Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16]C)=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)[Br:19].CO>ClCCl>[BrH:19].[NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(N)cccc1-c1coc(C(=O)O)c1
Reactant: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Nc1cccc(-c2coc(C(=O)O)c2)c1O
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
4-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, 1.4 mmol) was dissolved in 5 mL of dichloromethane followed by dropwise addition of boron tribromide (2.8 mL, 5.6 mmol). The mixture was reacted at room temperature for 4.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. 5 mL of methanol was added and then the mixture was concentrated under reduced pressure. The residue was diluted with 10 mL of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-amino-2-hydroxy-phenyl)-furan-2-carboxylic acid hydrobromide 28e (174 mg, yield 57.1%) as a grey solid.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH:3]=[CH:2]1>C(O)(=O)C.[Pd]>[O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2occc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1CCO2
Yield: 82.9 %

Procedure:
Benzofuran-4-carboxylic acid (10.0 g, 61.7 mmol) was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd/C (2 g) for 12 hr. The mixture was filtered and the filtrate was diluted with water (500 mL) to give 2,3-dihydrobenzofuran-4-carboxylic acid as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-187.5° C).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[O:3][CH:4]([C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:5]#[CH:6].OC(C(C)(C)CCCC)C#C.C([Si](CC)(CC)OC(CCCCC)C#C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:55]([SnH:59]([CH2:64][CH2:65][CH2:66][CH3:67])[CH2:60][CH2:61][CH2:62][CH3:63])[CH2:56][CH2:57][CH3:58]>>[CH2:64]([Sn:59]([CH2:55][CH2:56][CH2:57][CH3:58])([CH2:60][CH2:61][CH2:62][CH3:63])/[CH:6]=[CH:5]\[CH:4]([O:3][Si:2]([CH3:14])([CH3:15])[CH3:1])[C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:65][CH2:66][CH3:67]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(O[Si](C)(C)C)C(C)(C)CCCC
Agent: C#CC(CCCCC)O[Si](CC)(CC)CC
Agent: C#CC(O)C(C)(C)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C)(C)C(/C=C\[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g (8.83 mmole) of 3-trimethylsilyloxy-4,4-dimethyl-1-octyne [prepared from 3-hydroxy-4,4-dimethyl-1-octyne U.S. Pat. No. 4,007,210 and chlorotrimethylsilane (Method of Example 1)], 10 mg of azobisisobutyronitrile and 2.09 ml (7.9 mM) of tri-n-butylstannane is stirred in an oil bath under argon atmosphere at ambient temperature and then the temperature is gradually raised to 130° C. The resulting solution is stirred at 130°-135° C. for 2 hours, then cooled to furnish Z-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene. Vapor phase chromatography on a 6' 5% SE 30 column at an oven temperature of 230° C. shows a peak at retention time of 5.2 minutes. Further treatment of this solution containing the Z isomer with additional tri-n-butylstannane (3-4 mmole) and azobisisobutyronitrile (20 mg) at 130°-135° C. for 4-hour furnishes E-1-tri-n-butylstannyl-3-trimethylsilyloxy-4,4-dimethyl-1-octene. Vapor phase chromatography shows a peak at retention time of 4.7 minutes.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]3[CH:1]=[CH:2][CH:3]=[C:4]3[CH2:13]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)NCc1cccn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5 mmol of 4,5-dihydropyrrolo-[1,2-a]quinoxaline in 50 ml of methylene chloride under argon is added 10 mmol of triethylamine followed by ice bath cooling. A solution of 5 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product (from ethyl acetate) as a solid, m.p. 174°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC>ClCCl>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC[n+]1ccccc1Br
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To a stirred solution of 5-chloro-2-(4-fluorophenoxy)nicotinic acid (150 mg, 0.56 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (136 mg, 0.67 mmol), and triethylamine (0.31 mL, 2.24 mmol) in dichloromethane (8 mL) was added 2-bromo-1-ethylpyridinium tetrafluoroborate (230 mg, 0.84 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane (50 mL) and washed with 1N hydrochloric acid (30 mL), saturated aqueous sodium hydrogen carbonate solution (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 155 mg (67%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.59 (1H, dd, J=2.6, 0.9 Hz), 8.26–8.17 (1H, m), 8.13 (1H, dd, J=2.8, 0.9 Hz), 8.00 (2H, d, J=8.1 Hz), 7.41 (2H, d, J=8.1 Hz), 7.15–7.07 (4H, m), 4.76 (2H, d, J=5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 415 (M+H)+, 413 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH:8]([I:11])([CH3:10])[CH3:9]>C(#N)C>[I-:11].[CH:8]([N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1)([CH3:10])[CH3:9]
Reactant: CC(C)I
Reactant: Cc1ccncc1
Solvent: CC#N
Product: Cc1cc[n+](C(C)C)cc1
Product: [I-]
Yield: 85.2 %

Procedure:
To a stirred solution of 4-picoline (2.5 g, 26.8 mmol) in acetonitrile (50 ml) was added isopropyl iodide (9.1 g, 53.6 mmol) drop wise, the resultant mixture was heated at 90° C. for 24 hours. After cooling the solvent was evaporated to give a red solid which on trituration with ethyl acetate yielded 1-isopropyl-4-methyl pyridinium iodide (6.01 g, 85%) as a cream solid, 1H NMR D6-DMSO δ?1.6 (d, 6H, J=7), 2.6 (s, 3H), 4.95 (m, 1H), 8.0 (d, 2H J=6), 9.05 (d, 2H J=6).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:17])=[C:4]2[N:11]([OH:12])[C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:5]2=[N:6][C:7]=1[Br:8].CI.[C:20](=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOCC>[CH3:20][O:12][N:11]1[C:4]2[C:5](=[N:6][C:7]([Br:8])=[C:2]([NH2:1])[C:3]=2[Br:17])[N:9]=[C:10]1[C:13]([F:14])([F:16])[F:15]
Reactant: Nc1c(Br)nc2nc(C(F)(F)F)n(O)c2c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CC(C)=O
Product: COn1c(C(F)(F)F)nc2nc(Br)c(N)c(Br)c21

Procedure:
6-Amino-5,7-dibromo-2-trifluoromethyl-1-hydroxy-1H-imidazo(4,5-b)pyridine (1 gram) was mixed and stirred for two hours with 2 milliliters of methyl iodide, 2 grams of potassium carbonate, and 10 milliliters of acetone. The reaction mixture was then diluted with about 80 milliliters of ether and washed with five 15-milliliter portions of water. The ether layer was dried over magnesium sulfate and filtered with carbon, and the ether removed on a rotary evaporator. The resulting 1-methoxy-6-amino-5,7-dibromo-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product melted at 169°-72° C. A portion was recrystallized from methanol, m.p., 177°-8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[S:18]([C:21]1[CH:22]=[C:23]([C:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=3)[N:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>ClCCl>[CH3:37][C:36]1([CH3:38])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)=N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a stirred solution of aniline (50 mg, 0.52 mmol) and N,N-diisopropylethylamine (122 mg, 0.86 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (170 mg, 0.43 mmol) in dichloromethane (2 mL). The mixture was stirred for 18 h at room temperature and purified on preparative Thin layer chromatography to afford 170 mg of methyl 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([CH2:2][CH2:3][NH:4][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25]
Reactant: COC(=O)C=C(CC(=O)OC)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C=C(CC(=O)OC)NCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The solution of dimethyl 3-(2-hydroxyethylamino)-2-pentenedioate was cooled to 0° C., and triethylamine (235 mL, 170.6 g, 1.69 mol) was added in one portion. Methanesulfonyl chloride (168.8 g, 1.47 mol) was added dropwise via an addition funnel over 3.75 hours, with the temperature rising to 5°-7° C. The medium-yellow slurry darkened to yellow-orange as the last 10 mL methanesulfonyl chloride was added. The mixture was stirred at 0° C. for an additional 2 hours, and water (250 mL) added. The organic phase was washed with water (4×500 mL) and brine (250 mL), and dried overnight over anhydrous magnesium sulfate. After filtration, the solvents were evaporated on a rotary evaporator under reduced pressure at 50° C. to afford 310.0 g (93% yield) of dimethyl 3-(2-methanesulfonylethylamino)-2-pentenedioate as a red oil. The mesylenamine may be purified at this point, if necessary or desired, and may be converted to the haloenamine by the following method or used directly in Step 2, Alternate II.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])CCC.[C:15](=[O:17])=[O:16].C([O-])(O)=O.[Na+]>CCOCC.CCCCCC>[CH2:2]1[O:3][C:4]2[C:5](=[C:6]([C:15]([OH:17])=[O:16])[CH:7]=[CH:8][CH:9]=2)[O:1]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at -10° C. with 2.5M n-butyllithium (15 mL, 35 mmol) in hexane. When the addition was complete, the mixture was stirred under reflux for one hour. After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10% aq. NaHCO3 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HCl, and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure (1.1 g, 20%). EI-MS m/z 167 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 5.5 h
Yield: 89.5 %

Procedure:
The above general procedure was followed using 4-chlorobenzonitrile (138 mg, 1.00 mmol) and diphenylamine (169 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 2.0 mL of toluene. After 5.5 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 50% toluene/hexanes to give 242 mg (90%) of N-(4-cyanophenyl)diphenylamine as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+]>CO.O>[CH2:17]([N:6]([CH2:5][C:4]([OH:21])=[O:3])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1

Procedure:
Dissolve the crude ethyl-[butyl-(toluene-4-sulfonyl)-amino]-acetate (10 mmol) in methanol (25 mL) and water (25 mL). Add sodium hydroxide (10 mmol) and stir the reaction at room temperature for 5 hours. Dilute the reaction with water (100 mL) and rinse with methylene chloride. Neutralize the aqueous with 1N hydrochloric acid and extract with methylene chloride (3×75 mL). Combine the organic extracts and rinse with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum to provide [butyl-(toluene-4-sulfonyl)-amino]-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])[N:20]=[C:19]([CH3:33])[N:18]=2)=O)=[CH:6][C:5]=1[O:34][CH3:35])[CH3:2].[AlH3].N(CC)(C)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24]3[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])[N:20]=[C:19]([CH3:33])[N:18]=2)=[CH:6][C:5]=1[O:34][CH3:35])[CH3:2]
Reactant: CCOc1ccc(CC(=O)NCCNc2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Agent: CCN(C)C
Agent: [AlH3]
Solvent: C1CCOC1
Product: CCOc1ccc(CCNCCNc2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Heat a solution of 2-(4-ethoxy-3methoxy-phenyl)-N-{2-[2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-4-ylamino]ethyl}-acetamide (0.324 g, 0.68 mmol) in THF (10 mL) with AlH3.NMe2Et (14 mL, 6.78 mmol) to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (1.0 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuo to dryness and purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O)C.C(=O)([O-])O.[Na+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 12.9 parts of 4-(1-piperazinyl)-phenol dihydrobromide, 40 parts of ethanol and 50 parts of water are added 12.6 parts of sodium hydrogen carbonate. Then there are added dropwise 6.4 parts of methanesulfonyl chloride at 0° C. Upon completion, stirring is continued overnight. The precipitated product is filtered off and taken up in water. The whole is alkalized with a sodium hydroxide solution and stirred for 30 minutes at room temperature. The mixture is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and dried, yielding 2.8 parts of 1-(4-hydroxyphenyl)-4-(methylsulfonyl)piperazine; mp. 204.9° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:17][CH:14]2[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: NC1CC1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and cyclopropylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-N-cyclopropyl-2,5-difluorobenzenesulfonamide (0.17 g) after purification. HPLC purity 99.2% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C9H8BrF2NO2S−H+, 309.93544; found (ESI-FTMS, [M−H]1−), 309.93545
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C1\CCc2c(Cl)cccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C1\CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (E)-2-(4-chloro-1-indanylidene) acetic acid (5.5 g, 0.03 mol) in a mixture of dimethylformamide: dichloromethane (5 drops: 50 mL) was treated with oxalyl chloride (6.6 g, 0.05 mol) and allowed to stir at room temperature for 18 h. The resulting solution was concentrated in vacuo and the residue used without further purification.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[ClH:7].[CH2:8]([NH:11][CH:12]([CH3:15])[C:13]#[N:14])[CH:9]=[CH2:10]>ClC1C=CC=CC=1Cl>[CH2:8]([N:11]1[C:12]([CH3:15])=[C:13]([Cl:7])[N:14]=[C:1]([Cl:6])[C:2]1=[O:3])[CH:9]=[CH2:10]
Reactant: Cl
Reactant: C=CCNC(C)C#N
Reactant: O=C(Cl)C(=O)Cl
Solvent: Clc1ccccc1Cl
Product: C=CCn1c(C)c(Cl)nc(Cl)c1=O
Temperature: 100 °C

Procedure:
A stirred mixture of oxalyl chloride (30.5 ml, 0.35 mol) and α-(allylamino)-propionitrile hydrochloride (10.26 g, 70 mmol) in o-dichlorobenzene (100 ml) was heated to 100° C. for 15 h. The solvent was evaporated in vacuo and the residual black oil was purified by flash column chromatography on silica (eluting with 30% ethyl acetate hexanes) to give the title compound as a tan crystalline solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.[CH3:21][S:22]([Cl:25])(=[O:24])=[O:23]>>[ClH:25].[CH3:1][O:2][C:3]1[C:8]([O:9][S:22]([CH3:21])(=[O:24])=[O:23])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc3ncccc3[nH]2)c(OC)c1O
Product: COc1ccc(-c2nc3ncccc3[nH]2)c(OC)c1OS(C)(=O)=O
Product: Cl

Procedure:
Prepared analogously to Example 1 from 2-(2',4'-dimethoxy-3'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18](OC)=[O:19])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[NH3:22]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:22])=[O:19])[C:11]=3[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(C#N)cc3)nc12
Product: N#Cc1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1

Procedure:
Following standard procedure C, methyl 2-(4′-cyanophenyl)-1-H-benzimidazole-4-carboxylate (169.5 mg, 0.612 mmol) was treated with ammonia under pressure. The crude product was recrystallised from boiling methanol to yield the title compound pure as white crystals. (116.5 mg, 73%) mp >310° C.; Found C 67.81 H 3.89 N 20.87, C15H10N4O.0.2 MeOH Requires C 67.95 H 4.05 N 20.85; vmax(cm−1) 3332.27, 3274.86, 3177.98, 2230.85, 1658.54, 1608.10; δH 7.45-7.49 (1H, t); 7.87-7.91 (1H, d), 7.91 (1H, br s), 7.98-8.02 (1H, d); 8.13-8.17 (2H, d, J=8.3), 8.50-8.54 (2H, d, J=8.3), 9.2-9.4 (1H, br s), 13.6-13.8 (1H, br 8); m/z (EI) 262 (M+), 245, 217, 102.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]=O)=[CH:20][CH:19]=[CH:18][CH:17]=2.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([CH:23]=[C:29]3[S:25][C:26](=[O:31])[NH:27][C:28]3=[O:30])=[C:14]2[CH3:13])=[CH:6][CH:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: COC(=O)c1ccc(Cn2c(C)c(C=C3SC(=O)NC3=O)c3ccccc32)cc1

Procedure:
This compound was prepared in analogy with the compound described in example 200 from 4-(bromomethyl)benzoic acid methyl ester and 2-methylindole-3-carbaldehyde, followed by reaction with thiazolidine-2,4-dione.
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C(C)=O)C(C)C.[CH:29]([O:31][CH2:32][CH3:33])=[CH2:30]>O>[CH2:29]([O:31][CH2:32][CH2:33][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)[CH3:30].[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C=COCC
Reactant: C#Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCCOCC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a flask were charged 108.3 g of a solution of poly(p-hydroxystyrene)(weight-average molecular weight: about 15200, degree of dispersion: 1.20 (GPC method: reduced by polystyrene), 30.0 g as the weight of poly(p-hydroxystyrene)), 0.005 g of p-toluenesulfonic acid monohydrate and 102 g of methyl isobutyl ketone, and the mixture was stirred. Into this resin solution was dropped 8.7 g of ethyl vinyl ether (0.12 mol, 0.48 equivalent based on hydroxyl groups in poly(p-hydroxystyrene)) using a dropping funnel. The mixture was stirred at 25° C. for 3 hours, then, to this was added 15 g of methyl isobutylketone and 57 g of ion exchanged water, and the solution was separated. Further, the resulted organic layer was washed with 57 g of ion exchanged water and separated, four times.