Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available acetylchloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=1)=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>CO.[Pd].N1C=CC=CC=1>[CH3:28][S:29]([NH:25][C:24]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1NS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)cc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 86 %

Procedure:
A suspension of 3-methoxy-4-nitro-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.4 g) in methanol (20 ml) was stirred under hydrogen with palladium on carbon (10%, 50 mg) for 18 hours. The solvents were removed in vacuo to give a brown gum. The residue was dissolved in pyridine (5 ml) and cooled to 0° C. when methanesulfonyl chloride (0.5 ml) was added, the mixture was kept at 0° C. for a further 2 hours then brought to R.T. for 1 h. The mixture was poured onto ice (50 g) and hydrochloric acid (3M, 50 g), the resultant brown solid filtered and washed with water to give 4-methanesulfonylamino-3-methoxy-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.26 g, 86%) as a brown solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.ClC(OCC(C)C)=O.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[O:4]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(C1CCCC2(C1)OCCO2)N1CCN(c2ccccn2)CC1
Yield: 58.2 %

Procedure:
From 1,4-dioxaspiro[4.5]decane-7-carboxylic acid (Example A, Step A) (10 g), triethylamine (8 g), isobutyl chloroformate (7.9 g) and 1-(2-pyridyl)piperazine (8.3 g) using the procedure of Example A, Step B is obtained 9.8 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]O.N1C=CC=CC=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Cl:23]
Reactant: COc1ccc(CO)c(OC)c1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CCl)c(OC)c1OC
Temperature: 0 °C

Procedure:
5 g (24.47 mmol) of 2,3,4-trimethoxybenzyl alcohol (Aldrich, Steinheim, FRG) are dissolved, under argon, in 13.9 ml of abs. methylene chloride, and this solution is treated with 0.278 ml of pyridine. 3.05 ml of thionyl chloride in 6.94 ml of abs. methylene chloride are added dropwise to this solution, while cooling slightly (ice/water), within the period of 20 min. During this procedure, the internal temperature rises to approximately 18°-23° C. The mixture is left to react subsequently for 45 min and the slightly yellow solution is then poured onto ice/water. After the phases have been separated, the organic phase is washed once each with 1N sulfuric acid and water. After drying over Na2SO4, and removing the solvent, the oily residue is distilled under HV (b.p.: 93°-95° C./0.07 Torr) and the title compound is obtained. 1H-NMR (220 MHz, CDCl3): 7.05 (d, 1H); 6.65 (d, 1H); 4.61 (s, 2H); 3.97 (s, 3H); 3.85 (s, 3H). HPLC: tRet =8.1 min (gradient II).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH2:10][N:5]12.C([N:19](CC)CC)C.ClC(OCC)=O.N>O.CC(C)=O>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH:12]([C:14]([NH2:19])=[O:16])[CH2:11][CH2:10][N:5]12
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CCn2c(cc3ccccc32)C1
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)C1CCn2c(cc3ccccc32)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A stirred suspension of 27 g (126 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylic acid in 30 ml of water and 450 ml of acetone was cooled to 0° C. and treated in succession with 14.7 g (145 mmol) of triethylamine and 17.3 g (159 mmol) of ethyl chloroformate. After 0.5 hour, 6.3 ml of 0.880 ammonia was added and stirring was continued for 1 hour. The solvent was removed under reduced pressure and the residue was triturated with aqueous ethanol. The product was filtered off and dried to give 13 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide, as a white solid of melting point 165°-168° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([OH:13])[C:5]2[S:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=3[C:4]=2[S:3]1(=[O:23])=[O:22].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[CH3:1][N:2]1[C:7]([C:8]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:9])=[C:6]([OH:13])[C:5]2[S:14][C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=3[C:4]=2[S:3]1(=[O:22])=[O:23]
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Product: Cc1ccc2c3c(sc2c1)C(O)=C(C(=O)Nc1nc(C)cs1)N(C)S3(=O)=O
Yield: 40 %

Procedure:
Prepared analogous to Example 1 from ethyl 2,7-dimethyl-4-hydroxy-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 40% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:21](=[O:22])[N:20]([CH2:24][CH3:25])[CH2:18][CH3:19])[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCN(CC)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N2CCN(C(=O)N(CC)CC)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
In 90 ml of chloroform was dissolved 3.6 g (0.0152 mole) of 1-(4-ethoxycarbonylphenyl)piperazine at room temperature. The temperature was elevated at 50° C. and a solution of 1.54 g (0.0114 mole) of diethylcarbamoyl chloride in 45 ml of chloroform was dropped to the above solution over a period of 30 minutes. The mixture was heated and refluxed for 2 hours, and the insoluble substance was removed and the filtrate was subjected to distillation under reduced pressure. The residue was mixed with 50 ml of a 35% aqueous solution of sodium hydroxide, and 200 ml of toluene was added and the mixture was stirred at room temperature for 30 minutes. The water layer was removed, and the organic layer was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was mixed with 20 ml of benzene and the mixture was stirred for a certain time. The benzene-insoluble substance was removed and the filtrate was subjected to silica gel chromatography to obtain 3.6 g of 1-(4-ethoxycarbonylphenyl)-4-diethylcarbamoylpiperazine having a melting point of 77° to 82° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.CN([CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)C>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH2:9][CH2:10][N:11]([CH2:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:12][CH:13]=1
Reactant: C1=C(CCc2ccco2)CCNC1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: C1=C(CCc2ccco2)CCN(Cc2c[nH]c3ncccc23)C1
Yield: 22.7 %

Procedure:
A solution of 4-(2-[furan-2-yl]ethyl)-1,2,3,6-tetrahydropyridine (506 mg, 2.86 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.86 mmol) in toluene (10 ml) was stirred at reflux for 10 hours. The solvent was evaporated and the residue chromatographed with 3% methanol in dichloromethane as eluant to afford the title compound (200 mg, 23%) as a colourless solid, m.p. 105° C.; (Found: C, 73.84; H, 6.72; N, 13.31. C19H21N3O requires C, 74.24; H, 6.89; N, 13.67); δH (DMSO-d6) 2.00-2.06 (2H, m, tetrahydropyridinyl CH2), 2.22 (2H, t, J 7.7 Hz, CH2), 2.48-2.54 (2H, m, CH2), 2.68 (2H, t, J 7.3 Hz, tetrahydropyridinyl CH2), 2.84-2.89 (2H, m, tetrahydropyridinyl CH2), 3.66 (2H, s, NCH2Ar), 5.34-5.38 (1H, m, tetrahydropyridinyl 5-H), 6.06 (1H, d, J 2.9 Hz, furanyl 3-H), 6.31 (1H, dd, J 3.0, 1.9 Hz, furanyl 4-H), 7.02 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.32 (1H, d, J 2.3 Hz, furanyl 5-H), 7.46 (1H, d, J 3.0 Hz, 2-H), 7.99 (1H, m, dd, J 7.8, 4.1 Hz, 4-H), 8.18 (1H, dd, J 4.6, 1.4 Hz, 6-H), and 11.38 (1H, br s, NH); m/z (CI+, NH3) 308 (M+1)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]1[CH:14]2[CH2:15][NH:16][CH2:17][CH:13]2[CH2:12][O:11]1.[OH-].[Na+]>O>[C:1]([N:16]1[CH2:17][CH:13]2[CH2:12][O:11][CH2:10][CH:14]2[CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1NCC2COCC12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccccc1)N1CC2COCC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Benzoyl chloride (14.06 grams, 0.1 mole), Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, was slowly added to a mixture of [compound (X)] hexahydro-1H-furo(3,4-c)pyrrole (11.3 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml of water at 10°C. After the addition of benzoyl chloride, the reaction mixture was stirred at room temperature for 2 to 3 hours and the product was extracted with diethyl ether (4 × 200 ml). Removal of the ether gave the product 5-benzoyl-hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (XI), as a clear viscous liquid which solidified on standing. The product was crystallized from diethyl ether and had a melting point of 47° to 48°C.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:12]([Cl:22])=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:14]([O:16][CH3:17])=[O:15].O>C(#N)C>[Cl:22][C:12]1[C:11]([CH:10]=[O:5])=[C:20]([Cl:21])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At reflux, 696.2 g (2.97 mol) of aqueous 50% strength N-methylmorpholine N-oxide solution were added to a solution of 312.0 g (0.99 mol) of methyl 3-bromomethyl-2,4-dichlorobenzoate in 2 l of acetonitrile. After stirring for 48 hours at room temperature, the reaction solution was stirred into 6 l of water. The precipitate was filtered off with suction, washed with water and dried under reduced pressure. 141.3 g of methyl 2,4-dichloro-3-formylbenzoate were obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([O:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1)[CH3:22]>>[CH3:22][CH:21]([O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:26][CH:25]=1)[CH3:20]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)Oc1ccc(C=O)cn1
Product: CC(C)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-propan-2-yloxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-propan-2-yloxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4]1=[O:10].[H][H]>CO.[Rh]>[NH2:2][N:3]1[CH2:7][CH:6]([CH3:8])[N:5]([CH3:9])[C:4]1=[O:10]
Reactant: Cc1cn(N)c(=O)n1C
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: CC1CN(N)C(=O)N1C
Reaction time: 4 h

Procedure:
1.6 g of Rh/C are added to a solution of 1-amino-3,4-dimethyl-2-oxo-1,3-dihydroimidazole hydrochloride in 150 ml of methanol and the reaction mixture is hydrogenated with hydrogen under normal pressure. After 4 hours, 1.13 litres of hydrogen have been taken up and the reaction ceases. The reaction mixture is then filtered over Celite and concentrated by evaporation. The residue is stirred with tetrahydrofuran. The crystals are filtered off with suction and dried in vacuo at 60°. 7 g of the title compound in the form of the hydrochloride having a melting point of 162°-164° are obtained.
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][CH:11](Cl)[C:12](=O)[CH3:13]>C(O)C>[Cl:10][CH2:11][C:12]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:9][CH:13]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=S)N1CCOCC1
Solvent: CCO
Product: ClCc1csc(N2CCOCC2)n1

Procedure:
11.51 g (78.76 mmol) of 4-morpholinecarbothioamide and 10.00 g (78.76 mmol) of dichloroacetone in 100 ml of ethanol are heated under reflux for one hour. The colourless solid which precipitates from the pink solution is, after cooling, filtered off with suction and washed twice with ethanol. This gives 12.96 g (75% of theory) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: OB(O)c1cc(F)cc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3,5-difluorophenylboronic acid gave the title compound. ES-MS m/e (%): 493.1(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.8 %

Procedure:
11.7 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid [prepared as described in step (b) above] were dissolved in 100 ml of anhydrous acetonitrile. 4.9 g of N,N'-carbonyldiimidazole were then added to the solution, which was then stirred for 30 minutes at room temperature. At the end of this time, 3.5 g of N-methylpiperazine were added to the reaction solution, and it was then stirred at room temperature for 30 minutes, and then at 40° C. for 30 minutes. The reaction solution was then condensed to 30 ml by evaporation under reduced pressure, and the residue was diluted with 300 ml of ethyl acetate. The resulting solution was washed once with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate three times with 100 ml of water and once with 100 ml of a saturated aqueous solution of sodium chloride. The ethyl acetate layer was condensed by evaporation under reduced pressure, to obtain 1.36 g of a crystalline residue. Recrystallization of this crystalline residue from 100 ml of ethanol gave 13.0 g of the title compound as colorless needles, melting at 140°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH:20]=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:20][C:19]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:18]=1[Cl:17])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(F)cccc1Cl
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of (diethoxyphosphoryl)-acetic acid ethyl ester (87 g, 0.39 mol) in tetrahydrofuran (100 mL) was slowly added to a suspension of sodium hydride (60% in mineral oil, 15 g, 0.39 mol) in tetrahydrofuran (200 mL) at 0° C. After stirring for 20 minutes, a solution of 2-chloro-6-fluoro-benzaldehyde (40 g, 0.26 mol) in tetrahydrofuran (100 mL) while maintaining the temperature at 0° C. The mixture was heated to 50° C. for 1 hour and then cooled to room temperature. The reaction was quenched by addition of a saturated aqueous solution of ammonium chloride (300 mL). The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness to give 3-(2-chloro-6-fluoro-phenyl)-acrylic acid ethyl ester, which was used directly in the next step. 1H NMR (CDCl3) δ: 7.89 (d, 1H, J=16.4 Hz), 7.26-7.06 (m, 2H), 7.06-7.02 (m, 1H), 6.72 (d, 1H, J=16.4 Hz), 4.28 (q, 2H, J=7.6 Hz), 1.34 (t, 3H, J=7.6 Hz).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([NH:13][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])[CH:3]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cc(Br)c2cc(Cl)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1CNc1cc(Br)c2cc(Cl)ccc2n1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
4-Bromo-6-chloro-quinolin-2-ylamine (3.12 g, 12 mmol) was dissolved in 100 mL 1,2-dichloroethane. 2-Methoxybenzaldehyde (1.98 g, 15 mmol) and acetic acid (2.91 g, 48 mmol) were added. The reaction mixture was stirred at 40° C. for 3 h. Sodium triacetoxy borohydride (5.99 g, 25 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was quenched by addition of 200 mL sat. sodiumbicarbonate solution. The mixture was extracted three times with dichloromethane (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (4-Bromo-6-chloro-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as an off-white solid (2.2 g, 48%), MS: m/e=379.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCC(=O)O
Reactant: CCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCC(=O)NCC(=O)O
Yield: 27.6 %

Procedure:
Glycine (20 mmol) was reacted with octanoyl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 1 Part A. The crude crystalline product (3.06 g, 76%) was recrystallized from EtOAc (15 ml) to give the title compound (1.11 g, 28%), m.p. 105-107° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>C(O)(=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:32]2[S:26][C:27](=[S:28])[NH:29][C:30]2=[O:31])=[CH:13][CH:12]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccccc2C(F)(F)F)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(2-trifluoromethylphenyl)methoxy]benzaldehyde (2.98 g, 10.63 mmol), sodium acetate (3.05 g, 37.2 mmol), and rhodanine (1.42 g, 10.7 mmol) were dissolved in 53 ml of acetic acid. The reaction solution was then heated to reflux and maintained at this temperature for about three days.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][C:41]=1[F:55].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:42][C:41]=1[F:55]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 71.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.55 g, 1 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.0 g, 3 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.5 mL). The mixture was subjected to microwave irradiation for 2 h at 100° C. The resulting mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (360 mg, 68%) as a white solid: LC/MS m/e calcd for C28H25FN2O4S [M+H]+ 505.58, observed 505.0.