Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH:22]1(N)C2C(=CC=CC=2)CCC1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:22]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCCc2ccccc21
Product: CCc1cnc(CC)c(NC2CCCc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2 S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound-as a oil: 1H NMR (400 MHz, CDCl3) δ 7.81, 7.38, 7.19, 5.49, 4.56, 2.87, 2.69, 2.57, 2.12, 1.98, 1.91, 1.32; 13C NMR (100 MHz, CDCl3) δ 153.69, 151.42, 140.81, 138.70, 138.29, 129.85, 129.56, 129.18, 127.49, 126.58, 48.71, 30.07, 29.94, 28.56, 26.07, 20.42, 13.96, 11.16; HRMS (FAB) calcd for C18H23N3+H 282.1970, found 282.1975.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>O>[C:31]([O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)(=[O:33])[CH3:32]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) are added acetic anhydride (8.0 ml) and pyridine (2.0 ml). The mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the precipitated crystal is collected by filtration, and recrystallized from ethyl acetate/n-hexane to give 5-acetyloxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.56 g) as white powder, m.p. 193-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:12]=2[C:13]([NH2:15])=[O:14])=O)=[CH:4][CH:3]=1.[OH-].[Na+].CCOC(C)=O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:15][C:13](=[O:14])[C:12]3[C:11](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2nc(-c3ccc(Cl)cc3)[nH]c(=O)c2cc1OC
Reaction time: 0.08 h

Procedure:
To a solution of 2-((4-chlorophenyl)carbonylamino)-4,5-dimethoxybenzamide (1.0 g, 2.99 mmol) in ethanol (10 mL) was added aqueous NaOH solution (15 mL) at rt for 10 min. The reaction mixture was refluxed for 10 min and allowed to rt. The mixture was poured into ice cold water and stirred for 10 min EtOAc (20 mL) was added to the solution and stirred for 5 min. The separated solid was filtered, washed with ice cold water and dried to the product as a white color solid (900 mg, 95%), mp>360° C. 1H NMR (400 MHz, DMSO-d6): δ 12.47 (1H, s), 8.19 (2H, d, J=8.6 Hz), 7.62 (2H, d, J=8.6 Hz), 7.50 (1H, s), 7.23 (1H, s), 3.94 (3H, s), 3.90 (3H, s); LC-MS (positive ion mode): m/z 317, 319 (M+H)±.
Reaction SMILES: CC1C=CC(S(NC2C=C(C3C=CC4N(C=C(NC(=O)C)N=4)N=3)C=CC=2)(=O)=O)=CC=1.Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=2)[N:37]=1.[CH3:45][S:46][C:47]1[CH:48]=[C:49](B(O)O)[CH:50]=[N:51][CH:52]=1>>[CH3:45][S:46][C:47]1[CH:48]=[C:49]([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=3)[N:37]=2)[CH:50]=[N:51][CH:52]=1
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: CSc1cncc(B(O)O)c1
Agent: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Product: CSc1cncc(-c2ccc3nc(NC(C)=O)cn3n2)c1

Procedure:
Following the procedure described for N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.075 g, 0.36 mmol) was reacted with 5-(methylthio)pyridin-3-ylboronic acid (0.11 g, 0.64 mmol, Combi-Blocks, San Diego, Calif.) to afford the title compound as a white solid. MS (ESI positive ion) m/z: 300 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.94 (s, 1H), 9.00 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.34 (s, 1H), 8.27 (t, J=2.2 Hz, 1H), 8.12 (d, J=9.4 Hz, 1H), 7.90 (d, J=9.4 Hz, 1H), 2.64 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: CN(/[CH:4]=[N:5]/[C:6](=O)[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1)C.[C:21]([C:24]1[C:25]([C:31]([F:34])([F:33])[F:32])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=1)(=[NH:23])[NH2:22]>>[CH3:19][O:18][C:9]1[CH:8]=[C:7]([C:6]2[N:5]=[CH:4][N:22]=[C:21]([C:24]3[C:25]([C:31]([F:32])([F:34])[F:33])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=3)[N:23]=2)[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]=1[O:16][CH3:17]
Reactant: N=C(N)c1ccc[n+]([O-])c1C(F)(F)F
Reactant: COc1cc(C(=O)/N=C/N(C)C)cc([N+](=O)[O-])c1OC
Product: COc1cc(-c2ncnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of (E)-N-((dimethylamino)methylene)-3,4-dimethoxy-5-nitrobenzamide (1.12 g, 4 mmol) ethanol (30 mL) was added 3-carbamimidoyl-2-(trifluoromethyl)pyridine 1-oxide (0.82 g, 4 mmol). The reaction mixture was heated to reflux for 5 hours. It was cooled to room temperature and the solvent was removed by evaporation. The residue was then dissolved in dichloromethane/isopropanol mixture (50 mL, 70:30) and the organic phase was washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated, The crude product was recrystallized from ethanol to give 3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.27 g (75%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].Br[CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22].Cl>CO.O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(SC2CCOC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
Sodium hydroxide (0.20 g, 5 mmole) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.11 g, 4.6 mmole) in methanol (20 ml) and stirred at room temperature until dissolved. 2-Bromobutyrolactone (0.82 g, 5 mmole) was added and the mixture was stirred at room temperature for 48 hours. The mixture was diluted with water, acidified with 1 N hydrochloric acid, and extracted with diethyl ether. The ether extract was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a minimum of hexane and cooled to induce crystallization. Chromatography of the solid on silica gel and recrystallization from hexane gave the title compound, m.p. 98°'100°.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1.[CH3:14][I:15]>O1CCOCC1>[I-:15].[CH3:13][N+:2]([CH3:14])([CH3:1])[CH2:3][C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([OH:11])=[C:8]([CH3:10])[CH:9]=1
Reactant: CI
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Solvent: C1COCCO1
Product: Cc1cc(C[N+](C)(C)C)cc(C)c1O
Product: [I-]
Yield: 100 %

Procedure:
2,6-dimethylphenol (112.5 g, 0.92 mol) dissolved in 250 ml ethanol was added dropwise to a mixture of formaldehyde (139 ml of a 36.5% aqueous solution, 1.84 mol) and dimethylamine (300 ml of a 40% aqueous solution, 2.03 mol) and the resulting mixture was refluxed for 4 h. Ethanol was evaporated, the residue was partitioned between water and dichloromethane, the organic phase was dried over MgSO4 and evaporated to yield 165 g (100%) of an oil. To a dioxane solution (900 ml) of the dimethyl(3,5-dimethyl-4-hydroxybenzyl)amine thus obtained (165 g, 0.92 mol) was added methyl iodide (126 ml, 2.03 mol) and the resulting mixture was refluxed for 2 h. The solid formed was filtered and washed with dioxane to yield 296 g (100%) of the trimethyl(3,5-dimethyl-4-hydroxybenzyl)ammonium iodide salt. This latter (148 g, 0.46 mol) was suspended in 300 ml xylene, triethyl phosphite (120 ml, 0.69 mol) was added dropwise and the resulting mixture was refluxed for 16 h. The solid formed was filtered and the solvent and excess of phosphite were evaporated under vacuum to yield diethyl (3,5-dimethyl-4-hydroxybenzyl)phosphonate as a viscous oil (117 g, 93%).
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+:32].C(O)(C)C>O>[C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][K:32])=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: [K+]
Reactant: CCCN(CCCCCC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCN(CCCCCC(=O)O[K])S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A round bottom flask fitted with an overhead stirrer was charged with C4F9SO2N(C3H7)(CH2)5COOC2H5 (63.0 g; 0.143 mole), KOH (13.1 g; 0.234 mole; pellets) isopropanol (26 mL) and deionized water (21 mL). The ensuing mixture was refluxed overnight, cooled to room temperature, yielding a solution of C4F9SO2N(C3H7)(CH2)5COOK (61.3% solids).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH3:18])=[CH:10][CH:9]=2)=[O:4]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccccc3OC)ccc2sc1=O

Procedure:
4-Hydroxy-6-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 2-methoxy-phenylboronic acid. 1H NMR (200 MHz, CDCl3): 6 (ppm)=8.481 (s, 1H), 7.803 (d, 1H), 7.627-7.789 (m, 1H), 7.42-6.92 (m, 4H), 4.022 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].I[CH2:22][CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29].O>O1CCCC1>[CH2:3]([C:10]([CH2:22][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
60% sodium hydride (0.54 g, 13.5 mmol) was added to a solution of diethyl 2-(6-heptenyl)malonate (3.0 g, 11.7 mmol) in tetrahydrofuran (30 ml) followed by stirring for 30 minutes at room temperature. 1-Iodo-4,4,5,5,6,6,7,7,7-nonafluoroheptane (5.45 g, 14.04 mmol) was added to the mixture followed by stirring for 12 hours at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/25) to give diethyl 2-(6-heptenyl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)malonate (6.14 g, quantitative) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1.[OH:17][CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH:14]1([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:20]3[CH2:21][CH2:22][CH:18]([OH:17])[CH2:19]3)=[CH:7][CH:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: OC1CCNC1
Reactant: O=C(c1ccc(OCCCCl)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCN2CCC(O)C2)cc1)C1CC1
Yield: 68 %

Procedure:
The product from Example 151B (200 mg, 0.83 mmol), 3-hydroxypyrrolidine (72 mg, 0.83 mmol), potassium carbonate (121 mg) and potassium iodide (146 mg) in 10 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (68% yield).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[C:17]([C:19]([NH2:21])=[O:20])[CH:16]=C(C=C)[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([OH:29])[CH3:28].[OH2:30]>>[OH:29][C@H:27]([C:28]1[CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]3[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=2)[N:18]=[C:17]([C:19]([NH2:21])=[O:20])[CH:16]=1)[CH2:26][OH:30]
Reactant: O
Reactant: C=Cc1cc(C(N)=O)nc(-c2cccc(Oc3ccc(F)cc3)c2)c1
Reactant: CC(C)O
Product: NC(=O)c1cc([C@@H](O)CO)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Yield: 26 %

Procedure:
To a scintillation vial was added 6-[3-(4-fluoro-phenoxy)-phenyl]-4-vinyl-pyridine-2-carboxylic acid amide (0.066 g), 5 ml IPA, 5 ml water, and 0.270 g AD Mix beta. After the oxidation reaction was complete, the mixture was partitioned between 50 ml water and 50 ml EtOAc. The organic layer was separated, concentrated under reduced vacuum, and chromatographed by combiflash using a 12-gram silica column using a gradient of MeOH (0-40%) in chloroform as the eluent. The compound was purified further by prep TLC (100% EtOAc) followed by crystallization from chloroform and hexane to provide 0.019 g of 4-((R)-1,2-dihydroxy-ethyl)-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid amide as a white solid (26% yield) in very high purity. 1H NMR (CHCl3) 8.80-8.73 (m, 1 H), 8.22-8.14 (m, 1 H), 7.79-7.74 (m, 1 H), 7.71-7.64 (m, 1 H), 7.56-7.47 (s, 1 H), 7.31-7.03 (m, 7 H), 5.55-5.47 (m, 1 H), 4.86-4.80 (m, 1 H), 4.77-4.69 (m, 1 H), 3.55-3.44 (m, 1H). LC/MS: m/z=368[M]+.
Reaction SMILES: [CH2:1]([CH:3]1[C:7]2=[N:8][C:9]3[C:10]([C:17]([F:20])([F:19])[F:18])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]([OH:16])=[C:6]2[C:5](=[N:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[O:4]1)[CH3:2].[OH2:27]>C(O)(=O)CC>[OH:16][C:15]1[C:14]2[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH:3]([O:27][C:3](=[O:4])[CH2:1][CH3:2])[CH2:1][CH3:2])[C:6]=1[C:5]([NH:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:4]
Reactant: O
Reactant: CCC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Solvent: CCC(=O)O
Product: CCC(=O)OC(CC)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reaction time: 0.83 h

Procedure:
A suspension of 3 g of 1,3-dihydro-3-ethyl-1-[(2thiazolyl)-imino]-5-(trifluoromethyl)-furo-[3,4-b]-quinolin-9-ol in 60 ml of propionic acid was held in a bath at 100°-110° C. for 2 hours and 50 minutes and the solution obtained was cooled and poured into 600 ml of water. After separating and washing with water, 2.5 g of product were obtained which was purified by crystallization from 40 ml of ethyl acetate. The crystals were cooled and recovered by filtration to obtain 1 7 g of 4-hydroxy-2-[1-(1-oxopropoxy)-propyl] -N-(2-thiazolyl)-8-(trifluoromethyl)-3-quinoline carboxamide melting at 216° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[K+].C([O:15][C:16]([S-])=[S:17])C>CCO>[C:16]([C:3]1[C:2]([OH:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)([OH:15])=[S:17]
Reactant: CCOC(=S)[S-]
Reactant: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CCO
Product: OC(=S)c1ccc2cccnc2c1O
Temperature: 160 °C
Yield: 23.1 %

Procedure:
A mixture of 8-hydroxyquinoline (0.055 mol, 8.0 g) and O-ethylxanthic acid potassium salt (0.056 mol, 9.0 g) in abs. EtOH (20 mL) was placed in a pressure reactor and heated at 160° C. for 40 hours. After cooling, the reaction mixture was washed with a small amount of EtOH. The insoluble material was filtered off and treated with aqueous hydrochloric acid. The insoluble thioacid was separated by filtration and purified by heating with barium carbonate in water. The mixture was filtered off, the filtrate was acidified with hydrochloric acid, and precipitate was collected by filtration to give 7-thiocarboxy-8-hydroxyquinoline (2.61 g) in 18.4% yield.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH2:28])[CH:18]=[N:19][C:20]=1[N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C.O1CCOCC1>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:28][C:17]2[CH:18]=[N:19][C:20]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[C:15]([CH3:14])[CH:16]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Reactant: Cc1cc(N)cnc1N1CCN(C)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2cnc(N3CCN(C)CC3)c(C)c2)nc1Cl
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (500 mg), 5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-amine (470 mg), diisopropylethylamine (800 μL), and dioxane (10 mL) was stirred in a microwave reaction device at 150° C. for 30 minutes. After leaving to be cooled, water was added thereto, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 5-chloro-6-ethyl-3-{[5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}pyrazine-2-carboxamide (210 mg) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]=[CH:6][C:5]1=2.C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C.C(OCC)(=O)C>[N:25]1([CH2:2][CH2:3][CH:4]2[CH2:12][CH2:11][CH2:10][C:9]3[N:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:7]=[CH:6][C:5]2=3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: ClCCC1CCCc2c1cnn2-c1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(-n2ncc3c2CCCC3CCN2CCOCC2)cc1
Yield: 75.9 %

Procedure:
A mixture of 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (423 mg, 1.62 mmol), K2CO3 (336 mg, 2.43 mmol), morpholin (0.42 mL, 4.87 mmol) and a catalytic amount of KI in 20 mL of DMF is heated to reflux during 18 hours. The solvent is eliminated at reduced pressure, the crude is diluted with ethyl acetate, washed with water, and the organic phase is evaporated at reduced pressure. The resultant crude is purified by chromatography on silica-gel to obtain 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethyl)-1-phenyl-1H-indazole (384 mg, 1.23 mmol, 76%, oil)
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[N:11]>C(Cl)Cl>[CH3:12][C:9]([NH:8][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:13])[C:10]#[N:11]
Reactant: CC(C)(N)C#N
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Product: C=CS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a stirred mixture of 8.0 g (0.049 mole) 2-chloroethylsulfonyl chloride in 200 ml methylene chloride, cooled by an ice bath, 8.3 g (0.098 mole) 2-amino-2-methyl-propionitrile were added dropwise. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was washed twice with equal portions (about 200 ml) water, dried over magnesium sulfate, filtered and stripped to give a semi-solid. The semi-solid was triturated with ethyl ether/acetone and filtered to remove salts. The filtrate was stripped to give 7.9 g of the above-identified product as an amber oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH:4]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(C)C)(C)C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:12][C:25]([NH:24][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[S:26])[CH:13]=[CH:14][CH:15]=2)[CH:4]=1
Reactant: COc1ccnc(-c2cccc(N)c2)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1ccnc(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)aniline (357 mg) in acetone (5 ml) was added benzoyl isothiocyanate (0.252 ml), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added diisopropyl ether, and the precipitate was collected by filtration and dried to give N-(3-(4-methoxypyridin-2-yl)phenyl)-N′-benzoylthiourea (462 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]([CH3:27])([O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1)[CH3:26]
Reactant: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 75 °C
Yield: 63.6 %

Procedure:
A solution of benzyl 2-(4-bromophenyl)acetate (33.5 g, 0.11 mol), t-butyl acrylate (31.6 mL, 0.22 mol) and triethylamine (85 mL, 0.64 mol) in DMF (1000 mL) was deoxygenated with argon, whereupon bis(triphenylphosphine)palladium dichloride (5.1 g, 8.3 mmol) was added. After heating at 75° C. for 12 hours the solvent was removed in vacuo providing a brown residue that was purified by chromatography on silica gel using a mixture of hexanes and ethyl acetate (9:1) to give benzyl (E)-2-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]acetate as a pale yellow oil (23.3 g, 0.07 mol) in 60% yield.