Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH3:15][C@@H:16]1[CH2:18][O:17]1>C(O)C>[OH:17][C@H:16]([CH3:18])[CH2:15][N:4]1[CH2:5][CH2:6][C@@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C@H:2]([CH3:1])[CH2:3]1
Reactant: C[C@@H]1CNCC[C@H]1OC(=O)C(C)(C)C
Reactant: C[C@@H]1CO1
Solvent: CCO
Product: C[C@@H]1CN(C[C@@H](C)O)CC[C@H]1OC(=O)C(C)(C)C

Procedure:
A solution of piperidine 20 (3 g, 15.05 mmol) and (R)-2-methyl-oxirane (15.05 ml, 150.5 mmol) in 10 ml of ethanol is stirred for 24 hours in a closed flask. The solvent is evaporated and the residue distilled in a Kugelrohr apparatus (0.08 mbar, 80-90 C).
Reaction SMILES: O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH3:12][C:13]([C:15]([CH3:23])([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[OH-].[NH4+]>C(OCC)C>[CH3:22][C:15]([C:13]([Cl:7])=[CH2:12])([CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)C(C)(C)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: C=C(Cl)C(C)(C)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Into a 250 ml round bottomed flask equipped with magnetic stirring and a reflux condenser was placed 15 g (98 mmol) of POCl3, 30 g (145 mmol) of PCl5, and 19.9 g (123 mmol) of α,α-dimethylbenzyl methyl ketone. The reaction was heated in an oil bath to an external temperature of 110° C. Gas evolution ceased after one hour. The reaction was cooled and carefully poured onto ice and aqueous ammonium hydroxide. Extractive workup with diethyl ether gave a mixture of 1-(α,α-dimethylbenzyl)-1-chloroethylene and 1-(α,α-dimethylbenzyl)-1,1-dichloroethane. Vacuum distillation gave purified 1-(α,α-dimethylbenzyl)-1-chloroethylene bp (23 torr) 110-120° C.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:22][CH:21]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 100 °C

Procedure:
To a 150 mL pressure vessel was added ethyl 2-chloronicotinate (3.1 g, 17 mmol), 4-(pyridin-2-ylamino)phenol (3.14 g, 17 mmol), and cesium carbonate (5.8 g, 18 mmol) followed by DMSO. The solution was sealed and heated to 100° C. for 20 h. It was cooled and diluted with water and extracted five times with ethyl acetate. The combined organic were washed with brine, dried over sodium sulfate, filtered, and concentrated to a dark brown residue. The residue was taken up in dichlormethane and adsorbed onto silica gel before being purified with flash chromatography (0 to 50% ethyl acetate:hexanes), affording the product as a pale orange solid. MS (ESI, pos. ion) m/z: 336.0 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:2][CH:3]=[CH2:4].[BH4-].[Na+]>CO>[CH2:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCc1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 2-(but-3-en-1-yl)benzaldehyde (500 mg, 3.12 mmol) in MeOH (10 mL) was added NaBH4(118 mg, 3.12 mmol) and the mixture was stirred at rt for 1 h. It was then added water, extracted with EtOAc. The organic was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to obtain (2-(but-3-en-1-yl)phenyl)methanol (320 mg, 1.973 mmol, 63.2% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.44-7.37 (m, 1H), 7.33-7.21 (m, 3H), 5.91 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.13-4.99 (m, 2H), 4.76 (d, J=5.9 Hz, 2H), 2.86-2.77 (m, 2H), 2.44-2.35 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[S:10]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])N1)(=[O:12])=[O:11].N.S(=O)(=O)(O)O>O.C(#N)C>[CH3:1][Si:2]([N:3]1[C:14](=[O:15])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:12])=[O:11])([CH3:9])[CH3:8]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)N1C(=O)c2ccccc2S1(=O)=O
Yield: 102 %

Procedure:
2 ml (9.6 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 1.83 mg (10 mmoles) of saccharin, 10 mg (0.02 mmole) of di-4-nitrophenyl N-(4-toluenesulfonyl)-phosphoramidate and 20 ml of acetonitrile under dry nitrogen and the ammonia evolved was led into water by the nitrogen stream and was titrated with 1 N sulfuric acid. The calculated amount of ammonia was evolved within 0.5 hour and the solvent and other volatile materials were removed by evaporation in a rotating film evaporator. Then, the residue was dried under vacuum to obtain 2.50 g (98%) of trimethylsilylsaccharin melting at 90°-92° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])[C@H:5]([OH:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].C(N(CC)CC)C.[C:36]1([N:42]([CH3:46])[C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26])[C@H:5]([O:13][C:43]([N:42]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:46])=[O:44])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](OC(=O)N(C)c1ccccc1)c1ccccc1C
Reaction time: 15 h
Yield: 52.7 %

Procedure:
0.4 g (0.001 mol) of (2S,3R)—N-methyl-2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-hydroxy-3-o-tolylpropionamide was dissolved in methylene chloride, 0.13 g (0.0013 mol) of triethylamine and a spatula-tip of 4-dimethylaminopyridine were added, and 0.22 g of N-phenyl-N-methylcarbamoyl chloride in methylene chloride was added dropwise. The suspension was stirred for 15 hours and then extracted with 5% strength hydrochloric acid and NaHCO3 solution and dried. Chromatographic purification (silica gel column, cyclohexane/ethyl acetate) gave 0.28 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16]=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:19]=2)[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:16]=[N:17][N:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCCCCCc1ccccc1)c1nnn(-c2ccccn2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CCCCCCc1ccccc1)c1nnn(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115 %

Procedure:
7-Phenyl-1-(2-(pyridin-2-yl)-2H-tetrazol-5-yl)-heptan-1-ol (2.7 mg, 0.007 mmol) was dissolved in CH2Cl2 (0.24 mL) and Dess-Martin periodinane (4.5 mg, 0.011 mmol) was added. The mixture was stirred at room temperature for 2 h before the reaction mixture was reduced to half volume and this mixture was directly loaded onto silica gel and purified by flash chromatography (SiO2, 0.5×4 cm, 10-30% EtOAc-hexanes) to afford 7-phenyl-1-(2-(pyridin-2-yl)-2H-tetrazol-5-yl)-heptan-1-one (15b, 2.7 mg, 99%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.74 (m, 1H), 8.23 (m, 1H), 8.05 (dt, 1H, J=1.6, 7.9 Hz), 7.57 (dd, 1H, J=4.8, 7.5 Hz), 7.27 (t, 2H, J=7.6 Hz), 7.17 (m, 3H), 3.26 (t, 2H, J=7.4 Hz), 2.61 (t, 2H, J=7.7 Hz), 1.83 (m, 2H), 1.64 (m, 2H), 1.43 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 191.5, 162.5, 149.9, 148.6, 142.8, 139.8, 128.5, 128.4, 126.0, 125.8, 115.9, 41.0, 36.0, 31.4, 29.1, 29.0, 23.5; HRMS-ESI-TOF m/z 336.1813 ([M+H]+, C19H21N5O requires 336.1819). Purity 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:33])[C:6]=2[CH:34]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:33])[C:6]=2[CH:34]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2oc3ccc(Cl)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}phenyl)carbonyl](methyl)amino}propanoate (199 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.50 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.50 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (174 mg, 93%) as a white solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:22]([CH3:21])[C:18]([CH:16]1[CH2:15][C:14](=[O:13])[CH2:17]1)=[O:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)C1CC(=O)C1
Yield: 64.2 %

Procedure:
CDI (40 g, 0.25 mol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (23 g, 0.2 mol) in THF (100 ml) at 0° C. under stirring, the mixture was stirred at RT for 1 h. N-methylbenzylamine (32 ml, 0.25 mol) was added to the mixture and the mixture was stirred at RT for 3 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 500 g, CHCl3/MeOH 100:0→95:5). The title compound (27.9 g, 64%) was obtained as a colorless oil. 1H NMR data (DMSO-d6): 7.20 (m, 5H, Ph); 4.62 s, 4.55 s (2H, CH2); 3.46-3.62 (m, 1H); 3.28 (m, 4H,); 2.85 s, 2.94 s (3H, NCH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>[N+](C1C=CC=CC=1)([O-])=O.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[C:10]2[N:11]=[C:19]([C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][C:17]=3[C:23]([F:25])([F:24])[F:26])[NH:12][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1cncc(N)c1N
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)c1cncc2[nH]c(-c3ccc(F)cc3C(F)(F)F)nc12
Temperature: 220 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
A mixture containing ethyl 4,5-diaminonicotinate (79; 0.9 g, 5 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (82; 1.0 g, 5.2 mmol) in nitrobenzene (50 mL) was stirred at 220° C. for 18 h. Upon cooling to room temperature, the reaction mixture was diluted with ether. The resulting solids were collected by filtration, washed with ether, and dried to provide 2-(4-fluoro-2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester 83 (600 mg, 39%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([S:18]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[S:8][C:9]([S:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: ClSc1ccccc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: c1ccc(Sc2ccc(-c3ccccc3)s2)cc1
Reaction time: 96 h
Yield: 17.2 %

Procedure:
In a 500 ml flask were placed 36.9 g (0.23 mole) of 2-phenylthiophene, 200 ml of reagent carbon tetrachloride, 36.9 g (0.26 mole) of benzenesulfenyl chloride and 0.2 g of iron powder. The reaction mixture was allowed to stand four days at room temperature. Distillation of the carbon tetrachloride gave a crystalline residue which was recrystallized first from ethanol-ethyl acetate (9:1) and then from ethyl acetate-pentane (1:9) to give 10.6 g (17%) of 2-phenyl-5-(phenylthio)thiophene, m.p. 72.5°-74.5° C.
Reaction SMILES: [C:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C@H:26]([C:41]([OH:43])=[O:42])[CH2:27][CH2:28][CH2:29][NH:30]C(OCC2C=CC=CC=2)=O)=[O:24])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:44]1[C:53]2[C:52](=O)[CH2:51][CH2:50][CH2:49][C:48]=2[CH:47]=[CH:46][CH:45]=1.C([BH3-])#N.[Na+]>O1CCOCC1.O.CO.C(O)(=O)C.[Pd]>[C:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C@@H:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:52]2[C:53]3[N:44]=[CH:45][CH:46]=[CH:47][C:48]=3[CH2:49][CH2:50][CH2:51]2)[C:41]([OH:43])=[O:42])=[O:24])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cn1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC2CCCc3cccnc32)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 20.5 %

Procedure:
The compound obtained in Example 12-4 (149.9 mg) was dissolved in a dioxane/water (8/2) solution (7.5 ml). After the addition of 10% Pd—C (154.6 mg), the mixture was stirred for 4.5 hours under hydrogen atmosphere at room temperature. After the reaction, the catalyst was removed by filtration through celite and the solvent was removed by distillation under reduced pressure to obtain a crude product (100.2 mg). 75.4 mg of the crude product was dissolved in methanol (1.5 ml). Then, 5,6,7,8-tetrahydroquinolin-8-one (53.6 mg) and sodium cyanoborohydride (43.2 mg) were added. 25 drops of acetic acid was added to adjust the pH of the mixture to about 5. The mixture was stirred for 22 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (5 g, chloroform/methanol=10/1) to obtain the title compound (30.6 mg) as white foam.
Reaction SMILES: [Na].[C:2]1([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([O:23][CH2:22][N:10]1[C:9](=[O:14])[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:12][C:11]1=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1COCc1ccccc1
Temperature: 25 °C

Procedure:
5,5-Diphenylhydantoin sodium (27.5 g) was suspended in 250 ml of dimethylformamide. To the suspension was added 15 ml of chloromethylbenzylether with good stirring and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into 1 liter of ice cold water and stirred for one hour. The solid product was removed by filtration and dissolved in 150 ml of hot ethanol. To the boiling solution 1 g of activated carbon was added and the hot solution was filtered through a Buchner funnel which contained a compacted layer of finely-divided diatomaceous silica. The cake was washed three times with 10 ml of ethanol and the hot solution together with the washings was allowed to cool to room temperature. The resulting crystals were filtered and recrystallized two more times in the same manner as described for the first crystallization. There was obtained 13.1 g of 3-benzyloxymethyl-5,5-diphenylhydantoin, m.p. 151°-152°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)C.O.[OH-].[Na+]>C1COCC1>[CH2:25]([N:13]1[CH2:14][CH2:15][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH:12]1[CH2:10][OH:9])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Yield: 100 %

Procedure:
Lithium aluminium hydride (1M in THF) (4 mL, 3.93 mmol) was added to a stirred solution of 1,4-dibenzylpiperazine-2-carboxylic acid ethyl ester (1.33 g, 3.93 mmol) in THF (25 mL) cooled to −78° C. under a nitrogen atmosphere. Water (145 μL), NaOH (aq.) (10 wt %, 145 μL) and water (450 μL) was added at 45 min intervals. The reaction mixture was filtered through a pad of celite and solvent evaporated under reduced pressure to afford (1,4-dibenzylpiperazin-2-yl)methanol (1.16 g, 3.93 mmol, 100%) as a pale yellow oil. Data for (1,4-dibenzylpiperazin-2-yl)methanol: MS (ESI) m/z: 298 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
A solution of 3-chloro-2-(bromoacetamido)benzoic acid from Example 39 (7.5 g, 0.026 mol), aniline (5.8 mL, 250 mol %) and anhydrous DMF (60 mL) was heated at 95-100° C. for 20 h, cooled and stirred at rt for 4 h. The reaction mixture was poured into ice-water (400 mL) and the precipitated product was solubilized by adding aqueous 5% KOH (60 mL). The resulting milky homogenous solution was extracted with CH2Cl2 (3×70 mL). The combined CH2Cl2 extracts were set aside and the aqueous layer was acidified to pH=3 with aqueous 5% HBr. The resulting oil was extracted into EtOAc (3×100 mL) and the combined extract was washed with brine, dried, filtered and concentrated. Recrystallization of the resulting solid from diethyl ether afforded 3 g (38%) of the title compound as a white crystals, mp 184-185° C.; 1H NMR (CD3OD) δ 7.85 (dd, 1H, J=1.6, J=6), 7.66 (dd, 1H, J=1.6, J=6.4), 7.33 (t, 1H, J=8), 7.16 (t, 2H, J=7.2), 6.72 (dd, 3H, J=2, J=5.6), 3.91 (s, 2H); 13C NMR (CD3OD): 203.86, 196.95, 173.19, 173.17, 168.69, 149.44, 134.30, 130.41, 130.09, 128.42, 119.31, 114.44; MS (EI, m/z) 304 (M+)
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)cnc3c2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The ethyl (E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-2-propenoate (15 mg) obtained in (A) was dissolved in tetrahydrofuran (1 ml) and methanol (0.5 ml), added with a solution of 8 mg of lithium hydroxide dissolved in 0.5 ml of water, and stirred at room temperature for 3.5 hours, and the solvent was concentrated under reduced pressure. The residue was distributed between ether and water, and the aqueous layer was separated, made pH 3 with hydrochloric acid, extracted with ethyl acetate, and dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: CS[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14]>[Ni].C(O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[NH2:14]
Reactant: CSCc1cc(C(F)(F)F)ccc1N
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)ccc1N
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Activated Raney nickel (500 g wet paste, ˜50μ) was added portionwise to a solution of 2-[(methylthio)methyl]-4-(trifluoromethyl)benzenamine (55.3 g, 0.25 mole) in 1 L of ethanol over 30 minutes at 25-30° C. The heterogeneous mixture was stirred vigorously for 30 minutes after the addition. The stirring was stopped, and the solids were allowed to settle over one hour. The liquid was decanted from the solids and poured through filter paper. The filtrate was evaporated under reduced pressure, and the residue was taken up in dichloromethane. The organic phase was separated from a small volume of water, dried over magnesium sulfate and evaporated under reduced pressure to afford 37.6 g of the title compound as amber oil.
Reaction SMILES: C([N:11]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15])(OCC1C=CC=CC=1)=O>O.[Pd]>[NH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:11][CH2:12][CH2:13][S:14]([OH:17])(=[O:15])=[O:16])=[O:23]
Reactant: NCCCC(=O)N(CCS(=O)(=O)O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: NCCCC(=O)NCCS(=O)(=O)O
Reaction time: 2 h
Yield: 76 %

Procedure:
The N-carbobenzoxy-γ-aminobutyryl-taurine obtained as described in Example 2 is dissolved in 10 ml of water. 100 mg of 10% palladium-on-carbon catalyst are added to the solution, and the mixture is hydrogenated for 2 hours. The catalyst is filtered off, and the filtrate is evaporated in vacuo at 35° C. The obtained crude product is crystallized from a 1:10 mixture of water and acetone. 0.798 g (76%) of γ-aminobutyryl-taurine are obtained: m.p.: 247° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([OH:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CO.Br[CH2:25][CH2:26][CH3:27]>BrCCC.O>[C:1]1([C:7]2[C:11]([O:12][CH2:25][CH2:26][CH3:27])=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Reactant: CCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 98.4 %

Procedure:
A mixture of 3,5-diphenyl-4-pyrazolol (10.0 g, 0.042 mole), sodium methoxide (2.27 g, 0.042 mole) and methanol (60 ml) is heated at 60°C for 2 hours. Then 1-bromopropane (5.17 g, 0.042 mole) is added slowly (5 minutes) at 60°C. The reaction mixture is then held at 60°C for 7 hours, and slowly cooled to room temperature. Examination by glc at this point indicates that the reaction is incomplete. The mixture is heated to 60°C and more 1-bromopropane (0.26 g, 0.002 mole) added. When the reaction is complete (as shown by glc), the mixture is poured into water and the solid formed is isolated by filtration. The solid (11.5 g, 99.7% yield) m.p. 132° and 136°C contains 2 minor impurities as indicated by tlc (benzene/silica gel). Recrystallization from acetonitrile affords white crystals (7.4 g, 63%) m.p. 142° to 142.5°C.