Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH:9]1([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: BrC1CCC1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ccc(SC2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
A suspension of 4-fluorobenzenethiol (80 g, 0.625 mol), cyclobutylbromide (45 g, 0.33 mol) and Cs2CO3 (108 g, 0.33 mol) in DMSO (1.5 L) was heated to 70° C. and stirred overnight. TLC (petroleum ether) indicated the reaction was complete. After cooled to room temperature, the reaction mixture was filtered to remove inorganic salts, and the filtrate was partitioned between diethyl ether (1.5 L) and water (1 L). The aqueous layer was extracted with diethyl ether (700 mL×3). The combined organic phases were washed sequentially with water (1 L×2), then brine (1 L), dried over MgSO4 and concentrated in vacuum to give cyclobutyl(4-fluorophenyl)sulfane (64.8 g, 84.8%) as a pale yellow oil. Cyclobutyl(4-fluorophenyl)sulfane (61.8 g, 0.34 mol) was dissolved in CH2Cl2 (2 L) and cooled to −15° C., m-CPBA (150.4 g, 0.742 mol) was added portion wise while keeping the temperature between −15° C. and −10° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 3-4 h. TLC (petroleum ether: ethyl acetate=4:1) indicated the reaction was complete. The reaction mixture was partitioned between CH2Cl2 (2 L) and water (1 L). The organic layer was washed with saturated NaHCO3 solution (1 L) and brine (1 L), dried over MgSO4, filtrated and concentrated in vacuum to give the title compound (59 g, 81.1%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:22])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-thiophenesulfonamide 1.9 g, 10 mmole) in 10 ml of acetone was added aqueous sodium hydroxide (10 ml of 1N. 10 mmole) followed by a solution of 4-chlorophenyl isocyanate (1.54 g, 10 mmole) dissolved in 10 ml of acetone. This mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and acidified with aqueous hydrochloric acid (10 ml of 1N, 10 mmole). The precipitate was filtered and the residue washed with hexanes and water. The solid was dried in a vacuum oven.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]4[CH:33]=[CH:34][C:35]([CH2:37][OH:38])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OI1(=O)C2C=CC=CC=2C(=O)O1.C(OCC)(=O)C>CS(C)=O>[C:1]1([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:23]4[CH:33]=[CH:34][C:35]([CH:37]=[O:38])=[CH:36][C:22]=4[N:21]=3)[CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCN(CC1CCN(Cc2cccc3ccccc23)CC1)c1nc2cc(CO)ccc2n1COCC[Si](C)(C)C
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCN(CC1CCN(Cc2cccc3ccccc23)CC1)c1nc2cc(C=O)ccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-methanol (467 mg, 0.71 mmol) in dimethylsulfoxide (5 ml) was added to a solution of 297 mg of 1-hydroxy-1-oxo-1H-1λ5-benzo[d][1,2]iodoxol-3-one (1.06 mmol) in dimethylsulfoxide (5 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice water (200 ml) and stirred at room temperature for 30 minutes, after which ethyl acetate was added and stirring was continued vigorously for 10 minutes for extraction. After washing with saturated aqueous sodium bicarbonate and then with saturated brine, the mixture was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboaldehyde.
Reaction SMILES: [C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH2:5][CH2:4]1)#[N:2].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[C:6]=2[CH2:5][CH2:4]1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CC1CCc2c(C(=O)O)cccc21
Solvent: ClC(Cl)Cl
Product: N#CC1CCc2c(C(=O)Cl)cccc21
Reaction time: 15 h

Procedure:
To 6.0 g. of 1-cyanoindan-4-carboxylic acid are added 20 ml. of chloroform and 80 ml. of thionyl chloride and the mixture is allowed to stand at room temperature for 15 hours. The excess thionyl chloride and chloroform are distilled off under reduced pressure. To 1-cyanoindan-4-carbonyl chloride, which is thus obtained as the distillation residue, is added 100 ml. of chlorobenzene, followed by stirring under cooling with ice. Then, 6.0 g. of anhydrous aluminum chloride powder is added and the temperature is gradually increased to about 80°C, at which temperature the reaction mixture is stirred for 2.5 hours. After cooling, ice-hydrochloric acid is added, followed by extraction with ether. The extract is washed with water and dried. Then, the solvent is distilled off under reduced pressure and the residue obtained is purified by column chromatography on silica gel (700 g. silica gel; eluant: chloroform). The described procedure gives 4-(p-chlorobenzoyl)indan-1-carbonitrile as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].ClCCCl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(=O)CC2
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a stirred solution of 1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (236 mg, 0.00100 mol) in 1,2-dichloroethane (8 mL, 0.1 mol) at room temperature was added morpholine (0.23 mL, 0.0026 mol) followed by acetic acid (0.15 mL, 0.0026 mol) dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride was added in one portion. The reaction mixture was stirred at 0° C. for 2 h then warmed to room temperature overnight. Workup involved addition of 1N NaOH to bring pH to ˜10. The reaction mixture was extracted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to a orange oil. Purification was accomplished using ISCO chromatography on silica gel using hexane-ethyl acetate and methylene chloride-methanol to give 4-(1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine as a yellow solid (0.24 g, 78%). 1H NMR (400 MHz, CDl3) δ 6.70 (s, 1H, J=7.92 Hz), 6.51 (d, 1H, J=7.88), 3.70 (m, 9H), 3.29 (q, 1H, J=14.41, 8 Hz), 2.74 (q, 1H, J=14.28, 7.48 Hz), 2.55 (m, 6H), 2.31 (m, 1H), 2.10 (m, 2H), 1.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][C:25](=O)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.Cl.[NH:31]1[CH2:34][CH2:33][CH2:32]1>>[F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][CH:25]([N:31]5[CH2:34][CH2:33][CH2:32]5)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Reactant: C1CNC1
Agent: Cl
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(N4CCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and azetidine hydrochloride. 1H NMR (400 MHz, DMSO-d6): δ 10.08 (m, 1H), 8.81 (t, J=4.41 Hz, 1H), 8.06-8.03 (m, 1H), 8.00-7.96 (m, 1H), 7.81-7.77 (m, 1H), 7.62-7.58 (m, 1H), 4.17-4.06 (m, 5H), 4.06-4.04 (m, 1H), 3.29-3.26 (m, 2H), 2.50-2.44 (m, 5H), 2.07-2.03 (m, 3H), 1.90-1.84 (m, 7H), 1.78-1.74 (m, 1H), 1.31-1.27 (m, 2H). m/z: 462.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40](N2C=CN=C2)=[O:41])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])[CH2:35][CH2:34]1)(=[O:32])=[O:31]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CS(=O)(=O)N1CCC(NC(=O)n2ccnc2)CC1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)NC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.5 mg, 0.072 mmol) and imidazole-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (75.4 mg, 0.277 mmol) in CH2Cl2 (4 mL) was stirred at rt for 72 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (15.7 mg, 34.7%). HRMS (ES+) m/z Calcd for C29H34Cl2F2N4O3S+H [(M+H)+]: 627.1770; Found: 627.1770.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)C.Cl>>[Cl:1][C:2]1[C:3]2[N:4]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nnc2c(Cl)cc(C(F)(F)F)cn12
Temperature: 140 °C

Procedure:
A mixture of 3-chloro-2-hydrazinyl-5-(trifluoromethyl)pyridine (600 mg), diethyl oxalate (1.15 mL) and 2M hydrogen chloride ethanol solution (9 mL) was heated with microwave irradiation at 140° C. for 2 hr. The reaction mixture was allowed to be cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (290 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: OC1CCNCC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCC(O)CC5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and 4-piperidinol (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=538.
Reaction SMILES: Cl[CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[K+]>C(P(CCCC)CCCC)CCC>[C:10]([O:15][CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: CO[Si](CCl)(OC)OC
Reactant: C=C(C)C(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Product: C=C(C)C(=O)OC[Si](OC)(OC)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
170.7 g (1 mol) of chloromethyltrimethoxysilane, 6.1 g (0.03 mol) of tri-n-butylphosphine and 0.1 g (0.05 mol % based on silane) of phenothiazine are placed in a reaction vessel at 90° C. and 130.4 g (1.05 mol) of potassium methacrylate are added a little at a time over a period of 1 hour. After stirring at 90° C. for another 2 hours, the reaction is complete. After filtration from the potassium chloride formed, the product is distilled by means of a short-path evaporator, giving 207.1 g (94%) of methacryloxymethyl-trimethoxysilane having a purity of 98.5%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:20][CH3:21])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[F:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([N:20]([CH3:21])[CH2:27][CH2:26][CH2:25][F:24])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: FCCCBr
Reactant: CNC(=O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCF)C(=O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of 1-(4-iodophenyl)-N-methyl-3-isoquinolinecarboxamide (25 mg, 0.06 mmol) in DMF (4 mL) was added 60% NaH (10 mg, 0.25 mmol) in one portion. The mixture was stirred under Ar at room temperature for 30 min. Then, 3-fluoropropyl bromide (20 μl, 0.27 mmol) was added. After stirring at room temperature for overnight, the mixture was quenched by adding H2O (5 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane, 0.035% Et3N), thereby affording a semisolid (11 mg, 40%). 1H NMR (CDCl3) d 2.01-2.22 (m, 2 H, CH2), 3.15, 3.17 (two s, total 3 H, N-methyl), 3.60-3.76 (m, 2 H, N--CH2), 4.22-4.76 (qt, J=77.7, 47.1, 5.7 Hz, 2 H, CH2F), 7.36-7.47 (m, 1 H, aromatic), 7.50-7.81 (m, 4 H, aromatic), 7.82-7.99 (m, 2 H, aromatic), 7.83-8.16 (m, 2 H, aromatic). HRMS calcd. for C20H18FIN2O: 448.0448. Found: 448.0435.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14])([O-])=O>CO.C1COCC1.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14]
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2nc[nH]c(=O)c2c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of 6-nitroquinazolin-4(3H)-one (4.15 g, 21.7 mmol) and 10% Pd/C (0.3 g) in MeOH (25 mL) and THF (50 mL) was stirred under H2 (1 atm) at 40° C. for 18 h. The mixture was diluted with DMF (50 mL), stirred overnight under H2, then placed under an Ar atmosphere. After the addition of Pd/C (0.4 g), the mixture was placed under an H2 atmosphere and warmed to 50° C. and stirred for 4 h. The reaction mixture was filtered through Celite®, washed with warm DMF (75 mL) and the combined filtrates evaporated to yield 6-aminoquinazolin-4(3H)-one (3.10 g, 88% yield) as a yellow solid. MS (ESI) m/e (M+H+) 162.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:23][CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][NH:34][C:33]2=[O:42])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[C:33](=[O:42])[NH:34][CH:35]=2)=[O:40])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: O=C(O)c1c[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c[nH]c(=O)n(-c5ccc(F)cc5)c4=O)cc3OC)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenylamine (LCMS m/z=327 (M+1)) and 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. LCMS m/z=559 (M+1); 1H NMR (CDCl3) δ: 10.94 (s, 1H), 8.69 (s, 1H), 8.45 (d, 1H, J=6 Hz), 8.2 (d, 1H, J=5 Hz), 7.61 (s, 1H), 7.42 (s, 1H), 7.32-7.26 (m, 3H), 7.2 (s, 1H), 6.57 (d, 1H, J=7 Hz), 6.33 (d, 1H, J=7 Hz), 5.30 (s, 1H), 4.05 (s, 6H), 3.76 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[CH3:25][C:26]([CH3:33])([CH2:30][CH2:31]Br)[C:27](Cl)=[O:28].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[C:1]([C:3](=[C:27]1[C:26]([CH3:33])([CH3:25])[CH2:30][CH2:31][O:28]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:12])([F:13])[F:11])#[N:2]
Reactant: CC(C)(CCBr)C(=O)Cl
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CC#N)c1CC(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2OCCC2(C)C)c1CC(C)C
Yield: 121.8 %

Procedure:
A 250-mL round-bottom flask equipped with a mechanical stirrer was charged with 2.0 g (5.7 mmol) 5-(cyanomethyl)-4-(2-methylpropyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example d, above, 95 mL dichloromethane, 0.12 g of benzyltriethylammonium chloride, and 2.4 g (11.3 mmol) of 2,2-dimethyl-4-bromobutyryl chloride. The solution was stirred and 24 mL 50% NaOH was added. Two additional equivalents of acid chloride were added after 15 minutes. No further progress of the reaction was noted so the solution was quenched by pouring into water and extracted with ethyl ether. The organics were washed with water, filtered, and concentrated to give 3.1 g of the desired product as a crude light brown oil. Purification by chromatography using 18% ethyl acetate in hexanes yielded 200 mg of the desired product as an oil, an 8% yield. nD25 1.4840.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:24]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: Nc1cccc(CCN2CCCC2)c1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 71.1 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (180 mg, 0.635 mmol) was reacted with 3-[2-(pyrrolidin-1-yl)ethyl]aniline (120 mg, 0.635 mmol) to afford the desired product (198 mg, 71%) as a yellow solid: ESI MS m/z 438 [C23H24BrN3O+H]+.
Reaction SMILES: C[NH:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[OH:7][CH:4]([CH2:5][OH:6])[CH2:3][NH:2][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8]
Reactant: CNCC(O)CO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(O)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 22.5 g (0.21 mol) 3-methylamino-1,2-propanediol in 200 ml of tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.21 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 32.00 g (0.17 mol, 79% yield) of a colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]Cl)[CH2:35][CH2:34]3)[C:18]=2[CH:17]=1.[OH-].[Na+]>CS(C)=O.O>[ClH:15].[ClH:1].[ClH:15].[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][O:14][C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][NH:3][CH3:2])=[CH:13][CH:12]=4)[CH2:37][CH2:38]3)[C:18]=2[CH:17]=1
Reactant: CNCCCOc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CNCCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 4 h
Yield: 33.3 %

Procedure:
A solution of 4-(3-methylaminopropoxy)phenol hydrochloride (4.7 g) and 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (10.7 g) (as its dihydrochloride) in dimethylsulfoxide (125 ml) was stirred under nitrogen during the addition of sodium hydroxide (3.46 g) in water (5 ml). The reaction was then stirred at 55° for 4 hours and then was diluted with water (500 ml). The oil which separated was extracted into ethyl acetate and hydrogen chloride was bubbled into the solution previously dried over potassium carbonate to precipitate the crude product as its trihydrochloride salt (4.3 g). Crystallization of the salt from acetonitrile-methanol yielded 1.9 g of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy]-N-methylpropanamine trihydrochloride, mp 223°-226°.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.CCO.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.O>[Cl:17][C:18]1[CH:23]=[C:22]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)[CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OB(O)c1cccc(Cl)c1
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: CCO
Solvent: O
Product: Clc1cccc(-c2ccc3[nH]ccc3c2)c1
Yield: 100.5 %

Procedure:
A stirred slurry of 4.23 g (40 mmol) Na2CO3, 1.84 g (9.4 mmol) 5-bromoindole, 1.88 g (10 mmol) 3-chlorophenylboronic acid, and 0.29 g (0.25 mmol) Pd(PPh3)4 in 50 mL 1:1 EtOH-water was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool and was then poured into 400 mL water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, and concentrated to afford 2.15 g crude 5-(3-chlorophenyl)indole as a tan solid.