Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:22]1([CH:32]=O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:7]2[N:6]([CH3:19])[C:5]3[CH:20]=[CH:21][C:2]([CH2:32][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: O=Cc1cccc2ccccc12
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(Cc3cccc4ccccc34)ccc21

Procedure:
5-Amino-2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazole (35.5 g, 129.0 mmol) (obtainable according to Example 1, Step c) and 18.2 ml of naphthaline-1-carbaldehyde are reacted by reductive amination according to Example 5, Step a.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:12]
Reactant: CN1CCN(CCCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(CCCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate (0.059 g) in methanol (1.0 mL) and chloroform (1.0 mL), 10% palladium-carbon (0.023 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 20 minutes. To the reaction mixture, 10% palladium-carbon (0.058 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. Methanol (2.0 mL), chloroform (2.0 mL), and 10% palladium-carbon (0.055 g) were added to the reaction mixture, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 50 minutes. To the reaction mixture, 10% palladium-carbon (0.025 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 4 hours and 30 minutes. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.026 g of tert-butyl 2-(2-hydroxy-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1([NH:23][CH:24]1[N:29]([CH:30]([C:37]([F:40])([F:39])[F:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][C:27]([CH:53]([C:60]([F:63])([F:62])[F:61])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH:26]=[N:25]1)[CH2:21][CH3:22])=[O:6])[CH3:3].O.C(OCC)(=O)C>C(O)(=O)C>[CH2:2]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1([NH:23][CH:24]1[N:29]([CH:30]([C:37]([F:40])([F:38])[F:39])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][C:27]([CH:53]([C:60]([F:61])([F:62])[F:63])[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)([O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH:26]=[N:25]1)[CH2:21][CH3:22])=[O:6])[CH3:3]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2CCC1(CC)NC1N=CC(OCCCCC(=O)OC(C)(C)C)(C(c2ccccc2)C(F)(F)F)CN1C(c1ccccc1)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2CCC1(CC)NC1N=CC(OCCCCC(=O)O)(C(c2ccccc2)C(F)(F)F)CN1C(c1ccccc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
5N HCl (0.5 ml) was added to a solution of the compound obtained in Example 6 (250 mg) in acetic acid (1.5 ml) and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate was added to the mixture and the organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution three times and then with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the titled compound (183 mg). MS (m/z): 737 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:13]([C:15](=[O:25])[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:37].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:13]([C:15](=[O:25])[C:16]([N:18]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH3:37])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)C(=O)NC2CCCCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-c2noc(C)n2)c(C(=O)C(=O)N(C)C2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-[5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]N-cyclohexyl-2-oxoacetamide (reference example 14-15) (860 mg) and N,N-dimethylformamide (6 mL) was added sodium hydride (60%, 92 mg). After stirring at room temperature for 20 minutes, iodomethane (0.48 mL) was added to the mixture. After stirring at room temperature for 8 hours, the mixture was poured into a mixture of 2 mol/L hydrochloric acid and ice-water. Ethyl acetate was added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-50% ethyl acetate/hexane, gradient elution) to give the title compound (605 mg).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[H-].[Na+].[C:10]([C:12](=[C:17](SC)[S:18][CH3:19])[C:13](OC)=[O:14])#[N:11].O>CN(C)C=O>[CH3:2][CH:3]([C:4]1[NH:6][C:17]([S:18][CH3:19])=[C:12]([C:10]#[N:11])[C:13](=[O:14])[N:5]=1)[CH3:7]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1[nH]c(C(C)C)nc(=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 2-methylpropanimidamide hydrochloride (7.0 g, described in Example 7) in dimethylformamide (15 mL) was added dropwise to a suspension of sodium hydride (3.0 g, 50% in mineral oil, prewashed with hexane) in dimethylformamide (15 mL) and the whole mixture was left at 25° C. for 1 hr. 2-Cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (6.5 g) in dimethylformamide (15 mL) was then added dropwise, and the reaction mixture was stirred for an additional 4 hr at 25° C. Water (25 mL) was then added, and acidification with concentrated hydrochloric acid (10 mL) precipitated the product. The precipitate was collected and air dried to give the title compound (6.0 g): mp>260° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([OH:39])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([O:39][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
A mixture of 4-(4-chloromethylphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (2.04 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (3.00 g, yield 96%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 101-102° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(C(C)C)CC)(C)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:34]1([S:40]([NH:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 19 h
Yield: 75.1 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4, 5-b]indole-3(2H)-carboxylate (0.0403 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N2. Diisopropylethylamine (0.043 mL, 0.0316 g, 0.245 mmol, 2.00 equiv.) and benzenesulfonyl chloride (0.023 mL, 0.0324 g, 0.183 mmol, 1.50 equiv.) were added, then the reaction mixture was stirred for 19 h. Citric acid (10%) was added and the reaction mixture was stirred for 15 min. The reaction mixture was extracted with EtOAc, and the organic layer was washed sequentially with 10% citric acid, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (0.0649 g) was chromatographed (SiO2 25 g, eluted with 2:1 hexane:EtOAc) to give tert-butyl 6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0430 g) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.46, 1.52, 2.95-3.02, 3.22-3.30, 3.63-3.75, 4.24-4.31, 4.63, 4.79, 7.09-7.26, 7.45-7.51, 7.48, 7.58, 7.79; MS (ESI+) for C25H31N3O4S m/z 470.0 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[CH3:11][NH:12]N.Cl.[NH3:15]>O.CO>[NH2:15][C:3]1[N:12]([CH3:11])[N:6]=[CH:5][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: CNN
Reactant: N
Agent: Cl
Solvent: CO
Solvent: O
Product: Cn1ncc(N=O)c1N
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight, 1.01 g (21 mmol) of methylhydrazine with a purity of 97% by weight, 6 ml of methanol and 3.0 ml (36 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for 4 hours. After completion of the reaction, 5 ml of water was added to the mixture to cool the mixture up to 10° C., and 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 1.2 ml of cold water and 1.2 ml of cold methanol, and dried under reduced pressure to obtain 1.91 g of 5-amino-1-methyl-4-nitrosopyrazole (Isolation yield: 74.8%) as dark purple solid with a purity of 98.8% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [C:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[OH-].[NH4+]>C(OC(=O)C)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:29](=[O:31])[O:30][C:9]3=[N:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:4]3[C:1]=2[CH3:2])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(C)c(-c3ccc(Cl)cc3)c(=O)oc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate, (6.0 g, 0.0213 mol), 4-chlorophenyl acetic acid (3.64 g, 0.0213 mol) and triethylamine (3.0 g, 1.5 eq) are refluxed in 50 mL of acetic anhydride for three and one-half hours and then stirred at room temperature overnight. The reaction mixture is poured into 100 mL of ice cold water and the pH is adjusted to 8 with an ammonium hydroxide solution. The crystalline solid is filtered, washed with water, dried and dissolved in 100 mL of methylene chloride. The solution is dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the desired product (8.8 g, 99%), which is crystallized from ethyl acetate to give the pure product having a melting point 179°-181° C.
Reaction SMILES: [CH2:1]([P:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[Br-:26].[CH2:18]([P+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Product: CCCCCCCC[P+](CCCC)(CCCCCCCC)CCCCCCCC
Product: [Br-]
Reaction time: 1 h

Procedure:
Tri-n-octyl-n-butylphosphonium bromide is prepared by slowing dripping tri-(n-octyl)phosphine (740 grams) into refluxing 1-bromobutane (500 grams) in a nitrogen atmosphere. Reflux is continued one hour after final addition then the solution is cooled with stirring for about 18 hours, followed by vacuum removal of excess 1-bromobutane at 60° C. This product, 1210 grams from two successive preparations, is added to 880 grams of sodium 3,5-dicarbomethoxybenzenesulfonate in 2500 ml. of water and stirred for at least one hour at 85° C. then the heat is removed and the oil-in-water mixture is stirred for about 18 hours. The oil layer is separated from the water, rinsed with 1000 ml. of water and dried at about 80° C. at a pressure less than 2 torr for 18 hours. This product, an oil, is tri-n-octyl-n-butylphosphonium 3,5-dicarbomethoxybenzenesulfonate with 4.2% phosphorus and 4.7% sulfur by analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]#[N:13].[H-].[Na+].[H][H].[CH3:18]I>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[CH:7]=[C:6]2[C:12]#[N:13]
Reactant: [H][H]
Reactant: COc1ccc2[nH]cc(C#N)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C#N)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81307 %

Procedure:
A solution of 5-methoxy-1H-indole-3-carbonitrile (550 mg) in dry tetrahydrofuran (50 ml) was treated with NaH (152 mg of a 55% dispersion in oil). The solution was stirred under a dry nitrogen atmosphere until the evolution of hydrogen ceased. Methyl iodide (0.45 mg) was then added and the reaction allowed to stir at room temperature for one hour. The solvent was then removed under reduced pressure and the residue taken up in dichloromethane (50 ml), washed with water (2×25 ml), dried (MgSO4), filtered, and evaporated to dryness under reduced pressure. The residue was recrystallised from absolute ethanol to afford the title compound as white prisms (480 mg); m.p. 105°-108° C.; δH (360 MHz, CDCl3) 3.84 (3H, s, OCH3), 3.87 (3H, s, NCH3), 6.98 (1H, dd, J=7.5, 1.0 Hz, H-6), 7.12 (1H, d, J=1.0 Hz, H-4), 7.31 (1H, d, J=7.5 Hz, H-7), 7.61 (1H, s, H-2); m/z 186 (M+ 100), 171 (90), 143 (80), 116 (20), 101 (15), 89 (15).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[ClH:11].[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]=3[OH:10])=[N:17][CH:16]=2)(=[O:19])=[O:20])[CH2:22][CH2:23]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccccc34)nc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
Sodium hydride (46 mg, 60% dispersion in paraffin) was washed with hexane and dried in vacuo. N,N-Dimethylformamide (3 mL), oxindole (72 mg, 0.54 mmol) and 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (100 mg, 0.36 mmol; described in: Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203) were added to the sodium hydride and the reaction mixture was stirred at room temperature for 5 min. The reaction mixture was then heated for 10 min at 130° C. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted twice with methylene chloride and the combined organic layers were dried (Na2SO4), filtrated and the solvent was removed in vacuo. The residue was purified on a silica gel column using a gradient ethyl acetate/methanol, (40:1 to 1:1), as the eluent. The product was dissolved in a mixture of methylene chloride (5 mL) and methanol (5 mL). Hydrogen chloride (3 mL, 1 M in diethyl ether) was added and stirring was continued for 10 min. The precipitate was washed with diethyl ether and dried in vacuo to give 50 mg (37% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 7.95 (m, 1 H), 7.45 (d, J=2 Hz, 1 H), 7.43 (dd, J=9, 2 Hz, 1 H), 7.23 (m, 1 H), 7.14 (d, J=9 Hz, 1 H), 7.00 (m, 2 H), 3.88 (d, J=14 Hz, 2 H), 3.60 (d, J=12 Hz, 2 H), 3.23 (m, 2 H), 2.94 (m, 2 H), 2.90 (s, 3 H); MS (ES) m/z 373 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]([CH3:11])[C:9]#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([CH3:11])[C:9]#[N:10])[CH:6]=1
Reactant: Fc1cn[nH]c1
Reactant: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C#N)n1cc(F)cn1
Temperature: 100 °C
Yield: 82 %

Procedure:
4-Fluoro-1H-pyrazole (300 mg, 3.49 mmol), 2-chloropropanenitrile (374 mg, 4.18 mmol), cesium carbonate (1.84 g, 5.23 mmol) and anhydrous acetonitrile (5.0 mL) were added into a round bottom flask. The reaction mixture was heated to 100° C. for 2 h. Water was added and the mixture was extracted with ether (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-50% ethyl acetate in heptanes) to afford 2-(4-Fluoro-1H-pyrazol-1-yl)propanenitrile (398 mg, 82%). MS (EI+) (M+) 139, GCMS retention time: 0.78 min (Method O).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:17][CH3:18])(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].C1(C)C=CC=CC=1.N1CCCCC1>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([C:10]([O:17][CH3:18])=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(O)cc1)C(=O)OC
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (280.9 g), dimethyl malonate (289.2 mL) and toluene (1.12 mL) were successively added acetic acid (13.2 mL) and piperidine (11.4 mL). After dehydration under refluxing at internal temperature of 70° C.-75° C. for about 4 hr, the mire was cooled to internal temperature of not more than 10° C. and stirred further for 1 hr. The precipitated crystals were collected by filtration and washed with toluene (350 mL) to give the title compound (compound [8]; 523.7 g, yield 96.4%).
Reaction SMILES: [I-].[CH:2]1([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=O)[CH3:38]>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[C:45]([Cl:51])[CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A solution of cylcopentylmethyl triphenylphosphonium iodide (prepared in Example 33, 725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was treated with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.14 mL, 2.14 mmol). The reaction was stirred at 0° C. for 45 min. At this time, the reaction was treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355 mg, 1.37 mmol) in tetrahydrofuran (5 mL). The reaction was then warmed to 25° C. and stirred at 25° C. for 20 h. The reaction was then diluted with water (50 mL) and extracted with diethyl ether (3×25 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid ethyl ester (267 mg, 60%, 2:1 mixture of E:Z isomers) as a yellow oil and taken on without characterization.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC>CN(C=O)C.C1COCC1.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>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([CH:11]=[CH2:12])=[CH:7][N:6]=1)[CH2:9][CH3:10]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CCCc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(CCC)nc1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-propyl-pyridine (0.5 g, 2.5 mmol) was dissolved in DMF:THF (3:1, 8 mL). To this solution, tributylvinyltin (1.3 mL, 3.7 mmol) and Pd(PPh3)4 (0.057 g, 0.05 mmol) was added at RT under nitrogen and was heated at 100° C. for 2 h. The reaction mixture was cooled to RT and diluted with water (80 mL) and extracted with DCM (3×100 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (3% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—2.5.0 cm, Height of silica—approx. 5 inch) to provide 2-propyl-5-vinylpyridine as a light yellow liquid (0.15 g, 41% yield).