Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH2:25][C@@H:26]1[C@H:30]2[O:31]C(C)(C)[O:33][C@H:29]2[C@H:28]([N:36]2[CH:44]=[N:43][C:42]3[C:37]2=[N:38][CH:39]=[N:40][C:41]=3[NH2:45])[O:27]1)[CH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([C:20]4([CH3:24])[CH2:23][CH2:22][CH2:21]4)=[CH:19][C:13]=3[N:12]=2)[CH2:6]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>>[NH2:45][C:41]1[N:40]=[CH:39][N:38]=[C:37]2[C:42]=1[N:43]=[CH:44][N:36]2[C@H:28]1[C@H:29]([OH:33])[C@H:30]([OH:31])[C@@H:26]([CH2:25][N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]2[CH2:6][CH:7]([CH2:9][CH2:10][C:11]3[NH:15][C:14]4[CH:16]=[CH:17][C:18]([C:20]5([CH3:24])[CH2:23][CH2:22][CH2:21]5)=[CH:19][C:13]=4[N:12]=3)[CH2:8]2)[O:27]1
Reactant: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4(C)CCC4)ccc3[nH]2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4(C)CCC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
9-((3aR,4R,6R,6aR)-6-((isopropyl(3-(2-(5-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine 422 mg, 0.686 mmol) was dissolved in a mixture of Trifluoroacetic Acid (6.3 ml, 82 mmol) and water (0.7 ml, 40 mmol) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, upon which the ice bath was removed and the mixture was warmed to RT. The mixture was stirred at RT for 2.5 h upon which the residue was taken up in 12 ml MeOH, concentrated to dryness. This was repeated twice, the resultant glass was placed under high vacuum. The crude residue was diluted with 11 ml MeOH, treated with 600 mg K2CO3 and 0.5 ml H2O and allowed to stir at RT till the solution was basic as determined by pH paper. The mixture was filtered and the solids were washed with 20 ml MeOH. The solution was concentrated to a residue that was placed under high vacuum. The crude material was purified by flash chromatography (SiO2, eluting with 10-12% 7N NH3 in CH3OH/CH2Cl2) to give the desired compound as a stiff foam/glass (256 mg). 1H NMR (400 MHz, MeOD) δH ppm 8.30 (m, 1 H), 8.20 (d, J=1.04 Hz, 1 H), 7.38 (d, J=8.09 Hz, 1 H), 7.22 (br. s., 1 H), 6.98 (dd, J=8.50, 1.66 Hz, 1 H), 5.96 (m, 1 H), 4.74 (t, J=4.87 Hz, 1 H), 4.27 (d. J=3.11 Hz, 1 H), 4.08 (m, 1 H), 3.56 (m, 1 H), 3.13 (m, 1 H), 3.00 (m, 1 H), 2.90 (dd, J=14.51, 4.35 Hz, 1 H), 2.75 (m, 3 H), 2.41 (m, 2 H), 2.12 (m, 5 H), 2.00 (m, 1 H), 1.84 (m, 3 H), 1.58 (m, 1 H), 1.46 (s, 3 H), 1.02 (m, 3 H), 0.95 (d, J=6.63 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[C:13]([CH3:19])([CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][C:13]1([CH3:19])[CH3:18]
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(C(=O)OCc2ccccc2)CCC1N
Temperature: 5 °C
Yield: 155.9 %

Procedure:
1-Benzyloxycarbonyl-3,3-dimethyl-4-piperidone (290 g, 1.11 mol) was dissolved in methanol (1.5 L) and under stirring addition of ammonium acetate (600 g, 7.80 mol ) was made at 30-35° C. The reaction mixture was stirred for 5 hrs. Sodium cyanoborohydride (35 g, 0.55 mol) was added portion wise to the suspension. over 0.5 hrs by maintaining temperature between 0-10° C. The reaction mixture was stirred for 6-7 hrs. After completion of reaction, solvent was evaporated under reduced pressure and addition of 3.00 L water was made under stirring. The reaction mixture was stirred for 15 minutes. It was extracted with 1.5 L×2 CHCl3. Combined organic extract was evaporated under vacuum. The residue was dissolved in 3 N HCl till pH 1 and was extracted with 500 ml×2 dichloromethane. The aqueous layer was basified with 300 ml aqueous ammonia solution (23-25%) to pH 10-11 and then was extracted dichloromethane. Combined organic extract was washed with water and was dried over sodium sulfate. Evaporation of organic solvent afforded 225 g (77%) title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]1([C:30]2[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=2[C:32]([NH:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][N:13]([C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:43][CH:42]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNc3ccccc3C(=O)N2C1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3C(=O)N2C1
Yield: 95 %

Procedure:
The same procedures used in Example 25 were repeated using (2R, 11aS)-2-(tert-butyldimethylsilyloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 26 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give the title compound. Yield 95%.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:14]([CH3:25])[N:15]=[C:16]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:33]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:34]([NH2:36])=[O:35].O>CN(C)C=O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([C:16]2[C:5]3[C:4]4[CH:3]=[C:2]([O:1][CH:33]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)[C:34]([NH2:36])=[O:35])[C:11]([O:12][CH3:13])=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:14]([CH3:25])[N:15]=2)=[CH:18][CH:19]=1)#[N:22]
Reactant: NC(=O)C(Br)c1ccc(F)cc1
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(N)=O)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
4-(8-Hydroxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (97.7 mg, 296 μmol) is dissolved in N,N-dimethylformamide (3.7 ml). Potassium carbonate (102 mg, 738 μmol) and 2-bromo-2-(4-fluorophenyl)acetamide (170 mg, 733 μmol) are subsequently added. The reaction mixture is stirred at 120° C. for 18 h. When the reaction is complete, the mixture is poured into water (50 ml) and extracted three times with ethyl acetate (50 ml each time). The combined organic phases are dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue is then suspended in a little 2-propanol, filtered off with suction and dried in a high vacuum, giving 2-[1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-2-(4-fluorophenyl)acetamide (68 mg, 141 μmol) as a solid having a melting point of 249.2° C. MS: 482.1 (M+H+), TLC (HPTLC): Rf=0.31 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:24])[CH2:4][N:5]1[CH2:23][CH2:22][N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>[I-].[Na+].CC(C)CC(=O)C>[OH:24][CH:3]([CH2:2][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[CH2:23][CH2:22][N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1
Reactant: C1COCCN1
Reactant: OC(CCl)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC(CN1CCOCC1)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 43.6 %

Procedure:
5 g of 2-(3-chloro-2-hydroxypropyl)-1,2,3,4,10,14b-hexahydrodibenzo [c,f]pyrazino [1,2-a]azepine (prepared as described in Example 41), 2.7 g of sodium carbonate, 0.014 g of sodium iodide and 0.254 g of morpholine were added to 10 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was filtered, and then the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using ethyl acetate as the eluent, to afford 0.50 g (yield 87%) of the title compound as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of the diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (31.8 g, 88 mmol) in aqueous hydrochloric acid (6M, 1.4 L) was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and added very slowly to a saturated aqueous solution of aqueous sodium bicarbonate (4 L) at 0° C. The mixture was then extracted with dichloromethane (7 L), dried over magnesium sulfate and the solvent removed in vacuo to give 5-bromo-2-methyl-3-nitropyridine as an orange oil (13.8 g, 63.9 mmol, 72%) which solidified upon standing. 1HNMR (300 MHz, CDCl3): δ ppm 8.78 (s, 1H). 8.43 (s, 1H), 2.79 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][C:13]([OH:32])=[O:12])[CH2:20][CH2:19]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(CC(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.4 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of [4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-acetic acid tert-butyl ester (1.48 g, 4 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue was triturated with diethyl ether. Filtration yielded the product as a white solid (1.25 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 7.70 (dt, J=9.6, 2.4 Hz, 2H), 7.21 (dt, J=9.6, 2.4 Hz, 2H), 3.86 (m, 5H), 3.09 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([F:12])=[C:10](F)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:14])[C:3]=1[F:15].[CH3:16][O-:17].[Na+].[Na]>CO>[CH3:16][O:17][C:10]1[C:11]([F:12])=[C:2]([CH3:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1c(F)c(F)c(C)c(F)c1F
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(C)c(F)c1OC

Procedure:
Methyl 4-methyl-2,3,5,6-tetrafluorobenzoate (1.0 g) was added to a solution of sodium methoxide obtained by dissolving sodium metal (0.15 g) in dry methanol (15 cm3) and the mixture heated at the reflux temperature for 2 hours until the reaction was complete. The product was purified by h.p.l.c. (Gilson) using a silica column and as eluent a mixture of petroleum ether (boiling range 40°-60° C., 1800 cm3) and diethyl ether (200 cm3), to obtain methyl 2-methoxy-4-methyl-3,5,6-trifluorobenzoate (0.38 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A76) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:15]1[CH:14]=[C:13]([CH:9]([CH2:8][NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:10][CH2:11][OH:12])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: NCC(CCO)c1ccc(F)c(F)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC(CCO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Ethyl chloroformate (3.9 mL, 40.8 mmol) was added dropwise to a stirred cooled (−40° C.) solution of 4-amino-3-(3,4-difluorophenyl)-1-butanol (7.45 g, 37 mmol) and triethylamine (5.94 mL, 42.6 mmol) in DCM (180 mL). The solution was stirred at room temperature for 30 min and at room temperature overnight. The material was washed twice with 1N HCl, twice with saturated sodium bicarbonate; dried (Na2SO4), filtered and the solvent removed to provide the title compound (8.85 g, 88%) as a yellow oil. 1H-NMR (CDCl3) δ 1.18-1.23 (t, 3H, CH) 1.72-1.98 (m, 3H) 2.96-3.00 (m, 1H, CH) 3.24-3.29 (m, 1H, CH) 3.45-4.04 (m, 3H, CH), 4.06-4.14 (m, 2H, CH) 4.66 (br. s, 1H, OH or NH) 6.91-7.37 (m, 3H, ArH). MS m/z 274 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:29]=[C:30]=[S:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: COc1ccc(N=C=S)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(OC)c(OC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol), 3,4-dimethoxyphenyl isothiocyanate (0.787 g, 4.0 mmol), and ethyl acetate (25 mL) was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The reaction mixture was diluted with ethyl acetate (˜100 mL), heated to 80° C. briefly, then allowed to stand 5 days at room temperature. The precipitate was filtered off to afford the product (0.552 g); m.p. 170-171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12](OCC)=[O:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]([OH:13])=[CH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccncn1
Reactant: CCOC(=O)c1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(=Cc1ccncn1)c1cccc(Cl)c1
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a cold (0° C.) solution of 4-methylpyrimidine (4.56 mL 50.1 mmol) and ethyl 3-chlorobenzoate (7.90 mL 50.1 mmol) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl)amide (100 mL, 1.0M in tetrahydrofuran, 100 mmol) dropwise over 30 minutes. The resultant mixture was warmed to room temperature and stirred 16 hours. The reaction mixture was concentrated in vacuo. The resultant oil was diluted with methanol. Upon standing, a solid precipitated, which was collected on a filter to provide 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (11.2 g, 93%) as a yellow solid. Rf 0.31 (3:1 hexanes:ethyl acetate); 1H NMR (d6-DMSO) δ 8.37 (s, 1H), 7.98 (m, 1H), 7.81–7.76 (m, 2H), 7.38–7.32 (m, 2H), 6.71 (br, 1H), 5.65 (s, 1H); MS m/z 233 (M+1).
Reaction SMILES: [CH:1]1([CH:4]2[CH2:8][CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:6]([CH3:19])[NH:5]2)[CH2:3][CH2:2]1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[C:20]([N:5]1[CH:6]([CH3:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[CH2:8][CH:4]1[CH:1]1[CH2:2][CH2:3]1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC1NC(C2CC2)CC1c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1C(C)C(c2cccc(C(F)(F)F)c2)CC1C1CC1

Procedure:
13 G of 2-cyclopropyl-4-(m-trifluoromethylphenyl)-5-methylpyrrolidine, 6 ml of acetyl chloride and 8 ml of triethylamine in 50 ml of anhydrous benzene is stirred at ambient temperature for 18 hours. Ice is added to the reaction mixture and the organic products are extracted with ether; the ethereal extract is washed with water, with 5% sodium hydroxide and then again with water, and dried over sodium carbonate to give 14.4 g of N-acetyl-2-cyclopropyl-4-(m-trifluoromethylphenyl)-5-methylpyrrolidine, which is dissolved in 50 ml of anhydrous tetrahydrofuran and added dropwise to a suspension of 2.9 g of lithium aluminium hydride in 75 ml of anhydrous tetrahydrofuran at reflux temperature. Refluxing is then continued for 4 hours. The excess double hydride is destroyed with cold ethyl acetate. After adding water and ice, the mixture is extracted with ether; the ethereal extract is washed with water and dried over sodium carbonate. After evaporation of the ether, vacuum distillation of the residue gives 9.7 g of N-ethyl-2-cyclopropyl-4-(m-trifluoromethylphenyl)-5-methylpyrrolidine as a liquid. Boiling point 0.3 = 115° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9](OC)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].CO>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:6]1[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: COC(=O)c1nc(C(C)C)cs1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1csc(CO)n1
Yield: 5 %

Procedure:
Using the procedure of Example 5B, but replacing ethyl 2-isopropyl-4-thiazolecarboxylate with methyl 4-isopropylthiazole-2-carboxylate provided, after silica gel chromatography using 2% methanol in chloroform, the desired compound (Rf 0.3, 5% methanol in chloroform) in 96% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:20])[C:11]([C:21]([OH:23])=[O:22])=[CH:10]2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[F:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[N:6]=[N:7][C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:3][CH:4]=1)[CH:10]=[C:11]([C:21]([OH:23])=[O:22])[C:12]2=[O:20]
Reactant: O=C(O)c1cn(Cc2ccc(Cl)nn2)c2c(F)cccc2c1=O
Reactant: C1CCNCC1
Solvent: CS(C)=O
Product: O=C(O)c1cn(Cc2ccc(N3CCCCC3)nn2)c2c(F)cccc2c1=O

Procedure:
To a solution of 1-[(6-chloropyridazin-3-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.040 g, 0.12 mmol) in 1 mL of DMSO was added piperidine (0.015 mL, 0.16 mmol). The reaction mixture was irradiated in the microwave at 100° C. for 10 minutes, and purified via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 383.1 for M+H+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:5][CH:6]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:15]1[CH2:16][CH2:17][O:18][C@@H:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][S:7][C:4]2[S:3][C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:6][CH:5]=2)[CH2:14]1
Reactant: O=C(CSc1ccc(Br)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(CSc1ccc(-c2ccncc2)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
The resultant product (500 mg) of Example 31 and 4-pyridylboronic acid (250 mg) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (25 mL) and water (5 mL), sodium hydrogen carbonate (500 mg) and tetrakistriphenylphosphine palladium (60 mg) were added, and the mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent, and the obtained residue was recrystallized from ethyl acetate to give the title compound (90 mg) as a pale-brown powder.
Reaction SMILES: [C:1]([N:8]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:10]1[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:11]1)[CH3:9])([CH3:6])([CH3:7])[CH3:5]
Reactant: CCCCCBr
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCN1CCC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.6 %

Procedure:
To a solution of 3-(N-BOC-N-methylamino)pyrrolidine (150 mg, 0.75 mmol) in DMF (1.5 mL) was added potassium iodide (25 mg, 0.15 mmol) and potassium carbonate (207 mg, 1.50 mmol) followed by 1-bromopentane (0.097 mL, 0.78 mmol). The mixture was stirred 7 h at room temperature. Most of the DMF was then removed under low pressure and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated to give the title compound (198 mg, 98% yield) as an oil. MS m/e 271.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:3][CH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:17]([CH3:18])=[O:19])=[CH:8][CH:9]=1
Reactant: CCCc1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-n-Propylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (862 mg) and acetyl chloride (692 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed therefrom by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 4-n-propylphenyl acetate (1.09 g, yield 100%).