Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[C@H:3]1[C@@H:16]([OH:17])[C@@H:15]2[C@H:10]([CH2:11][CH2:12][C@:13]3([CH3:28])[C@@H:20]([C@@H:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:19][CH2:18][C@H:14]32)[C@:9]2([CH3:29])[C@H:4]1[CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2.O[C@@H:32]1CC[C@@]2(C)[C@H](CC(=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(O)=O)C1.OS(O)(=O)=O>CO>[CH3:32][O:27][C:25](=[O:26])[CH2:24][CH2:23][C@H:21]([C@@H:20]1[C@:13]2([CH3:28])[C@H:14]([C@H:15]3[C@H:10]([CH2:11][CH2:12]2)[C@:9]2([CH3:29])[C@@H:4]([CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2)[CH2:3][C:16]3=[O:17])[CH2:18][CH2:19]1)[CH3:22]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The present invention relates to a process for preparing obeticholic acid Form 1, comprising the steps of reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with CH3OH and H2SO4 to form 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester; reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester with Li[N(CH(CH3)2)2] and Si(CH3)3Cl to form 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester; reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH3CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester; reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid; reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid; reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH4 to form crystalline obeticholic acid, and converting crystalline obeticholic acid to obeticholic acid Form 1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].S(=O)(=O)(O)O>O1CCCC1.CCCCCC.C(OCC)C>[C:4]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([CH:22]=[O:23])=[CH:3]2
Reactant: BrC1=CC2(CCCC2)c2ccccc21
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=CC1=CC2(CCCC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To 3'-bromospiro(cyclopentane-1,1'-indene) (7.5 g) in tetrahydrofuran, (500 ml) is added at -70° C. a solution of n-butyllithium in hexane (200 ml of a 1.8 M solution) in two portions. The temperature is kept at -70° C. for a further 30 minutes. Dimethylformamide (73 g) is then added and the mixture is allowed to come to about 20° C. After 3 hours sulphuric acid (400 ml; 1 M) and diethyl ether (200 ml) are added. The ether phase is separated, washed with saturated sodium chloride solution and dried over sodium sulphate. Evaporation of the ether and distillation gives the title aldehyde; b.p. 130°-135° C./0.1 torr.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]([OH:13])=O)([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1.CCN(CC)CC.[F:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH2:41]>C1COCC1>[F:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH:41][C:11]([C:5]1([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1)=[O:13]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Thionyl chloride (1.09 mL, 15.0 mmol) was added slowly over 2 min to a stirring solution of 1,1-cyclopropanedicarboxylic acid (1.95 g, 15.0 mmol) and Et3N (4.29 g, 42.4 mmol) in THF (15 mL) at 0° C. After complete addition, the reaction was further diluted with THF (25 mL) and the reaction was stirred vigorously at 0° C. for 30 min. The hydrochloride salt of Example A1 (4.00 g, 12.5 mmol) was added in three portions and the resulting mixture was allowed to slowly warm to RT over 4 h. The reaction mixture was concentrated to dryness in vacuo and the residue was digested with aqueous MeOH. The remaining solids were collected by filtration. This solid was dissolved in 1 M aq NaOH (30 mL) and methanol. The methanol was removed in vacuo, the remaining aqueous phase was diluted with water to a volume of 150 mL and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with sat aq NaHCO3. The combined aqueous was acidified to pH 6 with 0.5 M HCl. The resultant fine precipitate was collected by filtration, washed with acetonitrile (20 mL) and dried in vacuo to provide 1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acid (1.177 g). The remaining aqueous was concentrated in vacuo to about ⅓ volume and the pH was reduced to pH 5 with 1 M aq HCl. The additional precipitate that formed was collected by filtration, washed with acetonitrile and dried in vacuo to provide an additional crop (1.34 g) of 1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acid (2.517 g total, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.51 (br s, 1H), 11.30 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.19 (t, J=9.0 Hz, 1H), 7.95 (s, 1H), 7.28 (dd, J=11.6, 2.7 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.01 (m, 1H), 6.69 (dd, J=5.6, 2.3 Hz, 1H), 3.84 (s, 3H), 1.58-1.51 (m, 4H); MS (ESI) m/z: 397.1 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:16]([C:21]([NH2:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([C:21]([NH2:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ncccc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1C(=O)Nc1cccnc1C(N)=O

Procedure:
In a similar manner to Example 1 a) reaction of 2-propoxybenzoyl chloride (0.99 g), 3-aminopicolinamide (0.69 g) and triethylamine (0.51 g) in acetonitrile (15 ml) afforded a crude product which was recrystallised from methanol to afford 3-(2-propoxybenzamido)picolinamide, 0.91 g, m.p. 116°-118° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:11]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1nc(C2CC2)c2cc[nH]c2n1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 0.452 g, 2.94 mmol), cyclopropylmagnesium bromide (17, 31.4 mL, 0.50 M in tetrahydrofuran, 15.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.240 g, 0.294 mmol) are combined with 15.4 mL of toluene. The reaction is heated at 60° C. overnight, then quenched with 1 M aqueous hydrochloric acid to pH 4 and filtered through a bed of celite. The layers of the filtrate are separated and the aqueous layer extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (18, 0.465 g). MS (ESI) [M+H+]+=160.1. This is reacted similarly to steps 2 and 3 of Scheme 4 to provide the desired compound 19.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:40](=[O:41])[NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1
Reactant: O=C=Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC(=O)Nc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(ff) In an analogous manner to that described in Example 24(m), by reacting tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-pyridyl isocyanate there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(pyridin-2-ylcarbamoyloxy)-phenyl]-piperidine-1-carboxylate as a white solid; MS: 554 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[NH:23][C:24]3[C:29]([C:30]=2CCNCCCCC2C=CC(NS(C)(=O)=O)=CC=2)=CC(C(N2CCOCC2)=O)=CC=3)[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[NH:12][C:9]3[C:10]([C:30]=2[CH2:29][CH2:24][NH2:23])=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:7][CH:8]=3)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Reactant: NNc1ccc(-c2nccs2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-c4nccs4)cc3c2CCN)c1
Yield: 14 %

Procedure:
Reaction of (4-thiazol-2-ylphenyl)hydrazine and 3-chloropropyl 3,5-dimethylphenyl ketone (EXAMPLE 4) was carried out according to the procedure of Example 7.1, Step D to give a 14% yield of the title compound as a yellow, stiff foam, mp 98.5°-100.5° C.; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=348.2 (M+H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]([NH2:16])([CH3:15])[CH3:14].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:16]([CH:13]([CH3:15])[CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:22]
Reactant: CC(C)N
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Product: CC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 76.6 %

Procedure:
3.6 g of D-galactose, 2.4 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.0 g of 1-(2-chloroethyl)-3-isopropyl-3-D-galactopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:20].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22].C(Cl)Cl>>[OH:27][C:21]([C:23]([F:26])([F:25])[F:24])=[O:22].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)N(c2ccccn2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2ccccn2)CC1C(=O)O

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 2 mmol) (prepared as described in step (iii) of Example 13) and 2-bromopyridine (316 mg, 2 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (977 mg, 3 mmol), Xantphos™ (87 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane (2 columns required) to give 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylate (198 mg, 36%). LC/MS [M+H]+=278. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylate (198 mg, 0.71 mmol) in TFA/DCM (1:2, 4.5 ml) was stirred at room temperature for 8 hours. The solution was evaporated and the residue was dried to give 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.71 mmol)) which was used in the next step. LC/MS [M+H]+=222.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:16](=[O:18])[CH3:17])=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(Cl)ncc1N
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc(Cl)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.36 g of 2-chloro-4-methylpyrimidin-5-ylamine was dissolved in 20 mL of dichloromethane, and under stirring on ice, 1.53 mL of pyridine, 2.7 mL of acetic anhydride and 1.16 g of 4-dimethylaminopyridine were added. After stirring at room temperature for 1 hour, water was added, extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), to afford 178 mg of the title compound as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH2:8][CH2:9]I.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.O>CN(C=O)C.C(OCC)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:9][CH2:8][F:7])=[CH:14][CH:13]=1
Reactant: FCCI
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: FCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 72.5 %

Procedure:
After adding 7.34 g of potassium carbonate and 8.31 g of 1-fluoro-2-iodoethane to a solution of 4.5 g of 4-fluorophenol in 50 ml of DMF, the mixture was stirred at room temperature for 27 hours. Water was added to the reaction mixture, and extraction was performed with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.6 g) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:40]=1)([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=3[F:1])[CH2:50][CH2:51]2)[CH:40]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3F)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (5 g, 27.01 mmol) was dissolved in acetonitrile (150 mL) and triethylamine (7.53 mL, 54.02 mmol). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.8 g, 40.52 mmol) was added, followed by N-tert-butyl-3(piperazin-1-ylmethyl)benzamide (7.44 g, 27.01 mmol). The reaction was stirred at room temperature for 18 hours and concentrated under vacuum. The residue was dissolved in ethyl acetate, filtered through dicalite, washed consecutively with water (×2) and brine and concentrated under vacuum. The product was purified by strong cation exchange chromatography, eluting macroporous polystyrene sulfonic acid with 2M ammonia in methanol. The resulting solution was concentrated under vacuum to afford the title compound as a pale yellow oil (2.6 g). MS (ESI) m/z 443.7 [M+H]+
Reaction SMILES: [C:1]([O:21]C)(=O)[C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:26][CH2:25][CH2:23][OH:24])=[O:21])=[CH:7][CH:6]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(SSc2ccc(C(=O)OC)cc2)cc1
Reactant: NCCO
Product: O=C(NCCO)c1ccc(SSc2ccc(C(=O)NCCO)cc2)cc1
Temperature: 140 °C
Yield: 68.7 %

Procedure:
A mixture of 16.5 g of dimethyl 4,4'-dithiobis[benzoate] [Werbel et al., J. Heterocycl. Chem.17, 497 (1980)] and 13.0 g of ethanolamine was heated at 140° C. while collecting the methanol which distilled from the reaction. After evolution of methanol had ceased, the reaction mixture was cooled and acidified with dilute hydrochloric acid. The solid product which formed was collected and dried to give 13.3 g of N,N'-bis(2-hydroxyethyl)-4,4'-dithiobis[benzamide], used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](SC)=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[CH3:23][NH2:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:24][CH3:23])=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CN
Reactant: CSC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Solvent: C1CCOC1
Product: CNC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21

Procedure:
400 mg of 6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline (see compound 1e) were heated with 2 g of methylamine in THF at 120° C. in a shaking autoclave under inert gas for 20 hours. Removal of the solvent by distillation was followed by MPLC chromatography on an MPRC cartridge with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]#[N:7].[BH4-].C1COCC1.CO.[C:22]([O:26][C:27](ON=C(C1C=CC=CC=1)C#N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH2:6][NH:7][C:27](=[O:28])[O:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A 3-methylamino-4-nitrobenzonitrile (2.91 g, 16.4 mmol, Journal of Medicinal Chemistry (2001), 44(17), 2753-2771) was treated with borohydride-THF solution (1M THF solution, 65.6 ml) and the mixture was stirred for 3 hours at 0° C. After the addition of MeOH, the mixture was partitioned with water and EtOAc. The crude product was extracted with EtOAc and the organic layer was washed with water and dried over MgSO4. Then, filtration, evaporation gave the yellow colored oil, which was used for the next reaction without purification. The residue was dissolved in 1,4-dioxane (10 ml), and then 2[{(tert-butoxycarbonyl)oxy}imino]-2-phenylacetonitrile (3.13 g, 12.7 mmol) was added. After stirring for 14 hours at room temperature, the residue was concentrated in vacuo followed by the purification through silica gel column chromatography eluting with hexane/EtOAc (20:1) to give tert-butyl [(3-methylamino-4-nitrophenyl)methyl]carbamate as yellow colored solid (864 mg, 19%). 1H NMR (CDCl3): δ 1.47 (9H, s), 3.02 (3H, d, J=5.3 Hz), 4.31 (2H, d, J=5.9 Hz), 4.96 (1H, s), 6.56 (1H, d, J=9.3 Hz), 6.73 (1H, s), 8.08 (1H, brs), 8.14 (1H, d, J=8.6 Hz). MS (ESI) m/z 282 (M−H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][CH2:16][C:17]1([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)[CH:26]=[C:25]2[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH2:16][C:17]1([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)[CH:26]=[C:25]2[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCOCC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (60 mL) is added to a solution of crude diethyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}tetrahydro-2H-pyran-4-yl)methyl]-1H-indole-2,6-dicarboxylate from the preceding step in CH2Cl2 (400 mL). The reaction mixture is stirred at room temperature for 2 h. Then the solvent is removed under vacuum and the residue is dissolved in EtOAc (300 mL) and washed with saturated NaHCO3 solution until the pH is about 7. The aqueous layer is separated and it is extracted with EtOAc (100 mL). The organic layers are combined, dried over Na2SO4 and concentrated to afford the crude title compound which is used in the next step without purification.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([CH:27]=1)[OH:26].N1C=CN=C1>CN(C=O)C.O>[CH3:19][O:20][C:21]1[CH:27]=[C:25]([O:26][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[C:23]([OH:28])[CH:22]=1
Reactant: COc1cc(O)cc(O)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 0.17 h
Yield: 33 %

Procedure:
tert-Butyldiphenylsilylchloride (TBDPSCl) (1.8 mL, 1.96 g, 7.14 mmol) was added to a suspension of 5-methoxyresorcinol 18 (1.0 g, 7.14 mmol) and imidazole (729 mg, 10.71 mmol) in dry DMF (5 mL) under argon at −22° C. and the mixture was stirred for 10 min. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with aq 1M of HCl (2×25 mL), and brine (2×25 mL). The organic layer was then dried (Na2SO4) and concentrated in vacuo. The crude silyl phenol 19 was purified by FCC on silica gel (5% ethyl acetate in hexane) to afford pure silyl phenol 19 (892 mg, 33%): 1H NMR (300 MHz, CDCl3) δ 7.89-7.75 (4H, m, HAr), 7.48-7.34 (6H, m, HAr), 5.98 (2H, t, J=2.1 Hz, HAr), 5.92 (1H, t, J=2.1 Hz, HAr), 5.13 (1H, br, s, HO—), 3.56 (3H, s, H3CO), 1.14 (9H, s, [(H3C)3C]; 13C NMR (75 MHz, CDCl3) δ 161.1, 157.3, 156.8, 135.4, 132.8, 129.9, 127.7, 100.1, 98.5, 95.0, 55.0, 26.4, 19.4; LRMS (CI), m/z (relative intensity): 378([M+1]+, 30), 321 (100), 243 (30), 213 (10), 199 (29). This material was employed directly in the next step.