Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[N:5]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[F:25][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:15])=[O:34])=[CH:10][CH:9]=2)[N:5]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc3c(c2)OCO3)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cc(C(F)F)nn2-c2ccc3c(c2)OCO3)cc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 30.1 %

Procedure:
A mixture of 3-(difluoromethyl)-1-[3,4-(methylenedioxy)phenyl]-5-[4-(methylthio)phenyl]pyrazole (2.7 g) and m-chloroperbenzoic acid (1.8 g) in dichloromethane (80 ml) was stirred at 5° C. for 4 hours. The mixture was washed with an aqueous solution of sodium bicarbonate, dried, and concentrated. The residue (2.9 g) was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (25:1). The purified product (1.3 g) was recrystallized from isopropanol to give 3-(difluoromethyl)-1-[3,4-(methylenedioxy)phenyl]-5-[4-(methylsulfinyl)phenyl]pyrazole (0.85 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCN(c2cccc3ccc(O)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc3ccc(OC(=O)c4ccccc4)cc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and benzoyl chloride (0.035 mL, 0.302 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) was stirred at room temperature. After several hours, a second equivalent of benzoyl chloride was added with continued stirring overnight. The reaction was diluted with ethyl acetate and the phases were separated. The organic layer was washed with 1N sodium hydroxide, water and brine; then it was dried over magnesium sulfate and concentrated to an oil which solidified (0.065 g, 69%). A sample recrystallized from ether/hexane as a light pink solid was submitted for analysis: mp 82°-82.5° C. Analysis calculated for C22H22N2O2 ·0.25 H2O: C, 75.30; H, 6.46; N, 7.98. Found: C, 75.51; H, 6.29; N, 7.97.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH:14]=[C:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc3ccccc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C1CCNCC1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-tert-Butoxycarbonyl-4-(2-quinolylmethylene)piperidine (17.6 g) was dissolved in dichloromethane (60 ml), and TFA (60 ml) was added to the solution under cooling on ice. The mixture was stirred for 2.5 hours at room temperature and concentrated under reduced pressure. A saturated solution of sodium hydrogencarbonate was added to the residue to neutralize, and the mixture was then extracted with chloroform. The organic phase was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The title compound was recovered from an etherhexane solvent as white powder. This powder was also used for subsequent reaction without further purification.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14](OCC)=[O:15])[CH3:10].O.Cl>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([OH:15])=[N:7][C:6]([NH2:8])=[N:5][CH:19]=1)=[O:23])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(N)nc1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 83.3 %

Procedure:
Guanidine carbonate (18.0 g, 200 mmol) is dissolved in ethanol (300 ml), and then sodium alcoholate (13.6 g) and ethoxymethylenemalonic acid diethyl ester (43.2 g, 200 mmol) are added at room temperature. After stirring at room temperature for 4 days, the mixture is concentrated to dryness under reduced pressure. To the residue obtained, water (500 ml) is added and neutralized with hydrochloric acid, and then the crystal precipitated is collected by filtration and recrystallized, to yield a white crystal (30.5 g, 83%).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[F:37][C:24]([F:23])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5 g, 26.8 mmol) in DCM (200 ml) was added DIPEA (9.85 ml, 56.4 mmol) and then 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (4.55 ml, 26.8 mmol). The reaction mixture was stirred for 1.5 hours at rt. The reaction mixture was then evaporated to dryness in vacuo. The residue was then dissolved in 1,4-dioxane (100 ml) and 4M HCl in 1,4-dioxane (50 ml) was added, along with a few drops of distilled water. The reaction mixture was stirred for 3 hrs. Then the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in DCM (200 ml) and washed with 2M aq. NaOH (50 ml, twice). The organic layer was dried over anhydrous magnesium sulphate, the solid removed by filtration, and filtrate evaporated to dryness in vacuo. The residue was not a solid so was dissolved in ether and evaporated in vacuo to remove any remaining solvent. The title compound (8.02 g) was obtained as a pale yellow solid.
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.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:20])[CH3:19]>CN(C)C=O>[C:18]([O:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:20])[CH3:19]
Reactant: CCCCC(OC(C)=O)c1cccc(CBr)c1
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(OC(C)=O)c1cccc(COc2cccc3cccnc23)c1
Reaction time: 8 h
Yield: 94 %

Procedure:
1.45 g of 8-hydroxyquinoline and 1.38 g of ground anhydrous potassium carbonate are stirred in 20 ml of dimethylformamide at 25° C. for 2 hours. 2.99 g of 1-(3-bromomethylphenyl)pentyl acetate, dissolved in 10 ml of dimethylformamide, are then added dropwise and the reaction mixture is stirred overnight. The solvent is distilled off in vacuo, the residue is partitioned between water/ethyl acetate and the organic phase is dried over Na2SO4 and then concentrated in vacuo. The residue is chromatographed over silica gel 60 (Merck 9385) with CH2Cl2 /methanol 100:5 (Rf =0.45). An oil is obtained in a yield of 94% of theory.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]1[O:11][CH2:10]1>C(O)C.C(N(CC)CC)C>[CH2:13]([O:12][CH2:8][C@H:9]([OH:11])[CH2:10][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O[C@@H](COCc1ccccc1)COc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A solution of phenol (3.3 g; 35 mmol), benzyl(R)-(+)-glycidyl ether (5 g; 30.5 mmol) and triethylamine (300 μl; 2.15 mmol) in absolute ethanol (80 ml) was heated to reflux and stirred for 2 hours and then cooled to 60° C. and stirred overnight. The crude reaction mixture was concentrated under reduced pressure and the residues purified by silica gel chromatography using an eluant of hexanes and ethyl acetate (85:15 v/v) to afford 5.7 g (72.5%) of the pure product. m/z (ES) 281.1 (M+Na)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:21]([CH2:22][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][N:21]1[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=[C:17]1[NH:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:11][CH2:12]1
Reactant: Brc1nccs1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1coc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 2.7 parts of 2-bromothiazole, 5.1 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine, 5 parts of sodium carbonate, 0.1 parts of sodium iodide and 9 parts of N,N-dimethylacetamide was stirred for 3 hours at about 140° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3 parts of 1-(2-furanylmethyl)-N-[1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 153.1° C. (compound 48).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][C:25](=[S:27])[O:24][N:23]=2)[CH:19]=[C:18]([O:28][CH2:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([C:22]2[N:26]=[C:25]([S:27][C:20]([CH3:22])([CH3:21])[CH3:19])[O:24][N:23]=2)[CH:21]=1)[O:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38])=[O:31])([OH:5])=[O:7]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(-c2noc(=S)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Sc1nc(-c2cc(OCC(=O)N3CCC[C@@H]3C(=O)O)cc(OCC(=O)N3CCC[C@@H]3C(=O)O)c2)no1
Reaction time: 8 h
Yield: 111 %

Procedure:
A solution of 315 mg (0.5 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 160 mg (57%) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[CH2:25][OH:26])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCO[CH2:30][CH2:29]1.[OH-].[Na+]>C(O)C>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[CH2:25][O:26][CH2:29][CH3:30])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1c(CO)c(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCc1c(C(=O)OCC)c(C)n(CCc2ccc(F)cc2)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 719 mg portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-4-(hydroxymethyl)-2-methyl-1H-pyrrole-3-carboxylate was suspended in 10 ml of ethanol, and 2.0 ml of 4 M hydrogen chloride/1,4-dioxane was added, followed by stirring overnight at room temperature. By adding 10 ml of a 1 M sodium hydroxide aqueous solution, ethanol was evaporated under a reduced pressure. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (Chromatorex (registered trademark), ethyl acetate:hexane=1:30-1:20-1:15) to obtain 623 mg of ethyl 5-tert-butyl-4-(ethoxymethyl)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:20]([CH3:19])(=[O:22])=[O:21])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cncc(C2CCCN2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 3-bromo-5-(2-pyrrolidinyl)pyridine (0.2 g, 0.881 mmol) and pyridine (0.157 mL, 1.937 mmol) in DCM (1 mL) is added methanesulfonyl chloride in DCM (1 mL) dropwise. The mixture is stirred at room temperature for 2 h. The mixture is concentrated. The resulting crude product is purified by normal phase chromatography using 0-3% MeOH in DCM as the gradient to afford 3-bromo-5-(1-methanesulfonyl-pyrrolidin-2-yl)-pyridine (211.2 mg, 79% yield).
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6](C)[CH3:7])=O.[OH:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:38][CH:37]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19].C(P(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[C:6]([O:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:40][CH:41]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19])(=[O:5])[CH3:7]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(CC[C@@H](OC(C)=O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
Diisopropyl azodicarboxylate (63 mg) was added to a solution of compound (100 mg) obtained from Example 1A above, tri-n-butylphosphine (93 mg) and acetic acid (1 ml) in dry tetrahydrofuran (3 ml) at 0° C. Reaction mixture was stirred for 1 hour and concentrated. Residue was taken in ethyl acetate and washed with water and brine. Organic layer was concentrated to get oily residue which was purified on preparative thin layer chromatography (2 mm thickness) using 10% methanol in dichloromethane to get the title compound (80 mg) (formed probably by esterfication of acetic acid (used in large excess) and not due to Mitsunobu reaction). Mass (m/z): 517.06 (M++1); 1HNMR: δ 8.37 (m, 2H), 8.15 (d, 1H, J=8 Hz), 7.97-7.93 (m, 1H), 7.82-7.80 (m, 1H), 7.41 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 6.83 (d, 1H, J=8 Hz), 5.28-5.27 (m, 1H), 4.56-4.58 (m, 2H), 4.01 (s, 3H), 2.85-2.80 (m, 1H), 2.55-2.75 (m, 2H), 2.31-2.29 (m, 2H), 2.25-2.10 (m, 2H), 2.063 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][CH3:14].[CH3:15][C:16]([CH3:18])=O>>[CH:16]([NH:9][C:7]1[CH:6]=[CH:5][C:4]([CH2:12][CH2:13][CH3:14])=[C:3]([CH3:2])[CH:8]=1)([CH3:18])[CH3:15]
Reactant: CCCc1ccc([N+](=O)[O-])cc1CCl
Reactant: CC(C)=O
Product: CCCc1ccc(NC(C)C)cc1C

Procedure:
By the procedure of Example 1, α-chloro-2-propyl-5-nitrotoluene is reacted with acetone to afford the desired title product.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][NH:20]2.C(O)C.[OH-].[Na+]>O>[Cl:14][C:15]1[C:16]2=[C:21]3[N:20]([CH2:19][CH2:18][CH2:17]2)[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[C:22]3=[C:23]([Cl:25])[CH:24]=1
Reactant: Clc1cc(Cl)c2c(c1)NCCC2
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(c(Cl)cc(Cl)c3c1=O)CCC2
Temperature: 140 °C
Yield: 67.8 %

Procedure:
3.1 g of ethyl ethoxymethylenemalonate was added to 2.7 g of 5,7-dichloro-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 30 g of polyphosphoric acid was added thereto followed by heating at 140° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into 100 ml of water and the resulting mixture was rendered neutral with a 40% aqueous sodium hydroxide solution to precipitate light brown crystals. Without further purification the crystals were mixed with 100 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted to a pH of 2 to obtain 2.7 g of 8,10-dichloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as light yellow crystals having a melting point of 300° to 304° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2Br)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH:29](/B(O)O)=[CH:30]/[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2/[CH:29]=[CH:30]\[CH3:31])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N2CCN(CCOCc3ccccc3)CC2)c(Br)c1
Reactant: C/C=C\B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Methyl 4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-bromobenzoate (78 mg, 0.180 mmol) was dissolved in N,N-dimethylformamide: water=3:1 (1.8 mL). At room temperature, (Z)-propenylboronic acid (containing about 10% E-isomer; Hereinafter the same is used for all) (37 mg, 0.433 mmol), tetrakistriphenylphosphine palladium (10 mg, 0.00902 mmol) and sodium carbonate (76 mg, 0.722 mmol) were added sequentially, and the mixture was stirred at 80° C. for 1 hour under microwave irradiation. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (61 mg (yield 86%)) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH2:12][CH3:13])=[N:7]2.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([CH2:12][CH3:13])=[N:7]2
Reactant: CC(C)(C)N
Reactant: CCc1nc2cccc(Br)c2nc1Cl
Solvent: CS(C)=O
Product: CCc1nc2cccc(Br)c2nc1NC(C)(C)C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A solution of 5-bromo-3-chloro-2-ethylquinoxaline (312a) (131 mg, 0.48 mmol) and t-butylamine (Aldrich) (0.25 mL, 2.41 mmol) in DMSO (1.0 mL) was stirred under argon in a sealed flask at 100° C. for 17 h. The reaction mixture was then cooled to RT and partitioned between Et2O (80 mL) and saturated aq. NaHCO3 (80 mL). The organic layer was separated and sequentially washed with water (50 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide 8-bromo-N-(tert-butyl)-3-ethylquinoxalin-2-amine (136 mg, 0.44 mmol, 92% yield) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, d, J=8.2 Hz), 7.82 (1H, dd, J=7.6, 1.2 Hz), 7.20 (1H, t, J=7.9 Hz), 4.87 (1H, br. s.), 2.84 (2H, q, J=7.4 Hz), 1.64 (9H, s), 1.42 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 308.3/310.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)[C:16](=[O:28])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:25][CH:26]=4)[C:16](=[O:28])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(OCC(F)(F)F)cc1
Yield: 20.3 %

Procedure:
To an N,N-dimethylformamide solution of 4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1-(4-hydroxybenzyl)-1,3,5-triazin-2(1H)-one (10.0 mg, 0.0260 mmol) synthesized in Synthesis Example 483a, cesium carbonate (10.3 mg, 0.0320 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.57 μL, 0.0320 mmol) were added and the resultant mixture was stirred at 70° C. for 2 and a half hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (chloroform/ethyl acetate=1/1) to obtain the title compound (2.43 mg, yield: 14%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2O.P(Cl)(Cl)([Cl:28])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:28]
Reactant: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 1.08 h

Procedure:
A round-bottomed flask containing a mixture of 6-bromo-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-4-ol (4.00 g, 8.29 mmol, Intermediate 58: step b), phosphorous oxychloride (3.50 mL, 37.3 mmol) and acetonitrile (27 mL) was placed into a metal heating block at 90° C. After 65 min, the reaction mixture was cooled to room temperature. The acetonitrile and excess phosphorous oxychloride was removed by rotary evaporation. The residue was dissolved in dichloromethane (100 mL) and the solution was cooled in an ice-water bath. Ice (50 mL) was added. Concentrated aqueous ammonia solution was added dropwise until the pH=8-9 by litmus paper test. The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried with sodium sulfate and the dried solution was filtered. Silica gel (8 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with hexanes initially, grading to 20% ethyl acetate-hexanes provided the title compound as an off-white solid.