Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]([NH2:15])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=2[N:21]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:9]1([CH2:8][CH:7]([NH:15][C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=3[N:21]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: N[C@@H](CC1CCCCC1)c1ccccn1
Reactant: Cc1ccc2oc(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2oc(NC(CC3CCCCC3)c3ccccn3)nc2c1

Procedure:
To a solution of 132.8 g (0.65 moles) 1-(+)-(S)-(2-pyridyl)-2-cyclohexylethylamine in 550 mL methylene chloride was added 109 g (0.65 moles) 2-chloro-5-methylbenzoxazole followed by 168 g (1.3 moles) diisopropylethylamine. The reaction mixture was heated to reflux for 5-40 hours, cooled and concentrated under reduced pressure. The mixture was dissolved in 2 L of ethanol. Addition of 2-3 L of water gave crude [(2-cyclohexyl-1-(2-pyridyl)ethylamino]-5-methylbenzoxazole. Recrystallization from ethanol/water gave 190 g (83%) as a hydrate; mp 80°-86° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH:9]=[N:8][CH:7]=[C:4]2[S:5][CH:6]=1.C([Li])CCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1.CCCCCC.[Cl-].[NH4+]>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[S:5][C:4]2=[CH:7][N:8]=[CH:9][N:3]2[C:2]=1[CH3:1])[CH2:25][CH2:26][CH3:27]
Reactant: Cc1csc2cncn12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sc2cncn2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-methylimidazo[5,1-b]thiazole (513.2 mg) in anhydrous THF (8 ml) was cooled to −78° C. under the atmosphere of argon, and a 1.6 N solution of n-butyl lithium in n-hexane (2.47 ml) was added dropwise. After the reaction was stirred at the same temperature for 1 hour, 1.06 ml of tri-n-butylstannyl chloride was added, and the mixture was further stirred at the same temperature for 1 hour and then for 30 minutes during which the mixture was allowed to be warmed to room temperature. The reaction mixture was diluted with 50 ml of a semi-saturated aqueous ammonium chloride solution, and extracted with 50 ml of diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2-(tri-n-butylstannyl)-3-methylimidazo[5,1-b]thiazole in a yield of 1.44 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1.Cl[C:14]1[C:15](=[O:28])[NH:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][N:10]2[C:14]2[C:15](=[O:28])[NH:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NCCC2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccc(OC)cc43)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 7-methoxy-1,2,3,4-tetrahydroquinoline (1.34 g, 8.21 mmol) in NMP (5 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.1 g, 4.61 mmol). The resulting solution was stirred for 1 h at 150° C. in an oil bath and then diluted with water (300 ml). The solids were collected by filtration to afford methyl 3-(7-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a red solid (844 mg, 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]CC1C=CC=CC=1>C(O)C.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]
Reactant: COc1ccccc1CCC=Cc1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CCCCc1ccccc1O
Yield: 60 %

Procedure:
Following a procedure similar to that described in the latter part of Preparation 3, the whole of the benzyl 2-[4-(2-methoxyphenyl)-1-butenyl]phenyl ether prepared as described above was dissolved in 50 ml of ethanol and hydrogenated at 50° C. in an atmosphere of hydrogen at atmospheric pressure and in the presence of 100 mg of 5% w/w palladium-on-charcoal for 6 hours. The crude product thus obtained was purified by column chromatography through silica gel, using 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.44 g (yield 60%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][CH3:22])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:31]([O:34][CH:35](Br)[CH3:36])(=[O:33])[CH3:32]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:24])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][CH3:22])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OC(C)Br
Product: COC/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Yield: 43 %

Procedure:
Esterification of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-3-methoxy-1-propenyl]-3-cephem-4-carboxylic acid (300 mg, 0.66 mmole) with 1-bromoethyl acetate in a similar manner to that described in Example 10 gave the title compound (154 mg, 43%). Mp. 102°-105° C. (dec.). Estimated purity 95% (by HPLC, 1:1 CH3CN-pH 7 phosphate buffer).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:31].O>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:31])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(O)O
Reactant: CCCCCc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g of 4-pentyl-4'-cyanobiphenyl in 150 ml of toluene was treated dropwise at 0° C. with 65 ml of a 1M solution of diisobutylaluminium hydride in toluene while gassing with nitrogen. The reaction mixture was stirred at room temperature overnight, then treated dropwise with 340 ml of 1N sulphuric acid, stirred at room temperature for 1 hour, poured into 1,000 ml of water and then extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of saturated sodium chloride solution each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) gave 10.1 g of 4-pentyl-4'-biphenylcarboxaldehyde.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C=O)C.[Br:15][C:16]1[C:17](=[O:42])[N:18]([CH2:33][C:34]2[CH:39]=[N:38][C:37]([CH2:40]O)=[CH:36][N:35]=2)[C:19]([CH3:32])=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]>ClCCl>[Br:15][C:16]1[C:17](=[O:42])[N:18]([CH2:33][C:34]2[CH:39]=[N:38][C:37]([CH2:40][Cl:3])=[CH:36][N:35]=2)[C:19]([CH3:32])=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CCl)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
Cyanurylchloride (0.42 g, 0.0023 mol) was added to DMF (0.52 mL) and stirred at room temperature for 15 min. Then added dichloromethane (15 mL) followed by the addition of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one 1.0 g, 0.0022 mol) and reaction mixture was stirred at room temperature under argon atmosphere. After 1 h, an additional 1.0 mL of DMF was added and the reaction was allowed to proceed for another hour, when a clear solution was obtained. The solution was diluted with dichloromethane (20 mL) and washed with water, dried (Na2SO4), and concentrated to dryness under reduced pressure. The residue was triturated with EtOAc, filtered, washed with EtOAc and dried to afford 0.79 g (77%) of the title compound as a pale yellow powder: 1H NMR (CD3OD/400 MHz) δ 8.66 (s, 2H), 7.73 (m, 1H), 7.05 (m, 2H), 6.56 (s, 1H), 5.52 (s, 2H), 5.33 (s, 2H), 4.74 (s, 2H), and 2.57 (s, 3H); ES-HRMS m/z 470.0051 (M+H C19H16N3O2BrClF2 requires 470.0077).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C.Br[C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 110 °C

Procedure:
4-Bromophenol (8.7 g, 50 mmol), Cs2CO3 (16 g, 50 mmol), CuOTf toluene complex (2:1) (0.625 mmol, 5 mol % Cu, 150 mg), ethyl acetate (0.25 ml, 2.5 mmol) were added to a solution of 2-bromo-5-methoxybenzoic acid (11.6 g, 50 mmol) in toluene (40 mL) in a sealed tube. The reaction mixture was purged with N2, and was heated to 110° C. until the aryl halide was consumed as determined by LC-MS (48 h). After cooling to rt, the mixture was filtered through a Celite plug. The Celite plug was washed with EtOAc. The mixture was acidified by 1N HCl, and extracted w/EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. This residue was purified via column chromatography on silica gel (gradient elution with 0-10% MeOH/DCM) to afford 2-(4-bromophenoxy)-5-methoxybenzoic acid. MS m/z=324.9 [M+H]+. Calc'd for C14H11BrO4: 323.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(Cl)cccc1Cl
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
40% Methanolic Triton B (0.23 mL, 0.49 mM) was added to a solution of the 9-[(2,6-dichlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (146 mg, 0.38 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (119 mg, 0.76 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 83 mg (48%) of the {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a tan solid. 1H NMR (DMSO-d6) δ7.5-7.0 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.8 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1). MS (ES) m/e 457, 459.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][C:18]=2[O:28][CH3:29])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:29][O:28][C:18]1[CH:19]=[C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:21]=[CH:22][C:17]=1[S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:16])=[O:15]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 4-(4-Acryloylamino-2-methoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 4.7 mmol) in DCM (20 ml) was added trifluoroacetic acid (5 ml) in one portion. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum to afford the title compound (1.3 g, 93% yield) as an orange gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)(O)[O-].[Na+].CO.ClCCl.[I:19](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[I:19])[NH2:5]
Reactant: Nc1cccc(F)c1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(I)c(F)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1 methanol-dichloromethane (20 mL) at 0° C. was added a solution of benzyl trimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) over 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour. The mixture was quenched by addition of water and the organic layer was extracted with water (2×). Drying (Na2SO4) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (2.20 g, 89%) as a pink solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.41 (dd, J=8.3, 7.3 Hz, 1H), 6.42 (dd, J=9.9, 2.5 Hz, 1H), 6.27 (dd, J=8.5, 2.5 Hz, 1H), 3.81 (s, 2H); MS+ESI m/z (rel abundance) 238 (100, M+H).
Reaction SMILES: [C:1]([C:6]([OH:8])=[O:7])#[C:2][C:3](O)=[O:4].[CH2:9]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[S:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO.O1CCCC1>[CH2:24]([N:23]1[C:3](=[O:4])[C:2](=[CH:1][C:6]([OH:8])=[O:7])[S:22][C:21]1=[N:20][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCCCCCCNC(=S)NCCCCCCCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
Acetylenedicarboxylic acid (4.8 g, 40 mmoles) is added to a warm solution of N,N'-diundecylthiourea (15.0 g, 39 mmoles) in methanol (200 mls) and tetrahydrofuran (100 mls). The mixture is stirred for 16 hours at ambient temperature, then concentrated under reduced pressure and cooled. The precipitate is filtered off, rinsed with cold methanol and dried. Recrystallization from methanol afforded the product (15.3 g), mp 67°-68° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=NC(N2CCC(N3CCCC3)CC2)=CC=1.BrC1C=C2C(=CC=1)[C:40](=[O:44])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:44][CH3:40]
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(N2CCC(N3CCCC3)CC2)nc1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (24), 0.53 g (86% yield) of brown solid is obtained from 0.335 g (1.24 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline 1,3(2H,4H)-dione, and 0.30 g (1.24 mmol) of 6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyridin-3-yl]amine; mp: 214-215° C.; MS (ESI) m/z 498.1 (M+H)+1
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]([CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[O:6]([CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCN(CCOc1ccccc1)C(=O)Cl
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCCN(CCOc1ccccc1)C(=O)n1ccnc1
Temperature: 25 °C

Procedure:
To 75 ml. dry tetrahydrofuran were added 6.8 g. imidazole and 12.075 g. N-2-phenoxyethyl-N-propylcarbamoyl chloride. The reactants were boiled together under reflux for 24 hours, cooled to room temperature and filtered to remove imidazole hydrochloride. The solvent was then removed by evaporation from the steam bath, the last traces being removed under vacuum. An oily residue remained which was extracted into ether, washed with water, dried over anhydrous sodium sulphate, the solvent removed and the residual oil distilled under vacuum, to give 1-(N-2-phenoxyethyl-N-propylcarbamoyl) imidazole, boiling point 209° C./1.0 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([NH:11][C:12](=[NH:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1.Cl[CH2:26][CH:27]=O.C(=O)(O)[O-].[Na+].CC(O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([N:11]2[CH:27]=[CH:26][N:21]=[C:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1
Reactant: O=CCCl
Reactant: COc1cccc(C(=N)Nc2c(C(C)C)cc(Br)cc2C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(-c2nccn2-c2c(C(C)C)cc(Br)cc2C(C)C)c1
Yield: 78.6 %

Procedure:
A 500 ml round bottom flask was charged with N-(4-bromo-2,6-diisopropylphenyl)-3-methoxybenzimidamide (19.73 g, 50.7 mmol), 2-chloroacetaldehyde (12.83 ml, 101 mmol), sodium bicarbonate (12.77 g, 152 mmole) and 2-Propanol (300 ml). The reaction was allowed to reflux for 16 hours. The reaction mixture was diluted with deionized water and extracted with ethyl acetate, the organic portion was combined and subjected to a column chromatography (SiO2 gel; 20% THF in heptane) to yield the desired product (16.47 g, 79%).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.[H][H].[ClH:25]>CO.[Rh]>[ClH:25].[CH:17]1([C:11]2([C:14]([OH:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: O=C(O)C1(C2CCCCC2)CCNCC1

Procedure:
4-Phenyl-1,4-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) ester (8-2) (202 g, 0.662 mol) was dissolved in 1700 mL of 10% HCl in methanol and rhodium on alumina (25 g) was added. The mixture was placed on a high pressure hydrogenator using 1500 psi of hydrogen at 100° C. for 17 h. The resulting mixture was filtered through Celite using methanol to rinse and concentrated. The resulting solid was triturated with diethyl ether and filtered to afford title compound 8-3 as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11].ClC1C=C[C:20]([S:23]([CH2:26]C#N)(=[O:25])=[O:24])=CC=1>>[Cl:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([S:10]([C:13](=[C:26]([S:10]([CH3:3])(=[O:12])=[O:11])[S:23]([CH3:20])(=[O:25])=[O:24])[C:14]#[N:15])(=[O:12])=[O:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(S(=O)(=O)CC#N)c(C)cc1Cl
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1cc(S(=O)(=O)C(C#N)=C(S(C)(=O)=O)S(C)(=O)=O)c(C)cc1Cl

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(2,5-dimethyl-4-chlorobenzenesulfonyl) acetonitrile was utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][C:10]#[N:11])=[N:7][CH:6]=[N:5]1.Br[CH2:13][CH2:14]Br>CS(C)=O>[CH3:3][N:4]1[C:8]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)=[N:7][CH:6]=[N:5]1
Reactant: Cn1ncnc1CC#N
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ncnc1C1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.06 g, 44.2 mmol) was washed twice with petroleum ether under nitrogen. Then dimethylsulfoxide (10 mL) was added at room temperature. A solution of 2-(1-methyl-1H-1,2,4-triazol-5-yl)acetonitrile (0.9 g, 7.36 mmol) and 1,2-dibromoethane (4.147 g, 22.1 mmol) in dimethylsulfoxide (20 mL) was added dropwise to the sodium hydride suspension over a period of 20 min. The reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 5-15% ethyl acetate in petroleum ether) to afford 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbonitrile (0.7 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]([CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[C:12]2=[S:26])=[CH:5][CH:4]=1)#[N:2].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[NH:40]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]([CH:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17]4)[C:12]3=[S:26])=[CH:7][CH:8]=2)=[N:2][N:42]=[N:41]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(CCn2ccn(C3CCc4ccccc4C3)c2=S)cc1
Solvent: Cc1ccccc1C
Product: S=c1n(CCc2ccc(-c3nnn[nH]3)cc2)ccn1C1CCc2ccccc2C1
Temperature: 120 °C
Yield: 100 %

Procedure:
A mixture 3-[2-(4-cyanophenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 mmol), prepared as in Example 15, and tributyltin azide (1.39 g, 4.2 mmol) in 3 mL of xylene was heated at 120° C. under nitrogen for approximately 16 hours. The mixture was purified by chromatography on silica gel eluting with methylene chloride/methanol and the purified product was recrystallized from ethyl acetate/methanol to give 3-[2-(4 (1H)-tetrazol-5-ylphenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 mmol), m.p. 218°-220° C.
Reaction SMILES: C([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=[O:23])C1C=CC=CC=1>CN(C)C=O.CCOCC.[Pd]>[OH:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[NH:18][CH:17]=[C:16]([C:21]#[N:22])[C:15]3=[O:23]
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1O
Yield: 154.3 %

Procedure:
A solution of 3.6 g (7.3 mmol) of 8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 0.7 g of 10% Pd/C in 240 mL of dimethyl formamide is hydrogenated in a Parr shaker at 40 psi for 24 hours. The catalyst is filtered through a pad of Celite, washed with dimethyl formamide and the solvent is reduced in vacuo to yield a solid. The crude product is suspended in ether, collected by filtration, further washed with ether and dried to yield 3.0 g of 8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.