Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].C([O-])(=[O:46])C.C[OH:49].[ClH:50]>C(OCC)(=O)C>[CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:36][CH2:37]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].[OH2:46].[OH2:49].[OH2:20].[ClH:50]
Reactant: CC(=O)[O-]
Reactant: CO
Agent: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: Cl
Solvent: CCOC(C)=O
Product: O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a 100 mL reactor was charged amorphous irinotecan acetate (2.0 g) and methanol (14 mL). The reaction mixture was heated to 50° C. 2N hydrochloric acid (6.2 wt %, about 1.7 mL) was added to adjust the pH level to less than 4 in order to dissolve the solid particles. Ethyl acetate (40 mL) was added slowly to the mixture. The mixture was cooled to 0˜10° C. and stirred at this temperature for 1 hour. The solid particles were filtered and washed with cooled ethyl acetate (6 mL). The wet cake was dried in vacuum to give 1.66 g of irinotecan hydrochloride trihydrate Form III.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]([CH2:14][C:15]([O:17]CC)=[O:16])[C:12](=[O:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22](=[O:39])[NH:23][CH2:24][CH2:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:12](=[O:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22](=[O:39])[NH:23][CH2:24][CH2:25][CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1C(=O)NC(C)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N(CC(=O)O)C(=O)N1
Reaction time: 12 h

Procedure:
59.7 mg (0.109 mmol) of ethyl [6-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-4-methyl-2-oxo-3,6-dihydro-2H-pyrimidine-1-yl]acetate was dissolved in 10 ml of methanol. 0.219 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution at room temperature, and they were stirred for 12 hours. 1 N hydrochloric acid was added to the reaction mixture. Methanol was evaporated under reduced pressure. Water was added to the residue, and precipitates thus formed were taken by the filtration, then washed with hexane/ethyl acetate (3/1) and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+].[Br:28][C:29]1[C:30](=[O:46])[NH:31][C:32](=[O:45])[N:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:34]=1.BrC1(Br)CN(C2C=CC=C(C(F)(F)F)C=2)C(=O)NC1=O.BrC1CN(C2C=CC=C(C(F)(F)F)C=2)C(=O)NC1=O.[Cl-].[Li+]>C(O)(=O)C.CN(C)C=O.O>[Br:28][C:29]1[C:30](=[O:46])[NH:31][C:32](=[O:45])[N:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:34]=1.[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)C(=O)N1
Agent: BrBr
Agent: O=C1NC(=O)C(Br)(Br)CN1c1cccc(C(F)(F)F)c1
Agent: O=C1NC(=O)N(c2cccc(C(F)(F)F)c2)CC1Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1

Procedure:
To a solution of 1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 96) (770.0 mg) in acetic acid (10.0 ml) was added bromine (0.18 ml) and the resulting mixture was stirred with heating under reflux for two hours. To the reaction mixture were added water (30 ml) and 10% aqueous sodium thiosulfate solution (5 ml) and the precipitated solids were collected by filtration with water to afford a mixture containing 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione, 5,5-dibromo-1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione and 5-bromo-1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (800.0 mg). A solution of the resulting mixture (800.0 mg) and lithium chloride (122.3 mg) in N,N-dimethyl formamide (5.0 ml) was stirred at 120° C. for one and a half hours. To the reaction mixture was added water (20 ml) and the resulting mixture was extracted with ethyl acetate (20 ml×2), and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (473.1 mg) and 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (135.8 mg).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: Cc1ccnc(N)c1
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)NC(=O)CO4)nc2c1
Yield: 48.4 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.15 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.3 g) and 2-amino-4-methylpyridine (2.5 g). mp. 239°-241° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)phenol (8.7 g) and sodium hydride (1.2 g) in dimethylformamide (60 ml) was stirred at 25° during 3 h. N-(4-Bromobutyl)phthalimide (12.8 g) was added and the mixture was stirred at 25° during 20 h then at 65° for 3 h. The reaction mixture was poured onto water and extracted with ethyl acetate. The solvent was concentrated and the crystalline impurity was removed by filtration. The filtrate was evaporated in vacuo and the residue was dissolved in ethanol and heated at reflux with hydrazine hydrate (2.5 ml) for 3 h. The mixture was filtered and the filtrate distilled to give the title compound as a colourless oil (4.1 g) b.p. 140°/0.1 mm TLC silica, ethyl acetate/water/isopropanol/0.88 ammonia 25:8:15:2, Rf 0.32.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)OCC3C=CC=CC=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C@H:13]2[CH2:12][CH2:11][C@H:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:15][CH2:14]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](c2ccc(N)cc2)CC1

Procedure:
Benzyl [4-(trans-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)phenyl]carbamate (0.50 g, 1.14 mmol) in EtOH (10 mL) and EtOAc (10 mL) was hydrogenated over 10% Pd/C (100 mg) at ambient pressure and 40° C. After 2 hours the catalyst was removed by filtration and the solution concentrated in vacuo to leave the title compound (320 mg, 86%) as a white solid; 1H NMR δ 0.95-1.02 (2H, m), 1.25-1.39 (12H, m), 1.73-1.75 (4H, m), 2.22-2.25 (1H, m), 2.80 (2H, t), 4.75 (2H, s), 6.46-6.49 (2H, m), 6.78 (1H, t), 6.85 (2H, d)
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([Br:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:20])[CH3:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[NH2:1][CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([Br:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:19])[CH3:20]
Reactant: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CN=[N+]=[N-])C3
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CN)C3
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
2-Azidomethyl-5-bromo-9,9-dimethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (492 mg, 1.40 mmol) was dissolved in tetrahydrofuran (10 ml). To the solution, triphenylphosphine (404 mg, 1.54 mmol) was added, and the mixture was stirred in a bath at 50° C. for 2 hours. After completion of the reaction, aqueous 2N-caustic soda solution (2 ml) was added to the reaction mixture, followed by stirring a further 1 hour at room temperature. The reaction mixture was condensed under reduced pressure, and extracted with chloroform and 2N-HCl. The aqueous phase was neutralized with aqueous 2N-caustic soda solution, and then extracted with a solvent mixture of chloroform-methanol (10:1), dried, and condensed under reduced pressure. The condensate was purified by silica gel column chromatography (developer=chloroform). Recrystallization from chloroform-methanol-ether yielded 330 mg of the title compound as pale yellow needles (72.1%).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=O)=O.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:13][C:8]([F:14])([C:9]([F:12])([F:11])[F:10])[CH2:7][CH:18]([C:17]#[N:21])[C:19]#[N:20]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)CC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
In 30 ml of ethylene glycol dimethyl ether, 8.4 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate and 5.9 g of malononitrile were dissolved. Thereto 12.3 g of potassium carbonate was added and the mixture was stirred at room temperature for 8 hours. Thereafter dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.1 g of 2-(2,2,3,3,3-pentafluoropropyl)malononitrile.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:34])[CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[C:33]3[C:28]([CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1ccc2ccncc2c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc3ccncc3c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and isoquinolin-7-ol: 1H-NMR (CDCl3) δ 9.27 (1H, s), 8.59 (2H, m), 8.13–8.10 (2H, m), 8.00 (2H, d, J=8.4 Hz), 7.94 (1H, d, J=8.9 Hz), 7.74 (2H, m), 7.50 (1H, dd, J=8.9, 2.3 Hz), 7.45 (2H, d, J=8.4 Hz), 5.40 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C=O.[C:20]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:20])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: [BH3-]C#N
Reactant: Cc1c(OC2CCCNC2)ccc2[nH]ncc12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(OC2CCCN(C)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
Acetic acid (0.060 ml) was added to a methanolic solution (1.0 ml) of the 4-methyl-5-(piperidin-3-yloxy)-1H-indazole (46 mg, 0.20 mmol) obtained in Example 422, followed by adding thereto paraformaldehyde (30 mg, 1.0 mmol), and the resulting mixture was stirred at room temperature for 2 hours. Then, a solution of sodium cyanoborohydride (63 mg, 1.0 mmol) in methanol (1.0 ml) was added thereto and the resulting mixture was stirred at room temperature for 18 hours. After a 1N-aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate/triethylamine=5/15/1) to obtain 4-methyl-5-[(1-methylpiperidin-3-yl)oxy]-1H-indazole (34 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[N:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:10]1[C:11]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[N:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:25])[N:9]=1
Reactant: CN(C)CCNc1ccc2c(O)nc(-c3cc(Cl)ccc3F)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCNc1ccc2c(Cl)nc(-c3cc(Cl)ccc3F)nc2n1

Procedure:
The 2-(5-Chloro-2-fluoro-phenyl)-7-(2-di-methylamino-ethylamino)-pyrido[2,3-d]pyrimidin-4-ol (0.18 g) was dissolved in P(O)Cl3 (10 mL) and heated to reflux for 2 hr. The mixture was reduced in volume and NaHCO3 (sat aq) was added. The mixture was extracted with CH2Cl2 (×3). The extracts were combined and dried over MgSO4, filtered and evaporated to dryness to afford N′-[4-Chloro-2-(5-chloro-2-fluoro-phenyl)-pyrido[2,3-d]pyrimidin-7-yl]-N,N-dimethylethane-1,2-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][C:7]1[S:8][CH2:9][C:10](=[O:12])[N:11]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:27][C:23]2[CH:24]=[CH:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][N:17]=3)[N:22]=2)[C:10](=[O:12])[N:11]=1
Reactant: O=C1CSC(NCc2ccc(F)c(Cl)c2)=N1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccc(F)c(Cl)c2)SC1=Cc1ccc2ncccc2n1
Temperature: 130 °C
Yield: 29.1 %

Procedure:
To a suspension of 2-(3-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.20 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min. The reaction mixture was then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give a brown solid: 32.6 mg (51.1%), which was dissolved in 0.5 mL hot DMF and diluted with water. The precipitates were collected and washed with water, acetone and ether, dried to give 2-(3-chloro-4-fluoro-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a light brown solid (18.6 mg, 29.2%). HR-ES (+) m/e calcd. for C19H12ClFN4OS: (M+H)+ 399.0477. Found: 399.0477.
Reaction SMILES: S(C)C.CC(CC)=C.[CH2:9]([C:12]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:14][CH2:13]1)[CH:10]=[CH2:11].[OH2:35]>C1COCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][N:15]1[CH2:14][CH2:13][C:12]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)([CH2:9][CH2:10][CH2:11][OH:35])[O:17][C:16]1=[O:18]
Reactant: O
Reactant: C=CCC1(c2ccc(F)cc2)CCN(Cc2ccc(Cl)cc2Cl)C(=O)O1
Solvent: C1CCOC1
Solvent: C=C(C)CC
Solvent: CSC
Product: O=C1OC(CCCO)(c2ccc(F)cc2)CCN1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A stirred solution of BH3.Me2S (0.7 mL, 7.0 mmol) in dry THF (7 mL) was cooled in an ice bath and 2 M 2-methylbutene in THF (7 mL, 14 mmol) was added dropwise over 3 min. The mixture was stirred in the ice bath for 1.5 h. An aliquot of this solution (0.25 mL, 0.12 mmol) was added to an ice-cold solution of 6-allyl-3-(2,4-dichlorobenzyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (3.2 mg, 8.0 μmol) in dry THF (0.5 mL). The mixture was stirred overnight at rt. Water (2 mL) was added and the mixture was stirred for 3 h. Solid NaBO3.H2O (10 mg) was added. The mixture was stirred overnight, applied to a 10-mL ChemElut cartridge and eluted with CH2Cl2 (20 mL). The eluate was concentrated and the residue was purified by prep HPLC to afford 3-(2,4-dichlorobenzyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (1.3 mg, 39%). LC-MS Method 1 tR=1.78 min, m/z=368; 1H NMR (CDCl3) 1.37 (m, 1H), 1.66 (m, 1H), 1.99 (m, 2H), 2.30 (m, 2H), 2.92 (m, 1H), 3.10 (m, 1H), 3.58 (t, 2H), 4.50 (d, 1H), 4.63 (d, 1H), 6.90-7.35 (7H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)=O.[BH4-].[Na+]>O1CCCC1.CO>[F:16][C:10]1[CH:9]=[C:8]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][NH:1]2)[CH:13]=[C:12]([F:14])[C:11]=1[F:15]
Reactant: NCCCCC(=O)c1cc(F)c(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cc(C2CCCCN2)cc(F)c1F
Reaction time: 18 h
Yield: 677.6 %

Procedure:
To 5-amino-1-(3,4,5-trifluorophenyl)pentan-1-one (0.11 g, 0.48 mmol) in tetrahydrofuran/methanol 4:1 (10 mL) was added in portions over 20 minutes solid sodium borohydride (0.20 g, 5.0 mmol) and stirring was continued 18 hours at 25° C. The reaction mixture was concentrated then taken into ethyl acetate (40 mL), washed with saturated sodium chloride/2 N aqueous sodium hydroxide 10:1 (11 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes, 1:1) to give 2-(3,4,5-trifluorophenyl)piperidine (0.70 g, 68% yield) as an oil. 1H NMR (400 MHz, CDCl3): 7.01 (m, 2H), 3.52 (m, 1H), 3.17 (m, 1H) 2.77 (m, 1H), 2.07 (br s, 1H), 1.88 (m, 1H), 1.74 (m, 1H), 1.64 (m, 1H), 1.55-1.35 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=1.[Li+].CC([N-]C(C)C)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=1.[S:17]([N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[CH:7]=[O:8])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=Cc1cc(Br)c[nH]1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)cc2C=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 154.4 %

Procedure:
4-Bromopyrrole-2-carboxaldehyde was prepared by the method of Sonnet, P. E., J. Org. Chem. (1971), Vol. 36, p. 1005. A solution of 4-bromopyrrole-2-carboxaldehyde (2.61 g) and tetrahydrofuran (100 mL) was cooled to 0° C. LDA (7.5 mL of a 2 N solution in THF) was added dropwise and the mixture was stirred at 0° C. for 1 hour. Tosyl chloride (2.88 g) was then added. The resulting reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated. The dark colored solid was chromatographed on SiO2 with 4:1 hexane/ethyl acetate to afford N-tosyl-4-bromo-2-pyrrolecarboxaldehyde (3.8 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCOCC>[Si:16]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: Brc1nccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)c1nccs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A solution of 2-bromothiazole (57.4 g) in ether (70 ml) was added slowly to a solution of n-butyllithium (1.6M solution in hexane, 241 ml) in ether (700 ml) under an atmosphere of argon, maintaining the temperature below -60° C. After stirring for 1 hour at -70° C., a solution of tert-butylchlorodimethylsilane (63.0 g) in ether (70 ml) was added slowly dropwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 16 hours. Saturated aqueous sodium bicarbonate solution was added, the layers were separated, and the aqueous phase extracted twice with ether. The combined organic phases were dried (MgSO4), concentrated, and the residue was purified by column chromatography, eluting with 25% ethyl acetate/hexane (v/v), and subsequent distillation to give 2-tert-butyldimethylsilylthiazole (Q) (46 g, 58% yield) as an oil (b.p. 88°-96° C. at 10 mm of mercury);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[CH2:15]([O:17][C:18]([N:20]1[C:24]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N+:40]([O-:42])=[O:41])=[C:23]2[CH2:44][NH:45][C:46]([CH3:48])([CH3:47])[C:22]2=[N:21]1)=[O:19])[CH3:16].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:15]([O:17][C:18]([N:20]1[C:24]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[N+:40]([O-:42])=[O:41])=[C:23]2[CH2:44][N:45]([S:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)(=[O:11])=[O:10])[C:46]([CH3:47])([CH3:48])[C:22]2=[N:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CNC2(C)C
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Reaction time: 4 h

Procedure:
3,5-difluoro-benzenesulfonyl chloride (1 eq., 3.9 g, 18.4 mmol) was added portion-wise to a stirred solution of 6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride (10 g, 18.4 mmol) and N,N-diisopropylethylamine (6 eq, 19.3 mL, 110.4 mmol) in dry dichloromethane (100 mL) at room temperature. Stirring was continued for about 4 hours. The reaction mixture was diluted with dichloromethane (100 mL) then washed with saturated sodium hydrogen carbonate (150 mL), dried over sodium sulphate, evaporated to dryness and purified by flesh chromatography on silica gel using acetone as the eluant. The title compound was obtained as yellow solid (9 g, 65% yield).