Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3/[CH:16]=[CH:17]/[C:18](=[O:20])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3/[CH:16]=[CH:17]/[CH:18]([OH:20])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(O)/C=C/c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 2.5 h

Procedure:
2.4 g (7.6 mmol) of 7-chloro-4,5-dihydro-3-[(E)-3-oxo-1-butenyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 50 ml of dimethylformamide while warming. Thereafter, the solution was diluted with 280 ml of ethanol. 0.6 g (15.8 mmol) of sodium borohydride was added to this solution and the mixture was stirred at 20° for 2.5 hours. Thereafter, a further 0.2 g of sodium borohydride was added thereto. After a total reaction period of 4.5 hours the mixture was evaporated in a vacuum. The residue, which still contained dimethylformamide, was poured on to ice/water and stirred at 0° for 1 hour. The crystallizate was filtered off under suction and dried. There was obtained 7-chloro-4,5-dihydro-3-[(E)-3-hydroxy-1-butenyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals of melting point 232°-233°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCCCC(Oc2ncccn2)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-chloropyrimidine are reacted to give the product after flash chromatography with CH2Cl2-MeOH. LC-MS: 481 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.50 (d, 2H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 6.92 (t, 1H), 6.85 (d, 1H), 5.55 (m, 1H), 5.15 (m, 1H), 4.10 (m, 1H), 3.70 (m, 4H), 3.23 (m, 4H), 1.80–2.25 (m, 7H), 1.50–1.70 (m, 3H).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][O:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12](=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[H][H]>C(O)C.[Pd].[C]>[F:33][C:31]([F:32])([F:34])[C:29]1[CH:28]=[C:5]([CH:4]=[CH:3][C:30]=1[C:31]([F:34])([F:33])[F:32])[CH2:6][O:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccncc1)NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCc1ccncc1)NCC(COCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)c1ccccc1
Yield: 131.1 %

Procedure:
Compound 45 (4.00 g, 7.8 mmol) was dissolved in ethanol (100 mL), a 5% Pd-carbon catalyst (0.5 g) was added thereto and the mixture was stirred for 20 hours in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was evaporated in vacuo and the crystals separated out therefrom were filtered after addition of petroleum ether to give the Compound 48 (2.61 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=2)[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)c1ccc(CBr)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)=O)cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.512 g, 2.51 mmol) in dry DMF (5.6 ml) at room temperature is treated with BEMP (1.17 ml, 4.01 mmol) dropwise. The reaction mixture is stirred at room temperature for 80 minutes and then treated with 1-bromomethyl-4-methanesulfinyl-benzene (0.934 g, 4.01 mmol). After stirring at room temperature for a further 2 hours, the reaction mixture is partitioned between ethyl acetate/ether (300 ml of a 1:1 mixture) and water (30 ml). The organic portion is separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with DCM/methanol (10:1) to yield the titled product. (MH+ 357)
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[C@H:17]([CH2:18][CH:19]([OH:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C@@H:16]([C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH3:36])[C:15]1=[O:45])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[C@H:17]([CH2:18][C:19](=[O:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C@@H:16]([C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[CH3:36])[C:15]1=[O:45])([C:10]([CH3:12])([CH3:11])[CH3:13])([CH3:9])[CH3:8]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Anhydrous chromium trioxide (10.0 mmol) is added to a soution of anhydrous pyridine (20.0 mmol) in 30 ml of anhydrous methylene chloride. After stirring at room temperature for 15 min., the reaction mixture is treated all at once with a solution of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-hydroxypropyl]-azetidin-2-one (1.00 mmol) in anhydrous methylene chloride (8 ml). The resulting mixture is stirred at room temperature for 5 min. The CH2Cl2 layer is decanted from the dark, tarry residue which is triturated with more CH2Cl2. The combined CH2Cl2 phase is concentrated in vacuo. The residue is triturated with ether (100 ml) and the ether extracts are filtered. The filtrate is washed with 5% aqueous sodium bicarbonate solution, 2.5 N HCl, 5% NaHCO3 and brine, dried over magnesium sulfate and concentrated in vacuo to yield (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1 -(t-butyldimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one. n.m.r. (CDCl3) δ7.85 (2d-aromatic, 4), δ5.27 (s,2), δ4.05 (m,2), δ3.6 (s,2), δ2.4-3.2 (dd overlapping ABq,3), δ1.2 (d,3,J=6.6), δ0.9 (2s,18), δ0.22 (s,6), δ0.05 (s,6).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CCN)CCCCC=1.C1(=O)CCCCC1>C(OC(=O)C)C>[C:23]1([CH2:22][CH2:21][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: NCCC1=CCCCC1
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CSc1cnc(NC(=O)N(CCC2=CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-(1-cyclohexenyl)-ethylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: C([NH:3][C@@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:8]([S:11][C:12]3[S:16][N:15]=[N:14][CH:13]=3)[CH2:9][S:10][C@H:5]12)=O.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.C1COCC1>[NH2:3][C@@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:17]([O:19][CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:8]([S:11][C:12]3[S:16][N:15]=[N:14][CH:13]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3cnns3)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3cnns3)CS[C@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (3.99 g) in a mixture of methanol (20 ml) and THF (10 ml) was added concentrated hydrochloric acid (2.75 ml) at the room temperature. After stirring at the same temperature for 4 hours, the mixture was poured into a mixture of ice water and ethyl acetate. The mixture was adjusted to pH 4 with aqueous sodium bicarbonate solution. The organic layer was separated washed with water and brine, dried over magnesium sulfate, and evaporated to give diphenylmethyl 7β-amino-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (3.24 g).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1>>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:3])[C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])O
Product: COc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a stirred solution of HNO3 (65 mL) was added 4-methoxy-2-nitro-phenylamine (15 g, 89.3 mmol). The reaction mixture was stirred at room temperature overnight. The dark red precipitate was filtered and washed with H2O (400 mL) affording 10.01 g (53%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[NH2:22][C:23]1[S:24][C:25]([S:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:27]=1.Cl.NC1SC(Cl)=CN=1.Cl[C:44](OC)=[O:45]>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:44](=[O:45])[NH:22][C:23]3[S:24][C:25]([S:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:27]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@@]2(CNc3ccc(Br)cc32)C1
Agent: Cl
Agent: Nc1ncc(Cl)s1
Product: CCOC(=O)CSc1cnc(NC(=O)N2C[C@@]3(CCN(C(=O)OC)C3)c3cc(Br)ccc32)s1

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that (R)-t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that the ethyl 2-((2-aminothiazol-5-yl)thio)acetate synthesized by a method described in the known methods (International Publication WO2005/066145 etc.) was used instead of 2-amino-5-chlorothiazole hydrochloride, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1.[NH:19]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:27])[CH:21]=[N:20]1>CN(C=O)C.CCOC(C)=O>[F:18][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([F:17])[CH:14]=1)[O:10][CH2:9][CH2:8][N:19]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:27])[CH:21]=[N:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cn[nH]c1
Reactant: Fc1cc(F)cc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As described for the synthesis of B5 above, cesium carbonate (64 mg, 0.27 mmol) followed by a solution of 1-(2-bromoethoxy)-3,5-difluorobenzene (76 mg, 0.30 mmol) in DMF (1 mL) were added to a solution of (E)-tert-butyl (2-(3-(1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (90 mg, 0.27 mmol) in anhydrous DMF (4 mL). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. It was then diluted with 30 mL EtOAc and washed with water (2×40 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The concentrated filtrate was purified by silica gel column chromatography using a gradient of 0-100% of EtOAc in hexanes to provide, after evaporation under reduced pressure of pooled fractions, 123 mg of (E)-tert-butyl (2-(3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. MS: ES+(M+Na)+: 507
Reaction SMILES: FCC[N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1.[F:39][CH2:40]N=[N+]=[N-]>>[F:39][CH2:40][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1
Reactant: O=C1C(=O)N(Cc2cn(CCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Reactant: [N-]=[N+]=NCF
Product: O=C1C(=O)N(Cc2cn(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
was prepared according to the procedure for compound 11, with the exception that fluoromethylazide was used in place of the 2-fluoroethylazide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[CH3:26][CH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=O)[O:28]1>C1COCC1>[CH3:26][CH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2/[C:29](=[C:3]2\[C:2](=[O:10])[NH:1][C:9]3[C:4]\2=[CH:5][CH:6]=[CH:7][CH:8]=3)/[O:28]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CC1OC(=O)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1O/C(=C2/C(=O)Nc3ccccc32)c2ccccc21
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 15.2 %

Procedure:
To a solution of oxindole (119 mg, 0.891 mmol) in THF (2.0 ml) cooled at 0° C. was added 1.0M LiHMDS/THF (1.78 ml). The mixture was stirred for 4 minutes at 0° C., then allowed to warm to room temperature for an additional 6 minutes. A solution of 3-methyl-2-benzofuran-1(3 H)-one (119 mg, 0.802 mmol) in THF (0.5 ml) was added, and the reaction was rapidly stirred for 1.5 hours. The reaction was quenched into 10% HCl aqueous solution (30 ml). The resulting mixture was stirred 5 minutes, and then extracted into EtOAc. The combined organic layers were washed with water, brine, dried with anhydrous Na2SO4, and rotary evaporated to a yellow oil. Upon standing at room temperature overnight a yellow crystalline solid formed from the yellow oil. The remaining oil was removed by pipet and the solid was recrystallized from EtOAc to produce (3E)-3-(3-methyl-2-benzofuran-1(3 H)-ylidene)-1,3-dihydro-2H-indol-2-one as a yellow solid (32 mg, 15%).
Reaction SMILES: [Br:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[OH:28]O>>[Br:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:28])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2Br)NC(=O)OC3(C)C)cc1
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2Br)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 7-bromo-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:17].O.[C:21](O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]=[C:6]1[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:21])=[O:15])[C:9]=2[N:5]1[CH2:4][CH:3]=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(Cn1c(=O)[nH]c2cccc(C(=O)[O-])c21)OC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc2[nH]c(=O)n(CC=O)c12
Yield: 61 %

Procedure:
The solution of 3-(2,2-dimethoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.4 g, 1.4 mmol) in methylene chloride (10 mL) with water (3 mL) and TFA (3 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-oxo-3-(2-oxoethyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.2 g, 61%): 1H NMR (500 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.61 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 1H), 4.95-4.94 (m, 2H), 3.79 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[SH-:6].[Na+:7].Cl[CH2:9][C:10]([O-:12])=[O:11].[Na+]>C(#N)C>[SH:1][CH2:2][CH2:9][C:10]([OH:12])=[O:11].[SH-:6].[Na+:7].[C:3]1(=[O:4])[O:5][CH2:9][CH2:2]1
Reactant: O=C(O)CS
Reactant: O=C([O-])CCl
Agent: [Na+]
Agent: [SH-]
Solvent: CC#N
Product: O=C(O)CCS
Product: O=C1CCO1

Procedure:
The acids from which the esters are derived are also generally available commercially but may be made if so desired by procedures of long-standing in the chemical arts. Mercaptoacetic acid, for example, may be made by the reaction of sodium hydro-sulfide with sodium chloroacetate and subsequent acidification. β-mercaptopropionic acid is obtained in about 80% yield from the reaction of sodium hydrosulfide with β-propiolactone in acetonitrile and subsequent acidification. Mercaptosuccinic acid may be made by adding hydrogen sulfide across the double bond of maleic anhydride followed by hydrolysis. Also suitable for the purposes of this invention are the alkyl esters of α-mercapto-propionic acid, which may be prepared from α-chloropropionic acid and sodium thiosulfate according to the procedure described in U.S. Pat. No. 2,413,361.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[C:33](Cl)(=[O:36])[O:34][CH3:35]>ClCCl>[CH3:35][O:34][C:33](=[O:36])[NH:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([C:10]3[C:5]4[O:4][CH2:3][O:2][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)[CH2:24][CH2:23]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 0 °C

Procedure:
The title compound was prepared from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.068 mmol) and triethylamine (20.6 mg, 28.4 μl, 204 μmol) in dichloromethane (1 mL). Methyl carbonochloridate (7.06 mg, 5.78 μl, 0.075 μmol) was added to the mixture stirring at 0° C. The ice bath was removed and the reaction mixture was stirred for 1 hour at room temp. The reaction was diluted with dichloromethane and quenched with sat NaHCO3 (4 mL). The aqueous layer was extracted with DCM (1×5 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as a white solid (11 mg, 41.6%), MS (ISP) m/z=389.1 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+].[I-:29].[Na+]>O1CCCC1.CC(C)=O.O>[I:29][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[N:10]=1
Reactant: [I-]
Reactant: OCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1cccc(-c2csc(CI)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution (5 mL) of the compound (1.2 g, 4.6 mmol) obtained in Example 190b in tetrahydrofuran was added oxalyl chloride (0.68 mL, 9.3 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To a solution (20 mL) of the residue in acetone was added sodium iodide (2.1 g, 14 mmol), and the mixture was stirred at 70° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=90/10) to give the title compound (530 mg, 31% in 2 steps) as colorless crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11](CC(N2CCOCC2)=S)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)COCCO[CH2:29][CH2:30][OH:31].[OH-:33].[K+].Cl>O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:29][C:30]([OH:31])=[O:33])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(CC(=S)N2CCOCC2)cc1
Reactant: [OH-]
Reactant: OCCOCCOCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 18 %

Procedure:
To 56.1 g of the 4-[2-(4-heptylphenyl)-1-thioxoethyl]morpholine thus obtained, were added 300 ml of triethylene glycol, 50 ml of water and 37.3 g of potassium hydroxide. The resulting mixture was heated under reflux for six hours and then allowed to cool to room temperature. Then 10% hydrochloric acid was added thereto by portions until the pH value of the solution became slightly acidic. The reaction product was extracted with 300 ml of ethyl acetate and the organic layer was washed with water until the aqueous layer became neutral. Then the organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was recrystallized from hexane. Thus 28.0 g of p-heptylphenylacetic acid was obtained. Yield: 18%.