Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1>ClCCCl.C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12]([N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:17][CH2:18]1)=[O:30]
Reactant: CC1=CC(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)Nc2ccccc2N)=CC2C=NNC12
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1=CC(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc3ccccc3[nH]2)=CC2C=NNC12

Procedure:
A solution of N-(2-aminophenyl)-2-((7-methyl-3a,7a-dihydro-1H-indazol-5-yl)methyl)-4-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)butanamide in 1,2-dichloroethane (8 mL) and acetic acid (1 mL) was heated under nitrogen at 65° C. for 5 h. The solvent was evaporated and the residue taken up in ethyl acetate (20 mL). The ethyl acetate layer was washed with 1M sodium hydroxide (5 mL) and water (2×5 mL), dried, filtered and concentrated. The final product was obtained by flash chromatography using 0% to 10% 2 M ammonia in methanol/methylene chloride. MS(ESI)[M+H]+=550.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][CH2:13][CH2:14][CH:15]=1)=[O:10]>CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1)=[O:10]
Reactant: Cc1cccc(C(=O)C2=CCCO2)c1Br
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)C2CCCO2)c1Br
Reaction time: 8 h

Procedure:
A solution of (2-bromo-3-methylphenyl)(4,5-dihydrofuran-2-yl)methanone (0.80 g, 2.99 mmol) (mass approximate, based on ˜8 mg/mL Et2O solution) was treated with 500 mL EtOAc and concentrated to ˜100 mL twice. The resulting solution was placed under N2 atmosphere, treated with 5% Pt/C, and then placed under a balloon of H2. Reaction mixture was allowed to stir overnight, then filtered through plug of celite and the filter agent was further washed with 100 mL EtOAc. The solution was concentrated in vacuo and the crude material was absorbed onto a plug of silica gel and purified by column chromatography eluting with a gradient of 20-100% Et2O in hexane to afford (2-bromo-3-methylphenyl)(tetrahydrofuran-2-yl)methanone.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH3:10])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[BH4-].[Na+].CO.[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]([CH2:9][CH3:10])=[CH:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7]
Reactant: CCC(C)=CCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(C)=CCCC(C)O
Reaction time: 2 h

Procedure:
Six grams of 6-methyl-5-octen-2-one is added to a solution of 3.0 g. of sodium borohydride, 80 ml. of methanol and 6 ml. of 2N sodium hydroxide solution. After about two hours, acetic acid is added to destroy excess sodium borohydride and the solution poured into water and extracted with ether. The combined ether extracts are washed with aqueous sodium bicarbonate, water and brine, dried and evaporated to yield 6-methyl-5-octen-2-ol which is purified by chromatography.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH2:16][CH3:17])[C:6]=2[CH:5]=1)[CH3:2].F[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH2:16][CH3:17])[C:6]=2[CH:5]=1)[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1)[CH3:2]
Reactant: CCNc1ccc2c(c1)C(CC)=CCC2(C)C
Reactant: O=C(O)c1ccc(F)nc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC1=CCC(C)(C)c2ccc(N(CC)c3ccc(C(=O)O)cn3)cc21
Temperature: 125 °C
Yield: 4.2 %

Procedure:
To a mixture of 0.35 g (1.5 mmol) ethyl-(8-ethyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 167 and 0.32 g (2.2 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (22 mg).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][S:9][CH2:8][CH:7]1[C:12]([O:14][CH3:15])=[O:13])(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[S:9]1[CH2:10][CH2:11][CH:6]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]1
Reactant: COC(=O)C1CSCCC1OS(C)(=O)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=CCCSC1
Temperature: 50 °C

Procedure:
To a solution of methyl 4-((methylsulfonyl)oxy)tetrahydro-2H-thiopyran-3-carboxylate (4.33 g, 17.0 mmol) in DCM (170 mL) was added DBU (3.89 g, 25.5 mmol). The resulting mixture was refluxed at 50° C. for 30 minutes. The mixture was cooled to ambient temperature and washed with 1N aqueous HCl. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 7.12-7.13 (m, 1H); 3.75 (s, 3H); 3.36 (q, J=2.2 Hz, 2H); 2.68 (t, J=5.8 Hz, 2H); 2.51-2.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][CH:18]3[CH:13]([CH:14]([NH2:21])[CH2:15][CH2:16][CH2:17]3)[CH2:12]2)=[CH:4][CH:3]=1.[C:22]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:23].CO>O1CCCC1>[C:22]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:21][CH:14]2[CH:13]3[CH:18]([CH2:19][CH2:20][N:11]([CH2:10][CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:12]3)[CH2:17][CH2:16][CH2:15]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:23]
Reactant: NC1CCCC2CCN(CCCc3ccc(F)cc3)CC12
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cccc(NC(=O)NC2CCCC3CCN(CCCc4ccc(F)cc4)CC32)c1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A solution of (4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propyl]decahydroisoquinolin-8-amine (15 mg, 50 μmol) in tetrahydrofuran (1 mL) was treated with 3-acetylphenylisocyanate (8.3 mg, 50 mmol). The mixture was stirred for 30 minutes, then treated with methanol (0.5 mL). The mixture was concentrated under vacuum to provide a residue. The residue was purified by flash column chromatography, eluting with 5% triethylamine/ethyl acetate, to provide a white solid (11.4 mg, 49%). 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J=8 Hz, 1H), 7.29 (t, J=8 Hz, 1H), 7.00 (m, 2H), 6.83 (m, 2H), 5.16 (d, J=10 Hz, 1H), 3.61 (m, 1H), 3.42 (m, 1H), 3.08 (m, 1H), 2.94 (m, 1H), 2.53 (s, 3H), 2.47 (t, J=8 Hz, 2H), 2.4-2.2 (m, 2H), 1.9-1.5 (m, 8H), 1.4-0.8 (m, 5H). Mass spec (ES+) m/z 452.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:6]2[O:5][CH:4]([CH2:3][N:2]([CH3:1])[C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CNCC1Cc2cccc(-c3ccccc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1Cc2cccc(-c3ccccc3Cl)c2O1)C(=O)OCc1ccccc1
Yield: 90.1 %

Procedure:
Treatment of (±)-[(N-methyl-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.932 g, 3.4 mmol) with diisopropylethylamine (0.66 g, 5.11 mmol) and benzyl chloroformate (0.778 g, 4.08 mmol) generally according to the procedure described for Intermediate 12 provided 1.25 g (86%) of (±)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[N:4]=[CH:5][N:1]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=3)[N:2]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: c1cncc(-c2nc[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-n2cnc(-c3cccnc3)n2)n1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
100 mg (684 μmol) of 3-(1H-1,2,4-triazol-3-yl)pyridine (preparation cf. J. Org. Chem. 1979, 44, 4160-4164), 124 mg (683 μmol) of 2-chloro-6-(trifluoromethyl)pyridine and 142 mg (1.03 mmol) of potassium carbonate were initially charged in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 120° C. for about 18 hours. After cooling, water was added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. This gave 180 mg (90% of theory) of 2-[3-(pyridin-3-yl)-1H-1,2,4-triazol-1-yl]-6-(trifluoromethyl)pyridine as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:5]=[CH:6][CH:7]=1.[CH:21]1[C:33]2[NH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CO.C(Cl)(Cl)Cl.CN1CCCN(C)C1=O>[CH:30]1[C:31]2[N:32]([C:2]3[CH:3]=[C:4]([C:8]4[N:12]5[CH:13]=[CH:14][C:15]6[C:20]([C:11]5=[N:10][N:9]=4)=[CH:19][CH:18]=[CH:17][CH:16]=6)[CH:5]=[CH:6][CH:7]=3)[C:33]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: Brc1cccc(-c2nnc3c4ccccc4ccn23)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN1CCCN(C)C1=O
Solvent: ClC(Cl)Cl
Product: c1cc(-c2nnc3c4ccccc4ccn23)cc(-n2c3ccccc3c3ccccc32)c1
Temperature: 180 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
To a 200-mL three-neck flask were added 1.6 g (5.0 mmol) of 3-(3-bromophenyl)-1,2,4-triazolo[3,4-a]isoquinoline synthesized in Step 2, 0.92 g (5.5 mmol) of 9H-carbazole, 0.16 g (0.61 mmol) of 18-crown-6-ether, 1.4 g (10 mmol) of potassium carbonate, and 3 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). To this mixture was added 82 mg (0.43 mmol) of copper(I) iodide, and the mixture was stirred at 180° C. for 6 hours under a nitrogen stream. After the stirring, this mixture was cooled to room temperature, and chloroform was added thereto. The organic layer of the resulting mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, and the organic layer was dried over magnesium sulfate. The obtained mixture was gravity-filtered, and the filtrate was concentrated to give a solid. This solid was purified by silica gel column chromatography (toluene:ethyl acetate=5:1) to give a solid. A methanol suspension of the obtained solid was irradiated with ultrasonic waves, and the solid was collected by suction filtration. Further, this solid was recrystallized from toluene, so that the substance which was the object of the synthesis was obtained as 1.6 g of a white powder in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[C:21]([O:25][C:26](=[O:34])[NH:27][CH2:28][C@H:29]1[CH2:32][C@H:31]([OH:33])[CH2:30]1)([CH3:24])([CH3:23])[CH3:22].C[Si](C)(C)N[Si](C)(C)C.[K]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:33][C@H:31]2[CH2:32][C@H:29]([CH2:28][NH:27][C:26](=[O:34])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:30]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](O)C1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (416 mg, 0.94 mmol), as prepared in Example 5, step 1, in THF (10 mL) was added tert-butyl(trans-3-hydroxycyclobutyl)methylcarbamate (175 mg, 0.94 mmol) and potassium hexamethyldisilazane (560 mg, 2.8 mmol, 3.0 mol eq) and the reaction was stirred at ambient temperature for 20 hrs. The reaction was then quenched with brine (3 mL) and stirred for 10 min, and diluted with ethyl acetate (60 mL) and water (10 mL). The organic layer was separated, washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to give an oil which was purified via flash chromatography (eluting with a gradient of 0 iodobenzene diacetate 100% EtOAc in heptanes) to give the title compound (452 mg, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (s, 1H) 5.48 (s, 2H) 5.38 (t, J=6.54 Hz, 1H) 4.86 (br. s., 1H) 3.44-3.59 (m, 2H) 2.81 (s, 3H) 2.61-2.74 (m, 2H) 2.27-2.43 (m, 2H) 1.40 (s, 9H) 0.71-0.97 (m, 2H) −0.08 (s, 9H). m/z (APCI+) for C22H34ClIN4O4Si 509.0 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[CH3:12].[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([CH2:23][C:24]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][S:11][C:5]=4[N:4]=[C:3]3[CH3:12])=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc2sccc2c(=O)n1N
Product: Cc1nc2sccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-2-methylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.58-1.74 (m, 12H), 1.93-1.98 (m, 3H), 2.08-2.18 (m, 2H), 2.39 (s, 3H), 7.39 (d, J=6.0 Hz, 1H), 7.59 (d, J=6.0 Hz, 1H), 10.89 (s, 1H) ppm; MS (DCI/NH3) m/z 358 (M+H)+; Elemental Analysis: Calculated for C19H23N3O2S.0.8H2O: C, 61.37; H, 6.67; N, 11.30. Found: C, 61.50; H, 6.86; N, 11.38.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:7][CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccc(Br)cc21
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a mixture of tert-butyl 7-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (0.500 g, 1.53 mmol) and morpholine (0.668 mL, 7.66 mmol) in toluene (10 mL) at 0° C. was added titanium(IV) chloride [1M in toluene] (0.843 mL, 0.843 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature overnight. The heterogeneous, orange reaction mixture was filtered under reduced pressure through a pad of Celite which was then rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give tert-butyl 7-bromo-4-morpholinoquinoline-1(2H)-carboxylate (0.598 g, 1.513 mmol, 99% yield) as a yellow oil. The product had LC/MS M+1=395.1 and 397.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.CN([CH:26]=[O:27])C>O1CCCC1>[CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH:26]=[O:27]
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(C=O)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
A solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (U.S. Pat. No. 5,175,296 Example 1 Part C, 25.64 g, 113.8 mmol) in tetrahydrofuran (THF) (450 mL) was cooled to −78° C. Butyllithium (45.5 mL of a 2.5 M solution in hexanes) was added dropwise over a period of ten minutes, and the resulting solution was stirred for ten minutes. DMF (20.1 mL, 274.4 mmol) was added, and the reaction was allowed to warm to room temperature and stirred for one hour. The THF was then removed under reduced pressure, and the residue was dissolved in ethyl acetate (400 mL). The resulting solution was washed with brine (400 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 0.5% and 1% methanol in dichloromethane) to provide 10.5 g of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde as a light brown solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[Cl:14][CH2:15][C:16](OCC)(OCC)OCC>C(O)C>[Cl:14][CH2:15][C:16]1[S:13][C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:3]=2[N:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: CCOC(CCl)(OCC)OCC
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc2sc(CCl)nc2c1
Temperature: 60 °C

Procedure:
To a solution of 2-amino-4-trifluoromethylthiophenol hydrochloride (30.0 g) in ethanol (125 ml) was added 2-chloro-1,1,1-triethoxyethane (31.0 g). The mixture was heated for 1 hour at 60° C. The solution was concentrated to remove excess ethanol and the resulting material was extracted with ether (500 ml). The organic extract was washed successively with 10% HCl (20 ml), water (100 ml), 10% sodium bicarbonate solution and water (100 ml), and then evaporated to obtain an amber colored oil, which crystallized upon standing at room temperature (28.9 g; m.p. 52° C.).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]([C:41]([F:44])([F:43])[F:42])=[CH:4][C:5]([NH:7][C@:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH:38]([CH3:40])[CH3:39])[CH:31]=1)([C:16]1[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1(C2C=C[N+]([O-:59])=CC=2)C=CC=CC=1.[O-]Cl.[Na+]>C(#N)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:8]([NH:7][C:5]([CH:4]2[C:3]([C:41]([F:43])([F:44])[F:42])([C:2]([F:1])([F:45])[F:46])[O:59]2)=[O:6])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C=C(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C2OC2(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
At 0° C. to a solution of (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291, 130 mg, 0.19 mmol) and 4-phenyl pyridine N-oxide (26 mg, 0.15 mmol) in acetonitrile (5 mL) was added NaOCl solution (206 μL, chlorine wt % 10-3%, 0.58 mmol). The reaction mixture was stirred at 0° C. for 10 min, then at rt for 1 h. The solvents were removed under reduced pressure and the residue was diluted with EtOAc (30 mL), washed with saturated Na2SO3 (30 mL), dried over MgSO4, filtered and concentrated. The resulting residue was right away purified by ISCO chromatography (40 g column, flow rate 25 mL/min) using hexanes/EtOAc (0-10% over 30 min) to give N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide as a diastereomer mixture at a retention time of 26 min (97 mg, 74% yield). The diastereomer mixture was separated by Chiral preparative HPLC chiralpak AD 20μ column, 5×50 cm, eluting with 5% IPA/Heptane with flow rate 50 mL/min
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][C:31]([CH3:35])=[CH:30]4)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1>C(O)(=O)C.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[NH:33][CH2:32][CH:31]([CH3:35])[CH2:30]4)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1cnc2c(S(=O)(=O)NC(Cc3ccc4[nH]cnc4c3)C(=O)N3CCC(C)CC3)cccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cccc3c2NCC(C)C3)CC1

Procedure:
Prepared by catalytic hydrogenation of N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxoethyl]-3-methyl-quinoline-8-sulphonamide in the presence of palladium/charcoal in 50% acetic acid and under a hydrogen pressure of 3 bar analogously to Example 35.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cccc(F)c1
Product: CC(C(=O)NCc1cccc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=473.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3-fluoro-benzyl)-malonamic acid.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:39][CH2:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43].N1C=CC=CC=1>ClCCCl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH2:40][Cl:39])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)CCl)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 82.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), chloropivaloyl chloride (166 mg) and pyridine (86 μl) were added, and the mixture was refluxed for 2 hours 30 minutes. The reaction mixture was successively washed with water,1N hydrochloric acid, and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 509 mg of the titled compound (Yield: 81%).