Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CI>C1COCC1>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([CH3:2])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a -78° C. solution of LDA (10.79 mmol) in THF (30 mL) was added 1-benzyl-4-piperidone (2.0 mL, 10.8 mmol). The reaction mixture was warmed to 0° C. for 20 min and then cooled back to -78° C. Methyl iodide (0.67 mL, 10.8 mmol) was added to the enolate solution which was stirred at 0° C. for 2 h then warmed to RT overnight. The reaction mixture was quenched with sat. NH4Cl and concentrated. The residue was suspended in H2O and extracted with CH2Cl2. The combined organic layers were dried with MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with 1:1 hexane-EtOAc to give the 1-benzyl-3-methyl-4-piperidone 4 as a yellow oil (0.65 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]12[CH2:13][CH2:12][C:8]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH:9](Br)[CH2:10]1)[O:7][CH2:6]2.[BH4-].[Na+]>CO.C(OCC)(=O)C.O1CCCC1.ClC1C=CC=CC=1.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]12[CH2:13][CH2:12][C:8]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH2:9][CH2:10]1)[O:7][CH2:6]2
Reactant: COC(=O)CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC12CCC(c3ccc(Cl)cc3)(CC1)OC2
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a stirred solution of [6-bromo-1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acetic acid methyl ester (0.75 g, 2.007 mmol) and nickel (II) chloride (0.182 g, 1.405 mmol) in methanol (30 ml), ethyl acetate (15 ml), tetrahydrofuran (15 ml) and chlorobenzene (2 ml) at −30° C., was added carefully sodium borohydride (0.228 g, 6.02 mmol). The reaction mixture was allowed to warm to room temperature for 40 minutes. The solvent was removed under vacuum at room temperature and then water (20 ml) and EtOAc (100 ml) were added. The organic phase was separated and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (heptanes/acetone 2/1) to afford [1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acetic acid methyl ester (0.39 g, 66%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.65-1.81 (m, 4H) 1.96 (t, J=8.00 Hz, 4H) 2.11 (s, 2H) 3.62 (s, 3H) 3.87 (s, 2H) 7.20 (d, J=8.60 Hz, 2H) 7.25 (d, J=8.60 Hz, 2H).
Reaction SMILES: C(OCC)(=O)C.[OH:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[C:20]1([NH:26][C:27]([O:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C(C)C(=O)Nc1cccc(O)c1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)Nc1cccc(OC(=O)Nc2ccccc2)c1
Temperature: 65 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate and 17.7 parts of 3'-hydroxy-2-methylacrylanilide and heated with stirring to about 65°C. Phenyl isocyanate, 12 parts, is added. No apparent reaction occurs until one part of triethylamine is added to the reaction mixture. After a slight exothermic increase in temperature, the reaction mixture is heated at reflux for one-half hour, cooled and filtered. The solids are washed with ethyl acetate and air dried to give 22.8 parts of 3'-(phenylcarbamoyloxy)-2-methylacrylanilide, m.p. 177°-178°C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:17][CH3:18])[C:10]([C@H:12]1[CH2:15][C@@H:14]([OH:16])[CH2:13]1)=O)[CH3:8].O.[OH-].[Na+]>O1CCCC1>[OH:16][C@@H:14]1[CH2:13][C@H:12]([CH2:10][N:9]([CH2:17][CH3:18])[CH2:7][CH3:8])[CH2:15]1
Reactant: CCN(CC)C(=O)[C@H]1C[C@@H](O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C[C@H]1C[C@@H](O)C1

Procedure:
To a solution of lithium aluminum hydride (78.4 mg, 2.07 mmol) in tetrahydrofuran (3.8 mL) was added the compound of Example 3-1 (322 mg, 1.88 mmol), and the mixture was heated to reflux for 3 hours. To the reaction solution were successively added water (79 μL), 4M aqueous sodium hydroxide solution (79 μL) and water (237 μL) at room temperature, and the mixture was filtered through celite. The filtrate was concentrated to give the titled compound (282 mg, 96%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13]C(=O)OC(C)(C)C)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].O1CCOCC1>Cl.C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
A solution of tert-butyl (S)-3-azido-1-phenylpropan-2-ylcarbamate (1.0045 g, 3.6 mmol) was dissolved in 4 M HCl in dioxane (20 mL, 80 mmol) and stirred at rt for 2 h. The solvent was stripped. The residue was taken up in CH2Cl2 (50 mL) and 1 N aq NaOH (10 mL), extracted with CH2Cl2 (3×10 mL), washed with brine (3×5 mL), dried (Na2SO4), decanted, and stripped to afford (S)-1-azido-3-phenylpropan-2-amine (812.9 mg, quant, 80% purity) as a clear oil. MS ESI+ve m/z 177 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CC(C)=O>[Cl:24][C:23]([Cl:25])([Cl:26])[CH2:22][O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: OCC1CCNCC1
Reactant: O=C(CCCBr)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCN1CCC(CO)CC1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A stirred solution of 4-piperidinemethanol (1.72 g, 15.0 mmol) in acetone (100 ml) was added K2CO3 (4.14 g, 30. mmol) and 2,2,2-trichloroethyl 4-bromobutyrate (4.47 g, 15.0 mmol) and heated under reflux for 3 h. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The residue was added CH2Cl2 (75 ml) and washed with brine (25 ml) and H2O (2×25 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to leave the title compound as a viscous oil (4.70 g, 94.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH:28]=[CH2:29])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][O-:31].[Na+].CO>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH2:28][CH2:29][O:31][CH3:30])(=[O:26])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[O-]
Reactant: C=CS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(ethenylsulfonyl)amino]methyl}-1,4-oxazepane-4-carboxylate (200 mg) in methanol (1 mL) was added 28% sodium methoxide-methanol (4 mL) solution at room temperature, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (132 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.O>C1C=CC=CC=1.S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:27])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(C(F)(F)F)cc3)c3c(c2[nH]1)CC(C)(C)O3
Reaction time: 1 h
Yield: 8.7 %

Procedure:
To a solution of 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.100 g, 0.268 mmol) in benzene (2 mL), thionyl chloride (3.0 mL) was added at 5-10° C. and the reaction mass was refluxed for 3 h. To the reaction mixture, stirred solution of 4-trifluoromethyl phenyl amine (0.065 g, 0.403 mmol) and DIPEA (0.069 g, 0.534 mmol) in THF (10.0 mL) for 1 h at RT under N2-atmosphere was added and stirring was continued for another 1 h at RT. Excess of thionyl chloride was co-evaporated with THF under vacuum. Water was added to the reaction mass and it was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 2.24 (s, 3H), 3.44 (s, 2H), 7.25-7.31 (m, 2H), 7.42 (d, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 9.09 (s, 1H), 10.01 (s, 1H), 10.94 (s, 1H); MS [M−H]−: 513.42.
Reaction SMILES: [O-]CC.[Mg+2:4].[O-]CC.[C:8]([OH:17])(=[O:16])[CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12].CC(C)=O>C(O)C>[C:8]([O-:17])(=[O:16])[CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12].[Mg+2:4].[C:8]([O-:17])(=[O:16])[CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(CCC)C(=O)O
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCC(CCC)C(=O)[O-]
Reaction time: 0.17 h
Yield: 66 %

Procedure:
11.4 g (0.1 mol) of magnesium ethoxide solid was added to a magnetically stirred, clear, colorless solution of valproic acid (28.8 g; 0.2 mol; Sigma Aldrich Chemical Co.) in 25 mL of absolute ethanol. Residual solid was rinsed into the reaction with 5 mL of absolute ethanol to provide a total volume of 30 mL of absolute ethanol. Within 10 minutes, the slurry became very warm to the touch, and the color of the solution phase changed to pale yellow. Complete dissolution of the magnesium ethoxide solid in ethanol was never achieved, but within minutes the solid phase converted from a slurry of a yellow granular solid to a suspension of white solid that was so thick that stirring stopped. 100 mL of acetone was added, and the thick slurry was stirred for 10 minutes. The precipitate was isolated by filtration, washed with fresh acetone, and dried to constant weight. The product, magnesium valproate, was obtained in 66% yield. Elemental analysis (Table 1) indicated that the product was an inhomogeneous mixture of magnesium valproate and other magnesium salts. The theoretical valproate content (%) of magnesium valproate is 92.2%; the valproate content found by HPLC analysis was 78.4%.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(CCCCCC(O)C(OC)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(=O)CCCC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COC(=O)C(O)CCCCCC(=O)OC(C)(C)C
Agent: [Na+]
Product: COC(=O)C(O)CCCC(=O)OC(C)(C)C
Yield: 78.2 %

Procedure:
Crude methyl 5-tert-butoxycarbonyl-2-oxopentanoate (1.08 g, 4.7 mmol) and sodium triacetoxyborohydride (1.0 g, 4.7 mmol) were reacted by the same procedure as described in Example 1 for the preparation of methyl 7-tert-butoxycarbonyl-2-hydroxyheptanoate to give the title compound (854 mg, 78%, 2 steps) as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][C:9]([S:14][CH3:15])=[N:8][C:7]=2[NH:6][CH:5]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[Cl:13][C:11]1[C:12]2[C:4]([CH2:3][CH2:2][O:1][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:5][NH:6][C:7]=2[N:8]=[C:9]([S:14][CH3:15])[N:10]=1
Reactant: CSc1nc(Cl)c2c(CCO)c[nH]c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The hydroxyethyl pyrrolopyrimidine (1.4) (1.91 g, 7.8 mmol) was dissolved in DMF (25 ml) and tert-butyldimethylsilyl chloride (1.77 g, 11.7 mmol) and imidazole (1.6 g, 23.5 mmol) added and the solution stirred at room temperature for 6 hours. The solvent was removed and the product dissolved in chloroform, washed with water and the solvent evaporated. The product was precipitated by trituration with methanol, filtered and dried to give an off-white solid. A second fraction was obtained by concentration of the mother liquors. Yield 2.51 g, 89%. δH −0.07 (6H, s, 2×CH3), 0.80 (9H, s, C(CH3)3), 2.52 (3H, s, SCH3), 2.94 (2H, t, J 7.0 Hz, OCH2CH2), 3.78 (2H, t, J 7.0 Hz, OCH2), 7.29 (1H, s, H6), 12.10 (1H, s, NH) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19]CC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C.CCCCCC>[CH2:25]([O:24][C:22]([CH:16]1[C:17](=[O:19])[C:3]2[C:2](=[C:11]3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8][CH:9]=[N:10]3)[N:1]=[CH:15]1)=[O:23])[CH3:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc2cccnc12
Solvent: CCO
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2c(ccc3cccnc23)C1=O
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 8-aminoquinoline (14.4 g) and diethyl ethoxymethylenemalonate (26 g) in ethanol (100 ml) was heated at reflux for 18 hours. The mixture was cooled, filtered and the solid washed with ethanol. The solid so obtained was added to refluxing diphenyl ether (1000 ml), and the resulting mixture stirred at reflux for 45 minutes. The mixture was cooled to approximately 60° C. and diluted with hexane (500 ml). The mixture was cooled to ambient temperature, filtered and the solid washed with hexane to give 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline in 84% yield, mp 242-244° C.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]1[N:15]2[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]2=[N:13][C:12]=1[CH3:26].[C:27](C(O[Na])=O)([F:30])([F:29])[F:28].CN(C=O)C.C1(C)C=CC=CC=1.CCCCCC>[Cu]I.CCOC(C)=O>[CH2:21]([CH:20]([C:19]1[C:14]2[N:15]([C:11]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[C:27]([F:30])([F:29])[F:28])=[C:12]([CH3:26])[N:13]=2)[N:16]=[C:17]([CH3:25])[CH:18]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3Br)c(C)nc12
Reactant: O=C(O[Na])C(F)(F)F
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3C(F)(F)F)c(C)nc12
Temperature: 210 °C

Procedure:
90 mg of 3-(3-Bromo-thieno[3,2-b]pyridin-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.21 mmol), 57 mg of CF3CO2Na (0.42 mmol) and 80 mg of CuI (0.42 mmol) are placed into microwave vessel with 3 ml of DMF/toluene=2/1. The vial is capped and heated at 210° C. for 60 min in microwave. The reaction mixture is applied onto silica-gel column (Hexane:AcOEt=8:1) directly to produce the tile compound. 27 mg (31%) mass spectrum (m/e): 419 (M+1); 1H-NMR (CDCl3): 8.88 (dd, 1H, J=4.9 Hz, 1.4 Hz), 8.22 (dd, 1H, J=7.8 Hz, 1.4 Hz), 7.4 (dd, 1H, J=7.8 Hz, 4.9 Hz), 6.74 (s, 1H), 3.31 (m, 1H), 2.53 (s, 3H), 2.79 (s, 3H), 1.85 (m, 4H), 0.88 (t, 6H, J=7.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH3:10])[CH3:8])[C:3]=1[C:11]#[N:12].[CH3:13][N:14]=[C:15]=[O:16].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>O1CCCC1>[CH3:13][NH:14][C:15]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:9][CH3:10])[CH3:8])[C:3]=1[C:11]#[N:12])=[O:16]
Reactant: CCN(C)c1nsc(N)c1C#N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCN(C)c1nsc(NC(=O)NC)c1C#N
Yield: 67.9 %

Procedure:
A mixture of 11 g of 5-amino-4-cyano-3-(ethylmethylamino)isothiazole, 6.8 g of methyl isocyanate, 2 ml of dibutyltin diacetate, and 50 ml of tetrahydrofuran was heated under reflux overnight. After cooling, the solution was evaporated under reduced pressure. The residue was recrystallized from toluene to yield 9.8 g of 1-methyl-3-(4-cyano-3-(ethylmethylamino)-5-isothiazolyl)urea, mp 175°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)N.C(O[CH:16](OCC)[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])C>C(O)(=O)C>[O:30]=[C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:29])[N:20]1[CH2:19][CH2:18][C:17]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]#[N:12])[CH:8]=2)[NH:2][CH:16]=1
Reactant: N#CCc1ccc(NN)cc1
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: N#CCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Yield: 80.4 %

Procedure:
A mixture of 4-hydrazino phenylacetonitrile hydrochloride (3.15 g) and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal diethyl acetal (4.95 g) in acetic acid (25%, 150 ml) was refluxed for 2 h, cooled to 25°, precipitate filtered, washed with water (2×20 ml) and ether (100 ml). The crude product was obtained as a dark solid (4.5 g) which was triturated with ethyl acetate to give the title compound (3.16 g) m.p. 185°-186°.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH2:13][C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10]C)[CH2:3][CH2:2]1.CCCCCC>C(O)C>[CH:1]1([C:4]2[C:9](=[O:10])[NH:8][C:7]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH2:13][C@H:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:18]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc3c(c2)CCO3)ccc1C1CC1
Solvent: CCO
Solvent: CCCCCC
Product: O=C1CC[C@H](CC(c2ccc3c(c2)CCO3)c2ccc(C3CC3)c(=O)[nH]2)N1

Procedure:
An (R,S) mixture of the title compound was obtained as a yellow amorphous (78 mg) by performing substantially the same reaction as in Examples 4-207 and 4-208(3) except for using (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-2-one. This was preparatively isolated by a chiral HPLC column (CHIRALPAK IB, hexane:ethanol=30:70 v/v, 40° C., 10 mL/min, 210 nm) to give one diastereomer (A) of the title compound as a colorless amorphous (50 mg) and the other diastereomer (B) of the title compound as a colorless amorphous (45 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])[CH:5]=[CH:6][CH:7]=1.[C:20]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH2:38][O:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33]Br)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([C:20]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[CH2:38][O:39][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH2:33][O:1][C:2]2[C:3]([CH3:19])=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=3[CH3:18])[CH:5]=[CH:6][CH:7]=2)=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(-c2cccc(O)c2C)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2C)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 515 mg (2 mmol) of methyl 3′-hydroxy-2,2′-dimethylbiphenyl-4-carboxylate with 880 mg (2 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 300 mg (2.2 mmol) of potassium carbonate, the desired product is obtained in the form of a colourless oil (m=1.22 g; Y=99%).
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:20]1[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (200 mg, 0.72 mmol), 1-(bromomethyl)-2,3-dichlorobenzene), prepared as described in Example 3, step f, (259 mg, 1.08 mmol and Na2CO3 (229 mg, 2.16 mmol) in DMF (10 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). It was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with MeOH/DCM=1/60 to afford the desired product as a black solid (243 mg, 78%); LC/MS: MS (ES+) m/e 435 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (s, 3H), 3.40 (t, J=4.2 Hz, 4H), 3.67 (t, J=4.2 Hz, 4H), 3.92 (s, 3H), 5.50 (s, 2H), 6.60 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[N:11]=[C:10]([NH:22][C:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1>COCCO>[N:1]1([C:8]2[N:9]=[C:10]([NH:22][C:23]([CH3:29])([CH3:28])[C:24]([CH3:26])([CH3:27])[CH3:25])[N:11]=[C:12]([NH:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Reactant: C1CNCCN1
Solvent: COCCO
Product: CC(C)(C)C(C)(C)Nc1nc(NC(C)(C)C(C)(C)C)nc(N2CCNCC2)n1
Temperature: 10 °C

Procedure:
A 21 g. portion of piperazine in 500 ml. of methyl cellosolve is treated with 17.1 g. of 2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine. The mixture is stirred at reflux for 8 hours and then at room temperature. The mixture is filtered and the filtrate is taken to dryness in vacuo. The residue is shaken with 200 ml. of water, filtered, the insolubles collected, washed with 500 ml. of water and dried. The solid is suspended in 500 ml. of boiling ethanol, 150 ml. of methyl cellosolve is added and the mixture is concentrated to 300 ml., clarified and cooled to 10° C. The mixture is then taken to dryness in vacuo and the residue is recrystallized from 250 ml. of 60% ethanol with charcoal. The solid is washed with 100 ml. of 50% cold ethanol and dried giving the desired product, m.p. 183°-185° C.