Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]=[C:3]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C.[C].[Pd]>[C:16]([NH:2][CH:3]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCCC(=O)C(=NO)C(=O)OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COCCCCC(=O)C(NC(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl 2-(hydroxyimino)-7-methoxy-3-oxoheptanoate (5.70 g) and palladium-carbon (900 mg) were suspended in acetic acid (60 ml)-acetic anhydride (25 ml) and the mixture was stirred under a hydrogen atmosphere (1 atom) at room temperature for 14 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (5.48 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+:21]([C:24]1[C:25]([CH:35]=O)=[N:26][N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:28]=1)([O-:23])=[O:22]>CO>[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][C:5]2[N:19]=[C:35]([C:25]3[C:24]([N+:21]([O-:23])=[O:22])=[CH:28][N:27]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[N:26]=3)[NH:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(OCCCCN2CCCCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(OCCCCN3CCCCC3)c(F)cc2[nH]1

Procedure:
A solution of 74 mg of 4-fluoro-5-(4-piperidin-1-ylbutoxy)benzene-1,2-diamine and 50.7 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde in 4 mL of methanol is stirred at ambient temperature for 18 hours. After evaporation of the solvent under reduced pressure in a rotary evaporator, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-4 cartridge with a dichloromethane/methanol eluent of 100% to 82/18. 77 mg of 6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-5-(4-piperidin-1-ylbutoxy)-1H-benzimidazoleare isolated in the form of a yellow foam. 1H NMR (300 MHz, DMSO-d6, δ in ppm) for this batch, we observe a 60%-40% resolution of tautomers with: from 1.29 to 2.44 (m, 22H); 3.70 (m, 1H); 4.00 (m, 1H) 4.10 (t, J=6.0 Hz, 2H); 5.60 (dd, J=3.0 and 10.0 Hz, 1H); 7.21 (d, J=8.5 Hz, 0.6H); from 7.36 to 7.46 (m, 0.8H); 7.53 (d, J=11.0 Hz, 0.6H); 9.17 (s, 1H); 12.8 (broad s, 0.6H); 12.9 (broad s, 0.4H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Ic1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Yield: 89 %

Procedure:
To a degassed solution of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (1.28 g, 5.00 mmol), iodobenzene (0.70 mL, 6.15 mmol), potassium carbonate (0.83 g, 6.00 mmol) and rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.08 mL, 0.50 mmol) in dioxane (50 mL) was added copper(I) iodide (0.10 g, 0.50 mmol). The reaction mixture was heated to reflux for 16 hours. The solvent was removed in vacuo, and the residue was suspended in water and filtered. The solid was collected and washed with water (200 mL) and t-butyl methyl ether (100 mL) to afford the title compound in 89% yield (1.49 g): 1H NMR (300 MHz, DMSO-d6) δ 7.69-7.08 (m, 5H), 4.28-4.13 (m, 6H), 2.62 (s, 3H), 1.30 (t, J=6.9 Hz, 3H); MS (ES+) m/z 332.4 (M+1).
Reaction SMILES: Cl[S:2][N:3]([CH3:10])[C:4](=[O:9])[O:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:16]=[CH:15][C:13]=1[NH2:14].C(N(CC)CC)C>C(OCC)C>[Cl:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=1[O:19][C:17]1[CH:16]=[CH:15][C:13]([NH:14][S:2][N:3]([CH3:10])[C:4](=[O:9])[O:5][CH2:6][CH2:7][CH3:8])=[C:12]([F:11])[CH:18]=1
Reactant: CCCOC(=O)N(C)SCl
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCOC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Yield: 97.7 %

Procedure:
A solution of propyl N-chlorosulphenyl-N-methylcarbamate (12.1g) in diethyl ether (20 ml) was added to a stirred solution of the compound of Example 1 (18.3 g) and triethylamine (7 g) in the same solvent (70 ml) over 20 minutes, the temperature being maintained at 15°-20° C. with cooling. Stirring was continued at room temperature for a further 11/2 hours. The reaction mixture was then diluted with diethyl ether (200 ml), washed with water, dried and stripped of solvent. The residue was added to 100 mls toluene, and the toluene was removed under reduced pressure to leave 26.5 g of the desired product in crude form as a brown oil.
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:30]2[C:20](=[O:21])[C@H:9]3[N:8]([C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:12]4[NH:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=5[C:11]=4[CH2:10]3)[C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Reactant: O=C=NC1CCCCC1
Product: O=C1[C@@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C(=O)N1C1CCCCC1

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and cyclohexyl isocyanate gave after recrystallisation from methanol, the title compound as white crystals m.p.: 248-250° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C)[CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12]C)=[CH:7][CH:6]=2.B(Br)(Br)Br.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[OH:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)=[C:3]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1cccc(O)c1
Reaction time: 2.5 h
Yield: 58.9 %

Procedure:
To a solution of (2E)-3-[4-({3-methyl-6-(methyloxy)-2-[3-(methyloxy)phenyl]-1-naphthalenyl}oxy)phenyl]-2-propenoic acid (250) (0.032 g, 0.07 mmol, 1 equiv) in CH2Cl2 (3 mL) at 0° C. was added boron tribromide (0.66 mL, 1.0 M, 9.0 equiv). After 2.5 h, the mixture was treated with saturated aqueous NaHCO3, reacidified to a pH of 2 with 1 M HCl, and extracted with EtOAc (3×5 mL). The pooled organic portions were dried (MgSO4) and concentrated. Radial chromatography (SiO2, 1 mm plate, 70:30; CHCl3/MeOH) furnished the title compound (251) as a pale yellow foam (0.017 g, 57%). 1H NMR (CD3OD, 400 MHz) δ 7.59 (d, J=9.0 Hz, 1H), 7.48 (s, 1H), 7.44-7.36 (m, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.10 (d, J=2.2 Hz, 1H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.94 (dd, J=9.0, 2.2 Hz, 1H), 6.64-6.62 (m, 1H), 6.57-6.55 (m, 4H), 6.39-6.24 (m, 1H), 2.20 (s, 3H). TLC (90:10; CHCl3/MeOH): Rf=0.54.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([CH:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4].[CH3:35][NH:36][CH3:37].O1CCCC1>C(#N)C.C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH3:35][N:36]([CH3:37])[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:34])[N:9]([CH:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:10]2=[O:15])=[O:4]
Reactant: CNC
Reactant: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 3-[4-(2-chloroacetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (1.1 g, 2.3 mmol) in acetonitrile (15 mL) was added dimethylamine in tetrahydrofuran (3.3 mL, 2 N, 6.6 mmol) at room temperature and kept for overnight. The solvent was removed in vacuo to give a solid. The solid was diluted with methylene chloride (50 mL) and sodium hydrogen carbonate (25 mL). The separated organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was purified with chromatography to give 3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-meth-oxyphenyl)-N,N-dimethylpropanamide as a white solid (640 mg, 57% yield). To a stirred solution of 3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide in ethyl acetate (4 mL) was added hydrogen chloride in ether (2 mL, 1N, 2 mmol) at room temperature. The resulting suspension was filtered and washed ethyl acetate to give 3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide hydrogen chloride as a white solid (580 mg, 84% yield): mp, 92-94° C.; 1H NMR (DMSO-d6) δ1.30 (t, J=6.9 Hz, 3H, CH3), 2.75 (s, 3H, CH3), 2.87 (s, 6H, 2CH3), 2.98 (s, 3H, CH3), 3.21 (dd, J=5.7, 16.6 Hz, 1H, CHH), 3.61 (dd, J=9.3, 16.5 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 3.98 (q, J=6.9 Hz, 2H, CH2), 4.26 (s, 2H, CH2), 5.62 (dd, J=5.6, 9.1 Hz, 1H, NCH), 6.90-6.91 (m, 2H, Ar), 7.01 (s, 1H, Ar), 7.65 (d, J=7.2 Hz, 1H, Ar), 7.85 (t, J=7.7 Hz, 1H, Ar), 8.21(d, J=8.2 Hz, 1H, Ar), 10.25 (brs, 1H, HCl), 10.56 (s, 1H, NH); 13C NMR (DMSO-d6) δ14.72, 26.37, 34.41, 34.81, 36.59, 43.34, 50.43, 55.52, 58.02, 63.78, 11.79, 112.38, 119.52, 127.79, 131.88, 131.94, 134.19, 135.79, 147.76, 148.47, 164.52, 167.25, 167.40, 169.16; Anal Calcd for C26H32N4O6+HCl+0.48 H2O: C, 57.65; H, 6.32; N, 10.34; Cl, 6.55; H2O, 1.60. Found: C, 57.70; H, 6.28; N, 10.28, Cl, 6.81; H2O, 1.61.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.B(Cl)(Cl)Cl>ClCCl>[OH:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: COc1cc(OC)c2c(c1)OC1(CCCCC1)CC2=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(O)c2c(c1)OC1(CCCCC1)CC2=O
Reaction time: 1 h

Procedure:
To a solution of 5,7-dimethoxy-spiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 8) (0.70 g, 2.54 mmol) in dry dichloromethane (5 ml) is added dropwise 2M boron trichloride solution in dichloromethane (3 ml, 6 mmol) at -35° C. After one hour stirring at -30° to 0° C., ice-cold water is added to the mixture and the mixture is extracted with dichloromethane. The dichloromethane layer is washed with water, dried, and concentrated to yield 5-hydroxy-7-methoxyspiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one as a crude crystalline solid (0.66 g, 99.5%). Recrystallization from hexane gives a product having a melting point of 69°-70° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34])(=[O:25])=[O:24].[CH3:35]I.O>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]([CH3:35])[S:23]([C:26]1[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32])(=[O:25])=[O:24]
Reactant: CI
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(C)c2ccccc2CSc2nccn2-c2ccccn2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg of 60% sodium hydride are suspended in 2 ml of dimethyl formamide, and a solution of one g of 1-(2-pyridyl)-2-[2-(2,4,6-trimethylphenyl)sulfonylaminobenzylthio]imidazole in 2 ml of dimethyl formamide is added thereto under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and 320 mg of methyl iodide are added thereto. The mixture is stirred for 2 hours. The reaction mixture is poured into water, and the resultant oily product is extracted with ethyl acetate. The extract is dried and evaporated. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:2), whereby 0.76 g of 1-(2-pyridyl)-2-{2-[N-methyl-N-(2,4,6-trimethylphenyl)sulfonylamino]benzylthio}imidazole is obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5](=O)[CH2:6][CH3:7])[CH3:4].F[B-](F)(F)F.[NH:14]=[C:15](SC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:6]([C:5]1[NH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:2][C:3]=1[CH3:4])[CH3:7]
Reactant: CCOC(=O)C(=N)SC
Reactant: CCC(=O)C(C)N
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCOC(=O)c1nc(C)c(CC)[nH]1
Yield: 60 %

Procedure:
The same operation as in Example (1b) was performed using 2-amino-pentan-3-one hydrochloride obtained in Example (15c) (about 10 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate obtained according to a method known in the literature (J. Med. Chem., 38, 1995, 2196-2201) (about 10 mmol), to obtain 1.1 g of the title compound as a yellow solid (60%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([Cl:24])[CH:26]=3)=[CH:16][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2N)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a solution of 1.65 g (4.83 mmol) of (3′-amino-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (100 mL) is added 0.64 mL (5.0 mmol) of 3-chlorobenzoyl chloride. After stirring at room temperature overnight the mixture is concentrated under reduced pressure. The residue is diluted with water and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash silica gel chromatography to provide 1.40 g (60.4%) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:18]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:17]=[CH2:16]
Reactant: COC(=O)c1ccc(OCCO)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(OCCO)ccc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-4-(2-hydroxy-ethoxy)-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-4-(2-hydroxy-ethoxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.12 (s, —CO2H); 7.65 (d, J=8.7, 1 arom. H); 6.55 (m, 2 arom. H); 5.97 (m, —CH═CH2); 5.48, 5.21 (2 d-like, CH═CH2); 4.84 (m, CH2CH2OH); 4.58 (d-like, CH2—CH═CH2); 3.99, 3.67 (2t, J=4.8, CH2CH2OH). 13C-NMR (100 MHz, d6-DMSO): 166.45 (C═O); 162.93; 159.39; 133.30; 133.24; 116.86; 112.86; 105.84; 100.43; 69.82; 68.58; 59.40.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Br:21])[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[C:10]=2[NH:14]C(=O)C)[CH2:5]1)(=O)C.[ClH:22]>>[ClH:22].[Br:21][C:7]1[C:6]2[CH2:5][NH:4][CH2:13][CH2:12][C:11]=2[C:10]([NH2:14])=[C:9]([N+:18]([O-:20])=[O:19])[CH:8]=1
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CCN(C(C)=O)C2
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CCNC2

Procedure:
A mixture of the product from Example 22 (8.8 g, 24.7 mmol) in 100 mL 6 N HCl was heated at reflux for 2.5 h. After cooling in an ice bath, the yellow precipitate was collected by filtration, washed with diethyl ether and air dried to give 7.08 g of a yellow solid. The filtrate was concentrated to give a red orange solid (2.1 g).
Reaction SMILES: C(OC(=O)NC(C)(C)C/C=C/[C:12](=O)[N:13](C)[C@@H:14]([C:26](=[O:41])[N:27]([CH3:40])[C@@H:28]([C:36](=[O:39])[NH:37][CH3:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:40][N:27]([C@@H:28]([C:36](=[O:39])[NH:37][CH3:38])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:26](=[O:41])[C@H:14]([NH:13][CH3:12])[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)NC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 130.1 %

Procedure:
((3E)-1,1-Dimethyl4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)-ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester (0.25 g; 0.40 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 5 min at room temperature. Methylene chloride (5 mL) and solid sodium hydrogen carbonate were added until pH 8. The reaction mixture was washed with methylene chloride (3×10 mL). The combined organic phases were dried (magnesium sulfate) and evaporated in vacuo to afford 0.21 g of the title compound.
Reaction SMILES: [CH2:1]([CH:4]([C:19]([O:21]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[C:5]([O:7]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[CH:2]=[CH2:3].C(N(CC)CC)C.[NH2:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=1>CC(C)=O>[CH2:1]([C:4]1[C:5](=[O:7])[N:42]2[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:41]2=[N:40][C:19]=1[OH:21])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: COc1ccnc(N)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CCc1c(O)nc2cc(OC)ccn2c1=O
Reaction time: 16 h
Yield: 64.8 %

Procedure:
Bis(pentachlorophenyl) allylmalonate (905 mg, 1.412 mmol) and triethylamine (0.359 ml, 2.58 mmol) were added to a slurry of 2-amino-4-methoxypyridine (160 mg, 1.289 mmol) in acetone (6.5 ml). The slurry was stirred for 16 hours, filtered, and washed with acetone to yield the title compound as a white solid (194 mg, 65%). LCMS (ES+) m/z 233.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[OH:1][CH:2]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)[CH2:3][NH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)COCc1cccc(CN2CCCCC2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(O)COCc1cccc(CN2CCCCC2)c1
Yield: 75.9 %

Procedure:
8.60 g (0.021 mol) of 2-[2-hydroxy-3-[3-(1-piperidylmethyl)-benzyloxy]propyl]-1H-isoindole-1,3-dione and 3.3 ml of hydrazine hydrate (80%) are boiled in 80 ml of ethanol for 3 hours. The residdue left after concentration of the mixture by evaporation is taken up in 50 ml of water; 8 ml of conc. hydrochloric acid are added and the reaction mixture is filtered. The filtrate is adjusted to pH 12 with conc. sodium hydroxide solution and extracted with 3×40 ml methylene chloride. The organic phase is dehydrated with Na2SO4 and concentrated by evaporation under vacuum. The residue is distilled in a high vacuum. 4.44 g (76%) of a colourless oil, boiling point 145°-155° C./1×10-2 mbar are obtained. ##STR4##
Reaction SMILES: [NH3:1].[CH:2]1([C:5]2[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](OC)[N:6]=2)[CH2:4][CH2:3]1>CO>[NH2:1][C:7]1[N:6]=[C:5]([CH:2]2[CH2:3][CH2:4]2)[N:10]=[C:9]([O:11][CH3:12])[N:8]=1
Reactant: N
Reactant: COc1nc(OC)nc(C2CC2)n1
Solvent: CO
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Gaseous ammonia is blown through a solution of 5 g of 2-cyclopropyl-4,6-dimethoxy-1,3,5-triazine in 30 ml of methanol at room temperature until saturation is reached. The solution is then stirred in a bomb tube (autoclave) at 140° C. for 1 hour; it is subsequently cooled, and the reaction mixture is filtered to thus obtain 0.5 g of the title product as light-brown crystals, m.p. 156°-157° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:13].[Cl:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Na].C(O)C>[ClH:14].[ClH:13].[CH2:18]([N:17]([CH2:16][CH2:15][N:10]1[C:9](=[O:12])[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:11]1)[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1ccc(-n2ccnc2)n[nH]1
Reactant: ClCCN(CCOc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=c1ccc(-n2ccnc2)nn1CCN(CCOc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
2.43 g (0.015 mole) of 6-(1-imidazolyl)-3(2H)-pyridazinone are dissolved in the solution of 0.35 g (0.015 g-atom) of sodium in 12 ml of absolute ethanol and the solution is stirred at room temperature for 15 minutes. To the thus-obtained suspension, the base liberated from the solution of 4.89 g (0.015 mole) of N-(2-chloroethyl)-N-(2-phenoxyethyl)-N-benzylamine hydrochloride [dissolved in 12 ml of absolute ethanol by adding a solution of 0.35 g (0.015 g-atom) of sodium in 12 ml of absolute ethanol] is added, thereupon the mixture is stirred at room temperature for 30 minutes and then boiled under reflux while stirring for 4 hours, set aside overnight at room temperature and evaporated. The residue is taken up in 200 ml of chloroform, filtered, the organic solution is washed with water, dried and evaporated under reduced pressure. The residue weighing 5.82 g is dissolved in absolute acetone and a calculated amount of ethanolic hydrogen chloride solution is added, diluted with isopropanol and kept in the refrigerator overnight. The precipitate is filtered off, washed with acetone and dried to give 5.9 g (80% yield) of the aimed product, m. p. 153°-156° C.