Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][CH3:10])=[N:6][CH:7]=1.O.I([O-])(=O)(=O)=[O:13].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9]([CH3:10])=[O:13])=[N:6][CH:7]=1
Reactant: CSCc1ccc(Br)cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To the stirred solution of 5-Bromo-2-methylsulfanylmethyl-pyridine (1.1 gm, 5.04 mmol) in MeOH: water (10:2 mL) at 0° C. is added sodium periodate (1.08 gm, 5.046 mmol) resulting reaction mixture is stirred RT for 5 h. After completion, solvent is evaporated under reduced pressure then residue is diluted with water and extract with EtOAc (3×50 mL). The combine organic layer is dried over sodium sulphate and evaporated under reduced pressure to get crude which is purified by combi flash using 8% MeOH:DCM as eluent to afford title compound (900 mg) as off white solid. 1NMR (400 MHz, DMSO) δ: 2.56 (s, 3H), 4.11 (d, J=12.6 Hz, 1H), 4.26 (d, J=12.64 Hz, 1H), 7.36 (d, J=8.28 Hz, 1H), 8.05-8.08 (dd, J1=2.44 Hz, J2=8.28 Hz, 1H), 8.71 (d, J=2.32 Hz, 1H). LC-MS (m/z): M+H=235.9.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with benzoyl chloride (9.1 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)=[N:7]2.[CH2:20](B(O)O)[CH:21]([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:19][C:14]1[CH:13]=[C:12]([C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH2:20][CH:21]([CH3:23])[CH3:22])[N:7]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: CC(C)CB(O)O
Reactant: Cc1cc(C)cc(-c2ccc3c(Cl)cccc3n2)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3c(CC(C)C)cccc3n2)c1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
5-Chloro-2-(3,5-dimethylphenyl)quinoline (4.3 g, 16.06 mmol), isobutylboronic acid (3.2 g, 31.4 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.538 g, 1.31 mmol), and potassium phosphate monohydrate (18.3 g, 79 mmol) were mixed in 114 mL of toluene. The system was degassed for 20 minutes. Pd2(dba)3 was then added and the system was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered through a Celite® plug and eluted with dichloromethane. The product was further purified by a Kugelrohr distillation and then further purified by column chromatography using 5% ethyl acetate in hexanes. This was followed by another Kugelrohr distillation to give 3.2 g (72% yield) of product.
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[CH3:23])=[C:7]([Cl:26])[CH:6]=1)(=O)C.CO.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:26][C:7]1[CH:6]=[C:5]([OH:4])[CH:25]=[CH:24][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH3:23]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(OC(C)=O)cc3Cl)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.2 %

Procedure:
To a mixture of methyl 3-(4-acetoxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.87 g), methanol (29 ml), 1,4-dioxane (29 ml) and water (2.9 ml) was added sodium hydrogencarbonate (968 mg), and the mixture was stirred at room temperature for 2.5 hr. 1,4-Dioxane (29 ml) was added to dissolve the insoluble matter, and the mixture was stirred for 2 hr. Sodium hydrogencarbonate (968 mg) was added and the mixture was stirred at room temperature for 2 days and at 60° C. for 3 hr and stood overnight. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was again extracted with ethyl acetate. The organic layers were combined and concentrated to dryness under reduced pressure. The residue was pulverized in ether to give the objective compound (1.94 g) as a pale-yellow powder.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=1.[N:30]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][N:30]=[N:17][C:12]=2[CH:11]=1
Reactant: O=N[O-]
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1ccc2[nH]nnc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To a solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester mono acetate (2.68 g, 6.65 mmol) in acetic acid (30 mL) and water (40 mL), at room temperature was added a solution of sodium nitrite (0.46 g, 6.65 mmol) in water (8 mL), dropwise over several minutes. The resulting mixture was stirred at room temperature for 20 min, then cooled to 0° C., concentrated ammonium hydroxide was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice in the presence of solid sodium chloride, and the organic layers were dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (6:4) as eluent to afford the title compound as a tan solid (94% yield). 1H-NMR (CD3OD, 500 MHz) δ 7.75 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 7.31-7.25 (m, 5H), 7.18 (d, J=8.5 Hz, 1H), 5.39 (d, J=8.0 Hz, 1H), 5.10 (d, J=12.0 Hz, 1H), 5.05 (d, J=12.0 Hz, 1H), 4.74 (dd, j=13.5, 6.0 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J=14.0, 5.5 Hz,1H), 3.22 (dd, J=13.5, 6.0 Hz, 1H). 13CNMR (CD3OD, 125 MHz) δ 172.1, 156.0, 136.1, 128.6, 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spec. 355.18 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([NH:27][C:28](N)=[O:29])([O-])=O>O.C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][NH:15][C:28]([NH2:27])=[O:29])([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Cc1cccc(NC2(CN)CCN(Cc3ccccc3)CC2)c1
Solvent: O
Solvent: CC#N
Product: Cc1cccc(NC2(CNC(N)=O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 48 h

Procedure:
A mixture of 1-benzyl-4-(3-methylphenylamino)-4-aminomethylpiperidine (247 mg, 0.79 mmol) and nitrourea (253 mg, 2.4 mmol) in mixture of acetonitrile (1 mL) and water (10 drops) was stirred at room temp. for 48 hrs. The resultant mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of 15% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(=O)(=O)(O)O>[Zn].CCOCC>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:12]([CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 2-chlorobenzoyl chloride (52.2 g, 0.298 mol), ethyl 2-bromoisobutyrate (58.2 g, 0.298 mol) and ether is added in portions to zinc foil (19.5 g, 0.298 mol) and the resultant mixture stirred at reflux for three hours and overnight at room temperature. The mixture is poured into cold, dilute sulfuric acid and the organic layer is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a yellow oil. The oil is chromatographed on silica gel with hexanes:ethyl acetate to afford the title compound as a colorless oil (41.8 g, 55.1%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([C:23]([OH:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:27]>C(Cl)Cl.CO>[C:17]1([C@H:15]([NH:14][C@@H:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@H:10]2[C:23]([O:25][CH3:27])=[O:24])[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O)c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 261A (280 mg, 0.80 mmol) in 6 mL of 1:1 CH2Cl2/MeOH was added a solution of TMSCHN2 (0.82 ml, 1.64 mmol, 2N in hexane). The mixture was stirred at room temperature for 30 min, then concentrated in vacuo and purified by flash chromatography (hexane/EtOAc: 80:20) on silica gel to give Compound 261B as an oil. It had an analytical HPLC retention time=2.187 min. (Chromolith SpeedROD column 4.5×50 mm, 10–90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm). Mass (M+1)+=363.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[S:7][CH2:8][CH2:9][C:10]([OH:12])=O)([O:3][CH3:4])=[O:2].C(=O)([O-])O.[Na+]>>[CH3:4][O:3][C:1]([C:5]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:6]=1[S:7][CH2:8][CH2:9][C:10]2=[O:12])=[O:2]
Reactant: COC(=O)c1ccccc1SCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1cccc2c1SCCC2=O
Temperature: 0 °C
Reaction time: 21 h

Procedure:
β-(2-carbomethoxythiophenoxy) propionic acid (6.00 g, 0.025 mol) (I. W. Still and M. J. Thomas J.Org. Chem 1968, 2733) was added slowly to ice cooled conc. sulphuric acid (75 ml) with stirring. After 21 h, the reaction mixture was poured into ice water and then made alkaline using solid sodium hydrogen carbonate. The resultant suspension was then extracted with CH2Cl2 (3×). The combined organic layers were then dried (Na2SO4), and evaporated under reduced pressure to give an orange oil which was dried in vacuo and crystallised on standing to give (2.40 g, 43%).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1.C(=O)(O)[O-:19].[Na+].OOS([O-])=O.[K+].[OH2:29]>CO>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([S:7]([CH2:8][C:9](=[O:11])[CH3:10])(=[O:19])=[O:29])=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: O
Reactant: CC(=O)CSc1ccc(-c2ccccc2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(=O)CS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 99 %

Procedure:
1-(1,1′-biphenyl-4-ylthio)propan-2-one (69 mg, 0.28 mmol) was stirred at room temperature with sodium bicarbonate (72 mg, 0.85 mmol), oxone ((525 mg, 0.85 mmol), water (5 ml) and methanol (10 ml) for 3 hours. Water (50 ml) was added and the product extracted into ethyl. acetate (3×25 ml). The extracts were brine washed, sodium sulphate dried and evaporated to give 78 mg (99%) product that was of sufficient purity to use with out further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)(O)[O-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCn1cncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCCn1cncn1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 1.26 g of 1H-1,2,4-triazole-1-propanamine in 30 ml of dichloromethane containing an excess of saturated sodium bicarbonate solution was added, all at once at room temperature, a solution of 1.27 ml of benzenesulfonyl chloride in 15 ml of dichloromethane. The mixture was stirred at room temperature for 16 hours. The layers were separated. The dichloromethane layer was evaporated in vacuo and gave the compound of the Example as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH2:18].[CH3:19][SH:20]>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([S:20][CH3:19])[CH:10]([OH:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS
Reactant: O
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CSC1CN(Cc2ccccc2)CC1O
Yield: 64 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). 14.4 g (0.3 mol) of methanethiol (produced by produced by Aldrich Chemical Co., Inc.) was continuously added to the reaction mixture and stirred for 5 hours under reflux. After completion, acetone and excess diethylamine were evaporated under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 14.3 g of 1-benzyl-4-methylthio-3-pyrrolidinol (yield 63.9%) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1)(=[O:6])=[O:5])[CH3:3].FC(F)(F)C(O)=O.ClCCl>C(OCC)(=O)C>[CH3:3][C:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[N:8]=1)(=[O:6])=[O:5])([CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 25 ml round bottom flask was added tert-butyl 4-(1-methyl-1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}ethyl)piperidine-1-carboxylate (0.806 g, 1.85 mmol), trifluoroacetic acid (1.5 ml) and dichloromethane (5 ml). The resulting solution was stirred at room temperature for 1 hour. It was diluted with 50 ml ethyl acetate, washed with 50 ml 10% KOH and then 30 ml brine. The organics were dried over sodium sulfate, filtered and concentrated to give 0.33 g desired product as cyrstalline solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[C:37]12([N:47]=[C:48]=[O:49])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2.C(N(CC)CC)C>CN(C)C=O>[C:37]12([NH:47][C:48]([NH:3][C:4]3[CH:36]=[CH:35][CH:34]=[C:6]([O:7][C:8]4[CH:9]=[CH:10][C:11]5[N:15]=[C:14]([CH2:16][O:17][C:18]6[CH:31]=[CH:30][C:21]([CH2:22][CH:23]7[S:27][C:26](=[O:28])[NH:25][C:24]7=[O:29])=[CH:20][CH:19]=6)[N:13]([CH3:32])[C:12]=5[CH:33]=4)[CH:5]=3)=[O:49])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)NC45CC6CC(CC(C6)C4)C5)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.9 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 1-adamantyl isocyanate (142 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (4 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→4:1→ethyl acetate as the eluant. The product insoluble in methanol was isolated by filtration and further purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=50:50→60:40→65:35→70:30 as the eluant to afford the title compound (66 mg, mp 227.1-231.4° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](Cl)(Cl)=S.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:17]([F:26])[C:16]=1[OH:27]>C1COCC1>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10]2[O:27][C:16]3[C:17]([F:26])=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: Cc1c(N)cccc1F
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2nc(Nc3cccc(F)c3C)oc2c1F
Temperature: 25 °C
Yield: 72.8 %

Procedure:
In THF (20 ml) was dissolved 3-fluoro-2-methylaniline (0.57 ml, 5.0 mmol). To the resulting solution was added thiophosgene (990 mg, 5.0 mmol) under stirring at room temperature. After the reaction mixture was stirred for 4 hours at room temperature, methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (996 mg, 5.0 mmol) was added thereto. The resulting mixture was stirred further at room temperature for 2 days. Mercuric oxide (yellow) (1.08 g, 5.0 mmol) was added and the mixture was stirred at 70° C. for 4.5 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (4/1) eluate fractions, methyl (2-(3-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.21 g, 73%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[Cl:40][C:41]1[CH:45]=[CH:44][NH:43][N:42]=1>>[CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:37])[F:38])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:43]3[CH:44]=[CH:45][C:41]([Cl:40])=[N:42]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1cc[nH]n1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2ccc(Cl)n2)cc1

Procedure:
The title compound was prepared by the method of Preparation 18a using {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester and 3-chloro-1H-pyrazole.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])[S:14][N:13]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32].C([BH3-])#N.[Na+]>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:14][N:13]=[C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:36][CH2:35][CH2:34][C@H:30]4[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)[N:16]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-(2-methylpropyl)benzonitrile (D62) (100 mg, 0.257 mmol) and L-proline (59.1 mg, 0.513 mmol) stirred in Ethanol (10 mL) for 20 min was added sodium cyanoborohydride (48.4 mg, 0.770 mmol). This mixture was stirred at room temperature for 2 h. The reaction was quenched with water, then dried and dissolved in DMF. The residue was purified by for Mass Directed AutoPrep to afford 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)ethyl]-L-proline (E76) (20 mg) as a TFA salt (white solid).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22])[CH3:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:12][CH3:13])=[O:22]
Reactant: CCc1ccccc1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: CCc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 45.1 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 43%). EI-MS m/z 302(M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C:14]([NH:13][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:3][CH:4]=1)[C:10]([OH:12])=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
(R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (4.0 g, 11.6 mmol), 3-chlorophenylboronic acid (2.36 g, 15.11 mmol), Pd(PPh3)4 (0.067 g, 0.058 mmol) and 2M Na2CO3 aqueous solution (8.0 mL) are refluxed in 1,2-dimethmethane (70 mL) for 2.5 h under N2 atomosphere. After cooling to room temperature, the reaction mixture is diluted with EtOAc and washed with 1M HCl and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, DCM/10% MeOH in DCM=100:0 to 0:100) to give (R)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (containing impurities). HPLC retention time=1.56 minutes (condition A): MS (m+1)=376.