Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11](=[O:13])[CH3:12].[C:14](O)(=O)C.N1CCCCC1.C=O>CC#N>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[CH2:14])[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cc1c(F)ccc(F)c1F
Reactant: CC(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: CC#N
Product: C=C(C(C)=O)c1c(F)ccc(F)c1F
Temperature: 70 °C
Yield: 205 %

Procedure:
A solution of 18 (3.5 g, 18.6 mmol), acetic acid (0.34 ml, 5.58 mmol), piperidine (0.37 ml, 3.72 mmol), formaldehyde (6.0 g, 37% aqueous solution) in MeCN (20 mL) was heated over weekend. The conversion was about 60%. Reaction was heated to 70° C. overnight. The mixture was concentrated and extracted with MTBE and HCl (0.5N). The organic layer was washed with aqueous K2CO3 (0.5N) and water, in turns. The organic layer was concentrated. The product was isolated by chromatography column (hexane and EtOAc), yielding 31 (2.29 g, 61.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]4[N:50]=[CH:49][C:48]([NH:51][C:52](=[O:54])[CH3:53])=[CH:47][CH:46]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][C:28]2[CH:29]=[C:30]([CH:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]5[N:50]=[CH:49][C:48]([NH:51][C:52](=[O:54])[CH3:53])=[CH:47][CH:46]=5)[CH:40]=4)[O:35]3)[CH:31]=[CH:32][CH:33]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(Oc4ccc([N+](=O)[O-])cn4)c2)O3)nc1

Procedure:
N-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-yl)acetamide was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from N-{6-[2-(3-hydroxyphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide. 1H NMR (400 MHz, d6-DMSO) δ: 10.03 (s, 1H), 9.05 (d, 1H, J 2.1 Hz), 8.63 (d, 1H, J 8.9 Hz), 8.26 (s, 1H), 8.00 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H), 7.27-7.31 (m, 2H), 7.20 (m, 1H), 6.92 (d, 1H, J 8.9 Hz), 6.85-6.87 (m, 3H), 5.17 (d, 1H, J 10.4 Hz), 2.96 (m, 1H), 2.71 (m, 1H), 2.20 (m, 1H), 2.04 (s, 3H), 1.99 (m, 1H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9](=[O:19])[C:10]([C:16]([NH2:18])=[O:17])=[C:11](OC(C)C)[C:7]=2[CH:6]=1>C(#N)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9](=[O:19])[C:10]([C:16]([NH2:18])=[O:17])=[C:11]([NH:2][CH3:1])[C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)C(OC(C)C)=C(C(N)=O)S2=O
Reactant: CN
Solvent: CC#N
Product: CNC1=C(C(N)=O)S(=O)c2ccc(OC)cc21
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Monomethylamine gas is passed into a room temperature solution of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide-1-oxide (250 mg, 0.89 mmol) [Boschelli, et al., U.S. Pat. No. 5,208,253 (1993)] in acetonitrile. A precipitate forms almost immediately and stirring is continued for 30 minutes. The solid is collected and dried to provide 5-methoxy-3-(methylamino)benzo[b]thiophene-2-carboxamide-1-oxide in 86% yield; mp=244°-244.5° C. dec.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=O)=[CH:36]1.N1CCCCC1>C1(C)C=CC=CC=1>[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=[C:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])[C:16]2=[O:17])=[CH:36]1
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Yield: 96 %

Procedure:
To a solution of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide (Preparation 7(A)) (1.2 g, 2.7 mmol) in toluene (15 mL) was added 1H-indole-3-carbaldehyde (0.46 g, 3.2 mmol) and piperidine (0.4 mL). The reaction mixture was heated to reflux for 14 hours. Activated 4 Å molecular sieves (2 g) were added and the reaction mixture was refluxed for 24 hours. The sieves were removed by filtration and the filtrate was concentrated. The residue was triturated with methylene chloride and the solid was collected via filtration and was dried in vacuo to give 1.5 g of 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. The filtrate was concentrated and was purified by chromatography (20% acetone/methylene chloride) to afford an additional 320 mg of 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. MS 579.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.C1(=O)O[CH2:14][CH2:13][O:12]1>>[OH:12][CH2:13][CH2:14][N:10]1[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: Cc1nc2cnccc2[nH]1
Reactant: O=C1OCCO1
Product: Cc1nc2ccncc2n1CCO
Temperature: 150 °C
Yield: 8.6 %

Procedure:
2-Methylimidazo[4,5-c]pyridine (10.6 g) was mixed with ethylene carbonate (8.3 g) and heated as a melt at 150° C. for 1/2 hour. The crude black product was chromatographed on silica eluting with 40% methanol in ethyl acetate. The fraction with Rf 0.33 in methanol, ethyl acetate, (2:3) was evaporated and was identified as a mixture of the title compound and of the isomeric 1-(2-hydroxyethyl)-2-methylimidazo[4,5-c]pyridine. The mixture was chromatographed on silica eluting with 20% methanol in acetone. Fractions containing the more mobile isomer were combined and evaporated yielding the title compound (1.22 g, 9%) as a foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:32]=[C:31]([OH:33])[C:24]3[CH2:25][CH:26]([CH:28]([F:30])[F:29])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1>>[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:32]=[C:31]([O:33][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:24]3[CH2:25][CH:26]([CH:28]([F:30])[F:29])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C(F)F)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C(F)F)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 33, from 4-fluorophenyl methyl sulfone (28.2 mg, 0.162 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (50 mg, 0.160 mmol) to give a white solid (18 mg, 24% yield). 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1 H) 7.85-8.02 (m, 2 H) 7.22-7.38 (m, 2 H) 7.02-7.21 (m, 3 H) 6.77 (d, J=2.02 Hz, 1 H) 5.94 (t, 1 H) 5.02 (br. s., 1 H) 3.78 (s, 3 H) 3.55-3.65 (m, 1 H) 3.23-3.33 (m, 1 H) 3.09 (s, 3 H); LCMS for C21H19F2N3O5S m/z 464.00 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=O>CC(C)=O>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:7]([C:8]#[N:9])=[C:2]3[N:1]([CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: N#CCc1ccccn1
Solvent: CC(C)=O
Product: Cc1ccc(-c2cn3ccccc3c2C#N)cc1
Yield: 44.1 %

Procedure:
A mixture of 2-pyridyl acetonitrile (5.0 g) and 2-bromo-4'-methylacetophenone (8.52 g) in acetone (10 ml) was heated at 80° C. for 24 hours, during which 2-pyridylacetonitrile (1 g, 2 g) was added to the reaction mixture. After being cooled, the solvent was removed in vacuo and the residue was chromatographed on silica gel eluted with a mixture of ethyl acetate and n-hexane (1:6 to 1:2, V/V) to give a solid product. This product was recrystallized from ethanol-water to give 2-(4-methylphenyl)indolizine-1-carbonitrile (4.1 g) as a pale brown powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[C:12]([O:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH:24]([O:29][C:30](=[O:32])[CH3:31])[O:25][C:26](=[O:28])[CH3:27])=[CH:18][C:17]=1[O:33][CH3:34])(=[O:14])[CH3:13]>O>[C:12]([O:15][C:16]1[C:17]([O:33][CH3:34])=[CH:18][C:19]([CH:24]([O:25][C:26](=[O:28])[CH3:27])[O:29][C:30](=[O:32])[CH3:31])=[C:20]([N+:1]([O-:4])=[O:2])[C:21]=1[O:22][CH3:23])(=[O:14])[CH3:13]
Reactant: COc1cc(C(OC(C)=O)OC(C)=O)cc(OC)c1OC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(C(OC(C)=O)OC(C)=O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Temperature: -15 °C
Yield: 96 %

Procedure:
32 cm3 of 100% nitric acid are cooled to -30° C. 100 cm3 of acetic anhydride then 40 g (0.123 mole) of 4-acetoxy-1-diacetoxymethyl-3,5-dimethoxybenzene are added with stirring. The temperature is left to increase to about -15° C. After stirring at this temperature for 30 minutes, the reaction mixture is poured into iced water. After filtration, washing with water and drying under vacuum, 43.8 g of the desired product are obtained in the form of a slightly yellow powder (yield=96%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=5)=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=2[N:3]=1.[C:45](Br)(=[O:47])[CH3:46].C(N(CC)C(C)C)(C)C>ClCCl>[C:45]([NH:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:17]([CH2:16][CH2:15][N:14]3[CH:12]4[CH2:11][CH2:10][CH:9]3[CH2:8][CH:7]([N:6]3[C:5]5[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=5[N:3]=[C:2]3[CH3:1])[CH2:13]4)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:18][CH2:19]2)=[O:24])=[CH:30][CH:29]=1)(=[O:33])=[O:32])(=[O:47])[CH3:46]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(S(N)(=O)=O)cc2)CC1
Reactant: CC(=O)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a precooled (0° C.) solution of 4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-benzene-sulfonamide (20 mg, 0.033 mmol) in dichloromethane (2 mL) was added acetyl bromide (4.2 mg, 0.034 mmol) and N,N-diisopropylethyl amine (12 μL, 0.66 mmol). The resulting mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 15-30% methanol in ethyl acetate to afford N-acetyl-4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide as amorphous solid (14 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J=8.1 Hz, 2H), 7.48-7.46 (m, 3H), 7.37-7.33 (m, 5H), 7.21 (br, 1H), 7.13-7.05 (m, 2H), 4.51 (t, J=8.1, 1H), 3.88 (br, 1H), 3.67-3.15 (m, 6H), 2.42 (s, 3H), 2.37-2.30 (m, 2H), 2.11-2.07 (br, 2H), 1.96-1.72 (m, 13H), 1.59 (d, J=7.4, 2H). HRMS m/z (M+H)+ calcd: 654.3114, obsd: 654.3095.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:9]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1C(=O)N1CCOCC1
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
Into an 8 mL screw cap vial were added 5-bromoisatoic anhydride (0.200 g, 0.826 mmol), anhydrous THF (5 mL), and morpholine (101 mg, 1.16 mmol). The vial was sealed and placed in a heat block at 60° C. for 1.5 h after which it was concentrated under vacuum. The crude product was triturated with Et2O/hexanes to afford 111 mg (94%) of (2-Amino-5-bromo-phenyl)-morpholin-4-yl-methanone as a tan solid. m/z 285/287 [MH+].
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]([Cl:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:14][C:13]1[C:4]([O:15][CH:19]([C:18]2[CH:4]=[N:5][CH:6]=[CH:16][CH:17]=2)[CH:8]([CH3:9])[CH3:7])=[N:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: C1CCOC1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Yield: 94 %

Procedure:
According to Reference Example 7-4, by use of Compound CE (360 mg, 2.4 mmol), tetrahydrofuran (17 mL), 60% sodium hydride (in oil) (168 mg, 4.2 mmol) and 2,3-dichloroquinoxaline (418 mg, 2.1 mmol), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/1) was performed to give 2-chloro-3-[2-methyl-1-(pyridin-3-yl)propoxy]quinoxaline (Compound BP) (620 mg, yield: 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15]>C(=O)(O)[O-].[Na+].O1CCCC1>[C:14]([CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11])([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(CC(C(=O)O)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 4 h
Yield: 80.9 %

Procedure:
3-(4-aminophenyl)propionic acid (250 mg, 1.5 mmol) in a 10 mL flask was dissolved in a mixture of 10% aqueous sodium bicarbonate (0.32 mL) and tetrahydrofuran (2.2 mL) then cooled in an ice/water bath. 9-fluorenylmethyl chloroformate (422 mg, 1.5 mmol) was added in small portions over 3 min. After 4 h the cooling bath was removed. After additional 4 h at room temperature, the reaction was extracted with deionized water (2 mL) and ethyl ether (2 mL) and the aqueous layer was brought to pH 4 with dilute HCl and placed in a refrigerator. After 1 h solid was collected by vacuum filtration and washed with deionized water then dried under vacuum to give 470 mg of product (80% yield). Mass spectrum (M+Na)+ calcd for C24H21NO4, 400.1. found 410.0.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]([C:27]1[CH:31]=[CH:30][S:29][C:28]=1[CH:32]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:32][C:28]2[S:29][CH:30]=[CH:31][C:27]=2[O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1sccc1Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2sccc2Oc2ccccc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 76.3 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 3-phenoxythiophene-2-carboxaldehyde (0.300 g, 1.47 mmol) in 4 mL of 4% KOH in EtOH for 3 hours at room temperature to afford 0.331 g (76%) of the title compound as an off-white solid, mp 135-137° C.: APCI-MS m/e 443.5 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)nnc1Cl

Procedure:
To a suspension of 3,6-dichloropyridazine-4-carboxylic acid (1.16 g, 6 mmol) in toluene (20 mL) were added DMF (2 drops) and SOCl2 (4 mL) and the mixture was heated at reflux temperature for 3 h. The volatiles were removed and the residue was stripped with toluene. The resulting brown oil (3,6-dichloropyridazine-4-carbonyl chloride) was used without purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2cc(C(F)(F)F)ccn2)CCN1
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To a solution of (R)-2-methyl piperazine (4.0 g, 40 mmol) in xylene (100 mL) at 140° C. under nitrogen was added 2-chloro-4-trifluoromethylpyridine (726 g, 40.0 mmol) slowly over a period of 30 min. The heating was continued for additional 12 h and cooled. The reaction mixture was evaporated to a residue and the residue was purified by chromatography using chloroform/methanol (8/2) as eluent to afford of the title compound as a liquid (3.5 g, 36%). TLC-Chloroform/MeOH (8/2); Rf: 0.25.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (328 mg, 1.00 mmol) was placed in a sealed tube with 4-amino-6-chloropyrimidine-5-carbonitrile (154.5 mg, 1.00 mol), DIPEA (0.7 mL, 4.00 mol) and IPA (1 mL). The tube was flushed with argon, sealed and the contents heated at 90° C. for 16 h. The cooled mixture was evaporated then diluted with EtOAc and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The crude residue was purified by chromatography on silica (Si—PCC, 1-80% EtOAc in DCM). The product containing fractions were pooled and evaporated almost to dryness. The residue was triturated in ether to afford 246 as a cream solid (240 mg, 65%). 1H NMR (CDCl3, 400 MHz): δ 8.01 (1H, s), 7.69 (1H, dd, J=8.8, 4.7 Hz), 7.59-7.49 (3H, m), 7.43-7.36 (2H, m), 7.02 (1H, td, J=9.2, 1.1 Hz), 6.77 (1H, dd, J=8.6, 2.4 Hz), 6.18 (1H, d, J=7.5 Hz), 5.52 (1H, quin, J=7.2 Hz), 5.30 (2H, br s), 1.54 (3H, d, J=6.9 Hz). LCMS (Method K): RT 3.80 min [M+H]+ 374
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][OH:15])[CH3:12]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:14][CH:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH3:19])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:14][CH:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CCCCC(CC)CO
Product: CCCCC(CC)CO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCC(CC)CCCC
Reaction time: 0.67 h
Yield: 98 %

Procedure:
500 g (2.01 mol) of dibutyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1047 g (8.04 mol) of 2-ethyl-1-hexanol (made by Wako Pure Chemical Industries, Ltd., Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 157° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational stirring and heating were carried out for approximately 40 minutes at normal pressure, and then the purge valve was closed, and the pressure in the system was gradually reduced, and water-containing 2-ethyl-1-hexanol was distilled off with the pressure in the system at from 40 to 20 kPa. This state was maintained for 2 hours, and then the pressure in the system was further reduced, and excess 2-ethyl-1-hexanol was distilled off. Once distillate stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 750 g of reaction liquid was obtained in the flask. According to 119Sn—, 1H—, and 13C-NMR analysis results, the product 1,1,3,3-tetrabutyl-1,3-bis(2-ethylhexyloxy)-distannoxane was obtained at a yield of 98% based on the dibutyltin oxide. The same procedure was carried out so as to produce 1,1,3,3-tetrabutyl-1,3-bis(2-ethylhexyloxy)-distannoxane to be used in the following step B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:29](OC(N1CC(=C)CC1C(O)=O)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:29])[CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Product: C=C1CC(c2ncc(-c3ccc(Br)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1

Procedure:
This compound was prepared using the procedure used to prepare (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester using 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].O=C1CCC(=O)N1[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1>>[CH3:2][C:1]([NH:9][C:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:21][CH:20]=1)=[O:17])([CH3:3])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: CC(C)(C)CC(C)(C)N
Product: CN(C(=O)Oc1ccc(C(=O)NC(C)(C)CC(C)(C)C)cc1)c1ccccc1

Procedure:
The title product was prepared from tert-octylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester, preparative HPLC (method C) (26%, white crystals). HPLC-MS m/z=383.5 (M+1), Rt: 4.67 min.