Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CCOCC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>[OH-].[Na+]>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: On1nnc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Yield: 91.4 %

Procedure:
In 1 N aqueous sodium hydroxide (300 ml) is dissolved 1-hydroxy-6-chloro-1,2,3-benzotriazole (38 g) and thereto is added ether (100 ml). To the solution is added dropwise p-chlorobenzenesulfonyl chloride (57 g) with stirring under ice-cooling during 15 minutes, and the mixture is stirred at the same temperature for 70 minutes. The reaction mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium hydrogen carbonate and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off, and the resulting crystals are recrystallized from benzene-petroleum ether to give 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (70.5 g), melting point: 125°-127° C. Infrared spectrum (Nujor): 1190, 1085 cm-1.
Reaction SMILES: C(O)=O.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]12[CH2:20][O:19][C@H:18]([CH2:21][O:22]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:17]1[CH2:16][S:15][C:14]([NH:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[N:13]2.C(N(CC)CC)C>O>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]12[CH2:20][O:19][C@H:18]([CH2:21][OH:22])[C@H:17]1[CH2:16][S:15][C:14]([NH:42][C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[N:13]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Reaction time: 0.42 h
Yield: 101.8 %

Procedure:
Formic acid (116 mL) was added to N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (33.30 g, 0.051 mol, 1.0 equiv.), the mixture was stirred at r.t for 25 min. Water (17 mL) was added dropwise then the reaction was stirred for another 30 min. The resulting suspension was filtered; the filtrate was dried by azeotropic distillation under vacuum with toluene (360 mL). Methanol (110 mL) was added followed by triethylamine (22 mL, 0.15 mol, 3.0 equiv.) and the solution was stirred for 2 h. The solvent was removed under vacuum and chased with toluene (66 mL). The residual oil was dissolved in CH2Cl2 (250 ml) and washed successively with aq.HCl (1M, 100 mL), sat aq.NaHCO3 (67 mL) and 18% aq.NaCl (67 mL). The organic phase was concentrated under reduce pressure. Toluene (66 mL) and THF (67 mL) were added to the residue then the solution was filtered through celite and concentrated under reduced pressure to yield the title compound (21 g). 1H NMR (500 MHz, DMSO) ppm 8.11 (dd, J=16.4, 4.2 Hz, 2H), 7.70-7.58 (m, 1H), 7.57-7.44 (m, 3H), 7.43-7.34 (m, 1H), 7.34-7.26 (m, 1H), 4.43 (d, J=9.5 Hz, 1H), 4.25-4.16 (m, 1H), 4.10 (d, J=9.2 Hz, 1H), 3.59 (d, J=4.5 Hz, 2H), 3.30-3.21 (m, 1H), 3.20-3.08 (m, 2H); 13C NMR (125 MHz, DMSO) δ ppm 169.08, 150.95 (dd, JCF=245.8, 13.1 Hz), 148.22, 148.09 (dd, JCF=248.7, 13.2 Hz), 133.46, 129.11, 128.99, 128.62, 125.43, 124.70, 118.16 (d, JCF=16.9 Hz), 81.36, 75.29, 66.76, 62.39, 40.77, 24.25.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([CH:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl.C1CCCCC1>[Cl:26][CH2:27][C:28]([NH:25][CH:15]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=[O:29]
Reactant: COc1cccc(CC(N)c2ccccc2)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: COc1cccc(CC(NC(=O)CCl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
Triethylamine (254.9 g, 2.5 mol) was added with stirring to a solution of 1-phenyl-2-(3-methoxyphenyl)ethylamine hydrochloride (166.0 g, 0.63 mol) in chloroform (4 L) under nitrogen at 0° C. Then chloroacetyl chloride (142.2 g, 1.26 mol) was added dropwise over a period of 2 hrs. The resulting mixture was stirred at ambient temperature (about 25° C.) for 16 hrs, washed with 10% HCl (3×1 L) and water (1 L), and then the organic phase was dried over MgSO4. Evaporation of the solvent gave a dark oily residue which was dissolved in cyclohexane (2 L). Upon standing, the resulting solution gave solid crystals which were collected by filtration and dried to give 142.5 g of N-chloroacetyl-1-phenyl-2-(3-methoxyphenyl)ethylamine. A sample recrystallized twice from cyclohexane had a mp. 104°-105° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1
Reactant: O=[N+]([O-])c1c[nH]nc1Cl
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cc([N+](=O)[O-])c(Cl)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of 3-chloro-4-nitro-1H-pyrazole (1.0 g, 6.8 mmol) in DMF (30 mL) was added ethyl 2-bromo-2-methylpropanoate (2.00 g, 10.2 mmol) and Cs2CO3 (4.40 g, 13.6 mmol). The mixture was stirred at 100° C. for 2 h. After filtration, the solution was poured into water and extracted with ethyl acetate for 3 times. The organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography to afford the title compound (1.2 g, 68%) as yellowish oil. LC-MS (ESI): m/z=262.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:9]=1)=[O:4]
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1cc(N)nn1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(NCc2cccc(Cl)c2)nn1C

Procedure:
5-Amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (644, 1.3 g, 8.0 mmol) was combined with 3-chlorobenzaldehyde (645, 0.95 mL, 8.4 mmol) and acetonitrile (40 mL). Trifluoroacetic acid (3.2 mL, 42.0 mmol) was added followed by triethylsilane (6.7 mL, 42.0 mmol). The reaction was heated to reflux overnight and then concentrated. Ethyl acetate was added and the solution was washed with 1N potassium carbonate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated. The compound (646, 0.944 g, 42%) was crystallized from a mixture of ethyl acetate: hexane.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].C([O:20][C:21](=O)[CH:22]([Cl:26])[C:23]([CH3:25])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[Cl:26][C:22]1[C:21]([OH:20])=[N:7][C:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[N:6][C:23]=1[CH3:25]
Reactant: CC(=O)Nc1ccc(C(=N)N)nc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(-c2nc(C)c(Cl)c(O)n2)nc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of compound of example 44 (0.01 g, 0.56 mmol) in water (2 mL) and ethanol (1 mL) was added ethyl-2-chloroacetoacetate (0.015 g, 0.89 mmol) and sodium carbonate (0.0107 g, 1.011 mmol). The reaction mixture was stirred at room temperature for a period of 26 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:28]=[C:14]2[C:15]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:16][CH:17]=[C:18]([F:19])[C:13]2=[N:12]1.I([O-])(=O)(=O)=[O:30].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:28]=[C:14]2[C:15]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:16][CH:17]=[C:18]([F:19])[C:13]2=[N:12]1)[CH:8]=[O:30]
Reactant: C=Cc1cc(Cl)c(-n2cc3c(Nc4cc(C)ncn4)ncc(F)c3n2)c(Cl)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4Cl)cc23)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a mixture of [2-(2,6-dichloro-4-vinylphenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)amine (193 mg, 0.47 mmol) in acetone (10 mL) and water (2.5 mL) was added osmium (VIII) oxide (2.5% wt in tert-butanol, 0.465 mL), followed by sodium periodate (257 mg, 1.2 mmol) and the reaction mixture was stirred at room temperature overnight. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (80% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (129 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 10.10 (s, 1H), 9.35 (d, J=2.6 Hz, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.31 (s, 2H), 8.01 (d, J=3.5 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:30]([OH:33])[CH2:31][CH3:32])=[CH:10][CH:9]=1.[C:34](OC=C)(=O)[CH3:35]>C1C(Cl)=CC=C(Cl)C=1>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:30]([O:33][CH:34]=[CH2:35])[CH2:31][CH3:32])=[CH:10][CH:9]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccc(Cl)cc1
Product: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
To a suspension of sodium carbonate (16.4 mg, 0.155 mmol) in dichlorobenzene (0.5 mL) were added di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium (I)] (8.7 mg, 0.0129 mmol), 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100.0 mg, 0.155 mmol) and vinyl acetate (47.7 μL, 0.517 mmol). The reaction mixture was stirred at 100° C. for 3.5 hrs. The mixture was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (66.4 mg, 0.161 mmol, 62%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2(C[CH:10]3[CH2:12][CH2:13][CH:7]2[CH2:8][CH2:9]3)[CH2:2]1.[CH2:14](Br)[CH2:15][C:16]1[CH:21]=C[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](O)[CH3:30]>>[CH2:2]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:19][C:18]21[CH2:17][CH:16]1[CH2:21][CH2:29][CH:30]2[CH2:14][CH2:15]1)[CH2:3][C:7]1[CH:8]=[CH:9][CH:10]=[CH:12][CH:13]=1
Reactant: BrCCc1ccccc1
Reactant: C1CNCC2(C1)CC1CCC2CC1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CCN2CCCCC23CC2CCC3CC2)cc1
Reaction time: 18 h

Procedure:
An amount of 6.0 g (0.030 mole) of spiro[bicyclo[2.2.2]-octane-2,3'-piperidine] is dissolved in 50 ml of ethanol; additions are then made of 6.8 g (0.033 mole) of phenethylbromide and 10 g (ca. 0.07 mole) of anhydrous potassium carbonate, and the whole subsequently refluxed, with stirring, for 18 hours. The reaction mixture is filtered, and the brown filtrate concentrated in vacuo (ca. 12 Torr). The viscous residue is distributed between 100 ml of methylene chloride and 100 ml of water. The methylene chloride phase is separated, and the aqueous phase afterwards washed twice with 100 ml of methylene chloride. The combined methylene chloride solutions are dried over sodium sulphate, and then concentrated in vacuo (ca. 12 Torr). There is obtained viscous 1'-phenethylspiro[bicyclo[2.2.2]octane-2,2'-piperidine]. This is dissolved in 50 ml of ether and there is then added to the solution, with stirring, 10 ml of saturated ethereal hydrogen chloride solution. The precipitated hydrochloride is filtered off. There is obtained, after recrystallisation from acetone, 1'-phenethyl-spiro[bicyclo[2.2.2]octane2,3'-piperidine]-hydrochloride, M.P. 263° (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[S:27][C:26](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:30](=[O:31])[CH:29]=[CH:28][C:26]4[S:27][C:23]([Cl:22])=[CH:24][CH:25]=4)[C@@H:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)s1
Reactant: CCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Product: CC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C=Cc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-ethyl-piperazine-2-one, EXAMPLE 77 and 3-(5-chloro-thiophen-2-yl)-(E)-acrylic acid, EXAMPLE 25. 1H NMR(d6-DMSO+1 drop TFA, 300 MHz) δ9.78 (bs, 2H), 8.79 (s, 1H), 8.37 (d, 1H), 7.65 (m, 2H), 7.50 (s, 1H), 7.41 (m, 1H), 7.11 (d, 1H), 6.98 (d, 1H), 4.88 (m, 2H), 4.60 (m, 1H), 4.31 (m, 1H), 3.52 (m, 1H), 3.30 (m, 2H), 1.96 (m, 2H), 0.88 (m, 3H). MS (ion spray), m/z, (M+H)=456, 458 (Cl pattern). Elemental analysis, cal C22H22ClN5O2S.1.5C2HF3O2% C=47.89, % H=3.78, % N=11.17; found % C=47.34, % H=4.00, % N=11.12.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[N:23]1(CCN)CCOC[CH2:24]1.C(Cl)CCl.[CH:36]1[CH:37]=[CH:38][C:39]2N(O)N=[N:42][C:40]=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][C:39]1[CH:40]=[N:42][CH:36]=[CH:37][CH:38]=1)=[O:14])=[O:7]
Reactant: NCCN1CCOCC1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2cccnc2)c1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (68 mg, 0.2 mmol) and 2-morpholine-4-yl-ethylamine (0.039 ml, 0.3 mmol) in DMF 3.0 mL was added EDC (57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:1) to give 3-[2-(2,4-dichloro-phenoxy)acetylamino]-N-pyridine-3-ylmethyl-benzamide as a white solid (34.1 mg, 38% yield).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]3[N:11]([C:13]([CH:16]=[CH2:17])=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CCO.[Pd]>[CH2:16]([C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]2=[N:15][CH:14]=1)[CH3:17]
Reactant: C=Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Reaction time: 2 h

Procedure:
100 mg 4-(6-phenyl-3-vinylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under example 15 are dissolved in a mixture of 5 ml THF and 5 ml EtOH. 10 mg 10% Pd/C are added and the mixture stirred under an atmosphere of hydrogen for 2 h. The mixture is filtered of celite, the solvens is evaporated and the crude product is purified by chromatography on silica gel (dichloromethane/methanol).
Reaction SMILES: O1CCN([C:7]23[C:34]4[CH:33]=[CH:32][C:31]([CH2:35][OH:36])=[CH:30][C:29]=4[O:28][CH2:27][CH:8]2[C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=2[C:23]([F:26])([F:25])[F:24])=[N:10][O:11]3)CC1.C(O)(C(F)(F)F)=O>ClC(Cl)C.ClCCl>[C:17]1([C:14]2[C:13]([C:23]([F:26])([F:25])[F:24])=[C:12]([C:9]3[C:8]4[CH2:27][O:28][C:29]5[CH:30]=[C:31]([CH2:35][OH:36])[CH:32]=[CH:33][C:34]=5[C:7]=4[O:11][N:10]=3)[O:16][N:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccc2c(c1)OCC1C(c3onc(-c4ccccc4)c3C(F)(F)F)=NOC21N1CCOCC1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1ccc2c(c1)OCc1c(-c3onc(-c4ccccc4)c3C(F)(F)F)noc1-2
Temperature: 80 °C
Yield: 46.4 %

Procedure:
To a solution of (9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazol-7-yl)methanol (Preparation 60G 0.070 g, 0.140 mmol) in dichloroethane (1.0 mL) at room temperature was added TFA (0.016 mL, 0.209 mmol). The reaction mixture was heated at 80° C. for 60 min. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a pale yellow solid which was triturated with methanol with sonication and dried to give (3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4H-chromeno[3,4-d]isoxazol-7-yl)methanol (0.027 g, 0.065 mmol, 47% yield) as a white solid. The product had an HPLC ret. time=3.18 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=414.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][C@@H:37]([NH2:39])[CH3:38])[CH:35]=1.CCN(C(C)C)C(C)C>CCO>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][C@@H:37]([NH:39][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:10][C:11]3[C:12]([N:28]=2)=[CH:13][C:14]2[CH2:15][N:16]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C:17](=[O:20])[C:18]=2[CH:19]=3)[CH3:38])[CH:35]=1
Reactant: Cc1ccc(Cl)cc1C[C@H](C)N
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1C[C@H](C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 59.7 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(5-chloro-2-methylphenyl)-1-methylethylamine (30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silica gel, DCM:MeOH 95:5) to give 2-(4-((1S)-2-(5-cloro-2-methylphenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (41 mg, 59%) as yellow solid. ESI-MS: m/z (MH+) 545.5. 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J=44.8 Hz, 1H), 7.51 (d, J=66.3 Hz, 1H), 7.20 (m, 2H), 7.03 (m, 2H), 5.86 (m, 1H), 4.59 (m, 2H), 3.93 (m, 3H), 2.96-3.13 (m, 8H), 2.32 (s, 3H), 1.91 (m, 4H), 1.38 (d, J=7.35 Hz, 3H).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].CC(C)([O-])C.[K+].O>CN(C=O)C>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 46.5 %

Procedure:
Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.50 g, 1.94 mmol) in DMF (5 mL) was mixed with ethyl acetate (0.38 mL, 3.88 mmol) and potassium tert-butoxide (0.33 g, 2.92 mmol). The mixture was heated to 50° C. for 20 hours. After cooling to room temperature, water was added (50 mL) and the product was extracted with diethyl ether. The ether extract was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluting with heptane-ethyl acetate to provide 4-(2-ethoxycarbonylacetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 47% yield). 1H NMR (300 MHz, CDCl3/TMS): δ=4.20 (q, 2H, J=7.2 Hz), 4.18-4.05 (m, 2H), 3.50 (s, 2H), 2.86-2.70 (m, 2H), 2.68-2.55 (m, 1H), 1.90-1.78 (m, 2H), 1.60-1.50 (m, 2H), 1.45 (s, 9H), 1.28 (t, 3H, J=7.2 Hz). 13C NMR (75 MHz, CDCl3/TMS): 6=204.21, 167.20, 154.67, 79.91, 61.70, 48.93, 47.56, 43.41, 28.73, 27.56, 14.46.
Reaction SMILES: [NH2:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:1][C@H:2]([CH3:20])[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](N)Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Product: C[C@H](Cc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1

Procedure:
Using a method similar to example 2, using (R)-6-[4-(2-amino-propyl)-phenoxy]-nicotinamide and benzyl bromide gives the title product: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6mm×15 cm×5 micron: Retention time: 3.46 minutes, Purity: 97.9%; mass spectrum (ion spray): m/z=362.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][NH:20][C:21](=[O:33])[CH:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:23][CH2:24]O)=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.P(Cl)(Cl)([Cl:36])=O>>[Cl:36][CH2:24][CH2:23][CH:22]([C:21]1[O:33][C:17](/[CH:16]=[CH:15]/[C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:19][N:20]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCO)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Product: COc1cc(/C=C/c2nnc(C(CCCl)c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-fluorophenyl)-4-hydroxybutyric acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (224 mg) in phosphorus oxychloride (1 mL) was stirred at 120° C. for two hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: ethyl acetate->ethyl acetate:methanol=3:1) to obtain 87 mg of the title compound. The property value of the compound is as follows.