Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc2cccnc12
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3cccnc23)cc1=O
Yield: 64 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 8-hydroxyquinoline and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(quinolin-8-yloxy)-6H-pyridazin-1-yl]-propionic acid (6.2 g, 64%) as a solid; LC-MS, [M+H+]=380.2; HPLC (0.05% trifluoroacetic acid in acetonitrile/water, 30%-90% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), 254 nm, 97.9%, 214 nm, 96.7%. 1H-NMR (DMSO-d6, 300 MHz) δ 1.13-1.22 (m, 2H), 1.46-1.61 (m, 7H), 1.97-2.01 (m, 1H), 2.16-2.25 (m, 1H), 5.30-5.35 (dd, J=10.5, 3.9 Hz, 1H), 5.56-5.57 (d, J=2.4 Hz, 1H), 7.65-7.81 (m, 3H), 8.05-8.07 (d, J=7.8 Hz, 1H), 8.24-8.25 (d, J=2.7 Hz, 1H), 8.53-8.56 (d, J=8.1 Hz, 1H), 8.93-8.94 (d, J=3.0 Hz, 1H), 13.02 (s, br, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]2([C:20]([O:22]CC)=[O:21])[CH2:19][CH2:18]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]2([C:20]([OH:22])=[O:21])[CH2:18][CH2:19]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1([C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(C(=O)O)CC1
Yield: 108.1 %

Procedure:
(3S,4R)-1-Benzyloxycarbonyl-3-(1-ethoxycarbonylcyclopropyl)-4-methylpyrrolidine (1.17 g, 3.66 mmol) was dissolved in ethanol (100 ml), and the solution was mixed with a 1 N sodium hydroxide aqueous solution (11 ml) and heated under reflux for 8 hours. After completing the reaction, the solvent was evaporated and the resulting residue was mixed with a 0.5 N hydrochloric acid aqueous solution (30 ml). This was extracted with ethyl acetate (50 ml×3), and the organic layer was washed with water (50 ml) and saturated sodium chloride aqueous solution (50 ml) in that order. This was dried over anhydrous sodium sulfate and then the solvent was evaporated to obtain 1.20 g of the title compound quantitatively.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[NH:14][CH:13]=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([NH:26][S:15]([C:12]1[CH:11]=[C:10]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[NH:14][CH:13]=1)(=[O:17])=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(S(=O)(=O)NCc2ccccc2)c[nH]1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonyl chloride (500 mg, 1.64 mmol) (from Example 17), benzylamine (351.5 mg, 3.28 mmol) and triethylamine (1 mL) in DCM (5 mL) was stirred at room temperature for 4 hours. The reaction was diluted with DCM, washed with water, dried and concentrated. The residue was purified on a silica gel column to give 5-(2-chloro-pyridine-3-carbonyl)1H-pyrrole-3-sulfonic acid benzylamide.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])=[O:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15]2)[C:8]2[C:9](=[N:11][N:12]([CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[O:24])[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.6 %

Procedure:
A mixture of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (11.6 mg, 41.1 μmol), 2-bromo-1-(2-chlorophenyl)ethanone (11.5 mg, 7.19 μl, 49.3 μmol) and DIPEA (10.6 mg, 14.4 μl, 82.2 μmol) were combined with DCM (250 μl) to give a light yellow solution. The reaction mixture was stirred at r.t. for 4 h and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 1.9 mg (11%) of the title compound as yellow gum. MS (m/e): 435.3 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH:6]2[CH2:11][CH2:10][N:9](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:7]2)=[N:2]1>C(O)C.[Pd]>[NH:1]1[CH:5]=[N:4][C:3]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[N:2]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc[nH]n2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1nc(C2CCNCC2)n[nH]1
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (7.3 g, 25 mmol) in ethanol (100 mL) was added 10% palladium on carbon (500 mg) and the reaction vessel was purged with hydrogen and stirred over an atmosphere of hydrogen for 3 hours. The reaction was filtered and concentrated to give 7-1 as a solid. MS (M+H+): 153.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.99 (s, 1H), 2.98-2.94 (m, 2H), 2.82-2.74 (m, 1H), 2.57-2.50 (m, 2H), 1.82-1.78 (m, 2H), 1.60-1.50 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]([F:23])([F:22])[F:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH:25]([CH2:28]Br)[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([C:20]([F:22])([F:21])[F:23])[N:9](/[CH:28]=[CH:25]/[C:26]#[N:27])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Reactant: N#CC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 41.1 %

Procedure:
From 4,5-bis(4-fluorophenyl)-2-trifluoromethyl-1H-imidazole (3.045 g), 2,3-dibromopropionitrile (5.33 g), anhydrous potassium carbonate (3.1 g) and triethylamine (5.2 ml) in dry DMF (19 ml) by the process as described for the preparation of Intermediate (3 a) to afford a dark brown residue which was purified by FCC using gradient elution with System A (5-15% with 5% incremental increase of ethyl acetate per 500 ml eluant) to afford the title compound (1.449 g) as a white solid. νmax (CHBr3) 2229 cm-1 (C≡N).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 8 g (0.02 mol) de 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester, obtained according A), and 71 g (0.059 mol) of pyridinium chlorochromate absorbed on alumina, was suspended in 200 ml of CH2Cl2. Then, the whole mixture was maintained with stirring at room temperature, along 8 hours. The remaining solid was eliminated by filtration, and the liquid was washed with water (3×250 ml). dried over anh. Na2SO4, and concentrated at reduced pressure, to dryness. The product was obtained as an oil, which was purified by column chromatography (Silicagel, n-hexane:EtAcO, 8:2) with a yield of 70%.
Reaction SMILES: [CH2:1]([NH:20][CH2:21][CH:22]([OH:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:33]([OH:37])(=[O:36])[CH2:34][OH:35].C[OH:39]>>[C:33]([OH:37])(=[O:36])[CH2:34][O:35][CH2:23][C:22]([OH:32])=[O:39].[CH2:1]([NH:20][CH2:21][CH:22]([OH:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CO
Reactant: O=C(O)CO
Agent: CCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCC
Product: O=C(O)COCC(=O)O

Procedure:
A solution of N,N'-(1,6-hexylene-bis[2-hydroxyundecylamine] (5 g.), glycolic acid (1.66 g.) and methanol was heated until the solids dissolved, then evaporated to dryness. Recrystallization of the solid from acetone afforded N,N'-(1,6-hexylene)bis[2-hydroxyundecylamine] diglycolate (4.6 g., m.p. 88.2°-94.6° C.).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:36](=[O:37])[CH2:35][O:34][CH3:33])=[CH:25][CH:24]=1
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (144 mg, 0.35 mmol) and Et3N (200 μL, 1.4 mmol) in CH2Cl2 (15 mL) at rt was added methoxyacetyl chloride (50 μL, 0.53 mmol). After 18 h at rt, the reaction mixture was partitioned between CH2Cl2 (150 mL) and satd. aq. NaHCO3 (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (127 mg, 89%). MS (ESI): mass calcd. for C22H23N3O3S, 409.15; m/z found, 410.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.74 (d, J=7.5 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.40 (m, 3H), 7.30 (m, 3H), 4.83 (br m, 0.5H), 4.46 (br m, 0.5H), 4.06 (m, 1H), 4.01 (s, 1H), 3.76 (m, 2.5H), 3.63 (br d, J=9.3 Hz, 0.5H), 3.58 (br s, 1H), 3.45 (s, 1.5H), 3.43 (s, 1.5H), 3.35 (br d, J=2.1 Hz, 0.5H), 3.33 (m, 0.5H), 3.01 (dd, J=9.9, 2.3 Hz, 0.5H), 2.87 (dd, J=9.8, 2.2 Hz, 0.5H), 2.78 (br d, J=9.9 Hz, 0.5H), 2.58 (d, J=9.5 Hz, 0.5H), 1.99 (br d, J=9.3 Hz, 0.5H), 1.96 (br d, J=9.8 Hz, 0.5H), 1.76 (br d, J=10.0 Hz, 0.5H), 1.66 (br d, J=10.0 Hz, 0.5H).
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][C:24]3=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([C:4]([OH:5])=[O:9])=[CH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: O=C1CCCc2ccc(-c3ccc(F)cc3)cc21
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1=Cc2cc(-c3ccc(F)cc3)ccc2CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (15.5 g), dimethyl carbonate (91 ml) and 7-(4-fluorophenyl)-1-tetralone (13.8 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C. and to the mixture was gradually added 3N hydrochloric acid (200 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (90 ml), and to the mixture was added sodium boron hydride (1.36 g) at 0° C. and then was dropwise added methanol (9 ml) for 30 minutes. The reaction mixture was stirred at 0° C. for 4 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in methanol (80 ml), and to the mixture was added 1N sodium hydroxide (100 ml). The mixture was refluxed for 4 hours and cooled to room temperature. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (50 ml), and to the mixture was added concentrated hydrochloric acid (10 ml). The mixture was stirred at 100° C. for 2 hours, and to the mixture was added water(500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethylether. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-(4-fluorophenyl)-3,4-dihydronaphthalene-2-carboxylic acid (6.01 g) as pale brown crystals.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.Cl[C:22]1[N:30]=[C:29]([NH2:31])[N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH:20][C:22]3[N:30]=[C:29]([NH2:31])[N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:19])=[C:9]([C:12]3[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 44.4 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (500 mg, 1.71 mmol), 6-chloro-9H-purin-2-amine (436 mg, 2.57 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.895 mL, 5.14 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was diluted with MeOH/DMSO and purified by preparative HPLC (basic mode) eluting with 20-30% ACN in water. The fractions containing the desired compound were collected and concentrated in vacuo. The residue was re-crystallized in an EtOAc/MeOH/hexane mixture to give the title compound (295 mg, 44.4%). 1H NMR (500 MHz, CD3OD) δ ppm 1.50 (d, J=6.83 Hz, 3 H), 3.59-3.66 (m, 3 H), 3.89 (br s, 3 H), 5.56 (br s, 1 H), 6.45 (d, J=1.95 Hz, 1 H), 6.68-6.73 (m, 1 H), 7.58-7.65 (m, 2 H), 7.77-7.89 (m, 2 H); ESI-MS m/z [M+H]+ calc'd for C19H20N10, 389; found 389.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:12])([F:11])[C:7]([CH3:10])([OH:9])[CH3:8].[C:13]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)(N1C=CN=C1)=[O:14].[CH3:25][I:26]>C(#N)C.O>[I-:26].[CH3:25][N+:22]1[CH:23]=[CH:24][N:20]([C:13]([O:9][C:7]([CH3:10])([CH3:8])[C:6]([F:12])([F:11])[F:5])=[O:14])[CH:21]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CI
Reactant: CC(C)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC#N
Product: C[n+]1ccn(C(=O)OC(C)(C)C(F)(F)F)c1
Product: [I-]

Procedure:
To a chloroform solution (10 mL) of 1,1,1-trifluoro-2-methylpropan-2-ol (500 mg, 3.90 mmol), 1,1′-carbonyldiimidazole (696 mg, 4.29 mmol) was added at room temperature and the resultant solution was stirred for 1 day. To the reaction solution, water was added and extraction with chloroform from the resultant mixture was performed twice. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To an acetonitrile solution of the obtained residue, methyl iodide (2.21 g, 15.6 mmol) was added and the resultant mixture was stirred for 1 week. The reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound and the crude product was used in the next reaction as it was.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH:25][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3cc(F)cc(F)c3)s2)c(C)[nH]c1=O
Yield: 26 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3,5-difluorobenzylamine as described in Step 5, Example 24 to give the title compound as a solid (26% yield). LC/MS: RT 3.67 min; m/e 425 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 8.58 (1H, t), 7.49 (1H, s); 7.25 (1H, s); 7.08 (2H, m), 6.96 (2H, m), 4.20 (2H, d), 2.49 (2H, q), 2.27 (3H, s), 1.10 (3H, t); 19F NMR −110.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[S:31])=[CH:18][CH:17]=1
Reactant: CN(C)CCN
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: S=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NCCN(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 5 hr. Next, N,N-dimethylethylenediamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (62 mg, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.[BH4-].[Na+]>C(O)C>[ClH:1].[ClH:1].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:17][CH:13]([C:9]2([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:14][CH2:15][CH3:16])=[CH:20][CH:19]=1
Reactant: O=Cc1ccncc1
Reactant: CCCC(N)C1(c2ccc(C)c(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCC(NCc1ccncc1)C1(c2ccc(C)c(Cl)c2)CCC1
Product: Cl
Temperature: 130 °C

Procedure:
A mixture of 1-[1-(3-chloro-4-methylphenyl)cyclobutyl]butylamine (2.5 g) [see Example 10(k) of British Patent Specification No. 2098602A] and 4-pyridinecarboxaldehyde (1.5 ml) was stirred and heated at 130° C. for 18 hours. The mixture was dissolved in ethanol (50 ml) and the solution added to a solution of sodium borohydride (2.5 g) in ethanol (120 ml) and heated under reflux for 2 hours. Excess ethanol was removed by evaporation and the mixture acidified, basified and extracted into ether. Hydrogen chloride gas was passed through the dried extract to give an oil which was triturated with acetone to give N-(4-pyridylmethyl)-1-[1-(3-chloro-4-methylphenyl)cyclobutyl]butylamine dihydrochloride (m.p. 203°-206° C.).
Reaction SMILES: [OH:1][B:2]([OH:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25]>CN(C=O)C>[OH:1][B:2]([OH:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][N:19]2[C:23](=[O:24])[CH2:22][CH2:21][C:20]2=[O:25])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCC(=O)Nc1cccc(B(O)O)c1
Solvent: CN(C)C=O
Product: O=C(CCC(=O)ON1C(=O)CCC1=O)Nc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
N-(3-dihydroxyborylphenyl)succinamic acid (16.0 grams, 0.063 mole) is dissolved in dry DMF (80 ml). To the solution is added N,N-dicyclohexylcarbodiimide (14.3 grams, 0.069 mole) followed by N-hydroxysuccinimide (8.05 grams, 0.070 mole). The reaction is stirred overnight at room temperature. N,N-dicyclohexylurea is filtered from the solution, and the filtrate extracted with ethyl acetate (200 ml). The extract is washed with water (3×400 ml) and saturated NaCl (400 ml). The water wash was back-extracted with ethyl acetate (200 ml), the extracts combined, dried over anhydrous Na2SO4, and concentrated on a rotary evaporator to afford 12.5 grams (57% yield) of N-(3-dihydroxyboryl-phenyl)succinamic acid, succinimidyl ester. Purity estimated at 98% by TLC (CHCl3 /CH3OH/CH3COOH; 85:10:5), Rf =0.7. The structure was confirmed by 300 MHz, 1H NMR spectrometry in d6 -DMSO.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)[CH3:2].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)[CH:7]=1)[CH3:2]
Reactant: CCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cn(Cc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
A mixture of 4-ethyl-1H-imidazole (2.46 g), 4-nitrobenzyl bromide (6.08 g), potassium carbonate (7.08 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1.95 g) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, v/v). A mixture of 4-ethyl-1-(4-nitrobenzyl)-1H-imidazole (1.95 g), 10% palladium carbon (200 mg) and ethanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 1-(4-aminobenzyl)-5-methyl-1H-imidazole (1.44 g) as colorless prism crystals. melting point: 137-138° C.