Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:29](N1CCOCC1)=[O:30].C(OCC)C>O1CCCC1>[CH:29]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:10]=1)=[O:30]
Reactant: Fc1ccc(-c2ocnc2-c2ccncc2)cc1
Reactant: O=CN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1nc(-c2ccncc2)c(-c2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4-[5-(4-fluoro-phenyl)-oxazol-4-yl]-pyridine (1.5 g, Reference Example 6) in dry tetrahydrofuran (50 ml), under an inert atmosphere and at −10° C., was treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (12.5 ml, 1M). After 0.5 hour the mixture was treated with N-formylmorpholine (1.5 ml). This mixture was stirred at room temperature for 16 hours then treated with diethyl ether (50 ml) and then filtered. The solid was suspended in 10% aqueous ammonium chloride solution (50 ml) and the resulting yellow solid filtered to give the title compound. MS: 269 [MH+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])=[N:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)=[O:12])=[N:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cccc2[nH]ncc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
(5-Chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)(4-methylsulfonylpiperazin-1-yl)methanone, 1H-indazol-4-yl-4-boronic acid (2.5 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 140° C. for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was washed with methylene chloride and the organic layer was purified by silica gel chromatography followed by reverse phase silica gel chromatography to give the product 141.
Reaction SMILES: C(N(CC)CC)C.N[C@H](C([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)C.Cl.[N:27]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30]>O1CCCC1>[C:38]([O:37][C:35]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:36])([CH3:41])([CH3:39])[CH3:40].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH3:15].[CH3:25][O:24][C:22](=[O:23])[C@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:13]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)Cc1ccccc1
Product: C[C@H](N)C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
447 mg of triethylamine are added to a mixture of 488 mg of Ala-Phe-OMe. HCl D 2 and 845 mg of Boc-Pro≈SO2 in 20 ml of absolute tetrahydrofuran, whereupon the color of the mixture becomes deep red. The mixture is stirred for 1 hour at 20° C. The pale yellow mixture is then worked up as described in Example D 1 and the product is digested with petroleum ether.
Reaction SMILES: C(N)CCC.[CH3:6][C:7]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21]C(C3C=CC=CC=3)=O)[CH:17]=[CH:16]2)[CH:8]=1.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>C(OCCCC)(=O)C>[C@@H:15]1([N:9]2[CH:8]=[C:7]([CH3:6])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]1.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]
Reactant: Cc1cn([C@H]2C=C[C@@H](COC(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Solvent: CN1CCCC1=O
Solvent: CCCCN
Solvent: CCCCOC(C)=O
Product: Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To n-butylamine (133 ml) was added 5'-benzoyl-d4T (7', 70.0 g). The reaction was heated at 70° C. for six hours. After cooling to 20°-25° C., N-methylpyrrolidinone (NMPO, 41.3 ml) and n-butyl acetate (350 ml) were added. Excess n-butylamine (~112.4 ml) along with 175 ml of n-butyl acetate was removed via vacuum distillation at 50° C. The resulting slurry was cooled to 20°-25° C. over one hour and stirred for 30 minutes. The slurry was then cooled to -10° to -15° C. and stirred for 1.5 hours. The cake was filtered and washed with 2×50 ml cold (-10° to -15° C.) n-butyl acetate and dried to give d4T.NMPO complex, 59.0 g (85.6%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:4](N)[N:3]=1.CS(C)=[O:41].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:14]([O:13][C@@H:12]1[C@H:32]([OH:33])[C@@H:34]([CH2:36][OH:37])[O:35][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:41])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CS(C)=O
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reaction time: 216 h

Procedure:
2,6-Diamino-9-(2'-O-octadecyl-β-D-ribofuranosyl)purine (10 g) in 0.1M sodium phosphate buffer (50 ml, pH 7.4), 0.1M tris buffer (1000 ml, pH 7.4) and DMSO (1000 ml) was treated with adenosine deaminase (1.5 g) as per the procedure of Example 3. At day 3, day 5 and day 7 an additional aliquot (500 mg, 880 mg and 200 mg, respectively) of adenosine deaminase was added. The reaction was stirred for a total of 9 day and after purification by silica gel chromatography yielded the product (2 g). An analytical sample was recrystallized from MeOH 1H NMR (DMSO-d6) δ 0.84 (t, 3, CH3), 1.22 [s, 32, O--CH2 --CH2 --(CH2)16 ], 5.07 (m, 2, 3'-OH 5'-OH); 5.78 (d, 1, 1'-H); 6.43 (s, 2, NH2), 7.97 (s, 1, 8-H) and 10.64 (s, 1, NH2). Anal. Calcd. for C28H49N5O5 : C, 62.80; H, 9.16; N, 12.95. Found: C, 62.54; H, 9.18; N, 12.95.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1>CO.O1CCCC1.[Pd]>[CH3:15][O:14][C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:17]=1)[C:2]([CH3:32])([CH3:1])[CH2:11]2)=[O:13]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)=N2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)N2
Yield: 75.9 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (170 mg, 0.38 mmol) and 10% Pd/C (150 mg) in methanol (4 mL) and tetrahydrofuran (5 mL) was hydrogenated by a H2 balloon at 30° C. After filtration, the filtrated was concentrated and purified on preparative thin layer chromatography to afford 130 mg of 3,3-Dimethyl-2-(3-phenylsulfamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][OH:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[OH:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:16]([CH3:18])[CH3:17])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)=[O:11]
Reactant: CC(C)c1ccccc1S
Reactant: O=C(CO)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Sc1ccc(C(=O)CO)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
Then 2-hydroxy-1-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-ethanone 28 was prepared as follows. To a solution of compound 27 (0.4 g, 1.8 mmole) and o-isopropylthiophenol (0.31 ml, 1.8 mmole) in DMF (10 ml) was added Cs2CO3 (0.59 g, 1.8 mmole). The mixture was stirred for 10 minutes and EtOAc (30 ml) was added. The mixture was filtered, concentrated and chromatographed on a silica gel column eluting with 30% EtOAc in hexane. The desired product 28 was obtained as an oil, 0.22 g, 34.8%. 1H-NMR (CDCl3, 300 MHz) δ 1.17 (d, J=7.0 Hz, 6 H), 3.40-3.46 (m, 2 H), 4.80 (s, 2H), 6.82 (d, J=8.4 Hz, 1H), 7.27-7.31 (m, 1H), 7.51-7.55 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 8.17 (s, 1H); MS (DCI/NH3) m/z 355 (M+H)+, 372 (M+NH4)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=2)[NH:6][CH:5]=1.[CH2:19]([OH:21])C>C(OCC)=O>[CH3:18][S:15]([NH:14][CH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH:1][CH:19]=[O:21])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCN)c2c1
Reactant: CCO
Solvent: CCOC=O
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCNC=O)c2c1

Procedure:
A solution of N-[[3-(2-aminoethyl)-1H-indol-5-yl]methyl]methanesulphonamide (2.1 g) in ethanol (20 ml) and ethyl formate (25 ml) was refluxed for 17 h. The solvent was evaporated in vacuo and the residue was partitioned between sulphuric acid (1N; 100 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic extracts were washed with brine (50 ml) and potassium carbonate solution (15%; 50 ml) and dried (Na2SO4). Evaporation of the solvent in vacuo gave the crude product as a very viscous oil (2.2 g). The oil was dissolved in THF (8 ml), scratched and left overnight at room temperature. Filtration gave the title compound (1.3 g) as a white solid m.p. 121°-5°.
Reaction SMILES: [CH2:1](O)[CH2:2]OCCO.[C:8]1([CH2:18][N:19]=[C:20]=[O:21])C(C[N:15]=[C:16]=[O:17])=CC=CC=1.C([C:26]1(C)[C:31]([OH:32])=C(C(C)(C)C)C=CC1)(C)(C)C>>[CH:1]([N:19]([CH:18]=[CH2:8])[C:20]([O:32][CH2:31][CH3:26])=[O:21])=[CH2:2].[N-:15]=[C:16]=[O:17]
Reactant: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Reactant: OCCOCCO
Reactant: O=C=NCc1ccccc1CN=C=O
Product: C=CN(C=C)C(=O)OCC
Product: [N-]=C=O

Procedure:
To 53 g of diethylene glycol (0.5 mole) was added 197 g (1.05 mole) of xylylene diisocyanate, and the mixture was reacted at 80° C. for 2 hours. Then 390 g (1.0 mole) of hydroxyethyl tetraphthalyl acrylate (OH value: 146; average molecular weight: 390) represented by the formula ##STR1## wherein n is the average degree of polymerization and was 1.4 and 0.30 g of 2,6-di-t-butyl cresol as a polymerization inhibitor were added. The resulting mixture was reacted at 80° C. while blowing air through the mixture for 8 hours, and thus a divinyl urethane compound with a remaining isocyanate value of 4.8 was obtained.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16].Cl>C(O)C.O>[OH:23][C:22]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH:21]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Temperature: 85 °C

Procedure:
To a solution of phenyl hydrazine (10 g, 92.6 mmol) in absolute ethanol (100 mL) is added dry K2CO3 (15.3 g, 111 mmol) and followed by slow addition of diethylacetylene dicarboxylate (10.6 g, 62.03 mmol) and the reaction mixture is heated at 85° C. for 12 h. The reaction mixture is then cooled to rt and 38 mL of 6N HCl is added dropwise. The reaction mixture is diluted with 150 mL water, extracted with ethylacetate. The organic layer is washed with water twice, dried over Na2SO4 and concentrated under vacuum. The residue is triturated with MTBE and the solid formed is filtered, washed with MTBE and dried to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.12 (bs, 1H), 7.72-7.70 (m, 2H), 7.51-7.47 (m, 2H), 7.37-7.34 (m, 1H), 5.93 (s, 1H), 4.26 (q, J=4.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). MS (ESI+): 233.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: c1cn[nH]c1
Product: Clc1ccc(-n2cccn2)cc1

Procedure:
1-(4-Chlorophenyl)-1H-pyrazole was prepared from 1-bromo-4-chlorobenzene and pyrazole according to the procedure of Cristau et al., Eur. J. Org. Chem. 2004, 4, 695-709.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[ClH:21]>C(OCC)(=O)C.C(O)C.[Pd]=O>[ClH:21].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Oc2ccccc2)cc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(CS(=O)(=O)Oc2ccccc2)cc1

Procedure:
A solution of phenyl 4-nitrobenzenemethanesulphonate (1.6 g) in ethyl acetate (200 ml) and concentrated hydrochloric acid (1 ml) was hydrogenated over prereduced 5% palladium oxide on charcoal (50% aqueous paste 0.4 g) in ethanol (10 ml) at atmospheric pressure and temperature. The catalyst was filtered off and the filtrate concentrated to give the title compound as a solid (1.55 g). A small sample (0.2 g) was crystallized from isopropyl acetate (10 ml) and a few drops of methanol to give analytically pure material (70 mg) m.p. 147°-148°.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.C[O-].[Na+].Cl>CO>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:2](=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dimethyl oxalate (15.27 g, 0.129 mol) and 4′-chloroacetophenone (20.0 g, 0.129 mol) were charged to a 500 mL round-bottom flask, with provisions made for magnetic stirring, and diluted with methanol (300 mL). Sodium methoxide (25% in methanol, 70 mL) was added in one portion. The reaction was stirred at room temperature for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then concentrated hydrochloric acid (70 mL) was added, and the white suspension was stirred vigorously at room temperature for sixty minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was washed with cold water (100 mL). Upon drying, methyl 4-[4-(chloro) phenyl]-2,4-dioxobutanoate was obtained (16.94 g, 54.4%) as the enol: 1H NMR (CDCl3/300 MHz) 7.94 (d. J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H), 3.48 (s, 1H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[O-2].[Al+3].[O-2].[O-2].[Al+3]>CO.[Pd]>[CH:22]1([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH2:23][CH2:24]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1

Procedure:
(trans)-N,N-Dibenzyl-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16a (1.41 g, 3.38 mmol) was dissolved in 15 mL of methanol followed by the addition of palladium/carbon (706 mg, 10%) and 0.1 mL of acetic acid, filled with hydrogen three times. The reaction mixture was reacted for 12 hours at 3 atmosphere of hydrogen, added with 3 g alkaline aluminum oxide (200-300 mesh) and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16b (900 mg, yield: 100%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[C:21](=[O:22])[N:20]4[C:23]([CH3:26])=[CH:24][S:25][C:19]4=[N:18][C:17]=3[CH3:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(OCC)(OCC)[O:31][CH2:32][CH3:33].[CH3:40][C:41]1C=CC(S(O)(=O)=O)=CC=1.N>C(O)C>[CH2:40]([O:7][C:6]([O:31][CH2:32][CH3:33])([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:29][CH:28]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[C:21](=[O:22])[N:20]3[C:23]([CH3:26])=[CH:24][S:25][C:19]3=[N:18][C:17]=2[CH3:27])[CH2:10][CH2:9]1)[CH3:41]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: N
Solvent: CCO
Product: CCOC(OCC)(c1ccc(F)cc1)C1CCN(CCc2c(C)nc3scc(C)n3c2=O)CC1

Procedure:
A mixture of 8.3 parts of 6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 10 parts of 1,1',1"-[methylidynetris(oxy)]trisethane, 4 parts of 4-methylbenzenesulfonic acid and 80 parts of ethanol was stirred and refluxed for 72 hours. After cooling, gaseous ammonia was introduced. The formed precipitate was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and ethanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by reversed phase chromatography over LiChroprep. RP 18 using a mixture of water (containing 0.5% ammonium acetate) and methanol (containing 0.1% of N-(1-methylethyl)-2-propanamine) (15:85 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 0.6 parts of 6-[2-[4 -[diethoxy(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 115.6° C. (compound 36).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Cl[CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1)[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: N#Cc1cccc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 5-methoxy-2-phenyl-1H-indole (200 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (dispersed in liquid paraffin, 50% or more, 45 mg) under ice-cooling. This mixture was stirred for 30 minutes at room temperature. Subsequently, 6-chloromethylpyridine-2-carbonitrile (216 mg) was added thereto, followed by stirring at 80° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (228 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.55 (2H, s), 6.55-6.65 (1H, m), 6.77 (1H, dd, J=2.4, 8.8 Hz), 6.91 (1H, dd, J=1.5, 7.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.26 (1H, d, J=8.8 Hz), 7.35-7.55 (5H, m), 7.85-7.95 (2H, m).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>C(Cl)Cl>[CH3:17][S:18]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.2 M solution of 2-(2-hydroxyethyl)pyridine (4.5 mmol) in methylene chloride is added triethylamine (24 mmol), followed by methanesulfonyl chloride (4.8 mmol.) The resulting mixture is stirred at room temperature overnight. The mixture is then poured into water and extracted with methylene chloride. The organic extracts are combined, washed with NaHCO3 (sat), and then 1M aq. HCl. The acidic aqueous extracts are neutralized with NaHCO3 (sat) and then extracted with methylene chloride. The organic extracts were combined, dried (MgSO4), filtered, and concentrated to afford the desired product (1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(C)ccc4N3)c2)cc1
Yield: 31.9 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 4-methyl-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 16 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 67 mg of 4-methyl-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 32%). MS (ESI+APCI) M+1=421.2.