Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([NH:18][CH:19]([CH3:34])[CH2:20][CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][N:18]([CH:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH3:17])[CH:19]([CH3:34])[CH2:20][CH2:21][CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C=O
Reactant: CC(CCCN1C(=O)c2ccccc2C1=O)NC(C)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(C(C)CCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1
Yield: 58 %

Procedure:
Using General Procedure B: Reaction of 3-methyl-pyridine-2-carbaldehyde and 2-[4-(1-pyridin-2-yl-ethylamino)-pentyl]-isoindole-1,3-dione in CH2Cl2 with NaBH(OAc)3 gave 2-{4-[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-pentyl}-isoindole-1,3-dione, as (one diasteroisomer (0.101 g) and a mixture of two diastereoisomers (0.0770 g), with a total yield of 58%. Deprotection with H2NNH2OH2O using General Procedure E gave a colorless oil. Conversion to the HBr salt using General Procedure D gave a white solid, which was isolated as a pure diastereoisomer. 1H NMR (D2O) δ 1.08 (d, 3H, J=6.3 Hz), 1.32 (d, 3H, J=6.6 Hz), 1.37-1.59 (m, 3H), 1.61-1.85 (m, 1H), 2.50 (s, 3H), 2.71-2.76 (m, 1H), 2.90-2.95 (m, 2H), 4.35 (s, 2H), 4.68 (q, 1H, J=6.6 Hz), 7.84 (t, 1H, J=6.6 Hz), 8.01 (t, 1H, J=6.9 Hz), 8.20 (d, 1H, J=8.1 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.56-8.63 (m, 2H), 8.81 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 17.01, 17.19, 19.97, 24.75, 27.37, 39.88, 46.16, 56.59, 59.71, 125.76, 127.08, 127.18, 136.58, 138.12, 142.58, 148.25, 148.62, 153.57, 156.65. ES-MS m/z 313 (M+H). Anal. Calcd. for C19H28N4.3.1HBr.0.4H2O: C, 40.00; H, 5.64; N, 9.82; Br, 43.42. Found: C, 39.93; H, 5.66; N, 9.71; Br, 43.54.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.[OH-].[Na+:27]>C(O)(C)(C)C>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:27]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 75 °C
Reaction time: 1 h

Procedure:
87.6 kg of behenic acid (Edenor C22-85R, trade name, manufactured by Henkel Co.), 423 L of distilled water, 49.2 L of a 5 N aqueous solution of NaOH, and 120 L of tert-butanol were mixed and reacted with stirring at 75° C. for one hour to obtain a solution of sodium behenate. Separately, 206.2 L of an aqueous solution containing 40.4 kg of silver nitrate (pH 4.0) was prepared and kept at 10° C. A mixture of 635 L of distilled water and 30 L of tert-butanol contained in a reaction vessel kept at 30° C. was added with the whole amount of the aforementioned sodium behenate solution, and with the whole amount of the aqueous silver nitrate solution at constant flow rates over the periods of 93 minutes and 90 minutes, respectively. In this procedure, the solutions were added in such a manner that only the aqueous silver nitrate solution was added for 11 minutes after starting the addition of the aqueous silver nitrate solution, and for 14 minutes after finishing the addition of the aqueous silver nitrate solution, only; the sodium behenate solution was added. In this operation, the outside temperature was controlled to adjust the temperature in the reaction vessel to 30° C. and keep the liquid temperature constant. The piping of the addition system for the sodium behenate solution was temperature-controlled by a double pipe, and cooled water was circulated in a jacket at the outer part of the double pipe to adjust the liquid temperature at the outlet orifice of the addition nozzle to 10° C. The addition position of the sodium behenate solution and the addition position of the aqueous silver nitrate solution were arranged symmetrically relative to the stirring axis as the center, and the positions are controlled at heights not to contact with the reaction mixture.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:17])([CH2:12][C:13]([F:16])([F:15])[F:14])[N:5]([CH3:18])[C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:18][N:5]1[C:4]2[CH:3]=[C:2]([C:24]3[CH:23]=[N:22][NH:21][C:20]=3[CH3:19])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:17])[CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(CC(F)(F)F)N2C
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A flask was charged with 6-bromo-1,2-dimethyl-2-(2,2,2-trifluoroethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (420 mg, 1.22 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.13 g, 3.7 mmol), sodium carbonate (366 mg, 6.1 mmol), 1,2-dimethoxyethane (6 mL) and water (3 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (98 mg, 0.12 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 2 h, 8 M aqueous NaOH (1 mL) was added. After stirring at 100° C. for 1 h, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/heptane) to give the title compound (212 mg, 50%) as a pale yellow solid:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCN1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: N#Cc1c(N2CCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 120 step A from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and pyrrolidin-2-one. Yellow solid. MS (ESI): 348.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:23][C:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].[H-].[Na+]>>[C:16]1([CH2:15][O:14][C:12](=[O:13])[CH2:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[CH:28][CH:29]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(CC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(Cc1ccc(C(C)(C)C)cc1)C(=O)OCC
Yield: 53 %

Procedure:
Prepared analogously to Example A62 from diethyl[(phenylmethoxycarbonyl)methyl]-malonoate and 4-(1,1-dimethylethyl)-benzylbromide in the presence of sodium hydride in a yield of 53% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:34]>C(O)C.CS(C)=O.[OH-].[Na+].OO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:34])[NH2:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D1, 220 mg) in ethanol (4 mL) and dimethyl sulfoxide (4 mL), 1.0 mol/L aqueous sodium hydroxide (2.4 mL) and 35% aqueous hydrogen peroxide (750 μL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain tert-butyl (3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D2, 195 mg) as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:14][C:13]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[OH:11])[O:18][CH2:19][CH:20]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])[CH3:21])=[O:25]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)Cc1cc(OCC(C)=O)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1cc(OCC(C)NCC(O)c2ccccc2)ccc1O
Yield: 3.7 %

Procedure:
Following a procedure similar to that described in Example 6, but using 0.72 g of 2-amino-1-phenylethanol, 1.5 g of methyl 2-hydroxy-5-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 21), 60 ml of benzene, 50 ml of absolute methanol and 1.9 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, 0.07 g of the title compound was obtained having an Rf=0.40 (thin layer chromatography over silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:25][C:24]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][CH2:20][N:19]([C:17]([O:16][C:13]([CH3:14])([CH3:12])[CH3:15])=[O:18])[CH2:25][C:24]=3[CH:26]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A suspension of 5-bromo-3-nitropyridin-2-amine (4.84 g, 22.2 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (6.51 g, 22.2 mmol), dichloro[1,1-bis(diphenyl)phosphino]ferrocenepalladium (II) dichloromethane adduct (1.60 g, 10 mol %) in dioxane (75 mL) and water (15 mL) was degassed with nitrogen, and then cesium carbonate (14.46 g, 44.4 mmol) was added. The reaction mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature, water (150 mL) was added and stirred for 30 min to give a precipitate. The product 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (8.1 g, 94% yield) was collected by filtration, dried under vacuum. MS (EI) for C19H22N4O5: 387.1 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][N:30]=[C:29]([NH:32][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5C(OC(C)(C)C)=O)=[O:34])[C:28]=4[CH:47]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][N:30]=[C:29]([NH:32][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)=[O:34])[C:28]=4[CH:47]=3)=[CH:22][CH:23]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1noc2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1noc2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc12)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of (S)-tert-butyl 2-(5-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[d]isoxazol-3-ylcarbamoyl)pyrrolidine-1-carboxylate (TFA salt 400 mg, 0.622 mmol) in DCM (5 mL) was added TFA (2 ml, 26.0 mmol) and the reaction mixture was stirred for 3 h at room temp. The solvents were removed in vacuo and the residue was taken up in 10% Methanol/CH2Cl2 and filtered through an MCX cartridge (Strata XC). The cartridge was washed with methanol and the compound was eluted with a solution of NH3 in methanol (2M). The appropriate fractions were concentrated in vacuo to afford the title compound (248 mg, 0.560 mmol, 90% yield) as yellow solid. 1H NMR (500 MHz, CD3OD) δ 8.31 (s, 1H), 7.93 (dd, J=1.8, 8.9 Hz, 1H), 7.83 (app d, J=8.5 Hz, 2H), 7.68 (app d, J=8.5 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 4.74 (t, J=7.9 Hz, 1H), 4.37 (s, br, 1H), 3.42-3.47 (m, 1H), 3.32-3.38 (m, 2H), 3.22-3.27 (m, 1H), 2.43-2.51 (m, 2H), 2.30-2.37 (m, 1H), 2.20-2.27 (m, 1H), 2.09-2.18 (m, 2H), 1.98-2.05 (m, 1H). LCMS: Anal. Calcd. for C25H26N6O2: 442; found: 443 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:3]=1)[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1cc(Cl)ccc1O
Yield: 49 %

Procedure:
4-Chlorphenol was reacted with succinic anhydride and aluminium chloride in a similar manner to the procedure described in Example 8 (i) to give 3-(5-chloro-2-hydroxybenzoyl)propionic acid (49%, m.p. 172°-173° C). (Found: M+, 228/230. C10H9Cl O4 requires: M, 228/230). (ii) 3-(5-Chloro-2-hydroxybenzoyl)propionic acid was esterified with methanol-hydrogen chloride in a similar manner to the procedure described in Example 1 (i) to give methyl 3-(3-chloro-2-hydroxybenzoyl)propionate (75%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([NH:31][C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([O:39][CH2:40][CH2:41][CH3:42])[CH:33]=3)=[O:30])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH2:40]([O:39][C:34]1[CH:33]=[C:32]([NH:31][C:29]([N:26]2[CH2:27][CH2:28][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:24][CH2:25]2)=[O:30])[CH:37]=[C:36]([F:38])[CH:35]=1)[CH2:41][CH3:42]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CCCOc1cc(F)cc(NC(=O)N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c1
Product: CCCOc1cc(F)cc(NC(=O)N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)-sulfonyl]-4-[[(3-propoxy-5-fluorophenyl)amino]-carbonyl]piperazine to give 1-[[(3-propoxy-5-fluorophenyl)amino]carbonyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:12][CH:11]=1)OS(C)(=O)=O.CCN(CC)CC.[OH:43][C@H:44]1[CH2:48][CH2:47][NH:46][CH2:45]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:12][CH:11]=1)[N:46]1[CH2:47][CH2:48][C@H:44]([OH:43])[CH2:45]1
Reactant: COC(=O)C(OS(C)(=O)=O)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: O[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-methanesulfonyloxy-acetic acid methyl ester (1.26 g, 2.5 mmol) and Et3N (0.76 g, 7.5 mmol) in CH2Cl2 (15mL) was added (S)-3-hydroxypyrrolidine (0.27 g, 3 mmol). This mixture was stirred overnight at room temperature, then diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 solution, water and brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid which was directly used in the next reaction without further purification. MS: calc'd 496 (MH+), exp 496 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+]([O-])=O)=[C:12]([CH:19]=[CH:20][N:21]3CCCC3)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.O.NN>[Ni].C1COCC1>[NH:21]1[C:13]2[C:12](=[CH:11][C:10]([C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[O:9])=[CH:15][CH:14]=2)[CH:19]=[CH:20]1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c(C=CN3CCCC3)c2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1

Procedure:
(4-Methylpiperazin-1-yl)-[4-nitro-3-(2-pyrrolidin-1-yl-vinyl)phenyl]methanone (2.907 mmol, 1.0 gram) (obtained from step (ii)) was taken in a 25 mL, two necked round bottom flask provided with a condenser, under nitrogen atmosphere. To this THF (7 mL) was added, followed by Raney-Nickel (Ra-Ni) (0.1 gram). Hydrazine hydrate (14.54 mmol, 0.73 gram) was added to the above reaction mixture in such a way that the reaction mixture starts refluxing. The reaction mixture was further refluxed for 3 hours. After the completion of reaction, Ra-Ni was removed by filtration, THF and methanol were distilled off and the concentrate was diluted with water (20 mL), basified with 20% sodium hydroxide solution to pH: 10 and the mixture was extracted with ethyl acetate (2×30 mL). The combined ethyl acetate extracts were then washed with water (2×30 mL), brine (30 Ml) and dried over anhydrous sodium sulfate. The volatiles were removed under the reduced pressure to obtain thick syrupy mass. This thick syrupy mass was purified over silica gel column, eluent being ethyl acetate and triethylamine (0.2 to 1.0%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([NH2:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22](Br)=[O:23]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:21][C:22](=[O:23])[NH:13][C:8]=2[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CCS(=O)(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Commercially available 4-ethylsulfonyl-2-aminophenol (4.02 g, 20 mmol) was dissolved in DMF (30 mL) and mixed with cesium carbonate (6.5 g, 20 mmol). The reaction mixture was cooled to 0° C. and bromoacetyl bromide (4.0 g, 20 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred overnight at room temperature. After aqueous work up, the product was purified by silica gel chromatography with methanol/dichloromethane to give the product as an orange solid, 1.7 g (35%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][OH:23])=[CH:16][C:15]=2[F:24])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6]>CCO.[Pd]>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:16][C:15]=2[F:24])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Yield: 93 %

Procedure:
Methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]benzoate was dissolved in absolute EtOH and hydrogenated in the presence of 5% Pd/C by the general procedure of Example 1, Step D. Purification of the resulting oil was carried out by column chromatography on silica gel (20% EtOAc/PE as eluant) to give methyl 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoate as a waxy white solid (93%), used directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 8.81 (s, 1 H), 7.78 (ddd, J=9.0, 6.1, 2.0 Hz, 1 H), 7.10-7.02 (m, 2 H), 6.98 (ddd, J=8.3, 8.3, 4.0 Hz, 1 H), 6.94 (dd, J=8.2, 1.9 Hz, 1 H), 4.46 (t, J=4.8 Hz, 1 H), 3.82 (s, 3 H), 3.43-3.37 (m, 2 H), 2.58 (t, J=7.7 Hz, 2 H), 1.74-1.66 (m, 2 H). LCMS (APCI−) 338 (M−H). Step C: Preparation of 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoic acid
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].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[O:10]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:5]=2)[NH:1]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
1,3-Dihydro-indol-2-one 13 (4.43 g, 33.3 mmol) was added slowly to cold chlorosulfonic acid (9 ml, 135 mmol). The reaction temperature was maintained below 30° C. during the addition. After the addition, the reaction mixture was stirred for 2 h at room temperature, then heated to 68° C. for 1 h, cooled and poured into ice water. The precipitate was washed with water and dried under vacuum to give 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 14 (5.4 g, 70%). MS m/z 229 [MH]+. 1H NMR, CD3CN 8.91 (S, 1H), 7.90-7.95 (m, 2H), 7.04 (d, J=0.11, 1H), 3.57 (S,1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[CH:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[CH:10][C:11]([OH:13])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCC1CCCCC1=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1CCCCC1=CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 2-(2-allylcyclohexylidene)acetate (1.00 g, 4.230 mmol) in dichloromethane (40 mL) at room temperature was added trifluoroacetic acid (0.688 mL, 8.883 mmol) and the solution was stirred at room temperature overnight. The solvent was then evaporated and excess of trifluoroacetic acid was removed by co-evaporation with toluene, giving 2-(2-allylcyclohexylidene)acetic acid (768 mg, 100%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 5.59 (1H, m), 5.46 (1H, s), 4.82 (2H, m), 3.36 (1H, m), 2.19 (1H, m), 2.12 (2H, m), 1.93 (1H, m), 1.71 (1H, m), 1.61 (1H, m), 1.55 (1H, m), 1.47 (2H, m), 1.22 (1H, m).