Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO.C(Cl)[Cl:17]>>[Cl:17][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: ClCCl
Solvent: CO
Product: O=C(CCl)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(4-Fluoro-3-nitrophenyl)ethanone (18.4249 g; manufactured by Sigma-Aldrich Co.) was dissolved in CH2Cl2 (400 mL), added with methanol (3.04 mL), followed by replacement with nitrogen gas and cooling to 0° C. To the resulting solution, SO2Cl2-CH2Cl2 solution [109.32 mL; solution obtained by dissolving SO2Cl2 (9.32 mL; manufactured by Wako Pure Chemical Industries, Ltd.) in CH2Cl2 (100 mL)] was added dropwise over 30 minutes, and the mixture was stirred overnight while warming to room temperature. The reaction solution was cooled to 0° C., added with methanol (1.52 mL), and then SO2Cl2-CH2Cl2 solution [64.66 mL; solution obtained by dissolving SO2Cl2 (4.66 mL; manufactured by Wako Pure Chemical Industries, Ltd.) in CH2Cl2 (60 mL)] was added dropwise thereto. While warming to room temperature, the mixture was stirred for 3 hours. The reaction solution was washed once with a saturated aqueous solution of sodium carbonate and once with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The solidified crystal, which had been obtained during purification of the resulting residue by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=88:12→67:33), was extracted with ethyl acetate, and then filtered. The filtrate was evaporated under reduced pressure, and as a result, the title compound was obtained (6.403 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N+:12]#[C-:13])[CH2:9][CH2:10][CH3:11].[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>Cl(O)(=O)(=O)=O>[CH2:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]2=[N:1][C:17]=1[C:16]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:15]=1[Cl:14])[CH2:9][CH2:10][CH3:11]
Reactant: Nc1cnccn1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: [C-]#[N+]CCCC
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCNc1c(-c2cccc(Cl)c2Cl)nc2cnccn12

Procedure:
Compound (11) was prepared in accordance with general instructions 1 from 1.0 ml aminopyrazine solution (0.1 M, MC), 0.575 ml n-butylisonitrile solution (0.2 M, MC), 0.500 ml 2,3-dichlorobenzaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:16]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:33])[CH:28]=[CH:29][CH:30]=2)O1>>[N:13]1[CH:14]=[CH:15][N:16]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:29]4[CH:28]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:37])([F:38])[F:39])=[O:33])[CH:26]=[CH:25][CH:30]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[N:12]=1
Reactant: Ic1cnc2cc(-c3nccnn3)ccn12
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nccnn4)ccn23)c1

Procedure:
3-Iodo-7-[1,2,4]triazin-3-yl-imidazo[1,2-a]pyridine (96 mg, 0.3 mmol) and 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea were coupled according to procedure D4 to furnish the title compound as a yellow solid (39 mg). 1H NMR (400 MHz, Me-d3-OD & CDCl3): 9.26 (1H, d), 8.91-8.80 (2H, m), 8.67 (1H, d), 8.16-8.04 (2H, m), 7.85 (2H, d), 7.48 (1H, t), 7.39 (1H, d), 7.30 (1H, d), 3.91 (2H, q). MS: [M+H]+414
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Br:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Br:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Br)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCNCC4)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c(Nc2ncnc3cc(O)cc(OC4CCNCC4)c23)c1
Temperature: 80 °C

Procedure:
A mixture of 7-benzyloxy4-(2-bromo-5-methoxyanilino)-5-piperidin-4-yloxyquinazoline (0.35 g) and trifluoroacetic acid (6 ml) was stirred and heated to 80° C. for 5 hours. The mixture was evaporated and the residue was dissolved in water (12 ml). The solution was basified to pH8 by the addition of sodium bicarbonate. The resultant precipitate was isolated, washed with water and with ethyl acetate and dried under vacuum. There was thus obtained the title compound (0.26 g); NMR Spectrum: (DMSOd6) 1.95–2.15 (m, 2H), 2.32 (d, 2H), 3.05 (t, 2H), 3.3–3.4 (m, 2H), 3.8 (s, 3H), 5.0 (m, 1H), 6.75 (m, 2H), 6.85 (s, 1H), 7.6 (d, 1H), 7.98 (s, 1H), 8.4 (s, 1H), 9.58 (s, 1H); Mass Spectrum: M+H+ 445 and 447.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:25][NH:26][O:27][CH3:28].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:3]([C:9]([N:26]([O:27][CH3:28])[CH3:25])=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ncc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a suspension of 3,5-difluoropicolinic acid (3.5 g) in THF (70 ml) was added CDI (3.92 g) at room temperature. The mixture was stirred at room temperature for 30 min and at 50° C. for 1 h. After cooling to room temperature, N,O-dimethylhydroxylamine hydrochloride (3.22 g) and DIPEA (5.76 mL) were added. The mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (2.5 g).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:27][CH:28]([CH3:32])[CH2:29][NH:30][NH2:31]>CO>[CH3:27][CH:28]([CH3:32])[CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: CC(C)CNN
Solvent: CO
Product: CC(C)Cn1nccc1-c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Yield: 14.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.: 379, MS Found: 380 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:24]4[CH:25]=[CH:26][C:27]([C:30]5([NH2:34])[CH2:33][CH2:32][CH2:31]5)=[CH:28][CH:29]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 0.01 h
Yield: 68.1 %

Procedure:
Tert-butyl (1-(4-(1-isobutyl-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (7 mg, 0.013 mmol) was dissolved in dichloromethane (1 mL); TFA (1 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (4 mg, 68% yield). LCMS (Method D): RT=0.844 min, M+1=452. 1H-NMR (500 MHz, CD3OD) δ 8.07 (1H, s), 7.52-7.45 (2H, d), 7.44-7.40 (2H, d), 7.38-7.33 (3H, m), 7.31-7.26 (2H, m), 5.66 (2H, s), 3.11 (2H, d), 2.81-2.68 (2H, m), 2.61-2.45 (2H, m), 2.32-2.17 (1H+1H, 2 m), 2.02-1.87 (1H, m), 1.10 (6H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15](Br)=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[CH:15]=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2cc3n(c2c1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Reaction time: 6 h
Yield: 49 %

Procedure:
To a solution of 1.52 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 15 ml ethanol was added 0.15 g 10% palladium on charcoal and the mixture was stirred under a hydrogen atmosphere for 6 h. A further 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6hunder a hydrogen atmosphere. Again 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6 h under a hydrogen atmosphere. The catalyst was removed by filtration over dicalite and the filtrate was evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate=4:1 to yield 0.59 g (R)-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester as a white foam. MS: (M+H)=301.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:7]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:6][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2F)n[nH]1
Temperature: 55 °C
Yield: 40.6 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 23; 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature was added 5-isopropoxy-1H-pyrazol-3-amine (0.50 g, 3.0 mmol), and DIEA (0.29 g, 2.2 mmol). The reaction was then heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was then extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.34 g, 40%). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=10.9 Hz, 1H), 7.45-7.35 (m, 2H), 7.07-7.03 (m, 2H), 5.88-5.71 (m, 1H), 5.48-5.30 (m, 1H), 4.58-4.29 (m, 1H), 1.68-1.56 (m, 3H), 1.34-1.28 (m, 6H). MS: Calcd.: 418. Found: [M+H]+ 419.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].O>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)=[O:22]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
To a stirred ice bath cooled solution of veratrole (2.55 mL, 20 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting mixture was added 3-nitrobenzoyl chloride (3.8 g, 20 mmol) in 30 mL of methylene chloride. The reaction was then allowed to warm to room temperature and followed by heating to refluxed. After 5 hours at reflux the reaction mixture was allowed to cool to room temperature and stirred for 72 hours. The reaction mixture was then poured into 100 mL of iced water and stirred for 20 minutes. This mixture was extracted with CH2Cl2 (3×60 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the crude product as a green solid. The crude product was purified by flash column chromatography (silica gel, CH2Cl2) to afford 2.21 g (39%) of the product as a yellow solid: mp 133-135° C.; 1H NMR (CDCl3) δ 8.64-8.56 (m, 1H), 8.49-8.39 (m, 1H), 8.10-8.05 (m, 1H), 7.76-7.65 (m, 1H), 7.55-7.47 (m, 1H), 7.36-7.29 (m, 1H), 7.00-6.87 (m, 1H), 3.99 (s, 3H), 3.97 (s, 3H); 13C NMR (CDCl3) δ 192.8, 153.8, 149.4, 147.9, 139.7, 135.2, 129.5, 128.9, 126.2, 125.6, 124.4, 11.8, 110.0, 56.2, 56.1; Anal. Calcd for C15H13NO5. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.74; H, 4.59; N, 4.89.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4](=O)[CH3:5].[NH2:7][N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:15].Cl>O.CO>[CH3:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH:13]([CH3:14])[N:8]1[NH:7][CH:4]([CH3:5])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: CC=O
Reactant: CC1CCCC(C)N1N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C#N)NN1C(C)CCCC1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.9 9 of sodium cyanide, dissolved in 25 ml of water, and 3.5 g of acetaldehyde, dissolved in 25 ml of methanol, are added dropwise with ice-cooling to a mixture of 7.75 g of 1-amino-2,6-dimethylpiperidine, 50 ml of water and 5.2 ml of concentrated hydrochloric acid. The pH of the solution is adjusted to 7 with hydrochloric acid and the reaction mixture is stirred at room temperature for 2 days. After stripping off the methanol, the mixture is extracted with dichloromethane, and the organic phase is dried with sodium sulphate and concentrated. The residue of 9.2 g of 2-((2,6-dimethylpiperidino)amino)propionitrile which remains is processed further without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[O:33][CH2:34][CH2:35][CH2:36][Br:37]>CC#N>[Br-:37].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:36][CH2:35][CH2:34][O:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccc2ccccc2c1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccc4ccccc4c3)(CC1)CC2
Product: [Br-]
Yield: 63.4 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0472 g, 0.160 mmol) and 3-bromopropyl 2-naphthalenyl ether (0.0618 g, 0.233 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0567 g, 63.7%). EI-MS m/z 478 (M+) Rt (2.22 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[S:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:29](Cl)Cl.CCN(C(C)C)C(C)C.FC(F)(F)S(OC)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])[S:11][CH3:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reactant: ClCCl
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=Nc1ccc(F)c(Cl)c1)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.08 h

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carbothioamide (0.18 g, 0.00039 mol) in anhydrous DCM (3 ml, 0.04 mol) under N2 was added DIPEA (82 μL, 0.00047 mol) followed by methyl trifluoromethanesulfonate (47 μL, 0.00043 mol). The reaction was stirred for 5 minutes and then concentrated in vacuo. The crude material was used in the next step. The product amount was estimated (185 mg, 100%). MF═C20H29ClFN3OS2Si; LCMS calculated for C20H30ClFN3OS2Si (M+H)+: m/z=474.1.
Reaction SMILES: CC(C)=O.[F:5][C:6]1[CH:13]=[CH:12][C:9]([NH:10][CH3:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)=[O:22]>O>[F:5][C:6]1[CH:13]=[CH:12][C:9]([N:10]([CH3:11])[C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)c1cc(OC(=O)Cl)ccc1Cl
Reactant: CNc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C(=O)Oc1ccc(Cl)c(C(C)(C)C)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To 20 ml of acetone were added 1.25 g of 4-fluoro-N-methylaniline and 1.38 g of anhydrous potassium carbonate, and a solution obtained by dissolving 2.5 g of 3-tert-butyl-4-chlorophenyl chloroformate into 20 ml of acetone was added thereto with stirring at room temperature. After stirring for 30 minutes as it is, the mixture was refluxed with heating for 2 hours. After cooled down to room temperature, the reaction mixture was poured into cold water and the resultant product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and thereafter benzene was distilled off under reduced pressure. The residue was purified through a column chromatography (employing silica gel as carrier and benzene as developing solvent) and further recrystallized from ethanol to give 2.7 g of 3-tert-butyl-4-chlorophenyl N-(4-fluorophenyl)-N-methylcarbamate having melting point of 92°-94° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[F:42])[C:36]([OH:38])=O.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:36](=[O:38])[C:35]2[CH:39]=[CH:40][C:41]([F:42])=[C:33]([F:32])[CH:34]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(F)c(F)c2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (30 mg, 0.068 mmol, prepared as described in Step (A) of Example 28) and 3,4-difluorobenzoic acid (10.8 mg, 0.068 mmol) in 0.68 ml of CH2Cl2 and 0.1 ml DMF, 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) was added. The reaction was stirred at room temperature for 5 hrs and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 19% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 81% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (22 mg, 56%) as a white solid, m.p. 122°-128° C. (amorphous).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:29]=1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:47]>ClCCl>[NH2:47][C:9]1[C:8]2[N:29]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
tert-Butyl 2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (2.8 g, 5.05 mmol) was dissolved in dichloromethane (35 mL) and ammonium hydroxide (25 mL). p-Toluenesulfonyl chloride (0.962 g, 5.05 mmol) was added in one portion and the reaction was stirred for 16 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organics were combined and evaporated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (silica gel, 2-25% CMA in chloroform) to provide 1.95 g of tert-butyl 2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as white crystals.