Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]([CH3:24])[CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:23][CH2:22][C:20]2[N:21]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([I:10])=[CH:12][CH:13]=3)[N:18]([CH3:24])[CH:19]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: Cn1cc(CN)nc1-c1ccc(I)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(CNC(=O)c2ccc(Cl)s2)nc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (23 mg, 0.14 mmol), (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl amine prepared above (21 mg, 0.067 mmol) and TEA (0.050 mL, 0.36 mmol) in DMF (2 mL) was added BOP (70 mg, 0.16 mmol). The mixture was stirred at room temperature overnight. It was then purified by HPLC to give 5-chloro-N-((2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (14 mg). MS 457.9 and 459.9 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C[C@H]1CC[C@H](CNC2C=CC(F)=C(F)C=2F)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([CH2:25][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:27][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C[C@H]2CC[C@H](C)CC2)c2ccc(F)c(F)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: C[C@H]1CC[C@H](CNc2ccc(F)c(F)c2F)CC1
Product: C[C@H]1CC[C@H](CN(C(=O)Nc2ncc(SCC(=O)O)s2)c2ccc(F)c(F)c2F)CC1

Procedure:
The title compound was prepared via {2-[3-(trans-4-methyl-cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using trans-4-methyl-cyclohexylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc([N+](=O)[O-])cn1)c1ccccc1
Yield: 41.4 %

Procedure:
A solution of 2-hydroxy-5-nitropyridine (1.40 g, 10.0 mmol), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (3.43 g, 10.0 mmol) and triethylamine (0.42 ml, 10.0 mmol) in acetonitrile (25 ml) was heated at 50° C. for 5 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate: heptane (25:75)) followed by crystallisation from ethyl acetate:heptane yielding the title compound (1.13 g, 41% yield) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:26])(=O)=O)=CC=1>O1CCCC1>[F:26][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
2,2′-Bithiophene (7.40 g) in tetrahydrofuran (90 ml) was cooled to −78° C. under argon atmosphere, and thereto were added dropwise n-butyl lithium (1.59 M hexane solution, 28.0 ml). The mixture was stirred at 0° C. for one 30 minutes, and cooled again to −78° C. Added thereto was N-fluorobenzenesulfonimide (15.5 g), and the mixture was gradually warmed, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice-cold water, and the solution was extracted with hexane twice, and the extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane) to give 2-(5-fluoro-2-thienyl)thiophene (5.89 g) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:11][C:12]1[CH2:13][C:14](=[O:19])[O:15][C:16](=[O:18])[CH:17]=1)(=[O:10])[CH3:9].O>C(O)(=O)C>[C:8]([O:11][C:12]([CH2:13][C:14](=[O:19])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][C:16]([OH:18])=[O:15])(=[O:10])[CH3:9]
Reactant: CC(=O)OC1=CC(=O)OC(=O)C1
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(=CC(=O)O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
65.7 g (0.705 mol) of aniline are added to a stirred suspension of 120 g (0.705 mol) of 4-acetyloxy-2H,3H-pyran-2,6-dione in 250 ml of acetic acid. The reaction medium is stirred for 1 h at room temperature and is then diluted by adding 500 ml of water. The solid is drained, washed with water and dried in an oven (50° C.) for 24 h. 150 g (81%) of the expected compound, melting point 125°-126° C., are obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][CH2:25][CH2:26][NH2:27]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:27][CH2:26][CH2:25][NH:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:16])=[CH:7][CH:8]=1)[CH2:14][CH3:15]
Reactant: CCCOc1ccc(OCC2CO2)cc1
Reactant: Cc1cccc(C)c1NCCN
Product: CCCOc1ccc(OCC(O)CNCCNc2c(C)cccc2C)cc1
Reaction time: 72 h

Procedure:
4.15 g. 4-Propoxyphenyl glycidyl ether and 6.6 g. N-(2,6-dimethylphenyl)-ethylenediamine are left to stand for 3 days at ambient temperature and the reaction mixture then separated by ion exchange chromatography in the manner described in Example 5. There are obtained 4.3 g. (58% of theory) of the desired product in the form of colorless crystals; m.p. 51°-54° C. The corresponding neutral fumarate, after recrystallization from ethanol, melts at 168°-169° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:61])[C@@H:45]([NH2:60])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:19])[NH:60][C@H:45]([C:44]([O:43][CH3:42])=[O:61])[CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 53.3 %

Procedure:
(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (50 mg) was coupled with (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (31 mg) according to General Procedure L to give (S)-8-[(S)-2-(4′-chloro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (39 mg). This intermediate was deprotected as described in General Procedure C to give (S)-3-(4′-chloro-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride salt. This compound was further reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to furnish (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. This compound, upon reaction with ethyl iodide and K2CO3 in DMF, gave (S)-2-({(S)-7-[2-(acetyl-ethyl-amino)-5-methyl-thiazole-4-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure 0. This product (15 mg) was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 950.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH2:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11][CH2:10]1.[Br:19]Br.O>CO>[Br:19][CH2:15][C:14](=[O:16])[CH2:13][C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:17])([F:18])[F:1])[CH2:10][CH2:11][CH2:12]1
Reactant: CC(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Reactant: BrBr
Solvent: CO
Solvent: O
Product: O=C(CBr)CC1(c2ccccc2C(F)(F)F)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
To an ice-cooled solution of 1-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propan-2-one (2.56 g, 10 mmol) in MeOH (15 ml) was added Br2 (0.5 ml, 10 mmol) slowly via a syringe. The reaction mixture was stirred for 15 min at 0° C., then 30 min at room temperature. To the reaction mixture was added H2O (15 ml) and the mixture stirred for 15 min at room temperature. The reaction was monitored by TLC, and TLC showed no starting material left 15 min after addition of H2O. The resulting solution was extracted twice with 25% n-hexane in EtOAc. The combined organic extracts were washed twice with saturated aqueous NaHCO3 solution, dried over sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel with 2% ether-hexane to yield 1.97 g of product.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 115.8 %

Procedure:
Sodium hydride (132 mg, 3.30 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AD8) (482 mg, 1.32 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (385 mg, 1.45 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and washed with saturated brine, dried (MgSO4) and evaporated to afford the product (908 mg) which was used without further purification. m/z (ES+) (M+H)+=594.52; HPLC tR=1.87 min.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[CH:30]=[C:29]([CH3:31])[O:28][N:27]=1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:25][C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: Cc1cc(CCl)no1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1Cc1cc(C)on1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of Example 244A (275 mg, 0.84 mmol) in DMF at 0° C. was treated with 60% NaH in mineral oil (40 mg, 1.03 mmol). After the gas evolution subsided, the reaction mixture was allowed to stir for 30 min and then treated with commercially available 3-(chloromethyl)-5-methylisoxazole (111 mg, 0.847 mmol). The resulting mixture was stirred at room temperature for 18 hr, poured into brine and extracted with EtOAc. The organics were combined and washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography over silica gel using 20% EtOAc in hexane to afford the title compound (165 mg, 37% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.32 (s, 9H), 2.38 (s, 3H), 3.77 (s, 3H), 5.39 (s, 2H), 6.23 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.45 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=3.1 Hz, 1H). MS (DCI) m/z 420 (M+H)+. Elemental analysis calculated for C20H22ClN3O3S: C, 57.20; H, 5.28; N, 10.01. Found: C, 57.16; H, 5.42; N, 9.75.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH3:33][CH:34]([SH:36])[CH3:35]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@:7]2([S:36][CH:34]([CH3:35])[CH3:33])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CC(C)S
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Reaction time: 26 h
Yield: 45.7 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.82 g, 4.22 mmol) and 2-propanethiol (0.470 mL, 5.06 mmol) in acetonitrile (20 mL) was added Scandium(III) trifluoromethanesulfonate (0.208 g, 0.422 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 26 h. TLC analysis showed starting material was completely consumed. Quenched with sat. ammonium chloride, extracted with EtOAc. Washed the organic with brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with gradient 5˜40% EtOAc-hexane to afford the mixture of diastereomers 1.44 g (70%). This oily mixture was purified by BIOTAGE® again, eluted with gradient 0˜20% EtOAc-toluene to yield the by-product (2S,4S)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(isopropylthio)pyrrolidine-1,2-dicarboxylate (1.05 g, 1.930 mmol, 45.8% yield) as a white foam and the desired product (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(isopropylthio)pyrrolidine-1,2-dicarboxylate (450 mg, 0.827 mmol, 19.61% yield) as a white foam. 1H NMR (500 MHz, MeOD) ppm 0.96 (d, J=6.71 Hz, 1.5H, rotamer), 1.00 (d, J=6.71 Hz, 1.5H, rotamer), 1.07 (d, J=7.02 Hz, 3H), 2.48-2.57 (m, 1H), 2.57-2.68 (m, 1H), 2.97-3.07 (m, 1H), 3.65 (s, 1.5H, rotamer), 3.77 (s, 1.5H, rotamer), 3.82-3.91 (m, 1H), 4.26-4.42 (m, 2H), 5.00-5.28 (m, 2H), 7.25-7.72 (m, 14H). LC-MS (retention time: 3.39 min, method B), MS m/z 490 (M+H).
Reaction SMILES: C([O:8][C:9](=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[C:21]3=[N:28][O:29][C:30]([CH3:31])=[C:20]3[C:19]2=[O:32])[CH2:13]1)C1C=CC=CC=1.I[Si](C)(C)C.C(O)(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH3:31][C:30]1[O:29][N:28]=[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][N:23]=3)[N:18]([CH:14]3[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:9](=[O:8])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:13]3)[C:19](=[O:32])[C:20]=12
Reactant: O=C(O)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccnc21
Yield: 80.3 %

Procedure:
Dissolve [3-(3-methyl-4-oxo-5H-2-oxa-1,5,9-triaza-cyclopenta[a]naphthalen-5yl)-cyclohexylmethyl]-carbamic acid benzyl ester (130 mg, 0.29 mmol) in dry dichloromethane (5 mL). Add iodotrimethylsilane (0.11 mL, 0.77 mmol) and stir overnight at ambient temperature. Quench with methanol (5 mL) and concentrate in vacuo. Dissolve in minimal dichloromethane and add excess diethyl ether. Decant and dry the dark solid crude amine salt in vacuo and use directly without purification. MS(ES): (M+1)+ 313.1, 314.1 m/z. Combine this amine salt with benzoic acid (36 mg, 0.29 mmol),1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol), 1-hydroxy-7-azabenzo-triazole (40 mg, 0.29 mmol), and N,N-diisopropylethyl amine (0.20 mL, 1.15 mmol), in N,N-dimethylformamide (5 mL) and stir overnight at ambient temperature. Concentrated in vacuo and take up in water and extract with dichloromethane. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel using methanoldichloromethane to give 97 mg (80%) of the desired product as a light tan solid. MS(ES): (M+1)+ 417.1, 418.1 m/z.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.05 g, 0.13 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.04 mL, 0.52 mmol) and benzoyl chloride (0.03 mL, 0.26 mmol). After stirring for twelve hours and room temperature, the reaction was quenched with a saturated, aqueous sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient), followed by re-crystallization from a mixture of ethyl acetate-hexane, to yield the title compound as a white solid (0.04 g, 59%);
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[CH2:4].NOS(O)(=O)=O.S(O)(O)(=O)=O.NO.[OH-].[Na+]>CO>[F:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4]
Reactant: C=C(CF)c1ccc([N+](=O)[O-])cc1
Agent: NO
Agent: NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(CF)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 17.5 g (0.1 Mol) 4(1-fluoromethylethenyl)-nitrobenzene in 400 ml CH3OH are added 100 g (0.8 Mol) 90% hydroxylamine-O-sulphonic acid and 67.2 g (0.41 Mol) hydroxylamine sulphate. The reaction mixture is then rendered alkaline (pH 8) at 15°-20° cooling with ice water) with 20% aqueous NaOH. After the addition of a further 500 ml portion of CH3OH the reaction mixture is stirred at room temperature for 24 hours, and then filtered. The filtrate is evaporated in vacuo. The residue is dissolved in CH2Cl2, this solution washed with H2O, dried over Na2SO4 and evaporated. The light yellow, chromatographically (this layer) pure liquid (Rf=0.5; CHCl3 /CCl4 1:1 on silica gel) is vaccum distilled, to give the title compound, b.p. 103°-104°/0.1 Torr.
Reaction SMILES: O1C(O)C[C@@H](C(C)C)C[CH:2]1[C@H]([C@@H]1[C@]2(C)[C@@H]([C@H]3[C@H](CC2)[C@]2(C)C(CC(O)CC2)CC3)C(=O)C1)C.[CH3:34][C@@:35]12[C:43](=[O:44])[CH2:42][CH2:41][C@H:40]1[C@@H:39]1[CH2:45][CH:46]=[C:47]3[CH2:52][C@@H:51]([OH:53])[CH2:50][CH2:49][C@:48]3([CH3:54])[C@H:38]1[CH2:37][CH2:36]2>>[C:2].[C:34].[CH3:34][C@@:35]12[C:43](=[O:44])[CH2:42][CH2:41][C@H:40]1[C@@H:39]1[CH2:45][CH:46]=[C:47]3[CH2:52][C@@H:51]([OH:53])[CH2:50][CH2:49][C@:48]3([CH3:54])[C@H:38]1[CH2:37][CH2:36]2
Reactant: CC(C)[C@@H]1CC(O)OC([C@@H](C)[C@H]2CC(=O)[C@@H]3[C@@H]4CCC5CC(O)CC[C@]5(C)[C@H]4CC[C@]23C)C1
Agent: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: [C]

Procedure:
The synthesis of 22,29-epoxy-3,29-dihydroxy-14β-stigmastan-15-one (260) can be accomplished in ten steps from dehydroisoandrosterone (247). Catalytic hydrogenation of the Δ5 carbon-carbon double bond in compound 247 yields compound 250, which contains a trans-fused A/B ring-system. Compound 247 is dissolved in EtOAc and 10% Pd/C is added. The mixture is stirred under H2 at room temperature overnight. Filtration through celite and concentration yields compound 250, which can be used directly in the next reaction.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6]([NH:22]C(=O)C)=[N:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-]>>[C:1]([N:4]1[N:5]=[C:6]([NH2:22])[S:7][C:8]1([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1=NN(C(C)=O)C(CCNS(C)(=O)=O)(c2ccccc2)S1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)N1N=C(N)SC1(CCNS(C)(=O)=O)c1ccccc1

Procedure:
In the same manner as that of the method described in WO2003/051854, from N-[4-acetyl-5-(2-methanesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]acetamide (5.22 g, 13.6 mmol) obtained in Step 2 mentioned above, sodium borohydride (5.14 g, 136 mmol), and cerium chloride heptahydrate (5.07 g, 13.6 mmol), N-[2-(3-acetyl-5-amino-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methane-sulfonamide was obtained.