Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[OH:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][OH:34])[CH2:38][CH2:39]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: OCCN1CCNCC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(CCO)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 1-(2-hydroxyethyl)piperazine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C26H38N7O5SF2 [(M+H)+] 598.2618, observed 598.2624.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(CC)CC>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][NH:7][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:15]
Reactant: CCOC(=O)CCCN
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 94.5 %

Procedure:
Methanesulfonyl chloride (4.10 g, 35.8 mmol) was added to a suspension of ethyl 4-aminobutyrate hydrochloride (6.00 g, 35.8 mmol) and Et3N (10.8 mL, 77.4 mmol) in THF (230 mL). The resulting suspension was stirred at room temperature for 43 h. The reaction mixture was filtered and the filtrate was concentrated. Flash chromatography (1:1 EtOAc:hexanes to EtOAc) afforded the title compound (7.08 g). 1H NMR (400 MHz, CDCl3) δ 4.51 (s, 1H), 4.12 (q, 2H), 3.18 (q, 2H), 2.94 (s, 3H), 2.40 (t, 2H), 1.85–1.92 (m, 2H), 1.24 (t, 3H); MS 210 (M++1).
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1[NH:12]C1C(C(F)(F)F)=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38]Cl.[H-].[Na+]>C1COCC1.C(Cl)(Cl)(Cl)Cl>[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38][NH2:12]
Reactant: ClSc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: NSc1nc2ccccc2s1
Reaction time: 3 h

Procedure:
The sulfenylated diphenylamine was prepared from N-[2-chloro-5-(trifluoromethyl)phenyl]-2,4-dinitro-6-(trifluoromethyl)benzenamine (4.3 g, 0.010 mol) in dry THF (20 ml), 2-benzothiazolesulfenyl chloride [2.0 g, 0.010 mol, Zh. Obshch. Khim. 45, 1127 (1975)] in carbon tetrachloride (45 ml) and 50% NaH (0.53 g, 0.011 mol) as outlined in Example 1 with the following exception: the reaction mixture was stirred at 0° for 3 hours and then at room temperature for 16 hours. Purification by dry column chromatography (silica gel, hexane/ethyl acetate, 8.5/1.5) gave N-[2-chloro-5-(trifluoromethyl)-phenyl]-N-[2,4-dinitro-6-trifluoromethyl)phenyl]-2-benzothiazolesulfenamide as a red-orange glass: mp 46°-53°; NMR (CDCl3) δ 7.20-8.25 (m, 7H, Ar-H), 8.8-9.05 (AB quartet, 1.6H, Ar-H); IR(KBr) 1600, 1540, 1500, 1330, 1270, 1170, 1150, 1130 and 1070 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([OH:19])[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:9])=[CH:4][CH:3]=1.Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:26])[CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:11]=2[CH2:27][C:28]([CH3:34])([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(Cl)cc1
Reactant: BrCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccn2c1C(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 101.7 %

Procedure:
A suspension of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (30 mg, 0.06 mmol), 2-(bromomethyl)quinoline (20 mg, 0.09 mmol), and potassium carbonate (17 mg, 0.12 mmol) in DMF (1.0 mL) is stirred for 96 h at 50° C. The mixture is cooled to 23° C. then filtered and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 1:1 hexanes:EtOAc) gives ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-(quinolin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate (39 mg, quant).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:36])[CH:3]=1.Cl.[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH2:42]>>[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH:42][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:36])[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]3[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=3)=[CH:22][CH:23]=2)=[CH:28][CH:29]=1)=[O:34]
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccc(=O)n(C)c3)c3ccc(F)cc3C)cc2)cc1

Procedure:
In analogy to example 228, from (E)-4′-(1-(4-fluoro-2-methylphenyl)-3-(hydroxyimino)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)propyl)biphenyl-4-carboxylic acid (example 225) and glycine-methylester hydrochloride was prepared the title compound as a light brown foam, MS (ESI+): m/z=556.22 [M+H]+.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC>C(Cl)Cl.[Ru]>[C:1]([NH:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Agent: [Ru]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Temperature: 50 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
In a 100 ml-volume stainless steel-made autoclave whose atmosphere had been displaced with nitrogen was charged a solution of 2.5 g (10 mmole) of methyl 2-(N-benzoylamino)methyl-3-oxobutanoate and 84.5 mg (0.05 mmole) of the ruthenium-optically active phosphine complex as synthesized in Reference Example 1 [Ru2Cl4 ((+)-BINAP)2 (NEt3)] in 17.5 ml of methylene chloride, and the mixture was stirred at 50° C. under a hydrogen pressure of 100 kg/cm2 for 20 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate as an eluent to obtain 2.25 g (yield: 90%) of methyl (2S, 3R)-2-(N-benzoylamino)methyl-3-hydroxybutanoate having an optical purity of 98 %ee.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: COc1cccc(S)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1cccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 1.8 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.0 mmol of 3-methoxybenzenethiol, and 2.0 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 61°-62° C.). 1H NMR (DMSO-d6) δ3.63 (s, 3H), 3.76 (s, 2H), 5.64 (bd, 1H), 6,42 (s, 1H), 6.54 (d, 1H), 6.74 (t, 1H), 7.32-7.47 (m, 10H).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH3:53])[N:10]=2)[N:5]=1)[CH3:3]>CO>[ClH:1].[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH3:53])[N:10]=2)[N:5]=1)[CH3:3]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OC)ccc2n1
Agent: Cl
Solvent: CO
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2nc(OC)ccc2n1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (20 ml) was added to a hot solution of 2-ethyl-6-methoxy-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A4) (9.4 g) in methanol (30 ml). The solution was cooled and left to stand for 1 hour. The precipitated solid was collected by filtration and washed with ethyl acetate (2×100 ml) to give 2-ethyl-6-methoxy-4-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methoxy]-1,5-naphthyridine hydrochloride (5.4 g), as a white solid, m.p. 181°-182° C.; NMR (d6DMSO): 1.4 (t, 3H), 3.1 (q, 2H), 4.05 (s, 3H), 5.65 (s, 2H), 7.2 (d, 2H), 7.5-7.8 (complex m, 8H), 8.55 (d, 1H); 13C NMR: (benzylic CH2) 71.8; mass spectrum (-ve FAB, DMSO/GLY): 437 (M-H)- ; microanalysis, found: C, 63.3; H, 5.0; N, 17.6; Cl, 7.3%; C25H22N6O2.HCl requires: C, 63.2; H, 4.9; N, 17.7; Cl, 7.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1>>[N:33]1[CH:34]=[CH:35][C:30]([NH:29][C:13]([C:12]2[S:11][C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:15])=[N:31][CH:32]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: Nc1ccncn1
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)Nc4ccncn4)s3)c2cc1OC
Yield: 69.6 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and 4-aminopyrimidine (9.5 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid pyrimidin-4-ylamide (34.3 mg, 69.7%) as a white solid. MS m/z 493 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][OH:11].N1C=CC=CC=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:18][C:19]([C:29]([F:30])([F:31])[F:32])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:11][CH2:10][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])=[O:25])[C:22]1([CH3:28])[CH3:27]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OCc1c(F)cc(F)cc1F
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
A stirred solution of 1.5 grams (0.009 mole) of 2,4,6-trifluorophenylmethyl alcohol and 0.8 gram (0.01 mole) of pyridine in 30 ml of toluene was warmed to 50° and 2.4 grams (0.009 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride was added. The addition caused a solid precipitate to form in the reaction mixture. Upon completion of the addition of the carbonyl chloride, the reaction mixture was heated under reflux for two hours, then allowed to cool to ambient temperature as it was stirred for 16 hours. The reaction mixture was placed on a column of 100 grams of silica gel and eluted with toluene. The appropriate fractions were combined and concentrated under reduced pressure to a clear residual oil. The residual oil was distilled under reduced pressure using a Kugelrohr distilling system. The appropriate fractions were combined to give 0.4 gram of 2,4,6-trifluorophenylmethyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate as an oil; nD25 1.4681.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH3:19]
Reactant: CCOC(=O)CCN
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and beta-alanine ethyl ester hydrochloride according to the procedure of Example 154 as a yellowish solid; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.1 Hz, 3 H), 2.56 (t, J=6.1 Hz, 4 H), 2.64 (t, J=5.7 Hz, 2 H), 3.55–3.65 (m, 6 H), 4.15(q, J=7.1 Hz, 2 H), 6.82 (t, J=5.7 Hz, 1 H), 6.95(d, J=8.9 Hz, 2 H), 7.70(d, J=8.9 Hz, 2 H); MS (ES) m/z: 319.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH3:14])[CH2:10][N:11]2[S:22]([C:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:26][CH3:27])(=[O:23])=[O:24])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)NCC2C
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CC2C

Procedure:
3-Methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester was reacted with 5-chloro-2-methoxybenzenesulfonyl chloride in analogy to example 34, step 2, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-3-methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester. Off-white solid, MS (ISP): m/e 395.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
(S)-tert-Butoxycarbonylamino-phenyl-acetic acid (1.00 g, 4 mmol) was dissolved in DCM (15 mL). Benzylamine (0.428 g, 4 mmol) and DIEA (0.65 g, 5 mmol) were added to the above mixture. The mixture which resulted was stirred at room temperature for a few minutes. PyBroP (2.10 g, 4.5 mmol) was added to the above solution in one portion and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (150 mL) and washed with NaHCO3 (50 mL×2, sat.). The organic layer was collected and dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was purified by chromatography to provide the desired product (0.859, 62%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.N1C=CN=C1.[CH3:27][Si:28](Cl)([CH3:35])[C:29]([CH:32]([CH3:34])[CH3:33])([CH3:31])[CH3:30]>ClCCl>[CH3:30][C:29]([Si:28]([CH3:35])([CH3:27])[O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)([CH3:31])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC=C1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 3 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
After a mixture of 149.9 g (523 mmol) (3β)-3-hydroxyandrosta-5,7-dien-17-one and 56.9 g (56.9 g (836 mmol) imidazole in 500 mL of dichloromethane was cooled to 3° C., 144 mL (732 mmol) dimethylthexylsilyl chloride was added dropwise over 90 min, keeping the temperature below 6° C. After stirring at room temperature overnight, the mixture was washed with 500 mL of water, and the aqueous layer was back-extracted with 200 mL of dichloromethane. The combined organic layers were washed with 500 mL of saturated aqueous NaHCO3, dried over sodium sulfate, and concentrated. The resulting solid was suspended in 700 mL of methanol containing 14 mL of triethylamine, and the suspension was refluxed for 20 minutes. After cooling in a refrigerator overnight, the precipitate was filtered, washed with 600 mL of methanol/H2O (9:1), and dried by suction for 2 hr. Further drying at 40° C. under high vacuum afforded 185.1 g (82.5% yield) of (3β)-3-[[(1,1,2-trimethylpropyl)dimethylsilyl]oxy]androsta-5,7-dien-17-one as a beige solid: mp 119°-125° C.; Anal. Calcd for C27H44O2Si: C, 75.64; H, 10.34; Si, 6.55. Found C, 75.82; H, 10.29; Si, 6.72.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]=[N:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][C:11]=1[CH3:16])[CH3:7]
Reactant: CCOC(=O)C=O
Reactant: Cc1cc(F)ccc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Nc1ccc(F)cc1C

Procedure:
A solution of ethyl glyoxalate (50% solution in toluene—40.8 mL) in toluene (180 mL) was heated to reflux for 1.5 hours under a Nitrogen atmosphere, in a flask equipped with a Dean Stark apparatus. Then, a solution of 4-fluoro-2-methyl-aniline (10 g) in dry toluene (20 mL) was slowly added. The mixture was heated to reflux for 3 hours, then it was concentrated in vacuo. The residue was purified by flash chromatography (toluene/CH/AcOEt 4:4:2) to give the title compound (13.06 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[C:9](=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.Br[C:14]1[CH:15]=[C:16]([CH3:22])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:11])([C:14]3[CH:15]=[C:16]([CH3:22])[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:9](=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1Nc2ncc(Br)cc2C1=O
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ncc(Br)cc21
Yield: 58.5 %

Procedure:
With 2.00 g of the compound obtained in Step 120-3 and 2.26 g of 3-bromo-4-methoxy toluene as starting materials, 1.80 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:38]=[CH:37][C:8]2[N:9]([CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[C:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][N:9]1[C:8]2[CH:37]=[CH:38][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89.7 %

Procedure:
1-(2-tert-Butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (327.0 mg) was prepared by following General Procedure E starting from 1-(2-tert-butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (374.0 mg) and sodium hydroxide (2.0 N solution, 1.0 mL) MeOH (0.5 mL) and THF (2.0 mL).
Reaction SMILES: N[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[OH-:15].[Na+]>O>[CH3:12][O:11][C:7]1[C:6]2[C:2](=[O:15])[NH:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: COc1cccc2c1C(N)=NS2(=O)=O
Agent: [Na+]
Solvent: O
Product: COc1cccc2c1C(=O)NS2(=O)=O
Yield: 79.7 %

Procedure:
2.5 gm (11.8 mmols) of 3-amino-4-methoxy-1,2-benzoisothiazole-1,1-dioxide were refluxed for 3 hours in a solution of 0.47 gm (11.8 mmols) of sodium hydroxide in 300 ml of water. The reaction mixture was filtered while still hot and acidified with hydrochloric acid. The resulting precipitate was filtered off, dried and recrystallized from benzene/ethyl acetate. 2.0 gm (9.4 mmols) of 4-methoxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide (m.p.: 224° C.) were obtained, which were dissolved in 500 ml of ethylene chloride, and the solution was admixed with 10 gm (40 mmols) of boron tribromide. The reaction mixture was slowly heated and refluxed for 1 hour. The reaction mixture was evaporated in vacuo and then repeatedly evaporated in vacuo after addition of ethanol. The obtained product was recrystallized from water, yielding 1.6 gm (68% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[C:9]([CH2:24][C:25](=[O:27])[CH3:26])[C:8]=2[CH:28]=1.O>C1COCC1>[Cl:3][C:4]1[C:5]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[C:9]([CH2:24][CH:25]([OH:27])[CH3:26])[C:8]=2[CH:28]=1
Reactant: CC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Sodium borohydride (49 mg, 1.30 mmol) was added to a solution of dimethylcarbamic acid 6-chloro-3-(3-nitrobenzyl)-2-oxo-4-(2-oxopropyl)-2H-1-benzopyran-7-yl ester (compound 7f-1-3CO) (300 mg, 0.65 mmol) in anhydrous THF (5.0 mL), and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate, and the title compound (280 mg, 93%) was obtained as a pale yellow powder.