Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)=O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cccc(NC(=O)OCc2ccccn2)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OCc2ccccn2)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 8-amino-2,3-dimethylimidazo[1,2-a]-pyridine (0.58 g), 2-pyridinylmethyl (2-chloromethyl-3-methylphenyl)carbamate (1.04 g), sodium carbonate (0.95 g) and sodium iodide (0.2 g) in acetone (25 ml) is stirred at RT for 16 h. The precipitate is filtered off and washed with acetone, and the filtrate is concentrated on a rotary evaporator. The residue is taken up in sodium hydrogencarbonate solution (40 ml) and extracted with dichloromethane (3×40 ml). The combined organic extracts are washed with water (70 ml), dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate). After concentration of the main fraction and crystallization from acetone, 0.4 g (27%) of the title compound of m.p. 163-165° C. is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)[CH:14]=1)#[N:2].[BH4-].[Na+].C[OH:33]>C(=O)([O-])O.[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]([CH2:15][C:17]2([OH:33])[CH:22]=[CH:21][CH:20]=[CH:19][NH:18]2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(C(=O)c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: CO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1ccccc1-c1cc(CC2(O)C=CC=CN2)cn(-c2ccccc2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 25 mg of 3-(2-cyanophenyl)-5-(2-pyridinecarbonyl)-1-phenyl-1,2-dihydropyridin-2-one in 5 ml of methanol was added 2 mg of sodium borohydride under ice-cooling. After 30 minutes, the mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate, followed by extracting with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate), to give 15 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[C:11]3=[N:12][C:13]=2[C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:11]3=[N:12][C:13]=2[C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)nc3)c(-c3ccc(C)nc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)nc2)N(CCCCCCC(=O)O)CCC3)cn1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A solution of ethyl 7-(2,3-bis(6-methylpyridin-3-yl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1)(16 mg, 0.034 mmol) in MeOH (2 ml) was treated with sodium hydroxide 1M (0.101 ml, 0.101 mmol) and the resulting solution was stirred at 25° C. for 68 hours. The solution was concentrated under vacuum and the residue was diluted with water and washed with EtOAc (×2). The aqueous was acidified (pH ˜4 with 1N HCl) and extracted with DCM (×3). The extracts were dried (MgSO4) and evaporated under vacuum to afford the titled compound;
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)Nc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccccc1F
Product: CC(=O)Nc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from N-{3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-phenyl}-acetamide (A-34) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=390.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2c(c1)-c1ccccc1C2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc2c(c1)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A solution of 3-amino-9-fluorenone (1.95 g, 10 mmols), triethylamine (2.07 ml, 15 mmols), in 25 ml of dried dichloromethane, is cooled to 10° C. and a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml of dried dichloromethane is then added drop by drop. The resulting mixture is kept stirring for 1 hour at room temperature overnight. The mixture is washed with 2×30 ml of water, dried over sodium sulfate and evaporated. 2.63 g 2-Chloro-N-(9-oxo-9H-fluoren-3-yl)-acetamide (97%) are obtained.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21]([CH3:23])=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=1.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:29][CH2:23][S:21][C:15]1[C@:16]2([CH2:18][C@H:19]([OH:20])[C@@:2]3([F:1])[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:17])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Product: CC(=O)OCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 110 °C

Procedure:
A mixture of 1.5 g of 9-fluoro-11β-hydroxy-17-(methylsulfinyl)androsta-1,4,16-trien -3-one, 70 ml of acetic anhydride and 2 g of fused sodium acetate is heated at 110° C. under nitrogen for 2 hours. The acetic anhydride is partially removed by distillation under vacuum and the resulting slurry is diluted with 1:1 chloroform-water. The organic layer is separated, washed with diluted sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in 4:1 chloroform-hexane and chromatographed on a 40 g-silica gel column. Elution with 1:4 hexane-chloroform gives 940 mg of slightly impure material. Two crystallizations from acetone-hexane give 350 mg of the title compound, melting point 193°-194° C., with consistent spectral data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[CH3:18])[CH:4]=1>O1CCCC1.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[CH3:18])[NH2:15])[CH:4]=1
Reactant: COc1ccnc(-c2cc([N+](=O)[O-])ccc2C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccnc(-c2cc(N)ccc2C)c1
Yield: 99.6 %

Procedure:
A suspension of 2-(4-methoxypyridin-2-yl)-4-nitrotoluene (293 mg) in tetrahydrofuran (3 ml) and ethanol (3 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 0.1 g) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4-methoxypyridin-2-yl)-4-methylaniline (256 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH3:13])=[N+:9]([O-])[CH:10]=1)=[N+:2]=[N-:3].[CH3:14][N:15](C)C(Cl)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[N:1]([CH2:4][C:5]1[C:10]([C:14]#[N:15])=[N:9][C:8]([CH2:12][CH3:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: CN(C)C(=O)Cl
Reactant: CCc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1ccc(CN=[N+]=[N-])c(C#N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 90.5 %

Procedure:
After dissolving 5-(azidomethyl)-2-ethyl-1-pyridiniumolate (2.16 g, 12.1 mmol) in acetonitrile (25 ml), 1.77 ml of trimethylsilylnitrile (13.3 mmol) and 1.23 ml of dimethylcarbamoyl chloride (13.3 mmol) were added under a nitrogen stream and the mixture was stirred at room temperature for 66 hours. Saturated aqueous sodium hydrogencarbonate was added for treatment and extraction was performed with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.05 g) as a colorless oil. (90.4% yield)
Reaction SMILES: [OH:1][CH:2]([C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH3:7])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].CS([C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[N:31]=1)(=O)=O>CN(C=O)C>[CH3:39][O:38][C:32]1[CH:33]=[C:34]([O:36][CH3:37])[N:35]=[C:30]([O:1][CH:2]([C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH3:7])[C:3]#[N:4])[N:31]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCC(c1ccccc1)(c1ccccc1)C(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)(c1ccccc1)C(C#N)Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
7.0 g (27.9 mmol) of 2-hydroxy-3,3-diphenylvaleronitrile were dissolved in 100 ml of DMF (abs.) and, under nitrogen, 7.57 g (55.7 mmol) of potassium carbonate and 6.1 g (27.9 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added, and the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, and the residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated off. The crude product was chromatographed on silica gel with n-heptane/ethyl acetate (20:1). 8.8 g (81%) of product were obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: ICC1CCCC1OC1CCCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (10.4 mL of a 0.31M stock solution, 3.22 mmol) cooled to −78° C. was treated with 3,4-dichlorophenylacetic acid methyl ester (prepared as in Example 1, 642 mg 2.93 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7.33 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. A solution of 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (1.0 g, 3.22 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was then added. The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with methylene chloride 3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (880 mg, 74.8%) as a pale yellow oil: EI-HRMS m/e calcd for C20H26Cl2O4 (M+) 400.1208. found 400.1203.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](B(O)O)=[CH:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccccc1-c1ccccc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 34.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.46 g, 10.0 mmol), 2-biphenylboronic acid (Aldrich; 1.94 g, 10.0 mmol), copper(II) acetate (1.81 g, 10.0 mmol) and triethylamine (1.4 mL, 10.0 mmol) in 1,2-dichloroethane (10 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5-40% ethyl acetate/hexanes, to give N′-biphenyl-2-yl-N-methyl-hydrazinecarboxylic acid tert-butyl ester (1.02 g, 34%) as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[C:26]1([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([C:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 15 h
Yield: 37.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g), triethylamine (1.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (1.6 g) in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling isopropanol (2 cc), 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1.5 g) is obtained, m.p. 88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:20][C:21]([F:28])([F:27])[CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:23]([CH2:22][C:21]([F:28])([F:27])[F:20])(=[O:25])=[O:24])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)CC(F)(F)F)c2)cc2ccc(Cl)cc21

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 205a) and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according to the method described in Example 186f to give 2,2,2-trifluoro-ethanesulfonic acid [5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 3.75 (d, J=0.6 Hz, 3H), 4.16-4.28 (m, 2H), 4.44 (s, 2H), 6.67 (s, 1H), 7.07 (ddd, J=8.4, 1.8, 0.8 Hz, 1H), 7.50 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 8.04 (d, J=0.6 Hz, 1H), 8.58 (d, J=1.4 Hz, 1H), 8.68 (d, J=1.6 Hz, 1H). HRMS (ESI) m/z 418.06107 [(M+H)+ Calcd for C17H16N3O2F3SCl: 418.06039].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[O:1][CH2:12]1
Reactant: N#Cc1ccc(O)c(O)c1
Reactant: BrCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)OCO2
Temperature: 120 °C
Yield: 94.8 %

Procedure:
To a solution of 3,4 Dihydroxy benzonitrile (5.0 g, 37.0 mmol) in 20 ml of DMF was added dibromomethane (19.25 g, 110.0 mmol) and potassium carbonate (25.50 g, 184.90 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), reaction mixture was cooled to room temperature. Water (50 ml) was added to the reaction mixture and extracted the compound with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to give the title compound as yellow solid (5.16 g, 94.8%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][OH:6].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.[OH-].[Na+]>CN(C)C(=O)C>[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][O:6][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred suspension of sodium hydride (3.9 g, 96 mmol, 60% in oil) in N,N-dimethylacetamide (160 mL) is added dropwise 2,2,3,3,3-pentafluoropropan-1-ol (6.4 mL, 64 mmol) at 0° C. After stirring for 10 minutes, a solution of methyl 6-chloronicotinate (5.5 g, 32 mmol) in N,N-dimethylacetamide (10 mL) is added dropwise at 0° C., and the mixture is stirred for 30 minutes at room temperature. Then, the mixture is stirred at 90° C. for 2 hours. After cooled to room temperature, 2M aqueous sodium hydroxide is added (pH is around 6). The mixture is extracted with n-hexane/ethyl acetate (1:2, 200 mL). The organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure, and the residue is purified by column chromatography on amine gel eluting with n-hexane/ethyl acetate (30:1) to give 3.1 g (34% yield) of the title compound as brown oil. MS (ESI) m/z: 286 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][S:8]([CH2:11][Br:12])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]([Cl:20])([S:18]Cl)[CH:15]([Cl:17])[Cl:16]>C(N(CC)CC)C>[CH:1]1([N:7]([S:18][C:14]([Cl:20])([Cl:13])[CH:15]([Cl:17])[Cl:16])[S:8]([CH2:11][Br:12])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(CBr)NC1CCCCC1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(CBr)N(SC(Cl)(Cl)C(Cl)Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.1 g (0.051 mol) sample of triethylamine was added dropwise to a cooled (20° C) solution of 11 g (0.043 mol) N-cyclohexyl bromomethanesulfonamide and 10.1 g (0.043 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride. After the addition was completed, the reaction was stirred at ambient temperature for 2 hours and then under reflux for 2 hours. The reaction mixture was then cooled, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the N-cyclohexyl-N-(1,1,2,2-tetrachloroethylthio)-bromomethanesulfonamide product, which after crystallization from dioxane melted at 38°-40° C. The elemental analysis for the product is tabulated in Table I under Compound No. 8.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Orange solid. MS (ISP) 582.0 [(M−H−]; mp 232° C.
Reaction SMILES: [I:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Br[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:4]2[C:5]([CH3:7])=[CH:6][C:2]([I:1])=[N:3]2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Cc1cc(I)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(I)nn1CCc1ccc(F)cc1
Temperature: 95 °C

Procedure:
A solution of 3-iodo-5-methyl-1H-pyrazole (1.45 g, 6.97 mmol) in dimethyl sulfoxide (10 mL) was treated with 1-(2-bromo-ethyl)-4-fluoro-benzene (1.41 g, 6.97 mmol) and potassium carbonate (2.89 g, 20.91 mmol), and the reaction mixture was heated to 95° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1:1) to provide 1-[2-(4-fluoro-phenyl)-ethyl]-3-iodo-5-methyl-1H-pyrazole as a yellow oil. MS (M+H)+=331.
Reaction SMILES: O.C([O:4][C:5]([CH:7]1[CH2:19][CH2:18][C:10]2[N:11]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[S:13][C:9]=2[CH2:8]1)=[O:6])C.[OH-].[Na+]>C(O)(=O)C>[C:15]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:19][CH2:18][C:10]=2[N:11]=1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)C1CCc2nc(NC(C)=O)sc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nc2c(s1)CC(C(=O)O)CC2
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 200 ml of water, 30 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(II), R1=ethyl, R═—NH—CO—CH3] and 52.2 g of 30% sodium hydroxide, keeping the temperature below 30° C.; during the addition the solid gradually solubilized until complete dissolution. After 2 hours, glacial acetic acid was dropwise added to pH=4.5-5.5; after approx. 1 hour the precipitated white solid was filtered, washed with 70 ml of water and dried to obtain 24.8 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid.