Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1[CH2:7][CH2:6]OCC1.[NH2:8][C:9]1[CH:13]=[C:12]([CH3:14])[NH:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(#N)CCCC>[ClH:1].[CH3:14][C:12]1[NH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([NH:8][C:9](=[NH:8])[CH2:10][CH2:15][CH2:6][CH3:7])[CH:13]=1
Reactant: C1COCCO1
Reactant: CCOC(=O)c1[nH]c(C)cc1N
Agent: Cl
Solvent: CCCCC#N
Product: CCCCC(=N)Nc1cc(C)[nH]c1C(=O)OCC
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride in dioxane (4M, 308 mL, 1.2 mol) was added dropwise to ethyl 3-amino-5-methyl-1H-pyrrole-2-carboxylate (38.3 g, 228 mmol) (J. Med. Chem. 2008, 51, 68) in valeronitrile (383 mL). The resultant mixture was heated at 50° C. overnight. An additional portion of acid (160 mL, 0.64 mol) was added and the mixture heated at 55° C. overnight. The reaction mixture was cooled to room temperature, filtered and the filtrate evaporated. The residue was slurried in TBME (1200 mL) for 30 minutes then the solid filtered and washed with TMBE and dried. The title compound was obtained as a brown solid (58.9 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:16][CH2:15]3)[O:9]2)=[CH:4][CH:3]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:26]([O:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([CH3:24])=[C:8]([CH:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:18][CH2:19]3)[O:9]2)=[CH:4][CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(O)ccc3c(=O)c2C)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Yield: 96.4 %

Procedure:
A solution of 7-hydroxy-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (250 mg, 0.73 mmol) obtained in Example 34-1, benzyl bromide (260 μL, 3.64 mmol), and potassium carbonate (503 mg, 3.64 mmol) in dimethylformamide (4 mL) was stirred at room temperature for 26 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue. Then, the supernatant was removed by decantation to obtain 305 mg of the title compound (yield: 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=[CH:5]2.S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc2c(C(=O)O)cccc2c1
Reactant: O=S(Cl)Cl
Product: Cc1ccc2c(C(=O)Cl)cccc2c1

Procedure:
6-Methyl-1-naphthoic acid (6 g; J. Amer. Chem. Soc., 1941, 63, 1857) was added to thionyl chloride (50 ml) and the mixture was heated to reflux for 30 minutes. The solution was evaporated to give 6-methyl-1-naphthoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[C:13](=[O:14])([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[O:15][CH3:16]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1Cl
Yield: 115.8 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl) carbonate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[F:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([S:22]([NH:13][C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[C:10]=2[N:9]=[CH:8][CH:7]=[CH:6]3)(=[O:23])=[O:24])=[C:15]([F:14])[CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: COc1cc(N)c2ncccc2c1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2F)c2ncccc2c1
Yield: 54.5 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (60 mg, 0.35 mmol), 2-fluoro-4-chlorobenzenesulfonyl chloride (100 mg, 0.45 mmol) gave the title compound (70 mg, 56%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:19][O:20][CH3:21])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH2:31][O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([CH2:31][O:32][CH3:33])[CH:30]=[C:25]([O:24][CH3:23])[C:26]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:19][O:20][CH3:21])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Reactant: COCc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COCc1cc(OC)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of tert-butyl N-[7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (300 mg) dissolved in 1,2-dimethoxyethane (10 mL) and water (5 mL) was added 2,6-dimethoxy-4-methoxymethylphenylboric acid (323 mg), tetrakis(triphenylphosphine)palladium(0) (146 mg) and barium hydroxide octahydrate (398 mg), and the reaction mixture was heated and stirred for 2 hours at 80° C. under a nitrogen stream. Water was added to the obtained reaction mixture, the reaction mixture was extracted with ethyl acetate, and the organic extract was washed with brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (245 mg) was obtained as a light yellow amorphous solid from the n-hexane:ethyl acetate (1:1) fraction.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:20]([N:23]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:20]([N:23]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)Cc1ccc(C=O)cc1
Reactant: Cn1ccnc1CN(CCCCN)Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)Cc1ccc(CNCCCCN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (349 mg) obtained in Example 117-4 was dissolved in methanol (7.0 ml). Then, the solution was added with the compound (323 mg) obtained in Example 117-1 and trimethyl orthoformate (0.340 ml) and stirred at room temperature for 2 hours, followed by cooling to 0° C. The solution was added with sodium borohydride (75.5 mg) and stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with an aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform) and treated with hydrochloric acid, thereby obtaining hydrochloride (89.8 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[NH:4].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][C:20](OCC)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[CH:5]1([C:3]2[N:4]=[C:20]([CH2:19][CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[O:1][N:2]=2)[CH2:7][CH2:6]1
Reactant: N=C(NO)C1CC1
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1nc(C2CC2)no1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
3.10 g (30.96 mmol) N-hydroxy-cyclopropanecarboxamidine are placed in 10 ml dimethylformamide and molecular sieve. 1.32 g (34.06 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 7.40 g (34.06 mmol) ethyl 3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: C(N(CC)CC)C.ClC(O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH3:19][O:20][C:21](=[O:43])[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:43])[CH2:22][N:23]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]2[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=2)=[CH:28][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CNc1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccccc1)c1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1
Temperature: 50 °C

Procedure:
1.2 ml of triethylamine and 3 ml of benzyl chloroformate (50% in toluene) were added to a solution of 675 mg of N-[p-[2-(p-cyanobenzamido)ethyl]phenyl]glycine methyl ester in 15 ml of chloroform. The reaction mixture was maintained at 50° C. overnight. After working up and chromatography on silica gel with ether/petroleum ether 2:1, 500 mg of crystalline N-benzyl-N-[p-[2-(p-cyanobenzamido)ethyl]phenyl]glycine methyl ester, melting point 123°-124° C., were isolated.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][Cl:14]
Reactant: OCc1c(F)ccc(F)c1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c(CCl)c1F

Procedure:
To a solution of 2,3,6-trifluorobenzyl alcohol (41 g) in dichloromethane (100 ml) is added dropwise a solution of thionyl chloride (50 ml) in dichloromethane (80 ml) under ice cooling with stirring, and the mixture is stirred at room temperature overnight. To the mixture is added triethylamine (10 ml), and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl chloride (28.6 g), as colorless oil, b.p. 63;L ° C. (13 mmHg).
Reaction SMILES: [C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([OH:3])=[O:2].[CH3:12]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([O:3][CH3:12])=[O:2]
Reactant: COC(C)(C)OC
Reactant: O=C(O)C1Cc2cscc2C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2cscc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5-(carboxy)-2,4,5,6-tetrahydrocyclopenta[c]thiophene (3.95 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.5 mL). Stir at room temperature for 1 day. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 5-(carbomethoxy)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH:16]=[O:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1.C[Mg+].[Br-].[CH2:23](OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH:16]([OH:17])[CH3:23])[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: CCOCC
Reactant: Cn1c(-c2cnccc2C=O)nc2ccc(Cl)cc21
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1ccncc1-c1nc2ccc(Cl)cc2n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(6-chloro-1-methyl-1H-benzoimidazol-2-yl)-pyridine-4-carbaldehyde (75 mg, 0.276 mmol) in THF (4 mL) at −78° C. was added 3 M MeMgBr in diethyl ether (0.138 mL, 0.414 mmol) and the mixture was stirred at −78° C. for 0.5 hr. The reaction was quenched with water (0.5 mL) and the mixture was warmed to room temperature. It was concentrated in vacuo. The crude was taken up in MeOH (5 mL) and purified on RP-HPLC using RP18 column and gradient 0.1% aqueous NH4OH in acetonitrile, followed with a second purification by silica gel flash chromatography DCM-MeOH (9:1) to afford 1-[3-(6-chloro-1-methyl-1H-benzoimidazol-2-yl)-pyridin-4-yl]-ethanol. 1H NMR (400 MHz, MeOD) δ ppm 1.34 (d, J=6.6 Hz, 3H), 3.73 (s, 3H), 4.81-4.86 (m, 1H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.86 (d, J=5.3 Hz, 1H), 8.63 (s, 1H), 8.79 (d, J=5.3 Hz, 1H); HRMS: (ESI) ink 288.0894 [(M+H)+ Calcd for C15H14ClN3O 288.0904].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)c(O)c([N+](=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccccc2)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 30.00 g. of 3,5-dinitro-2-biphenylol, 15 ml. of dimethylformamide, and 113 ml. of phosphorous oxychloride is heated on a steam bath for 2.25 hours. The mixture is then cooled to room temperature and poured slowly into approximately 600 g. of crushed ice. The precipitate that forms is isolated by filtration and washed with water. The solid is dissolved in chloroform and the chloroform solution is washed several times with 10% Na2CO3 and once with water. The chloroform solution is dried over MgSO4 and concentrated. The product is recrystallized from benzenehexane to give 19.07 g. of material (melting at 119°-20° ).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)CC(=O)c2c(-c3ccccc3)cn(-c3ccccn3)c2C1
Yield: 61.2 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (100 mg, 0.31 mmol), phenylboronic acid (153 mg, 1.25 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol) and Na2CO3 (197 mg, 1.9 mmol) in ethylene glycol dimethyl ether (10 mL) and water (4 mL) was heated at reflux for 8 h. The solvent was evaporated and the residue partitioned between DCM and aqueous K2CO3 (10% (w/v)). The organic layer was separated and the aqueous phase re-extracted with DCM (2×). The combined organic layers were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with isohexane: EtOAc (9:1), to afford the title compound (60 mg, 61%) as a yellow solid. mp 160-162° C. Found: C, 78.23; H, 6.26; N, 8.57%. Calc. C21H20N2O.0.35(H2O): C, 78.16; H, 6.47; N, 8.68%. 1H NMR (360 MHz, CDCl3) δ 1.13 (6H,s), 2.45 (2H,s), 2.99 (2H,s), 7.17 (1H,s), 7.24-7.38 (5H,m), 7.67 (2H,d, J=7.2 Hz), 7.86 (1H,d of t, J=7.9 and 1.9 Hz), 8.56-8.61 (1H,m). MS (ES+) 317 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:19]#[N:20]
Reactant: [C-]#N
Reactant: COc1c(CBr)cccc1Oc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccc(Cl)cc1
Yield: 94.8 %

Procedure:
A solution of 4-chlorophenyl 2-methoxy-3-bromomethylphenyl ether (14.9 g) in dimethyl sulfoxide (40 ml) and powdered sodium cyanide (2.3 g) were treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(4-chlorophenoxy)phenyl]acetonitrile (11.8 g).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:30][CH2:29][C:28]4[CH:31]=[CH:32][C:25]([CH3:24])=[CH:26][CH:27]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1ccc(CN)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1ccc(CNC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 27.4 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-methylbenzylamine (41.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylphenylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (18.1 mg).
Reaction SMILES: [CH:1]1[C:6]([NH:7][NH2:8])=[CH:5][CH:4]=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:2]=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=O)[CH:20]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:18]2>C(O)C>[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]3[N:7]([C:6]4[CH:1]=[CH:2][C:3]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][CH:5]=4)[N:8]=[C:26]([C:27]([F:28])([F:29])[F:30])[C:20]=3[CH2:19][CH2:18][C:17]=2[CH:16]=1
Reactant: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)CCc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Reaction time: 14.8 h
Yield: 63.9 %

Procedure:
4-Sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0 mmol) was added to a stirred solution of the diketone from Step 1 (1.86 g, 7.3 mmol) in ethanol (10 mL). The reaction was heated to reflux and stirred for 14.8 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, washed with water and with brine, dried over MgSO4 and reconcentrated in vacuo to give the pyrazole as a brown solid (1.90 g, 64%): mp 215°-218° C. 1H NMR (acetone-d6) 300 MHz 8.10 (d, 2H), 7.80 (d, 2H), 7.24 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 2H), 6.88 (d,1H), 3.02 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H). 19F NMR (acetone-d6) 282 MHz -62.46 (s). High resolution mass spectrum Calc'd. for C19H17F3 O2S: 408.0994. Found: 408.0989.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:12][CH2:11]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:14][CH2:15]1
Reactant: FC(F)(F)c1nnc2ccc(C3=CCNCC3)nn12
Reactant: O=Cc1cccc(F)c1
Product: Fc1cccc(CN2CC=C(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 46 %

Procedure:
A mixture of 3-fluorobenzaldehyde and 6-(3,6-dihydro-2H-pyridin-4-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[1-(3-fluorobenzyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 46% yield.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([CH2:14][O:15][N:16]=[C:17]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][CH2:29][S:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH3:18])=[CH:11][CH:10]=1.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:32][C:20]1[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][CH2:29][S:28][CH2:27]2)[CH2:23][C:24](=[O:25])[C:19]=1[C:17](=[N:16][O:15][CH2:14][C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:18])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C2CCCSC2)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
In this example, 0.52 g (5.1 mmol) of triethylamine was admixed to a solution containing 1.46 g (3.7 mmol) of 2-[1-[(5-chlorothien-2-yl)methoxyimino]ethyl]-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one in 30 ml of methylene chloride at room temperature (about 20°-25° C.) followed by the dropwise addition of 0.35 g (4.4 mmol) of acetyl chloride. The mixture was stirred at room temperature overnight (about 14 hr) and then washed with saturated aqueous sodium bicarbonate solution, followed by saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by column chromatography on silica gel to afford 1.0 g of the title compound as a pale yellow oil; IR (neat) 1775 cm-1 ; 1H NMR spectrum (90 MHz CDCl3) ε 1.00-2.60 (m, 14H), 1.93 (s, 3H), 2.00 (s, 3H), 5.07 (s, 2H) 6.73 (s, 2H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 77 (200 mg, 0.47 mmol) in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue is crystallized from dichloromethane and Et2O to give 130 mg of the product 78. 1H NMR (DMSO-d6) δ 9.80-8.30 (m, 3 H), 7.60-7.30 (m, 5 H), 7.20-7.00 (m, 6 H), 7.00-6.85 (m, 4 H), 5.49 (s, 2 H), 4.59 (d, 2 H); MS: m/z 328 (M++1).