvents, as shown in Table 2. The screening revealed that BuPAd₂ was the most effective ligand in facilitating the a-arylation of Compound (a-1) using Compound (b-1) to product Compound (c-1). Additionally, the use of phenol as an additive appeared to increase the yields for all solvents screened. a-Arylation performed in toluene produced the highest conversion to Compound (c-1).

[0180] Thus, an additional screening was performed using different amounts of phenol and base and using different reaction temperatures. The results are shown in Table 3. The screening study revealed that very high yields of Compound (c-1) could be achieved via the a-arylation reaction, reaching well over 90% by HPLC. In particular, based on the results of this screening and the data shown in Table 3, the test using 1.2 equivalents Compound (b-1), 0.025 equivalents Pd₂(dba)₃, 0.1 equivalents BuPAd₂, 0.2 equivalents phenol, and 1.5-55- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359equivalents K3PO4, in toluene at 90°C, produced Compound (c-1) with a yield of 97.54% by HPLC.-56- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Table 2. Ligand / Solvent Screening for a-Arylation of Compound (a-1) with Compound (b-1)Analysis Entry Solvent Catalyst Base Additive Ligand b-1 Temp.(10 v) (0.025 eq.) (2.5 eq.) (0.2 eq.) (0.1 eq.) (eq.) (°C) a-1 c-1(%) (%) 1 Toluene Pcfclba’, K3PO4Phenol PPh31.5 90 99.21 0.28 2 Toluene Pcbclba; K3PO4Phenol P(o-t01)3 1.5 90 98.64 0.00 3 Toluene Pcfclba’, K3PO4Phenol PCy3HBF4 1.5 90 94.56 2.94 4 Toluene Pclidba’, K3PO4Phenol PtBu3HBF4 1.5 90 98.47 0.22 5 Toluene Pthdbas K3PO4Phenol BuPAd₂ 1.5 90 3.20 105.98 6 Toluene Pclidba’, K3PO4Phenol Aphos 1.5 90 95.93 2.44 7 Toluene Pclidba’, K3PO4Phenol Xphos 1.5 90 93.43 1.60 8 Toluene Pclidba’, K3PO4Phenol Sphos 1.5 90 91.80 6.02 9 Toluene Pclidba’, K3PO4Phenol Brettphos 1.5 90 97.22 0.56 10 Toluene Pclidba’, K3PO4Phenol Ruphos 1.5 90 92.48 5.96 12 Toluene Pclidba’, K3PO4Phenol DPPP 1.5 90 100.86 0.00 13 Toluene Pclidba’, K3PO4Phenol DPPF 1.5 90 124.09 1.15 14 Toluene Pclidba’, K3PO4Phenol s-Binap 1.5 90 91.14 0.13 15 Toluene Pclidba’, K3PO4Phenol Xantphos 1.5 90 104.08 0.00 16 Toluene Pclidba’, K3PO4none PPh3 1.5 90 98.33 0.84 17 Toluene Pclidba’, K3PO4none P(o-tol)3 1.5 90 102.73 0.00 18 Toluene Pclidba’, K3PO4none PCy3HBF4 1.5 90 88.60 7.02 19 Toluene Pclidba’, K3PO4none PtBu3HBF4 1.5 90 99.90 0.32 20 Toluene Pthdbas K3PO4none BuPAd₂ 1.5 90 45.28 31.96 21 Toluene Pclidba’, K3PO4none Aphos 1.5 90 97.41 0.43 22 Toluene Pclidba’, K3PO4none Xphos 1.5 90 97.17 2.16 23 Toluene Pclidba’, K3PO4none Sphos 1.5 90 97.80 1.58 24 Toluene Pclidba’, K3PO4none Brettphos 1.5 90 98.06 1.48 25 Toluene Pclidba’, K3PO4none Ruphos 1.5 90 101.83 1.70 27 Toluene Pclidba’, K3PO4none DPPP 1.5 90 97.73 0.13 28 Toluene Pclidba’, K3PO4none DPPF 1.5 90 97.04 0.76 29 Toluene Pclidba’, K3PO4none s-Binap 1.5 90 100.62 0.3930 Toluene Pclidba’, K3PO4none Xantphos 1.5 90 106.57 0.00-57- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Analysis Solvent Catalyst Base Additive Ligand b-1 Temp.Entry(10 v) (0.025 eq.) (2.5 eq.) (0.2 eq.) (0.1 eq.) (eq.) (°C) a-1 c-1(%) (%) 31 2-MeTHF Pclidba’, K3PO4Phenol PPh3 1.5 90 86.82 0.30 32 2-MeTHF Pcbclba; K3PO4Phenol P(o-tol)3 1.5 90 93.54 0.00 33 2-MeTHF Pcbclba; K3PO4Phenol PCy3HBF4 1.5 90 91.31 2.16 34 2-MeTHF Pcbclba! K3PO4Phenol PtBu3HBF4 1.5 90 94.68 0.09 35 2-MeTHF Pthdbas K3PO4Phenol BuPAd₂ 1.5 90 4.65 90.95 36 2-MeTHF Pcbclba; K3PO4Phenol Aphos 1.5 90 90.24 3.18 37 2-MeTHF Pcbclba; K3PO4Phenol Xphos 1.5 90 86.52 1.50 38 2-MeTHF Pcbclba; K3PO4Phenol Sphos 1.5 90 85.74 5.52 39 2-MeTHF Pcbclba; K3PO4Phenol Brettphos 1.5 90 90.24 0.21 40 2-MeTHF Pcbclba; K3PO4Phenol Ruphos 1.5 90 83.92 5.98 43 2-MeTHF Pcbclba; K3PO4Phenol DPPF 1.5 90 91.61 0.84 44 2-MeTHF Pcbclba! K3PO4Phenol s-Binap 1.5 90 91.63 0.11 45 2-MeTHF Pcbclba; K3PO4Phenol Xantphos 1.5 90 96.38 0.00 46 2-MeTHF Pcbclba; K3PO4none PPh3 1.5 90 91.47 1.33 47 2-MeTHF Pcbclba; K3PO4none P(o-tol)3 1.5 90 96.51 0.00 48 2-MeTHF Pcbclba; K3PO4none PCy3HBF4 1.5 90 87.45 5.81 49 2-MeTHF Pcbclba! K3PO4none PtBu3HBF4 1.5 90 93.49 0.00 50 2-MeTHF Pthdbas K3PO4none BuPAd₂ 1.5 90 25.61 79.27 51 2-MeTHF Pcbclba; K3PO4none Aphos 1.5 90 94.31 0.78 52 2-MeTHF Pcbclba; K3PO4none Xphos 1.5 90 94.14 1.26 53 2-MeTHF Pcbclba; K3PO4none Sphos 1.5 90 89.59 2.24 54 2-MeTHF Pcbclba! K3PO4none Brettphos 1.5 90 92.60 0.49 55 2-MeTHF Pcbclba; K3PO4none Ruphos 1.5 90 92.89 2.36 57 2-MeTHF Pcbclba; K3PO4none DPPP 1.5 90 93.54 0.08 58 2-MeTHF Pcbclba; K3PO4none DPPF 1.5 90 93.68 0.82 59 2-MeTHF Pcbclba; K3PO4none s-Binap 1.5 90 88.57 0.13 60 2-MeTHF Pcbclba; K3PO4none Xantphos 1.5 90 100.68 0.00 61 tamylOH Pclidba’, K3PO4Phenol PPh3 1.5 90 103.88 0.00 62 tamylOH Pclidba’, K3PO4Phenol P(o-tol)3 1.5 90 100.50 0.00 63 tamylOH Pcbclba! K3PO4Phenol PCy3HBF4 1.5 90 85.72 6.0464 tamylOH Pclidba’, K3PO4Phenol PtBu3HBF4 1.5 90 92.48 0.12-58- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Analysis Solvent Catalyst Base Additive Ligand b-1 Temp.Entry(10 v) (0.025 eq.) (2.5 eq.) (0.2 eq.) (0.1 eq.) (eq.) (°C) a-1 c-1(%) (%) 65 tamylOH Pthdbas K3PO4Phenol BuPAd₂ 1.5 90 4.44 87.10 66 tamylOH Pcbclba! K3PO4Phenol Aphos 1.5 90 80.43 6.00 67 tamylOH Pcbclba; K3PO4Phenol Xphos 1.5 90 81.37 3.67 68 tamylOH Pclidba’, K3PO4Phenol Sphos 1.5 90 76.28 7.86 69 tamylOH Pclidba’, K3PO4Phenol Brettphos 1.5 90 88.50 0.20 70 tamylOH Pclidba’, K3PO4Phenol Ruphos 1.5 90 84.49 8.22 72 tamylOH Pclidba’, K3PO4Phenol DPPP 1.5 90 91.87 0.00 73 tamylOH Pclidba’, K3PO4Phenol DPPF 1.5 90 98.11 1.03 74 tamylOH Pclidba’, K3PO4Phenol s-Binap 1.5 90 94.55 0.00 75 tamylOH Pclidba’, K3PO4Phenol Xantphos 1.5 90 94.29 0.12 76 tamylOH Pclidba’, K3PO4none PPh3 1.5 90 92.64 0.00 77 tamylOH Pclidba’, K3PO4none P(o-tol)3 1.5 90 106.40 0.00 78 tamylOH Pclidba’, K3PO4none PCy3HBF4 1.5 90 90.67 5.80 79 tamylOH Pclidba’, K3PO4none PtBu3HBF4 1.5 90 95.77 0.09 80 tamylOH Pthdbas K3PO4none BuPAd₂ 1.5 90 5.67 84.00 81 tamylOH Pclidba’, K3PO4none Aphos 1.5 90 82.07 5.04 82 tamylOH Pclidba’, K3PO4none Xphos 1.5 90 83.63 3.21 83 tamylOH Pclidba’, K3PO4none Sphos 1.5 90 81.66 6.79 84 tamylOH Pclidba’, K3PO4none Brettphos 1.5 90 89.93 0.31 85 tamylOH Pclidba’, K3PO4none Ruphos 1.5 90 73.05 11.13 86 tamylOH Pclidba’, K3PO4none Davephos 1.5 90 95.36 1.36 87 tamylOH Pclidba’, K3PO4none DPPP 1.5 90 97.86 0.00 88 tamylOH Pclidba’, K3PO4none DPPF 1.5 90 98.57 0.89 89 tamylOH Pclidba’, K3PO4none s-Binap 1.5 90 92.25 0.00 90 tamylOH Pclidba’, K3PO4none Xantphos 1.5 90 94.91 0.11 91 MeCN Pcbclba; K3PO4Phenol PPh3 1.5 90 84.09 0.00 92 MeCN Pcbclba; K3PO4Phenol P(o-tol)3 1.5 90 95.09 0.50 93 MeCN Pcbclba; K3PO4Phenol PCy3HBF4 1.5 90 92.87 0.18 94 MeCN Pcbclba; K3PO4Phenol PtBu3HBF4 1.5 90 92.70 0.17 95 MeCN Pdzdbas K3PO4Phenol BuPAd₂ 1.5 90 61.21 13.0796 MeCN Pcbclba; K3PO4Phenol Aphos 1.5 90 87.08 3.54-59- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Analysis Solvent Catalyst Base Additive Ligand b-1 Temp.Entry(10 v) (0.025 eq.) (2.5 eq.) (0.2 eq.) (0.1 eq.) (eq.) (°C) a-1 c-1(%) (%) 97 MeCN Pclidba’, K3PO4Phenol Xphos 1.5 90 93.95 0.08 98 MeCN Pcbclba; K3PO4Phenol Sphos 1.5 90 89.09 3.58 99 MeCN Pcbclba; K3PO4Phenol Brettphos 1.5 90 90.67 0.00 100 MeCN Pcbclba! K3PO4Phenol Ruphos 1.5 90 83.03 5.50 101 MeCN Pclidba’, K3PO4Phenol Davephos 1.5 90 97.52 0.32 102 MeCN Pclidba’, K3PO4Phenol DPPP 1.5 90 91.00 0.14 103 MeCN Pclidba’, K3PO4Phenol DPPF 1.5 90 97.78 0.66 104 MeCN Pclidba’, K3PO4Phenol s-Binap 1.5 90 93.32 0.00 105 MeCN Pclidba’, K3PO4Phenol Xantphos 1.5 90 95.15 0.00 106 MeCN Pclidba’, K3PO4none PPh3 1.5 90 87.53 0.00 107 MeCN Pclidba’, K3PO4none P(o-tol)3 1.5 90 94.59 0.45 108 MeCN Pcbclba! K3PO4none PCy3HBF4 1.5 90 93.01 0.40 109 MeCN Pclidba’, K3PO4none PtBu3HBF4 1.5 90 93.92 0.18 110 MeCN Pthdbas K3PO4none BuPAd₂ 1.5 90 45.66 35.24 111 MeCN Pclidba’, K3PO4none Aphos 1.5 90 88.24 1.17 112 MeCN Pclidba’, K3PO4none Xphos 1.5 90 88.46 0.00 113 MeCN Pcbclba! K3PO4none Sphos 1.5 90 85.69 3.24 114 MeCN Pclidba’, K3PO4none Brettphos 1.5 90 92.41 0.00 115 MeCN Pclidba’, K3PO4none Ruphos 1.5 90 85.17 3.96 116 MeCN Pclidba’, K3PO4none Davephos 1.5 90 96.75 0.33 117 MeCN Pclidba’, K3PO4none DPPP 1.5 90 95.58 0.10 118 MeCN Pcbclba! K3PO4none DPPF 1.5 90 93.36 0.46 119 MeCN Pclidba’, K3PO4none s-Binap 1.5 90 94.29 0.00 120 MeCN Pclidba’, K3PO4none Xantphos 1.5 90 97.13 0.13 121 DMF Pclidba’, K3PO4Phenol PPh3 1.5 90 93.17 0.98 122 DMF Pclidba’, K3PO4Phenol P(o-tol)3 1.5 90 95.64 0.53 123 DMF Pclidba’, K3PO4Phenol PCy3HBF4 1.5 90 89.58 5.01 124 DMF Pclidba’, K3PO4Phenol PtBu3HBF4 1.5 90 95.26 0.49 125 DMF Pthdbas K3PO4Phenol BuPAd₂ 1.5 90 18.33 60.87 126 DMF Pcbclba! K3PO4Phenol Aphos 1.5 90 58.72 34.17127 DMF Pclidba’, K3PO4Phenol Xphos 1.5 90 93.95 0.55-60- 4902-2817-2415.2Aty. Dkt. No.: 111346-2359Analysis Solvent Catalyst Base Additive Ligand b-1 Temp.Entry(10 v) (0.025 eq.) (2.5 eq.) (0.2 eq.) (0.1 eq.) (eq.) (°C) a-1 c-1(%) (%) 128 DMF Pd2dba3 K3PO4Phenol Sphos 1.5 90 86.03 4.27 129 DMF Pd2dbas K3PO4Phenol Brettphos 1.5 90 97.39 0.10 130 DMF Pd2dbas K3PO4Phenol Ruphos 1.5 90 90.10 2.89 131 DMF Pd2dbas K3PO4Phenol Davephos 1.5 90 90.08 0.25 132 DMF Pd2dbas K3PO4Phenol DPPP 1.5 90 93.56 0.49 133 DMF Pd2dbas K3PO4Phenol DPPF 1.5 90 91.77 2.38 134 DMF Pd2dbas K3PO4Phenol s-Binap 1.5 90 91.77 0.00 135 DMF Pd2dbas K3PO4Phenol Xantphos 1.5 90 92.51 0.24 136 DMF Pd2dbas K3PO4none PPh3 1.5 90 94.97 0.66 137 DMF Pd2dbas K3PO4none P(o-tol)3 1.5 90 90.73 0.20 138 DMF Pd2dbas K3PO4none PCy3HBF4 1.5 90 92.61 5.47 139 DMF Pd2dbas K3PO4none PtBu3HBF4 1.5 90 91.99 0.46 140 DMF Pdidbas K3PO4none BuPAd₂ 1.5 90 40.93 55.24 141 DMF Pd2dbas K3PO4none Aphos 1.5 90 68.17 23.45 142 DMF Pd2dbas K3PO4none Xphos 1.5 90 104.71 0.66 143 DMF Pd2dbas K3PO4none Sphos 1.5 90 91.45 3.69 144 DMF Pd2dbas K3PO4none Brettphos 1.5 90 92.82 0.13 145 DMF Pd2dbas K3PO4none Ruphos 1.5 90 94.76 1.95 146 DMF Pd2dbas K3PO4none Davephos 1.5 90 94.77 0.27 147 DMF Pd2dbas K3PO4none DPPP 1.5 90 92.07 0.91 148 DMF Pd2dbas K3PO4none DPPF 1.5 90 93.00 2.67 149 DMF Pd2dbas K3PO4none s-Binap 1.5 90 92.32 0.15150 DMF Pd2dbas K3PO4none Xantphos 1.5 90 97.14 0.08,, QMe»< " T NHAcb-1: MHAc;c-1: Bn4902-2817-2415.2Atty. Dkt. No.: 111346-2359Table 3. Phenol, K3PO4, and Temperature Screening for a-Arylation of Compound (a-1) Using Compound (b-1) to Produce Compound (c-1)Temp SM Entry a-1 b-1 Pdz(dba)s BuPAdz K3PO4Phenol Toluene c-1(eq.) (eq.) (eq.) (eq.) (eq.) (eq.) (v) (°C) Yield (%) (%) 1 1 1.2 0.025 0.1 1.5 0.1 5 80 83.99 0.00 2 1 1.2 0.025 0.1 1.5 0.3 5 80 95.33 0.00 3 1 1.2 0.025 0.1 3.5 0.1 5 80 55.87 15.77 4 1 1.2 0.025 0.1 3.5 0.3 5 80 65.18 0.00 5 1 1.2 0.025 0.1 1.5 0.1 15 80 84.07 13.20 6 1 1.2 0.025 0.1 1.5 0.3 15 80 89.75 9.52 7 1 1.2 0.025 0.1 3.5 0.1 15 80 62.30 20.35 8 1 1.2 0.025 0.1 3.5 0.3 15 80 74.82 11.07 9 1 1.8 0.025 0.1 1.5 0.1 5 80 89.78 7.16 10 1 1.8 0.025 0.1 1.5 0.3 5 80 93.71 0.00 11 1 1.8 0.025 0.1 3.5 0.1 5 80 29.73 31.65 12 1 1.8 0.025 0.1 3.5 0.3 5 80 73.85 0.00 13 1 1.8 0.025 0.1 1.5 0.1 15 80 71.96 21.20 14 1 1.8 0.025 0.1 1.5 0.3 15 80 81.73 14.55 15 1 1.8 0.025 0.1 3.5 0.1 15 80 59.37 30.24 16 1 1.8 0.025 0.1 3.5 0.3 15 80 70.80 21.76 17 1 1.5 0.025 0.1 2.5 0.1 10 80 52.61 10.26 18 1 1.5 0.025 0.1 2.5 0.3 10 80 92.32 5.89 19 1 1.5 0.025 0.1 1.5 0.2 10 80 95.35 0.00 20 1 1.5 0.025 0.1 3.5 0.2 10 80 62.65 0.00 21 1 1.5 0.025 0.1 2.5 0.2 5 80 94.37 0.00 22 1 1.5 0.025 0.1 2.5 0.2 15 80 62.18 14.86 23 1 1.2 0.025 0.1 2.5 0.2 10 80 94.46 0.00 24 1 1.8 0.025 0.1 2.5 0.2 10 80 86.92 0.00 25 1 1.5 0.025 0.1 2.5 0.2 10 80 87.54 0.00 26 1 1.5 0.025 0.1 2.5 0.2 10 80 90.48 0.00 27 1 1.5 0.025 0.1 2.5 0.2 10 80 82.02 0.00 28 1 1.5 0.025 0.1 2.5 0.2 10 80 93.68 0.00 29 1 1.5 0.025 0.1 2.5 0.2 10 80 90.97 0.00 30 1 1.5 0.025 0.1 2.5 0.2 10 80 90.38 6.78 31 1 1.2 0.025 0.1 1.5 0.1 5 90 97.54 0.0032 1 1.2 0.025 0.1 1.5 0.3 5 90 97.10 0.00-62- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359a-1 b-1 Pdz(dba)s Phenol Toluene Temp c-1 SM Entry BuPAdz(eq.) (eq.) (eq.) (eq.) (eq.) (eq.) (v) (°C) Yield (%) (%) 33 1 1.2 0.025 0.1 3.5 0.1 5 90 76.82 7.56 34 1 1.2 0.025 0.1 3.5 0.3 5 90 79.85 0.00 35 1 1.2 0.025 0.1 1.5 0.1 15 90 82.72 8.11 36 1 1.2 0.025 0.1 1.5 0.3 15 90 95.81 0.00 37 1 1.2 0.025 0.1 3.5 0.1 15 90 87.35 11.43 38 1 1.2 0.025 0.1 3.5 0.3 15 90 83.75 5.64 39 1 1.8 0.025 0.1 1.5 0.1 5 90 36.60 17.31 40 1 1.8 0.025 0.1 1.5 0.3 5 90 97.14 0.00 41 1 1.8 0.025 0.1 3.5 0.1 5 90 63.92 13.19 42 1 1.8 0.025 0.1 3.5 0.3 5 90 80.90 0.00 43 1 1.8 0.025 0.1 1.5 0.1 15 90 87.48 11.40 44 1 1.8 0.025 0.1 1.5 0.3 15 90 92.21 9.30 45 1 1.8 0.025 0.1 3.5 0.1 15 90 84.64 14.71 46 1 1.8 0.025 0.1 3.5 0.3 15 90 84.42 10.99 47 1 1.5 0.025 0.1 2.5 0.1 10 90 90.96 0.00 48 1 1.5 0.025 0.1 2.5 0.3 10 90 77.67 0.00 49 1 1.5 0.025 0.1 1.5 0.2 10 90 89.05 0.00 50 1 1.5 0.025 0.1 3.5 0.2 10 90 71.83 0.00 51 1 1.5 0.025 0.1 2.5 0.2 5 90 92.97 0.00 52 1 1.5 0.025 0.1 2.5 0.2 15 90 80.03 11.22 53 1 1.2 0.025 0.1 2.5 0.2 10 90 83.03 0.00 54 1 1.8 0.025 0.1 2.5 0.2 10 90 88.89 0.00 55 1 1.5 0.025 0.1 2.5 0.2 10 90 93.73 0.00 56 1 1.5 0.025 0.1 2.5 0.2 10 90 82.78 0.00 57 1 1.5 0.025 0.1 2.5 0.2 10 90 81.68 0.00 58 1 1.5 0.025 0.1 2.5 0.2 10 90 85.70 0.00 59 1 1.5 0.025 0.1 2.5 0.2 10 90 89.37 0.00 60 1 1.5 0.025 0.1 2.5 0.2 10 90 94.79 0.00 61 1 1.2 0.025 0.1 1.5 0.1 5 100 88.01 0.00 62 1 1.2 0.025 0.1 1.5 0.3 5 100 85.74 0.00 63 1 1.2 0.025 0.1 3.5 0.1 5 100 76.64 0.00 64 1 1.2 0.025 0.1 3.5 0.3 5 100 58.50 0.00 65 1 1.2 0.025 0.1 1.5 0.1 15 100 94.23 0.00 66 1 1.2 0.025 0.1 1.5 0.3 15 100 95.83 0.00 67 1 1.2 0.025 0.1 3.5 0.1 15 100 80.70 8.21 68 1 1.2 0.025 0.1 3.5 0.3 15 100 83.13 0.0069 1 1.8 0.025 0.1 1.5 0.1 5 100 69.02 0.00-63- 4902-2817-2415.2Aty. Dkt. No.: 111346-2359Entry a-1 b-1 P(h(dba)3 BuPAdz K3PO4Phenol Toluene Temp c-1 SM (eq.) (eq.) (eq.) (eq.) (eq.) (eq.) (v) (°C) Yield (%) (%) 70 1 1.8 0.025 0.1 1.5 0.3 5 100 89.96 0.00 71 1 1.8 0.025 0.1 3.5 0.1 5 100 93.73 0.00 72 1 1.8 0.025 0.1 3.5 0.3 5 100 88.19 0.00 73 1 1.8 0.025 0.1 1.5 0.1 15 100 77.92 0.00 74 1 1.8 0.025 0.1 1.5 0.3 15 100 0.87 20.68 75 1 1.8 0.025 0.1 3.5 0.1 15 100 92.72 0.00 76 1 1.8 0.025 0.1 3.5 0.3 15 100 91.77 0.00 77 1 1.5 0.025 0.1 2.5 0.1 10 100 88.93 0.00 78 1 1.5 0.025 0.1 2.5 0.3 10 100 92.34 0.00 79 1 1.5 0.025 0.1 1.5 0.2 10 100 2.08 7.58 80 1 1.5 0.025 0.1 3.5 0.2 10 100 75.83 0.00 81 1 1.5 0.025 0.1 2.5 0.2 5 100 92.25 6.38 82 1 1.5 0.025 0.1 2.5 0.2 15 100 89.07 6.29 83 1 1.2 0.025 0.1 2.5 0.2 10 100 80.68 12.26 84 1 1.8 0.025 0.1 2.5 0.2 10 100 91.25 0.00 85 1 1.5 0.025 0.1 2.5 0.2 10 100 85.29 0.00 86 1 1.5 0.025 0.1 2.5 0.2 10 100 85.67 0.00 87 1 1.5 0.025 0.1 2.5 0.2 10 100 65.19 0.00 88 1 1.5 0.025 0.1 2.5 0.2 10 100 77.70 0.00 89 1 1.5 0.025 0.1 2.5 0.2 10 100 71.38 0.0090 1 1.5 0.025 0.1 2.5 0.2 10 100 79.58 0.00A: A 'A.,i NHACa-1: Br. D" -z'•-.b.1:NHAC;c-1:; SM: BnQ4902-2817-2415.2Atty. Dkt. No.: 111346-2359Example 2. Synthesis of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l, 2.3.4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)), Via Asymmetric Hydrogenation of the Ketone (Compound (c-1)) (Dynamic Kinetic Resolution)

[0181] To assess favorable conditions for asymmetric hydrogenation of the aryl ketone (Compound (c-1)) to produce Compound (1-1), a screening of seven ruthenium catalysts was performed using a hydrogen pressure of 1 MPa, at a temperature of 50°C, using 1.1 equivalents KOtBu. The results are shown in Table 4. The ruthenium catalysts are shown in Scheme 6. Table 4. Screening of Ru Catalysts for Asymmetric HydrogenationProduct SM Entry Catalyst SolventCompound (1-1) Compound (c-1) 1 Ru(OAc)2[(S)-binap] THF 18.4% 78.6% 2 Ru(OAc)2[(S)-binap] Toluene 0.0% 64.0% 3 Ru(OAc)2[(S)-binap] dioxane 22.9% 54.3% 4 Ru(OAc)2[(S)-binap] DMF 10.7% 80.4% 5 Ru(OAc)2[(S)-binap] DCE 9.4% 91.3% 6 Ru(OAc)2[(S)-binap] IPA 19.0% 63.4% 7 Ru(OAc)2[(S)-binap] EA 21.8% 71.0%8 (S-BINAP)RUC12THF 29.3% 58.0%9 (S-BINAP)RUC12Toluene 0.0% 75.2% 10 (S-BINAP)RUC12dioxane 17.2% 82.1% 11 (S-BINAP)RUC12DMF 10.9% 75.8% 12 (S-BINAP)RUC12DCE 9.0% 90.7%[RuCl(p-cymene)((S)- 13 THF 18.2% 64.8%binap)]Cl14 [RuCl(p-cymene)((S)- Toluene 0.0% 60.6% binap)]Cl[RuCl(p-cymene)((S)- 15 dioxane 18.1% 58.2%binap)]Cl16 [RuCl(p-cymene)((S)- DMF 15.0% 81.3%binap)]Cl[RuCl(p-cymene)((S)- 17 DCE 8.8% 93.2%binap)]Cl[RuCl(p-cymene)((S)- 18 IPA 10.1% 85.9%binap)]Cl[RuCl(p-cymene)((S)- 19 EA 7.9% 86.0%binap)]Cl20 RuCl2[(R)-binap][(R, R)- THF 27.7% 74.2%dpen]21 RuCl2[(R)-binap][(R, R)- Toluene 0.0% 87.0%dpen]4902-2817-2415.2Atty. Dkt. No.: 111346-2359Product SM Entry Catalyst SolventCompound (1-1) Compound (c-1) 22 RuCl2[(R)-binap][(R, R)- dioxane 27.7% 66.1%dpen]23 RuCl2[(R)-binap][(R, R)- DMF 13.7% 82.4%dpen]24 RuCl2[(R)-binap][(R, R)- DCE 3.8% 88.5%dpen]25 RuCl2[(R)-binap][(R, R)- IPA 18.4% 100.0%dpen]26 RuCl2[(R)-binap][(R, R)- EA 9.1% 87.4%dpen]27 (R)-Ru(OAc)2(segphos) THF 16.5% 64.2% 28 (R)-Ru(OAc)2(segphos) Toluene 0.0% 69.6% 29 (R)-Ru(OAc)2(segphos) dioxane 17.8% 60.6% 30 (R)-Ru(OAc)2(segphos) DMF 15.2% 73.7% 31 (R)-Ru(OAc)2(segphos) DCE 3.8% 88.1% 32 (R)-Ru(OAc)2(segphos) IPA 13.2% 52.5% 33 (R)-Ru(OAc)2(segphos) EA 20.0% 64.3% RuCl(p-cymene)[(S, S)-Ts- 34 THF 11.4% 73.7%DPEN]35 RuCl(p-cymene)[(S, S)-Ts- Toluene 0.0% 74.7% DPEN]RuCl(p-cymene)[(S, S)-Ts- 36 4.9% 64.0%DPEN] dioxane37 RuCl(p-cymene)[(S, S)-Ts- DMF 10.8% 78.8%DPEN]RuCl(p-cymene)[(S, S)-Ts- 38 DCE 15.0% 73.9%DPEN]39 RuCl(p-cymene)[(S, S)-Ts- IPA 11.2% 67.6%DPEN]RuCl(p-cymene)[(S, S)-Ts- 40 EA 8.8% 85.2%DPEN]Ru(OAc)2[(S)-OMe- 41 THF 31.5% 57.9%BIPHEP]Ru(OAc)2[(S)-OMe- 42 0.0% 86.0%BIPHEP] Toluene43 Ru(OAc)2[(S)-OMe- dioxane 28.4% 57.2% BIPHEP]Ru(OAc)2[(S)-OMe- 44 DMF 18.7% 78.6%BIPHEP]45 Ru(OAc)2[(S)-OMe- DCE 8.9% 96.5%BIPHEP]Ru(OAc)2[(S)-OMe- 46 IPA 9.3% 78.6%BIPHEP]4902-2817-2415.2Atty. Dkt. No.: 111346-2359Product SM Entry Catalyst SolventCompound (1-1) Compound (c-1) Ru(OAc)2[(S)-OMe- 47 EA 8.6% 81.1%BIPHEP]OMe9IT MHA;?.Product:; SM: BnO" '

[0182] The data in Table 4 shows that none of the screened catalyst / solvent combinations achieved a conversion higher than 31.5%, which was deemed too low for this reaction step. Accordingly, a further screening was carried out using “hydrogen transfer” conditions, using different catalysts, solvents and hydrogen sources. The data is shown in Table 5 and Table 6.Table 5. Catalyst / Solvent Screening for Ru-catalyzed Asymmetric Hydrogenation Using Formic Acid / Triethylamine as Hydrogen SourceHydrogen Product SM Entry Catalyst SolventSource Compound (1-1) Compound (c-1) 1 HCO2H / NEt3Ru(OAc)2[(S)-binap] THF 1.5% 91.0%2 HCO2H / NEt3Ru(OAc)2[(S)-binap] Toluene 0.0% 100.0% 3 HCO2H / NEt3Ru(OAc)2[(S)-binap] DMF 2.0% 90.4%4 HCO2H / NEt3Ru(OAc)2[(S)-binap] DCE 1.5% 73.0%5 HCO2H / NEt3Ru(OAc)2[(S)-binap] iPrOH 1.0% 97.7%6 HCO2H / NEt3Ru(OAc)2[(S)-binap] EA 0.8% 92.4%7 HCO2H / NEt3(S-BINAP)RUC12THF 1.8% 89.6%8 HCO2H / NEt3(S-BINAP)RUC12Toluene 0.0% 93.5%9 HCO2H / NEt3(S-BINAP)RUC12DMF 2.6% 73.6%10 HCO2H / NEt3(S-BINAP)RUC12DCE 1.1% 97.9%11 HCO2H / NEt3(S-BINAP)RUC12iPrOH 1.4% 64.9%12 HCO2H / NEt3(S-BINAP)RUC12EA 0.6% 91.1%[RuCl(p-cymene)((S)- 13 HCO2H / NEt3THF 0.6% 90.9%binap)]Cl[RuCl(p-cymene)((S)- 14 HCO2H / NEt3Toluene 0.0% 94.3%binap)]Cl-67- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Hydrogen SM Entry ProductCatalyst SolventSource Compound (1-1) Compound (c-1)[RuCl(p-cymene)((S)- 15 HCO2H / NEt3DMF 0.9% 96.9%binap)]Cl[RuCl(p-cymene)((S)- 16 HCO2H / NEt3DCE 0.9% 97.5%binap)]Cl[RuCl(p-cymene)((S)- 17 HCO2H / NEt3iPrOH 0.5% 97.2%binap)]Cl[RuCl(p-cymene)((S)- 18 HCO2H / NEt3EA 0.4% 94.3%binap)]ClRUC12[(R)- 19 HCO2H / NEt3THF 0.5% 76.1%binap] [(R, R)-dpen]RUC12[(R)- 20 HCO2H / NEt3Toluene 0.0% 73.1%binap] [(R, R)-dpen]RUC12[(R)- 21 HCO2H / NEt3DMF 0.8% 93.3%binap] [(R, R)-dpen]RUC12[(R)- 22 HCO2H / NEt3DCE 0.4% 72.2%binap] [(R, R)-dpen]RUC12[(R)- 23 HCO2H / NEt3iPrOH 2.2% 69.4%binap] [(R, R)-dpen]RUC12[(R)- 24 HCO2H / NEt3EA 0.5% 92.2%binap] [(R, R)-dpen](R)- 25 HCO2H / NEt3THF 0.5% 99.0%Ru(OAc)2(segphos)(R)- 26 HCO2H / NEt3Toluene 0.0% 100.0%Ru(OAc)2(segphos)(R)- 27 HCO2H / NEt3DMF 0.4% 75.1%Ru(OAc)2(segphos)(R)- 28 HCO2H / NEt3DCE 0.4% 99.3%Ru(OAc)2(segphos)(R)- 29 HCO2H / NEt3iPrOH 1.0% 96.7%Ru(OAc)2(segphos)(R)- 30 HCO2H / NEt3EA 1.4% 63.7%Ru(OAc)2(segphos)4902-2817-2415.2Atty. Dkt. No.: 111346-2359Entry Hydrogen SM Source Catalyst Solvent ProductCompound (1-1) Compound (c-1) RuCl(p- HCO2H / NEt331 THF 66.4% 10.3% cymene) [(S, S)-T s- DPEN]RuCl(p- HCO2H / NEt332 0.0% 93.2% cymene)[(S, S)-Ts- TolueneDPEN]RuCl(p- HCO2H / NEt333 DMF 25.5% 73.7% cymene)[(S, S)-Ts- DPEN]RuCl(p- HCO2H / NEt334 DCE 83.3% 14.9% cymene) [(S, S)-T s- DPEN]RuCl(p- 35 HCO2H / NEt3iPrOH 13.2% 85.8% cymene)[(S, S)-Ts- DPEN]RuCl(p- 36 EA 42.8% 53.5% HCO2H / NEt3cymene)[(S, S)-Ts- DPEN]Ru(OAc)2[(S)-OMe- 37 THF 0.5% 97.2% HCO2H / NEt3BIPHEP]Ru(OAc)2[(S)-OMe- 38 0.0% 100.0% HCO2H / NEt3TolueneBIPHEP]Ru(OAc)2[(S)-OMe- 39 DMF 0.9% 98.3% HCO2H / NEt3BIPHEP]Ru(OAc)2[(S)-OMe- 40 DCE 0.7% 95.5% HCO2H / NEt3BIPHEP]Ru(OAc)2[(S)-OMe- 41 iPrOH 0.6% 94.2% HCO2H / NEt3BIPHEP]Ru(OAc)2[(S)-OMe- 42 EA 0.5% 92.6% HCO2H / NEt3BIPHEP]-69- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359OMeOHis? TNHAc NH Ac- Product:BnO"; SM: BnOTable 6. Catalyst / Solvent Screening for Ru-catalyzed Asymmetric Hydrogenation Using Borane / Morpholine as Hydrogen SourceHydrogen SM Entry ProductCatalyst SolventSource Compound (1-1) Compound (c-1) Borane1 Ru(OAc)2 [(S)-binap] THF 12.5% 78.4% morpholineBorane2 Ru(OAc)2 [(S)-binap] DMF 3.0% 92.5% morpholine3 BoraneRu(OAc)2 [(S)-binap] DCE 7.3% 91.4% morpholine4 BoraneRu(OAc)2 [(S)-binap] iPrOH 11.7% 70.2% morpholine5 BoraneRu(OAc)2 [(S)-binap] EA 8.9% 67.7% morpholine6 Borane (S-BINAP)RuC12 THF 27.3% 60.9% morpholineBorane7 (S-BINAP)RuC12 DMF 7.0% 68.4% morpholineBorane8 (S-BINAP)RuC12 DCE 15.8% 81.7% morpholine9 Borane (S-BINAP)RuC12 iPrOH 25.1% 58.2% morpholine10 Borane (S-BINAP)RuC12 EA 12.9% 63.7% morpholine[RuCl(p- Borane11 cymene)((S)- THF 22.2% 66.4% morpholinebinap)]Cl[RuCl(p- 12 Boranecymene)((S)- DMF 4.3% 81.5% morpholinebinap)]Cl[RuCl(p- 13 Boranecymene)((S)- DCE 21.5% 74.4% morpholinebinap)]Cl[RuCl(p- 14 Boranecymene)((S)- iPrOH 17.3% 58.7% morpholinebinap)]Cl[RuCl(p- Borane15 cymene)((S)- EA 13.4% 79.1% morpholinebinap)]ClRuC12[(R)- 16 Borane THF 27.2% 64.2%morpholine binap] [ (R, R)-dpen]4902-2817-2415.2Atty. Dkt. No.: 111346-2359Hydrogen SM Entry ProductCatalyst SolventSource Compound (1-1) Compound (c-1)RuC12[(R)- 17 Borane DMF 5.4% 72.3% morpholine binap] [ (R, R)-dpen]Bo RuC12[(R)- 18 rane DCE 30.4% 61.1% morpholine binap] [ (R, R)-dpen]19 Borane RuC12[(R)- iPrOH 40.9% 49.2% morpholine binap] [ (R, R)-dpen]Borane RuC12[(R)- 20 EA 19.4% 66.9% morpholine binap] [ (R, R)-dpen]Borane (R)- 21 THF 21.4% 63.1% morpholine Ru(O Ac)2(segpho s)(R)- 22 Borane DMF 4.3% 71.7% morpholine Ru(O Ac)2(segpho s)(R)- 23 Borane DCE 12.9% 83.2% morpholine Ru(OAc)2(segphos)(R)- 24 Borane iPrOH 12.4% 68.9% morpholine Ru(O Ac)2(segpho s)(R)- 25 Borane EA 9.3% 64.0% morpholine Ru(O Ac)2(segpho s)RuCl(p- 26 Boranecymene) [(S, S)-T s- THF 42.0% 53.8% morpholineDPEN]RuCl(p- Borane27 cymene)[(S, S)-Ts- DMF 19.4% 72.8% morpholine DPEN]RuCl(p- 28 Boranecymene)[(S, S)-Ts- DCE 27.4% 53.4% morpholine DPEN]RuCl(p- 29 Boranecymene) [(S, S)-T s- iPrOH 54.1% 35.4% morpholineDPEN]RuCl(p- 30 Boranecymene)[(S, S)-Ts- EA 24.3% 58.6% morpholineDPEN]Borane Ru(OAc)2[(S)-OMe- 31 THF 35.0% 56.4% morpholine BIPHEP]Borane Ru(OAc)2[(S)-OMe- 32 DMF 7.3% 85.6% morpholine BIPHEP]33 Borane Ru(OAc)2[(S)-OMe- DCE 11.3% 83.5% morpholine BIPHEP]34 Borane Ru(OAc)2[(S)-OMe- iPrOH 15.6% 64.9% morpholine BIPHEP]35 Borane Ru(OAc)2[(S)-OMe- EA 4.1% 77.0%morpholine BIPHEP]OH O•K A „-J.. Ji JI JA,.<> L > NHAc, J<..->1.. J NHAeProduct:SnO' ■ SM: BnO’4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0183] Comparing the data shown in Table 5 and Table 6, better yields of Compound (1-1) were obtained using formic acid / triethylamine as hydrogen source than with borane-morpholine as the hydrogen source. For both hydrogen sources, the best-performing catalyst was RuCl(p- cymene)[(S,S)-Ts- DPEN] (see Table 5, Entries 31 and 34; Table 6, Entries 26 and 29). However, given the relatively modest conversion achieved, even with formic acid / triethylamine, a further study was performed evaluating the effect of reaction temperature on yield and enantiomeric excess of Compound (1-1). The results are shown in Table 7.Table 7. Temperature Screening for Ruthenium-catalyzed Asymmetric Hydrogenation (catalyst: RuCl(p- cymene)[(S,S)-Ts- DPEN]; hydrogen source: HCO2H / NEt3; solvent: THF)SM Product YieldTemp.Entry Compound (c-1) Compound (1-1) e.e.% (°C) (%) (%)1 10°C 93.5 4.9 87.0 2 20°C 84.1 14.6 95.4 3 30°C 63.2 35.7 98.4 4 40°C 18.0 81.0 99.05 50°C 9.8 89.2 98.1O is ji A J" ~ OH J h "'tA [f " AV. > V V NHACA AA if A > r NHAcSM:8i-,O; Product:

[0184] As shown in Table 7, yield of Compound (1-1) was significantly increased at 40°C and 50°C, when compared to lower temperatures down to 10°C. An additional catalyst screening was conducted using these reaction conditions (hydrogen source: HCO₂H / NEt₃; temperature: 50°C). The results are shown in Table 8.Table 8. Catalyst / solvent Screening for Ruthenium-catalyzed Asymmetric Hydrogenation (hydrogen source: HCO₂H / NEt₃; temperature = 50°C)SM Product Entry Catalyst SolventCompound (c-1) Compound (1-1) 1 RuCl(p- cymene)[(S,S)-Ts- DPEN] THF 18.96% 68.65%2 RuCl(p- cymene)[(S,S)-Ts- DPEN] 2-Me-THF 64.66% 27.30%3 RuCl(p-cy mene) [(S, S)-T s-DPEN] DME 64.01% 31.49%4 RuCl(p- cymene)[(S,S)-Ts- DPEN] dioxane 41.18% 50.20%-72- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359SMEntry Product Catalyst SolventCompound (c-1) Compound (1-1) 5 RuCl(p-cy mene) [(S, S)-T s-DPEN] DCE 61.39% 31.73%6 RuCl(p- cymene)[(S,S)-Ts- DPEN] DCM 41.80% 52.41%7 RuCl[(R, R)-Tsdpen(mesitylene) THF 5.21% 80.46%8 RuCl[(R, R)-Tsdpen(mesitylene) 2-Me-THF 36.91% 56.26%9 RuCl[(R,R)-Tsdpen(mesitylene) DME 10.61% 73.14%10 RuCl[(R, R)-Tsdpen(mesitylene) dioxane 14.43% 74.34%11 RuCl[(R, R)-Tsdpen(mesitylene) DCE 6.11% 79.01%12 RuCl[(R, R)-Tsdpen(mesitylene) DCM 6.97% 79.48%13 RuCl[(S, S)-FsDPEN](p -cymene) THF 53.02% 34.57%14 RuCl[(S, S)-FsDPEN](p -cymene) 2-Me-THF 76.74% 8.29%15 RuCl[(S, S)-FsDPEN](p -cymene) DME 80.98% 8.20%16 RuCl[(S, S)-FsD PEN] (p -cymene) dioxane 80.15% 16.73%17 RuCl[(S, S)-FsDPEN](p -cymene) DCE 72.97% 16.00%18 RuCl[(S, S)-FsDPEN](p-cymene) DCM 73.32% 23.49%19 RuCl(R, R)-Teth-TsDpen RuCl THF 2.48% 83.57%20 RuCl(R, R)-Teth-TsDpen RuCl 2-Me-THF 2.92% 86.17%21 RuCl(R, R)-Teth-TsDpen RuCl DME 3.79% 76.62%22 RuCl(R, R)-Teth-TsDpen RuCl dioxane 3.02% 83.25%23 RuCl(R, R)-Teth-TsDpen RuCl DCE 2.77% 82.81%24 RuCl(R, R)-Teth-TsDpen RuCl DCM 4.48% 84.16%OMe. OMeNHAc NHAcSM: BnO' Product:|0185] Based on the results of the screening at 50°C, it was determined that the highest yields and enantiomeric excesses are obtained using RuCl[(R, R)-Tsdpen(mesitylene)] as catalyst, with HCO₂H / NEt₃ as hydrogen source and THF as solvent.Example 3. Synthesis of N-(2-(6-hydroxy)- 1.2.3.4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (III-l) Via Benzylic De-hydroxylation and Debenzylation of N-(2-(( lR.2S)-6-( benzyloxy)-! -hydroxy- 1.2.3.4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1))

[0186] Removal of the benzylic hydroxyl group of Compound (1-1) with concurrent deprotection of the benzylic moiety, is usually performed using a catalytic hydrogenation or other reducing agents, such as borohydrides or silyl hydrides. To assess advantageous conditions for this reaction, the standard palladium catalyzed hydrogenation was investigated by screening a-73- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359panel of solvents. The results are shown in Table 9. The results show that solvent significantly affects the reaction performance. Higher e.e. and product yield was obtained for DMAc as solvent when compared to the other solvents screened. However, for every solvent screened, more than 40% of an impurity was detected by HPLC. To investigate potential conditions for increasing enantiomeric excess and yield, reaction temperature was screened. The results are shown in Table 10.Table 9. Solvent Screening for Palladium-catalyzed Hydrogenation (catalyst: Pd / C 5%, 200% wet basis; PH2 = 4 MPa; temperature = 75°C, time = 16 hr)Product Yield e.e.Entry Solvent(%) (%)1 DMAc 50.17% 86.69%2 DMF 39.58% 84.54%3 NMP 45.37% 81.56%4 MeCN 25.84% 78.53%5 IPA 36.85% 74.03%6 2-MeTHF 39.62% 72.64%7 DME 48.96% 73.71%8 ethyl acetate 33.57% 62.51%9 toluene 53.04% 40.71%OMeNHProduct:HOTable 10. Screening for Temperature and Catalyst Amount for Palladium-catalyzed Hydrogenation (catalyst: Pd / C 5%; solvent: DMAc; PH2 = 4 MPa; time = 16 hr)Temp. Catalyst,Product Yield SM e.e. Entry wet basis(°C) (w / w%) (%) (%) (%) 1 75 200 51.7 0.0 86.8 2 75 100 51.7 0.0 78.0 3 75 50 49.2 0.0 68.0 4 75 30 50.8 0.0 78.8 5 75 20 0.0 113.0 0.0 6 75 10 0.0 114.6 0.0 7 65 200 53.5 0.0 87.8 8 65 100 58.2 0.0 81.29 65 50 50.5 0.0 71.94902-2817-2415.2Atty. Dkt. No.: 111346-2359Catalyst,Temp. Product Yield SM e.e. Entry wet basis(°C) (w / w%) (%) (%) (%) 10 65 30 55.2 0.0 75.0 11 65 20 25.8 1.0 81.7 12 65 10 8.5 5.0 86.8 13 55 200 57.8 0.0 87.4 14 55 100 55.1 0.0 80.8 15 55 50 54.1 1.8 76.5 16 55 30 49.6 0.0 76.9 17 55 20 12.8 36.9 72.3 18 55 10 0.0 127.6 0.0 19 45 200 46.5 0.0 87.9 20 45 100 47.3 0.0 79.8 21 45 50 40.8 0.0 75.2 22 45 30 25.6 0.0 74.0 23 45 20 21.0 0.0 72.0 24 45 10 0.0 92.9 0.0 25 35 200 52.6 0.0 88.1 26 35 100 53.9 0.0 82.8 27 35 50 40.0 0.0 80.8 28 35 30 19.3 0.0 79.3 29 35 20 1.7 71.3 73.7 30 35 10 0.5 89.7 0.0 31 25 200 62.5 0.0 88.7 32 25 100 43.1 0.0 87.9 33 25 50 19.9 0.0 82.2 34 25 30 11.4 0.0 82.0 35 25 20 9.2 0.0 83.836 25 10 0.0 106.7 0.0.. OMe OMeOH if '"'YA f ",. V< Y,XY JY Y NH,.> f<. ".■V■■:■■< Y YY Y NHAGProduct:H0~; SM: SnO

[0187] The results in Table 10 show that the reaction temperature has a limited influence on the yield and enantiomeric excess when the catalyst loading is less than 50 w / w%, wet basis, and the reaction temperature is in the range of 55-75°C. When using the viable catalyst amount of 50%, the reaction achieved enantiomeric excess of 70-75% and a yield of not higher than 55% due to the formation of considerable quantities of a cyclic impurity. Thus, a screening of different catalyst types was performed. The results are shown in Table 11.-75- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Table 11. Catalyst Screening for Palladium- catalyzed Hydrogenation (solvent: DMAC; PH2 = 4 MPa; temperature = 55°C; time = 16 hr)SMEntry Product Yield e.e.Catalyst(%) (%) (%) 1 Pd / C 54.25% 0.34% 81.96% 14 Pt / C 0.00% 85.96% 0.00% 17 Pd(OH)2 / C 22.30% 0.26% 83.67%35 Raney Ni 1.33% 0.14% 0.00% OMeJ 'U T JU'X > NH. NHAcProduct:HO ~; SM:

[0188] As shown in Table 11, Pd / C afforded better results than Pd(OH)2 / C, Pt / C and Raney Ni.. Using Pd / C as catalyst (5% assay, 50 w / w%) afforded the best enantiomeric excess (-82%) and yield (IPC, 54%), with -0.34% of remaining starting material.

[0189] To further improve the reaction yield and enantiomeric excess, different sources of hydrogen and different solvents were investigated for the catalytic hydrogenation. The results are shown in Table 12.Table 12. Hydrogen Source and Solvent Screening for Palladium-catalyzed Hydrogenation (catalyst: Pd / C 5%, 50 w / w%; temperature = 25°C; time = 16 hr)Entry HydrogenDonor Solvent SM Impurity Impurity Impurity Impurity Impurity (%) 1 2 3 4 5 1 none DMAc 97.7 0 0 2.3 0 0 2 none MeCN 97.4 0 0 2.6 0 0 3 none MeOH 97.8 0 0 2.2 0 0 4 none THF 97.3 0 0 2.7 0 0 5 none 1,4- 97.8 0 0 2.2 0 0 dioxane6 none Toluene 97.4 0 0 2.6 0 0 7 none DCE 97.7 0 0 2.3 0 0 8 Et3SiH DMAc 3.0 0 0 0 0 97.0 9 Et3SiH MeCN 45.5 0 0 1.0 0.4 48.4 10 Et3SiH MeOH 66.0 26.3 1.4 1.0 0 3.1 11 Et3SiH THF 9.6 0 0 1.3 3.5 67.7 12 Et3SiH 1,4- 22.0 0.7 0 1.1 0.6 69.8 dioxane13 Et3SiH Toluene 14.5 0 0 0.5 0.6 80.0-76- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Hydrogen SMEntry Impurity Impurity Impurity Impurity Impurity Donor Solvent(%) 1 2 3 4 5 14 Et3SiH DCE 3.5 0 0 0 0 85.9 15 NaBH4DMAc 96.1 0 0 2.1 0 1.8 16 NaBH4MeCN 83.1 0 0 2.0 0 0 17 NaBH4MeOH 94.1 3.7 0 0 0 18 NaBH4THF 97.6 0 0 2.4 0 0 19 NaBH41,4- 97.8 0 0 2.2 0 0 dioxane20 NaBH4Toluene 97.5 0 0 2.5 0 0 21 NaBH4DCE 97.5 0 0 2.5 0 0 22 BH3THF DMAc 86.3 0 0 12.6 0 1.1 23 BH3THF MeCN 33.7 0 0 40.8 0.7 1.9 24 BH3THF THF 2.9 0 0 24.4 16.6 32.8 25 BH₃·THF 1,4- 3.1 0 0 26.3 16.4 33.8 dioxane26 BH₃·THF Toluene 7.0 0 0 22.7 20.3 34.5 27 BH₃·THF DCE 3.2 0 0 23.9 25.7 35.4 28 LiAlH4DMAc 63.6 0.4 0 3.8 0 0 29 LiAlH4MeCN 93.8 0 0 4.8 0 0 30 LiAlH4THF 19.4 3.1 0 73.2 0 0 31 LiAlH41,4- 14.4 3.7 0 78.3 0 0 dioxane32 LiAlH4Toluene 11.1 4.3 0 80.9 0 0 33 LiAlH4DCE 3.3 0 0 92.4 0 3.2 34 HCO2H DMAc 97.7 0 0 2.3 0 0 35 HCO2H MeCN 0 0 0 1.7 0 0 36 HCO2H MeOH 36.5 0 0 1.6 0 0 37 HCO2H THF 96.9 0 0 1.5 0 0 38 HCO2H 1,4- 98.4 0 0 1.6 0 0 dioxane39 HCO2H Toluene 3.9 0 0 1.3 0 0A,.-<k > MHAcSM: enO' '•-

[0190] As shown in Table 12, no reaction product (Compound (III-l)) was obtained with any of the hydrogen sources tested.

[0191] To further investigate improvements in reaction yield and enantiomeric excess, different activation agents were screened for the catalytic hydrogenation, as shown in Table 13.However, as shown in the data, none of the activation agents screened produced satisfactory yield and enantiomeric excess.-77- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Table 13. Activation Agent and Solvent Screening for Palladium- catalyzed Hydrogenation (catalyst: Pd / C 5%, 50 w / w%; temperature: 55°C; base: DIPEA; Pm: 4 MPa; time: 16 hr)SMEntry Product Yield e.e Additive Solvent(%) (%) (%) 1 Tf2O DMAc 4.3 0.2 7.5 2 Tf2O MeCN 0.8 0.6 0.0 3 Tf2O MeOH 49.4 0.0 2.4 4 Tf2O THF 52.1 0.0 3.5 5 Tf2O 1,4-dioxane 68.0 0.0 2.2 6 Tf2O toluene 36.2 1.6 5.6 7 Tf2O DCE 33.4 1.3 14.8DMAc8 Tf2O 0.0 0.0 0.0(no dipea)9 CBZ-C1 DMAc 45.6 0.3 5.5 10 CBZ-C1 MeCN 43.5 0.3 8.4 11 CBZ-C1 MeOH 41.8 0.4 4.2 12 CBZ-C1 THF 50.6 0.3 6.9 13 CBZ-C1 1,4-dioxane 64.9 0.3 4.0 14 CBZ-C1 toluene 49.0 2.0 10.6 15 CBZ-C1 DCE 26.2 0.2 58.0 16 DMAcCBZ-C1 6.9 0.4 35.3(no dipea)17 Ac2O DMAc 1.1 47.2 0.0 18 Ac2O MeCN 4.8 0.6 0.0 19 Ac2O MeOH 3.6 0.0 0.0 20 Ac2O THF 1.1 0.5 0.0 21 Ac2O 1,4-dioxane 0.5 1.7 0.0 22 Ac2O toluene 3.4 0.2 0.0 23 Ac2O DCE 1.9 0.3 0.0 24 DMAcAc2O 11.3 30.5 0.0(no dipea)25 (Boc)2O DMAc 0.0 41.3 0.0 26 (Boc)2O MeCN 1.1 13.0 0.0 27 (Boc)2O MeOH 2.0 11.3 0.0 28 (Boc)2O THF 0.8 14.8 0.0 29 (Boc)2O 1,4-dioxane 0.6 8.8 0.0 30 (Boc)2O toluene 0.9 1.0 0.0 31 (Boc)2O DCE 1.3 0.8 0.0DMAc32 (BOC)2O 6.6 16.0 0.0(no dipea)33 TBSCl DMAc 0.8 63.8 0.0 34 TBSCl MeCN 32.6 0.3 6.4 35 TBSCl MeOH 35.7 0.0 4.8 36 TBSCl THF 9.3 0.0 7.6 37 TBSCl 1,4-dioxane 7.5 0.7 4.1 38 TBSCl toluene 14.2 8.7 9.8 39 TBSCl DCE 39.0 3.3 15.2 40 DMAcTBSCl 12.4 0.8 17.8(no dipea)-78- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Product Yield SM e.e Entry Additive Solvent(%) (%) (%) 41 none DMAc 0.9 10.3 0.0 42 none MeCN 1.8 0.3 0.0 43 none MeOH 1.6 0.0 0.0 44 none THF 1.3 0.2 0.0 45 none 1,4-dioxane 1.3 0.2 0.0 46 none toluene 1.9 3.7 0.0 47 none DCE 3.7 0.8 0.0DMAc48 none 8.0 1.4 76.3(no dipea)x. OMe, QMe[ " T if ''YY' Y*) Y rf Y ' Y& Y,. A. „.-. A NH-,,. X..,■.<■•%,9 NHAsiProduct:HO v; SM:

[0192] To further investigate improvements in reaction yield and enantiomeric excess, a series of acid activation agents were screened for the catalytic hydrogenation, as shown in Table 14. Table 14. Acid Activation Agent and Solvent Screening for Palladium- Catalyzed Hydrogenation (catalyst: Pd / C, 5%, 200% w / w; Pm: 4 MPa; temp.: 75°C; time: 16 hr)Product Yield SM e.e. Entry Solvent Additive (%) (%) (%) 1 MNP none 52.3 0.2 81.9 2 MNP PhCO₂H 48.0 0.2 80.7 3 MNP TsOH 40.4 0.2 73.5 4 MNP TfOH 38.0 0.2 74.7 5 MNP Oxalic acid 47.2 0.1 81.3 6 MNP CH3CO2H 51.3 0.3 79.7 7 MNP o-DCB 53.8 0.2 23.9 8 DMAc none 58.5 0.2 86.7 9 DMAc PhCO2H 56.8 0.2 82.9 10 DMAc TsOH 38.4 0.2 85.2 11 DMAc TfOH 41.8 0.0 80.4 12 DMAc Oxalic acid 58.9 0.2 85.3 13 DMAc CH3CO2H 47.3 0.2 85.9 14 DMAc o-DCB 47.0 0.1 54.3 15 1 -Butanol none 4.9 0.2 88.5 16 1 -Butanol PhCO2H 10.1 0.1 95.0 17 1 -Butanol TsOH 2.4 0.1 70.6 18 1 -Butanol TfOH 1.4 0.1 100.0 19 1 -Butanol Oxalic acid 1.8 0.0 100.0 20 1 -Butanol CH3CO2H 0.7 0.0 0.021 1 -Butanol o-DCB 3.9 0.0 74.5-79- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Product Yield SM e.e. Entry Solvent Additive (%) (%) (%) 22 1,4-dioxane none 28.8 0.0 71.8 23 1,4-dioxane PhCO₂H 32.6 0.2 69.2 24 1,4-dioxane TsOH 16.1 0.2 75.3 25 1,4-dioxane TfOH 6.8 0.1 21.2 26 1,4-dioxane Oxalic acid 16.5 0.1 74.9 27 1,4-dioxane CH3CO2H 19.5 0.1 72.6 28 1,4-dioxane o-DCB 45.5 0.2 74.1 29 DCE none 2.7 0.2 100.0 30 DCE PhCO2H 1.6 0.0 100.0 31 DCE TsOH 0.8 0.0 100.0 32 DCE TfOH 1.4 0.1 100.0 33 DCE Oxalic acid 1.4 0.1 100.0 34 DCE CH3CO2H 2.7 0.0 100.035 DCE o-DCB 2.6 0.0 100.0OMe,.~vOMe9* r rA if 'V > T NH-; A f V -A' '' J A T NHAcProduct:HO -- ' ■ SM: SnO' -

[0193] As shown in the data, none of the activation agents screened produced satisfactory yield and enantiomeric excess. The data shows that with 200% (w / w) Pd / C (wet basis) and in the absence of an additive, a 59% yield and 87% enantiomeric excess was obtained. (See Entry 8.) The cyclic structure shown below was detected as an impurity.

[0194] Moreover, the screened acid additives did not improve enantiomeric excess or yield relative to those obtained in reference experiments using no additive. (See Entries 1 and 8.)

[0195] To further investigate potential improvements in reaction yield and enantiomeric excess, reduction systems based on trialkyl silanes, in the presence of acids, were screened for the catalytic hydrogenation, as shown in Table 15.-80- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Table 15. Acid and Solvent Screening for Et3SiH / Acid Reduction System (Et3SiH 5%; temp.: 0°C; time: 16 hr)SM Main Impurity Entry Solvent Acid (%) (area%)1 DMAc None 97.35% 0.00%2 MeCN None 97.83% 0.00%3 MeOH None 97.64% 0.00%4 THF None 97.68% 0.00%5 1,4-dioxane None 97.62% 0.00%6 toluene None 97.73% 0.00%7 DCE None 97.59% 0.00%8 DMAc TFA 53.58% 35.14%9 MeCN TFA 0.00% 74.03%10 MeOH TFA 0.00% 98.58%11 THF TFA 3.54% 90.99%12 1,4-dioxane TFA 1.92% 93.41%13 toluene TFA 5.21% 77.17%14 DCE TFA 0.00% 72.39%15 DMAc Oxalic acid 83.54% 12.55%16 MeCN Oxalic acid 0.00% 98.48%17 MeOH Oxalic acid 0.00% 95.95%18 THF Oxalic acid 31.07% 58.12%19 1,4-dioxane Oxalic acid 35.82% 51.51%20 toluene Oxalic acid 3.90% 92.39%21 DCE Oxalic acid 0.00% 98.56%22 DMAc CH3CO2H 96.83% 0.00%23 MeCN CH3CO2H 97.64% 0.00%24 MeOH CH3CO2H 97.73% 0.00%25 THF CH3CO2H 97.46% 0.00%26 1,4-dioxane CH3CO2H 97.43% 0.00%27 toluene CH3CO2H 97.52% 0.00%28 DCE CH3CO2H 97.32% 0.00%29 DMAc PhCO2H 96.83% 0.00%30 MeCN PhCO2H 97.64% 0.00%31 MeOH PhCO2H 97.73% 0.00%32 THF PhCO2H 97.46% 0.00%33 1,4-dioxane PhCO2H 97.43% 0.00%34 toluene PhCO2H 97.52% 0.00%35 DCE PhCO2H 97.32% 0.00%OH: Rj ■NHAcSM: BnC

[0196] For all silane / acid reduction systems tested, no significant amount of product Compound (III-l) was obtained.4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0197] Lastly, to further investigate potential improvements in reaction yield and enantiomeric excess, various catalysts (including PdCl2) and hydrogen donors were screened for the catalytic hydrogenation, as shown in Table 16.Table 16. Catalyst and Hydrogen Donor Screening (temp.: 25°C; time: 16 hr)Hydrogen Product Yield SMEntry e.e.CatalystDonors (%) (%) (%) 1 PdCl2Et3SiH 17.95% 0.00% 9.94% 2 Pd(OAc)2Et3SiH 0.00% 47.14% 0.00% 3 NiCl2Et3SiH 0.00% 103.54% 0.00% 4 FeCl2Et3SiH 0.00% 98.48% 0.00% 5 CoCl2Et3SiH 0.00% 103.30% 0.00% 6 PdCl2PhSiH350.17% 0.95% 11.36% 7 Pd(OAc)2PhSiH30.00% 93.56% 0.00% 8 NiCl2PhSiH30.00% 35.98% 0.00% 9 FeCl2PhSiH30.00% 95.20% 0.00% 10 CoCl2PhSiH30.00% 96.29% 0.00% 11 PdCl2NaBH40.00% 93.72% 0.00% 12 Pd(OAc)2NaBH40.00% 99.45% 0.00% 13 NiCl2NaBH40.00% 94.43% 0.00% 14 FeCl2NaBH40.00% 101.30% 0.00%15 CoCl2NaBH40.00% 97.16% 0.00%... i JA s' " Y " NrH-: s'.. " J. A'Y > 'ife ' Nr JHAcProduct:HO' -- ■ SM: SnO"

[0198] As shown in Table 16, the product yield and enantiomeric excess did not exceed 50.17% and 11.36%, respectively, regardless of the catalyst or hydrogen source.

[0199] In conclusion, good optical purity (e.e. > 85%) and acceptable yields (> 60%) were obtained only with high loading of Pd / C catalyst (100% and 200% on wet basis).Example 5. Step 3A - Synthesis of (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l)) by Benzylic Dehydroxylation of Compound (1-1)

[0200] Dehydroxylation of Compound (I-1) was investigated using LiBH4 / oxalic acid in different solvents. The results are shown in Table 17.-82- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Table 17. Solvent Screening for Dehydroxylation of Compound (1-1)SMLiBH4 ProductEntry Scale Solvent or Oxalic Temp. Compound Compound Dehydration acid Time (1-1)NaBH4(°C) (H-l) Impurity (%) (%)10V LiBH460.01 0.5g 0 Hi N. D. 50.30 21.45 THF 10.0 eq. ~10°Ceq.10V2 L1BH4 60.00.5g HDCM 10.0 eq. 0~10°C i N. D. 1.26 94.6eq.3 10V L1BH4 60.00 0~10°C Hi 51.46 2.31 43.58.5g DCM 10.0 eq. eq.60.01 10V NaBH0.5g4Hi N. D. 63.T 0~10°C 10 29.68 HF 10.0 eq.£q-

[0201] As shown in Table 17, the screened dehydroxylation conditions produced a large amount of the main impurity observed for this reaction, shown below:

[0202] To reduce the obtained amounts of the dehydration impurity, acid additives (TFA and PTS A) were screened, as shown in Table 18. However, these conditions resulted in poor product yield and high amounts of the dehydration impurity.Table 18. Acid Additive Screening for Dehydroxylation of Compound (1-1)II’CTemp. Entry Scale Solvent Acid Time SM Dehydration LiBH4 Product(°C) Impurity (%) (%)6.0 eq. 10V 1 2.0 eq. Ih 0.44 0.77 95.06 0~10°C 0.5g THF PTSA6.0 eq. 10V2 2.0 eq. Ih 33.33 18.41 42.87 0~10°C 0.5g THF TFA

[0203] Lastly, screening was performed for reaction temperature and temperature of addition for oxalic acid, as shown in Table 19 below.-83- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Table 19. Reaction Temperature and Oxalic Acid Addition Temperature Screening for Dehydroxylation of Compound (II-1) with NaBH4 / Oxalic AcidOxalic II’CAcid ReactionEntry OxalicScale Solvent NaBH< Charging Temp. TimeAcid SM Product Dehydration Temp. (°C) (%) (%) Impurity (°C)10V 10.0 20.0 -50—1 0.5g 0~10°C Ih N. D. 80.10 17.31 THF eq. eq. 40°C10V 10.0 20.02 0.5g -10~0°C 0~10°C Ih N. D. 73.34 25.09 THF eq. eq.10V 10.0 20.0 -50—3 0.5g Ih N. D. 84.73 13.72THF _ ecr _ eq- _ 40°C 20~10°CExample 6. Exemplary Procedure for Step 1 – Synthesis of Compound (c-1) by α-Arylation of Compound (a-1) Using Compound (b-1)

[0204] A solution of 20 g (1.0 eq.) of Compound (a-1), 21.6 g of Compound (b-1) (1.2 eq.), 23.5 g of K3PO4(1.5 eq.), and 1.4 g phenol (0.2 eq.) in 200 ml (10 vol) of degassed toluene was flushed with nitrogen for 1 hour under stirring, 1.7 g of Pd₂(dba)₃ (0.025 eq.) and 2.64 g of BuPAd₂ (0.1 eq.) were added under nitrogen. The mixture was maintained at 90°C under stirring for 16 hours.

[0205] After cooling at room temperature, the reaction mixture was filtrated, and the cake was washed with a total of 120 ml of DCM (2 vol x 3 times). The filtrated organic phase was concentrated under vacuum, and the residue was purified by silica gel chromatography (n-heptane: ethyl acetate = 5:1 to 1:1 as eluent).

[0206] This procedure obtained 24.7 g of Compound (c-1) (yield = 75%) having a purity of 99.55% (HPLC). 'H-NMR (DMSO-de); 8 (ppm*): 1.99 (s, 3H), 2.15-2.30 (m, 2H), 2.85-3.15 (m, 2H), 3.71 (s, 3H), 4.01 (dd, 1H), 5.20 (s, 2H), 6.70 (d, 1H), 6.85-7.15 (m, 4H), 7.25-7.60 (m, 5H), 7.85 (d, 1H), 9.18 (bs, 1H).

[0207] *Chemical shifts (8) were referenced on the residual proton of internal standard TMS (8 = 0.00 ppm).-84- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359Example 7. Exemplary Procedure for Step 2 - Synthesis of Compound (c-1) by a-Arylation of Compound (a-1) Using Compound (b-1), with Purification by Crystallization

[0208] A solution of 50 g (1.0 eq.) of Compound (a-1), 54.0 g of Compound (b-1) (1.2 eq.), 58.75 g of K3PO4(1.5 eq.), and 3.5 g of phenol (0.2 eq.) in 500 ml (10 vol) of degassed toluene was flushed with nitrogen for 1 hour under stirring, Then, 1.7 g of Pd2dba3 (0.025 eq.) and 2.64 g of BuPAd₂ (0.1 eq.) were added under nitrogen. The mixture was maintained at 90°C until Compound (a-1) was present at < 1% (about 21 hours).

[0209] After cooling at 30-35°C, 500 ml (10 vol) of DCM was added to the reaction mixture, and the obtained mixture was stirred at 30-35°C for 1 hour and filtrated. The filter was washed with 150 ml (3 vol) of DCM, and the solid was slurried with 500 ml (10 vol) of DCM at 30-35°C for 1 hour. The organic washing phases were combined and concentrated under vacuum at T < 40°C to 2-3 vol. Ethanol (300 ml, 6 vol.) was added to the residue, and the mixture was concentrated under vacuum at T < 50°C to 5-6 vol.

[0210] This operation was repeated two further times. The obtained mixture (about 5-6 vol) was cooled at 0-10 °C, stirred for 2-4 hours, and filtrated. The solid was washed with 150 ml (3 vol) of ethanol and dried under vacuum at T < 45°C. 69.9 g of Compound (c-1) was obtained (yield 83%) having 99.21% purity (HPLC).Example 8. Preparation of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l, 2.3.4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) with THF as Solvent and Purification by Chromatography

[0211] To a solution of 5 g Compound (c-1) (1.0 eq.) in 50 ml (10 vol) of degassed THF, 0.15 g RuCl[(R, R)-TsDpen(mesitylene)] (2% mol), 3.78 g HCOOH (5.25 eq), and 3.7 g NEt3 (3.05 eq) were added under inert atmosphere. After heating at 50°C for 16 hours, the reaction mixture was cooled at room temperature and was concentrated under vacuum to dryness.

[0212] The residue was purified by silica gel chromatography (heptane / ethyl acetate 1:4 as eluent) obtaining 3.52 g of the title compound (Compound (1-1)) (yield = 70%) having a purity of 95% and e.e.=98.7%.-85- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0213] ¹H-NMR (DMSO-d6); δ (ppm*): 1.50 (d, 1H), 1.99 (s, 3H), 2.25-2.45 (m, 1H), 2.70-2.90 (m, 2H), 3.10 (d, 1H), 3.69 (s, 3H), 4.46 (bs, 1H), 5.08 (s, 2H), 6.65-6.85 (m, 3H), 7.02 (d, 1H), 7.12 (d, 1H), 7.22 (d, 1H), 7.31 (d, 1H), 7.35-7.55 (m, 4H), 9.40 (bs, 1H).

[0214] *Chemical shifts (8) were referenced on the residual proton of internal standard TMS (8 = 0.00 ppm).Example 9. Preparation of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l, 2.3.4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)) with DCM as Solvent and Purification by Crystallization

[0215] 22.68 g HCOOH (5.25 eq) and 22.2 g NEt3 (3.05 eq) were added to a solution of 30 g (Compound (c-1)) (1.0 eq.) in 300 ml (10 vol) of DCM. The reactor was purged with nitrogen and 0.90 g RuCl[(R, R)-TsDpen(mesitylene)] (2% mol) were added under nitrogen. The mixture was refluxed until Compound (c-1) was present at < 1%. The reaction mixture was cooled at room temperature and washed with 180 ml of 2N HC1, with 180 ml of water and the organic phase was concentrated under vacuum to about 3 volumes. 150 ml of ethyl acetate were added to the residue and concentrated to about 3 volumes, this operation was repeated two further times. The residue (about 3 volumes) was cooled at 0-10°C and 150 ml of heptane were added. The mixture was stirred at 0-10°C for 1-2 hours, filtrated and the solid washed with 60 ml of heptane. After drying under vacuum at T < 45°C, 27.13 g of the title product Compound (1-1) was obtained (yield 90 %) having a purity of 96.99% and e.e. = 99.3%.Example 10. Preparation of (R)-N-(2-(6-hydroxy-l,2,3,4-tetrahydronaphtalen-l-yl)-5-methoxyphenyl)acetamide (Compound (III-l)) Via Dehydroxylation and Debenzylation of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)), T = 65°C, 100 % Pd / C wet basis

[0216] 10 mg of Compound (1-1) (1 eq) were added in an autoclave, followed by 10 mg of Pd / C wet 50%, 0.1 ml of DMAC degassed under nitrogen. The reaction mixture was replaced with hydrogen 5-10 times and finally pressurized to P=4.0 MPa with hydrogen and heated at 65°C for 16 hours. After work-up, Compound (III-l ) was obtained with a yield of 58% and e.e. =81%.-86- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0217] 'H-NMR (DMSO-de); 8 (ppm*): 1.66-1.89 (m, 2H), 2.01 (s, 3H), 2.60 (m, 1H), 2.68-2.86 (m, 3H), 2.99-3.12 (m, 1H), 3.71 (s, 3H), 6.46-6.55 (m, 2H), 6.76 (dd, 1H), 6.84 (d, 1H), 6.94 (d, 1H), 7.21 (d, 1H), 9.00 (s, 1H), 9.33 (s, 1H).

[0218] *Chemical shifts (8) were referenced on the residual proton of internal standard TMS (8 = 0.00 ppm).Example 11. Preparation of (R)-N-(2-(6-hydroxy-l,2,3,4-tetrahydronaphtalen-l-yl)-5-methoxyphenyl)acetamide (Compound (III-l)) Via Dehydroxylation and Debenzylation of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1)), T = 25°C, 200 % Pd / C wet basis10219] 10 mg of Compound (1-1) (1 eq) were added in an autoclave, followed by 20 mg of Pd / C wet 50%, and 0.1 ml of DMAC degassed under nitrogen. The reaction mixture was replaced with hydrogen 5-10 times and finally pressurized to P=4.0 MPa with hydrogen and heated at 25 °C for 16 hours. After work-up Compound (III- 1) was obtained with a yield of 62% and e.e.=88.7%.Example 12. Preparation of (R)-N-(2-(6-(benzyloxy)- 1.2.3.4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l) by Dehydroxylation of N-(2-((lR,2S)-6-(benzyloxy)-l-hydroxy-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (1-1))

[0220] 27.2 g (10.0 eq.) of NaBH4 were added to a solution of 30 g (1.0 eq.) of Compound (1-1) in 300 ml THF (10 vol). The mixture was cooled at -50 ~ -40 °C and 129.4 g (20.0 eq.) of oxalic acid was added. The reaction mixture was stirred at -20 ~ -10 °C until the starting material was present at < 1% by HPLC analysis (about 1 hour). After quenching the reaction with HC12N at 0 ~ 10 °C, the mixture was filtered, and the filter was washed with DCM.

[0221] The two phases were separated, and the organic phase was evaporated under vacuum to dryness. The residue was purified by column chromatography: silica gel, eluent: ethyl acetate / heptane = from 1 / 5 to 1 / 3. 11.68 g of Compound (II-l) were obtained (yield 60 %) having a purity of 99.71% and a e.e.=98.7%.-87- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0222] 'H-NMR (400 MHz, DMSO-de, 298K); 8 (ppm*): 1.68-1.92 (m, 2H), 2.01 (s, 3H), 2.64 (dd, 1H), 2.72-2.92 (m, 3H), 3.71 (s, 3H), 3.01-3.15 (m, 1H), 5.06 (s, 2H), 6.71-6.84 (m, 3H), 6.90-7.01 (m, 2H), 7.21 (d, 1H), 7.29-7.47 (m, 5H), 9.33 (s, 1H);13C-NMR (100 MHz, DMSO-de, 298K); 8 (ppm**): 23.2, 29.6, 29.8, 33.5, 35.8, 55.0, 69.0, 111.5, 111.8, 112.7, 114.3, 126.8, 127.5, 127.7, 128.4, 129.0, 129.6, 132.7, 136.1, 137.0, 137.4, 156.3, 157.2, 168.7.

[0223] *Chemical shifts (8) were referenced on the residual proton of TMS (8 = 0.00 ppm). " Chemical shifts (8) were referenced on the signal of DMSO-de (8 = 39.5 ppm).Example 13. Preparation of (R)-N-(2-(6-hydroxy-l,2,3,4-tetrahydronaphtalen-l-yl)-5-methoxyphenyl)acetamide (Compound (III-l)) by Debenzylation of (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l)

[0224] (R)-N-(2-(6-(benzyloxy)-l,2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l)) (22.36 g, 0.056 mol), 5% Pd / C catalyst (1.343 g; 0.5 mol %) and 300 mL of MeOH / THF (1:1) were added together in an autoclave. The autoclave was purged with N2 five times without stirring and three times with stirring and then purged with H2 at 2 bar and vented. The autoclave was pressurized at 2 bar with H2 under agitation and heated to 30°C for 20 hr, then was cooled to room temperature and vented. The mixture was heated to 40°C and filtrated, and the cake was rinsed with 67 mL (3 vol) of THF / MeOH (1:1) preheated at 40°C. The organic contents were combined and, after a solvent switch, a suspension with 130 mL (5.7-6 vol) of EtOAc (THF and MeOH < 2% w / w) formed. The precipitate was collected by filtration and rinsed with 34 mL of EtOAc (1.5 vol). (R)-N-(2-(6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl) acetamide (Compound (III-l )) was obtained (15.1 g, 87 % yield, 99.9 % purity; e.e. > 99%)Example 14. Preparation of (R)-6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) by Hydrolysis of (R)-N-(2-(6-hydroxy-l,2,3,4-tetrahydronaphtalen-l-yl)-5-methoxyphenyl)acetamide (Compound (IH-1))

[0225] In a flask, under N2, MeOH (90 ml, 9.0 v / w) and (R)-N-(2-(6-hydroxy-l, 2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl) acetamide (Compound (III-l)) (10 g, 0.037 mol, 1 eq) were charged, and the resulting suspension was stirred at 20°C. HC1 (37%) (12,5 ml, 4.7 eq)-88- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359was charged and the suspension was stirred and heated to 63°C. After 24 hr, the mixture was cooled and the solvent switched (MeOH residual < 20% w / w), and a suspension in 160 mL 2-Me THF was obtained. The suspension was added to 32 g of 12% (w / w) NaOH solution and 18.7 g of 20% (w / w) KHCO3 solution to obtain a biphasic mixture (pH 8-10). After phase separation, the organic layer was collected and washed twice with a solution of NaCl 4.8% (2 x 10.5 g, 2.1 w / w). The organic layers were collected and concentrated at T < 51 °C, under reduced pressure, to 2.5-3.5 v / w (60 ml). The mixture was cooled to 20°C, and n- heptane (70 ml, 7 v / w) was slowly added to the residue and stirred overnight. The suspension was filtered and the wet cake rinsed with n-heptane (20 ml, 2.02 v / w). (R)-6-(2-amino-4-methoxyphenyl)-5, 6,7,8-tetrahydronaphthalen-2-ol (Compound (d)) was obtained (8.2 g, 93% corrected yield; 99.8% purity, e.e. > 99.9%).Example 15. Preparation of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphtalen-2-ol (Compound (d)) by Debenzylation and Hydrolysis of (R)-N-(2-(6-(benzyloxy)-l, 2,3,4-tetrahydronaphtalen-2-yl)-5-methoxyphenyl)acetamide (Compound (II-l)

[0226] 28 ml (4 vol) of HBr (33%) in acetic acid were added to a solution, cooled at -10°C -0°C, after which 7 g (1 eq) Compound (II-l) in 35 ml of DCM (5 vol) was added. The reaction mixture was stirred at -10°C - 0°C for 2 hours and filtrated at-10°C - 0°C. The filter was washed with 14 ml (2 vol) of DCM. The solid was transferred to a reactor, and 70 ml (10 vol) of MeOH was added.

[0227] Concentrated HC1 (1.5 w / w) was added, and the reaction mixture was heated at 59-65°C until Intermediate < 1% (HPLC, about 20 hours).

[0228] The reaction mixture was concentrated under vacuum at T < 50°C to about 3 volumes. 21 ml (3 vol) of 2-methyl THF was added to the residue, and the mixture was evaporated under vacuum at T < 50°C to about 21 ml (3 vol). This solvent swap was repeated two further times.

[0229] 70 ml (10 vol) of 2-methyl THF were added to the residue, the pH was adjusted to 8-9 with an aqueous solution of NaOH and the two phases were separated. The organic phase was-89- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359washed with NaCl aq twice and concentrated under vacuum at T < 50°C to about 21 ml (3 vol).21 ml of Heptane was added to the residue for the crystallization of the product.

[0230] After filtration, filter washing with 14 ml (2 vol) heptane and drying under vacuum, 3.27 g of Compound (d) were obtained. (Yield=70%, HPLC purity 97.6 %, e.e.=96.8%.)

[0231] 1H-NMR (DMSO-d6); 8 (ppm*): 1.60-1.75 (m, 1H), 1.75-1.90 (m, 1H), 2.55-3.00 (m, 5H), 3.63 (s, 3H), 4.89 (bs, 2H), 6.11 (dd, 1H), 6.23 (d, 1H), 6.45-6.55 (m, 2H), 6.80-6.95 (m, 2H), 8.96 (s, 1H).

[0232] *Chemical shifts (8) were referenced on the residual proton of internal standard TMS (δ = 0.00 ppm).Example 16. Preparation of 7-Benzyloxy-3-bromo-l,2-dihydronaphthalene10233] 7-Benzyloxy-3-bromo-l,2-dihydronaphthalene was synthesized according to the procedure outlined in J. E. Orlander et al., 49 J. Org. Chem. 4226 (1984). To a suspension of 6-benzyloxy-3,4-dihydro-2H-naphthalen-l-one (200 g) in diethyl ether (2 L) was added dropwise bromine (60 ml) on an ice bath, and the solution was stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with diethyl ether, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, after which the solvent was evaporated in vacuo.

[0234] To the resulting 6-benzyloxy-2-bromo-3,4-dihydro- 2H-naphthalen-l-one (250 g) was added ethanol (2.5 L), the solution was stirred, sodium borohydride (25 g) was added thereto on an ice bath followed by stirring overnight at room temperature. The reaction mixture was poured into ice water, and the resulting solid was washed with water to provide 6-benzyloxy-2-bromo-1,2,3,4-tetrahydronaphthalen-l-ol (290 g). To a suspension of this compound (260 g) in toluene (800 ml) was added p-toluenesulfonic acid monohydrate (6.0 g), and the solution was refluxed for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, then-90- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (34 g) with an overall yield of 13.6%. See US 2006 / 0116364 (Example 106).

[0235] ¹H-NMR (400 MHz, CDCl3); δ (ppm): 2.73 (t, 2H), 2.92 (t, 2H), 5.04 (s, 2H), 6.72-6.76 (m, 3H), 6.90 (d, 1H), 7.30-7.44 (m, 5H).-91- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359ENUMERATED EMBODIMENTS1. A compound of Formula (I):wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH₂-aryl.2. The compound of embodiment 1, wherein Pi is (C=O)-Ci alkyl.3. The compound of embodiment 1 or 2, wherein P2 is CH2-aryl.4. A method of making a compound according to Formula (I), the method comprising:stereoselective reduction of a compound of Formula (c) in the presence of a chiral catalyst and a hydrogen source to produce the compound of Formula (I):-92- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=0-(CH2)n-C=0)- wherein n is 2 or 3; andwherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CFE-aryl.5. The method of embodiment 4, wherein the compound of Formula (c) is prepared by a method comprising:performing an a-arylation of a compound of Formula (a) with a compound of Formula (b) in the presence of a Pd compound, a ligand, and an additive,wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3;wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH₂-aryl; andwherein X is Cl, Br, I or OTf6. The method of embodiment 4 or 5, wherein X is Cl or Br.7. The method of any one of embodiments 4-6, wherein P2 is CFE-aryl.8. The method of any one of embodiments 4-7, wherein Pi is (C=O)-Ci alkyl.-93- 4902-2817-2415.2Atty. Dkt. No.: 111346-23599. The method of any one of embodiments 4-8, wherein P2 is CH2-aryl and Pi is (C=O)-Ci alkyl.10. The method of any one of embodiments 4-9, wherein the chiral catalyst is a ruthenium-based catalyst.11. The method of any one of embodiments 4-10, wherein the chiral catalyst comprises RuCl[(R, R)-TsDpen(mesitylene)], RuCl(p- cymene)[(S,S)-Ts- DPEN], or RuCl(R, R)-Teth-Tsdpen RuCl.12. The method of any one of embodiments 4-11, wherein the ruthenium catalyst comprises RuCl[(R, R)-TsDpen(mesitylene)].13. The method of any one of embodiments 4-12, wherein the hydrogen source comprises formic acid / triethylamine or borane / morpholine.14. The method of any one of embodiments 4-13, wherein the stereoselective hydrogenation is performed in tetrahydrofuran (THF), 2-methyl-THF, dimethyl ether (DME), dioxane, 1,2-dichloroethane (DCE), or dichloromethane (DCM).15. The method of any one of embodiments 4-14, wherein the stereoselective hydrogenation is performed in THF or DCM.16. The method of any one of embodiments 4-15, wherein the stereoselective hydrogenation is performed at 40°C to 70°C.17. The method of any one of embodiments 4-16, wherein the obtained compound of Formula (I) has an enantiomeric excess (e.e.) of greater than or equal to 95%.18. The method of any one of embodiments 4-17, wherein the obtained compound of Formula (I) has an enantiomeric excess (e.e.) of greater than or equal to 98%.19. The method of any one of embodiments 5-18, wherein the Pd compound comprises Pd₂(dba)₃.-94- 4902-2817-2415.2Atty. Dkt. No.: 111346-235920. The method of any one of embodiments 5-19, wherein the ligand comprises BuPAd₂.21. The method of any one of embodiments 5-20, wherein the additive comprises phenol.22. A method of making a compound of Formula (II), the method comprising:performing a dehydroxylation reaction on a compound of Formula (I) in the presence of a hydride reagent;OHwherein the compound of Formula (I) is obtained by the method of any one of embodiments 4-21.23. The method of embodiment 22, wherein the hydride reagent comprises NaBH4.24. A compound of Formula (c)wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; and-95- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl.25. The compound of embodiment 24, wherein P2 is CH2-aryl.26. The compound of embodiment 24 or 25, wherein Pi is (C=O)-Ci alkyl.27. The compound of any one of embodiments 24-26, wherein P2 is CH2-aryl and Pi is (C=O)-Ci alkyl.28. A method of making a compound of Formula (c), the method comprising:reacting a compound of Formula (a) with a compound of Formula (b) in the presence of a Pd compound, a ligand, and an additiveOwherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3;wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-C5 alkyl) and CH2-aryl; and-96- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein X is Cl, Br, I, or OTf.29. The method of embodiment 28, wherein X is Cl or Br.30. The method of embodiment 28 or 29, wherein the Pd compound comprises Pd₂(dba)₃.31. The method of any one of embodiments 28-30, wherein the ligand comprises BuPAd₂.32. The method of any one of embodiments 28-31, wherein the additive comprises phenol.33. The method of any one of embodiments 28-32, wherein P2 is CH2-aryl.34. The method of any one of embodiments 28-33, wherein Pi is (C=O)-Ci alkyl.35. The method of any one of embodiments 28-34, wherein P2 is CH2-aryl and Pi is (C=O)-Ci alkyl.36. A method of making a compound of Formula (d), the method comprising:deprotection, followed by acid hydrolysis, of a compound according to Formula (II)wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; and-97- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl.37. The method of embodiment 36, wherein Pi is (C=O)-Ci alkyl.38. The method of embodiment 36 or 37, wherein P2 is CH2-aryl.39. The method of any one of embodiments 36-38, wherein Pi is (C=O)-Ci alkyl and P2 is CH2-aryl.40. The method of any one of embodiments 36-39, wherein the deprotection is a debenzylation performed in the presence of HBr and acetic acid.41. The method of any one of embodiments 36-40, wherein the compound of Formula (II) is42. The method of any one of embodiments 36-41, wherein the compound of Formula (II) is obtained by the method according to embodiment 22 or 23.43. A method of making a compound of Formula (d), the method comprising:deprotecting a compound of Formula (III) by acid hydrolysis to obtain the compound of Formula (d)(in)-98- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3; andwherein the compound of Formula (III) is obtained starting from a compound of Formula (I)44. The method of embodiment 43, wherein the compound of Formula (III) is obtained by deprotection of the compound of Formula (I)wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)-, wherein n is 2 or 3; andwherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-C5 alkyl) and CH2-aryl.45. The method of embodiment 44, wherein the deprotection is performed using Pd / C.4902-2817-2415.2Atty. Dkt. No.: 111346-235946. The method of any one of embodiments 43-45, wherein Pi is (C=O)-Ci alkyl and P2 is CH2-aryl.47. The method of any one of embodiments 43-46, wherein P2 is CH2-benzyl, and the deprotection is a debenzylation.48. The method of embodiment 45, wherein the compound of Formula (III) is obtained by deprotection of a compound of Formula (II)wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)-, wherein n is 2 or 3; andwherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-C5 alkyl) and CFE-aryl.49. The method of embodiment 48, wherein the compound of Formula (II) is obtained by the method according to embodiment 22 or 23.50. The method of embodiment 48 or 49, wherein the compound of Formula (II) is; andthe deprotection is a debenzylation performed in the presence of a Pd catalyst and hydrogen.-100- 4902-2817-2415.2Atty. Dkt. No.: 111346-235951. The method according to any one of embodiments 43-50, wherein the compound of Formula (d) is obtained in at least 20% overall yield.52. A method of synthesizing elacestrant, wherein the method comprises making or providing a compound according to Formula (I) or Formula (c).

[0236] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0237] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.-101- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359

[0238] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0239] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range comprises each individual member.

[0240] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.[02411 While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.-102- 4902-2817-2415.2

Claims

Atty. Dkt. No.: 111346-2359WHAT IS CLAIMED IS:

1. A compound of Formula (I):wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=0-(CH2)n-C=0)- wherein n is 2 or 3; andwherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CH2-aryl.

2. The compound of claim 1, wherein P₁ is (C=O)-C₁ alkyl or P₂ is CH₂-aryl.

3. A method of making a compound according to Formula (I), the method comprising:stereoselective reduction of a compound of Formula (c) in the presence of a chiral catalyst and a hydrogen source to produce the compound of Formula (I):-103- 4902-2817-2415.2Atty. Dkt. No.: 111346-2359wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=0-(CH2)n-C=0)- wherein n is 2 or 3; andwherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-Cs alkyl) and CFE-aryl.

4. The method of claim 3, wherein the compound of Formula (c) is prepared by a method comprising:performing an a-arylation of a compound of Formula (a) with a compound of Formula (b) in the presence of a Pd compound, a ligand, and an additive,wherein Pi is H, Et, or an amino protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, (C=O)-O-Ci-Cs alkylaryl, (C=O)CF3, (C=O)CH2C1, (C=O)CCl3, or (C=O-(CH2)n-C=O)- wherein n is 2 or 3;wherein P2 is H or a phenol protecting group selected from (C=O)-Ci-Cs alkyl, (C=O)-aryl, (C=O)-heteroaryl, Si(Ci-Cs alkyl)3, Si(aryl)2(Ci-C5 alkyl) and CH₂-aryl; andwherein X is Cl, Br, I or OTf5. The method of claim 3 or 4, wherein X is Cl or Br.

6. The method of any one of claims 3-5, wherein P₁ is (C=O)-C₁ alkyl and P₂ is CH₂-aryl.

7. The method of any one of claims 3-6, wherein the chiral catalyst is a ruthenium-based catalyst.-104- 4902-2817-2415.2Atty. Dkt. No.: 111346-23598. The method of any one of claims 3-7, wherein the chiral catalyst comprises RuCl[(R, R)-TsDpen(mesitylene)], RuCl(p- cymene)[(S,S)-Ts- DPEN], or RuCl(R, R)-Teth-Tsdpen RuCl.

9. The method of any one of claims 3-8, wherein the ruthenium catalyst comprises RuCl[(R, R)-TsDpen(mesitylene)].

10. The method of any one of claims 3-9, wherein the hydrogen source comprises formic acid / triethylamine or borane / morpholine.

11. The method of any one of claims 3-10, wherein the stereoselective hydrogenation is performed in tetrahydrofuran (THF), 2-methyl-THF, dimethyl ether (DME), dioxane, 1,2-dichloroethane (DCE), or dichloromethane (DCM).

12. The method of any one of claims 3-11, wherein the stereoselective hydrogenation is performed at 40°C to 70°C.

13. The method of any one of claims 3-12, wherein the obtained compound of Formula (I) has an enantiomeric excess (e.e.) of greater than or equal to 95%.

14. The method of any one of claims 3-13, wherein the Pd compound comprises Pd₂(dba)₃.

15. The method of any one of claims 3-14, wherein the ligand comprises BuPAd₂.-105- 4902-2817-2415.2

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