Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>ClC1C=CC=CC=1Cl>[CH:18]1([C:14]2[N:13]3[C:3]4[C:2]([NH:1][C:23](=[O:24])[C:17]3=[CH:16][N:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=4)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1cc(N)c(-n2ccnc2C2CCCC2)cc1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc2[nH]c(=O)c3cnc(C4CCCC4)n3c2cc1C
Temperature: 190 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
A mixture of 1.79 g of methyl 5-amino-4-(2-cyclopentyl-1H-imidazol-1-yl)-2-methylbenzoate, 1.04 g of 1,1′-carbonyldiimidazole, and 18 mL of 1,2-dichlorobenzene was stirred at 190° C. for 3 hours. After air-cooling, the reaction mixture was purified by silica gel column chromatography (chloroform/methanol) to obtain 0.91 g of methyl 1-cyclopentyl-8-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate.
Reaction SMILES: [CH2:1]1[CH2:19][CH2:18][C:17]2[C:12](=[C:13]([OH:21])[CH:14]=[C:15]([OH:20])[CH:16]=2)[C:10](=[O:11])[O:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([OH:22])[CH2:3][CH2:2]1.[C:23](#N)C.C>O>[CH3:23][C@@H:8]1[O:9][C:10](=[O:11])[C:12]2[C:17](=[CH:16][C:15]([OH:20])=[CH:14][C:13]=2[OH:21])[CH2:18][CH2:19][CH2:1][CH2:2][CH2:3][C@@H:4]([OH:22])[CH2:5][CH2:6][CH2:7]1
Reactant: CC#N
Reactant: O=C1OCCCC[C@@H](O)CCCCCc2cc(O)cc(O)c21
Solvent: O
Product: C[C@H]1CCC[C@H](O)CCCCCc2cc(O)cc(O)c2C(=O)O1
Reaction time: 12 h
Yield: 38.99 %

Procedure:
3.59 kg of an α, β-zeranol mixture (55:45), acetonitrile with 0.5% water (80 l) and active charcoal (0.05 kg) were placed into a 150 l crystallizer. The mixture was refluxed for 30 min., warm filtered and the filtrate was refluxed again. The obtained clear solution was cooled adjusting the fall in temperature to about 8°-10° C./hour, under strong mechanic stirring, so as to obtain a controlled crystallization. Crystal withdrawals were carried out at 42° C., 36° C. and 30° C. on which crystals HPLC analysis was effected a described in Example 1: content in α-zeranol proved to be extremely constant (91.9%, 92.3% and 91.8%, respectively, at the above cited temperatures). Stirring was continued overnight and for 12 hours more at 30° C.; then the product was filtered and dried to obtain 1.40 kg (38.99%) of an α-zeranol with a 93.5% titre. This product was dissolved in 42 l of acetonitrile with 1% of water and crystallized following the same procedure as above. 1.01 kg of final product was obtained, with a 98.6% titre (HPLC), m.p.=181°-182° C., [α]D20 =46.2 (c=1.0; methanol).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Li]CCCC.Cl[Si:21]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26]([CH3:32])=[C:25]1[CH3:33])([CH3:23])[CH3:22]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[C:5]([NH:6][Si:21]([CH:24]2[C:28]3[S:29][CH:30]=[CH:31][C:27]=3[C:26]([CH3:32])=[C:25]2[CH3:33])([CH3:22])[CH3:23])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2sccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C(C)C)cc(Br)cc2C(C)C)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a solution of 18.9 g (73.8 mmol) of 4-bromo-2,6-diisopropylaniline in 200 ml of THF, 29.5 ml of 2.5 M (73.8 mmol) nBuLi in hexanes was added at −80° C. This mixture was warmed for ca. 1 hour to ambient temperature. Then, the resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 17.9 g (73.8 mmol) of chloro(4,5-dimethyl-6H-cyclopenta[b]thien-6-yl)dimethylsilane in 100 ml of THF. The resulting mixture was stirred overnight at ambient temperature, and then, evaporated to dryness. To the residue, 150 ml of toluene was added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 180° C./0.1 mm Hg. The product crystallizes slowly at ambient temperature. Yield 11.9 g (35%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=2)[CH:18]=[N:19][CH:20]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:27][CH:28]=2)[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1ccc(OCc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(COc2ccc(CC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a mixture of methyl 2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetate (1.50 g), tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. Dilute hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.36 g, 94%) of 2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:36])[CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:24]3[O:26][N:36]=[C:29]([CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34])[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: CC(C)OCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: CC(C)OCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
100 mg (0.27 mmol) of the compound from Example 101A and 66 mg (0.40 mmol) of the compound from Example 65A were reacted according to the General Method 2. Yield: 28 mg (20% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH3:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:7]1[C:6]2[C:10](=[C:2]([NH:1][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1[nH]c2c(N)cccc2c1C
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2c(NS(=O)(=O)c3cccs3)cccc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a mixture of ethyl 7-amino-3-methyl-1H-indole-2-carboxylate (0.95 g) and pyridine (10 mL) was added thiophene-2-sulfonyl chloride (0.95 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (1.13 g, yield 70%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 198-199° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>CCOCC.O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:4][CH:3]=1.[ClH:10].[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1CCN(C(=O)C(C)(C)Oc2ccc(Br)cc2)CC1

Procedure:
1-(2-(4-Bromophenoxy)-2-methylpropanoyl)-4-methylpiperazine was prepared in accordance to the procedure described in Example 29(a) from 2-(4-bromophenoxy)-2-methylpropanoyl chloride and 1-methylpiperazine (5.3 mL, 17.5 mmol). This compound (2.37 g, 6.95 mmol) was dissolved in Et2O and HCl in dioxane (4M, 2.26 mL) was added dropwise with stirring. The precipitate was filtered off and dried to yield the sub-title compound (2.5 g, 95%).
Reaction SMILES: C[C@@:2]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([OH:28])(=[O:27])=[O:26])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O-:5])=[O:4].[K]>O.C(O)C.[OH-].[Na+]>[S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:13]1[N:12]([C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4])[CH:16]=[CH:15][N:14]=1)=[O:29])([OH:28])(=[O:26])=[O:27]
Reactant: CCCCCC[C@](C)(C(=O)[O-])n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC[C@H](C(=O)O)n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Reaction time: 3 h
Yield: 43.3 %

Procedure:
The potassium salt (22.5 g) was dissolved in a mixture of 200 mL H2O and 100 mL of ethanol. To this solution was added in NaOH (53 mL). The reaction was allowed to stir for 3 hours. The solvent ethanol was then removed in vacuo, and the aqueous acidified to pH=1.5 with 5N HCl. This solution was extracted with 10% ethanol/ethyl acetate (3×200 mL). The organic was dried (Na2SO4) and concentrated in vacuo to give 8.65 g (46% for two steps) of (R)-[(2-sulfobenzoyl)amino-1H-imidazol-1-yl]-octanoic acid as a white solid. MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH3:16])[CH2:14][NH:15][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 36 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (95 mg, yield 36%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.59-8.58 (t, J=1.5 Hz, 1H), 8.28-8.26 (dt, J=7.8 Hz, 1.3 Hz, 1H), 8.17-8.14 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.09-8.05 (m, 2H), 7.90 (m, 1H), 7.67-7.63 (t, J=7.8 Hz, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.14-7.10 (m, 2H), 3.99-3.93 (ddd, J=13.2 Hz, 6.4 Hz, 4.3 Hz, 1H), 3.53-3.46 (ddd, J=13.2 Hz, 8.8 Hz, 4.3 Hz, 1H), 3.19-3.12 (m, 1H), 1.41-1.39 (d, J=7.0 Hz, 3H). MS (ESI) m/z: Calculated for C22H16F4N4O3: 460.12. found: 461.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 30 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 3-nitro-1H-1,2,4-triazole (2 g, 17.54 mmol, 1.00 equiv) in dichloromethane (100 mL), 3-(trifluoromethyl)phenylboronic acid (6.66 g, 35.05 mmol, 2.00 equiv), Cu(OAc)2 (4.79 g, 26.32 mmol, 1.50 equiv), pyridine (2.77 g, 35.06 mmol, 2.00 equiv), and molecular sieves (5.2 g). The resulting solution was stirred overnight at 30° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:10) to give 2.2 g (49%) of product as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]([O:16][C:17](C)=O)=O>>[CH2:14]([O:16][CH:17]=[C:4]([C:3]([C:2]([F:11])([F:12])[F:1])=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Yield: 98 %

Procedure:
A solution of ethyl 4,4,4-trifluoroacetoacetate (46 g, 0.25 mol) triethyl orthoformate (74 g, 0.50 mol) and Ac2O (77 g, 0.75 mol) was heated at 120-140° C. for 7 h. The mixture was concentrated and distilled to give the title compound in a 98% yield (58.6 g); b.p. 80-90° C., 1.5 mm/Hg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[Br:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc2[nH]ncc2c1
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]nc(Br)c2c1

Procedure:
A solution of 1H-Indazole-5-carbaldehyde (2.05 mmol) and N-bromosuccinimide (3.08 mmol) in DMF (8 mL) was stirred at rt for 3 h, then concentrated under reduced pressure. Chromatographic purification of the residue (silica gel, hexanes to hexanes:EtOAc, 1:1) afforded 3-bromo-1H-indazole-5-carbaldehyde as pale yellow solid.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@@H:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)C1C=CC=CC=1.O1CCCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:21]([O:20][C:18]([NH:17][C@@H:10]([CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[C:9]([OH:25])=[O:8])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 100 mL round bottom flask was charged with 2-(S)-tert-butoxycarbonylamino-3-thiazol-2-yl-propionic acid benzyl ester (370 mg, 1.02 mmol), tetrahydrofuran (9.0 mL), water (0.9 mL), and lithium hydroxide (48 mg, 1.14 mmol) and the resulting mixture was stirred at room temperature for 6 h. The resulting mixture was then neutralized with 10% citric acid and extracted with ethyl acetate (100 mL), and dichlormethane (100 mL). The organic layers were dried with MgSO4, filtered, and concentrated in vacuo to yield (S)-2-(tert-butoxycarbonylamino)-3-(thiazol-2-yl)propanoic acid. MS (ES+) 273 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].S([CH2:37][N+:38]#[C-:39])(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]3[O:18][CH:39]=[N:38][CH:37]=3)=[CH:19][CH:20]=2)[O:4][N:3]=1
Reactant: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(CCCCCOc2ccc(-c3cnco3)cc2)on1
Yield: 47.5 %

Procedure:
A suspension of 10.00 g of 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde, 10.0 g of potassium carbonate and 7.14 g of tosylmethyl isocyanide (4-CH3C6H4 -SO2CH2NC) in 90 ml of methanol was heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with methylene dichloride. The extract was washed with water, the product isolated and recrystallized from isopropyl acetate-hexane. Further purification by flash filtration through a silica gel pad, eluting with isopropyl acetate, and recrystallization from isopropyl acetate-hexane gave 5.43 g (48%) of 3-methyl-5-{5-[4-(5-oxazolyl)phenoxy]pentyl}isoxazole, yellow powder, m.p. 91°-93° C.
Reaction SMILES: I.[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](SC)[NH:4]1.[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>C(#N)C.C(O)(C(F)(F)F)=O>[CH:16]1([NH:15][C:5]2[NH:4][CH:3]([CH3:2])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CSC1=Nc2ccccc2C(C)N1
Reactant: NC1CCc2ccccc21
Agent: I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC1NC(NC2CCc3ccccc32)=Nc2ccccc21
Temperature: 85 °C

Procedure:
4-Methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (31 mg, 0.10 mmol) and (+/−)-1-aminoindane (17 mg, 0.12 mmol) were suspended in acetonitrile (1 ml) and heated in a screw-capped vial to 85° C. (12 h). The product was isolated from the reaction mixture by preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7.0 min, λ=230 nm, flow rate 40 ml/min) to give the title compound (MS: m/e=264.2 [M+H+]).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:1][C:2]2[N:4]([CH:5]=[CH:6][N:7]=2)[N:3]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nccnn1
Solvent: CCO
Product: CCOC(=O)c1cnc2nccn2n1
Temperature: 25 °C
Yield: 1.8 %

Procedure:
A solution of 3-amino-1,2,4-triazine (5.0 g, 52 mmol) and ethyl bromopyruvate (11 mL, 88 mmol) in ethanol (50 mL) was heated to reflux for 20 minutes. The reaction was cooled to room temperature, and then partitioned between 200 mL of EtOAc and 200 mL of water. The layers were separated, and the organic layer was dried over MgSO4. The solids were removed by filtration, and then the solvent was removed by rotary evaporation. The residue was purified by chromatography (90 g SiO2, 50 to 70% EtOAc in hexanes) to give the desired product (181 mg, 1.8%). MS (ESI): 192.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:23]1[C:27]2([CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:24]2[CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:26][C:27]3([CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)[CH2:23]2)=[CH:21][CH:22]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Reactant: O=Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
Under an argon atmosphere, 4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzaldehyde (International Publication WO 2007/058322 pamphlet, Example 28; 21.0 g) and 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (JP 2004-002470, Example 21f; 21.2 g) were dissolved in acetic acid (4.5 mL) and anhydrous N,N-dimethylformamide (225 mL), followed by stirring at room temperature for 10 minutes. To this solution, sodium triacetoxyborohydride (17.3 g) was added. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution, an aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (300 mL) and the solution was heated at reflux for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (n-hexane:ethyl acetate=1:1→1:2→0:1→ethyl acetate:ethanol=19:1→9:1) to obtain the title compound (24.4 g) having the following physical properties.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[O:23][CH3:24].[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:38]>>[ClH:1].[ClH:38].[ClH:1].[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[C:7]=2[O:23][CH3:24])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Product: COc1c(SCCCN2CCN(Cc3ccccc3)CC2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 59 %

Procedure:
According to the procedure indicated in Examples 1), 3) and 6), reaction of 2-{[[4-(3-chloropropylthio)-3-methoxy-2-pyridinyl]methyl]thio}-1H-benzimidazole with N-benzylpiperazine and subsequent conversion into the hydrochloride gives the title compound; m.p. 180° C., dec.; colorless crystals; yield 59% of theory.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=3[CH:21]=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]>C(Cl)Cl>[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=3[C:21]([I:8])=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccnc2c1cc1ccnc(NC(C)=O)n12
Solvent: ClCCl
Product: COc1ccnc2c1c(I)c1ccnc(NC(C)=O)n12
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
NIS (18 mg, 0.078 mmol) was portionwise added to a cooled (0° C.) solution of 9-Acetylamino-4-methoxypyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine (20 mg, 0.078 mmol) in CH2Cl2 (15 ml). The mixture was stirred for 15 min. The solution was diluted with CH2Cl2 (50 ml) and washed twice with water. The organic layer was dried and evaporated to obtain 20b (27 mg, 93%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:31])=[CH:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[C:5]([F:31])=[CH:4][N:3]=2)=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)cc1
Reactant: COc1cc(Cl)ccc1B(O)O
Product: COc1cc(Cl)ccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
Example 217 was synthesized in a similar manner to Example 212, except that 1-chloro-4-fluoro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate QQQ) and (4-chloro-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 25 to 100% EtOAc:Heptane) to afford 1-(4-chloro-2-methoxyphenyl)-4-fluoro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.70 (s, 1H), 8.58 (d, J=10.4 Hz, 2H), 8.21 (s, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.40-7.30 (m, 2H), 7.19 (dd, J=2.0, 8.0 Hz, 1H), 7.10-6.80 (m, 1H), 3.67 (s, 3H). m/z (ESI) 445.2 (M+H)+.