Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][C:11]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][C:23]=2[F:34])([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2ccc(F)c(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCOc4ccc(F)c(F)c4)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 83.4 %

Procedure:
A mixture of 0.38 g of ethyl 1-[2-(3,4-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 2.1 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 1-[2-(3,4-difluoro-phenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:27](Cl)(=[O:29])=[O:28])=[CH:15][CH:14]=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:32][CH:31]=1)(=[O:28])=[O:29]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (0.48 mmoles, 85 mg), NaH (1.2 mmoles, 48 mg), 2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride (0.53 mmoles, 0.19 g) and THF (3 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from methanol and water provided 46 mg (20%) of a white crystalline solid, m.p. 120-122° C.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:38][CH3:39])([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:38][CH3:39])([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Next, 1.40 g (2.48 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[methyl(4-trifluoromethylphenyl)phosphono]butanoate and 1.61 g (14.9 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.99 g (7.44 mmol) of aluminum trichloride at room temperature. After stirring was carried out at room temperature for 1 hour, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of ether three times and the water layer was separated, and methanol was added to the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, the effluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol (flow rate of 6 mL/min) and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[methyl(4-trifluoromethylphenyl)phosphono]butanoic acid (0.53 g, yield 63%) as a colorless solid.
Reaction SMILES: [N+]([C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-])=O.[H][H]>[Pd].CO>[C:9]1([CH:4]([CH2:5][OH:6])[CH2:7][OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])C(CO)(CO)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCC(CO)c1ccccc1

Procedure:
12 g. (0.06 mole) of 2-nitro-2-phenyl-1, 3-propanediol, 400 mg. of 5% palladium on calcium carbonate and 150 ml. of methanol are placed in a Parr hydrogenator bottle and reduced with hydrogen overnight. The mixture is filtered through Celite, concentrated to an oil and recrystallized from 30 ml. of toluene. The yield is 7.4 g. (80%) of product, M.P. 52°-4° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20]>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(CCC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.6 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min at RT. 2-Propyl-5-vinyl-pyridine (0.18 g, 0.5 mol) was added and stirred for further 15 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.015 g, 9% yield). 2,8-Dimethyl-5-[2-(6-propyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.015 g, 0.043 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.006 g, 0.043 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.008 g, 42% yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCc3ncnc(Nc4ccc(C(F)(F)F)cc4)c3C2)c1
Reaction time: 6 h
Yield: 4.7 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.2 mg, 5%).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[BH4-].[Na+].O>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH:23][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.4 %

Procedure:
4-Trimethylsilanyl-benzaldehyde (800 mg, 4.5 mmol) and 2-(3,4-dichloro-phenyl)-ethylamine (1023 mg, 5.4 mmol) were dissolved in methanol (5 ml) and the solution was stirred at rt for 5 min. Sodium borohydride (166 mg, 4.5 mmol) was added under nitrogen and the reaction mixture was stirred at rt for 1 h. Water was added and methanol was evaporated in vacuo. The reaction was extracted twice with diethyl ether and the combined organic layers were washed once with water and once with sat. aq. NaCl solution, dried with sodium sulfate, filtered and concentrated in vacuo to yield [2-(3,4-dichloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine (1640 mg, 100%) as a colorless oil. MS (ISP): 352.2/354.2 (100/74) (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 7.48 (d, 2H), 7.25-7.35 (m, 4H), 7.02 (dd, 2H), 3.79 (s, 2H), 2.75-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[CH2:8]([CH2:10][NH2:11])[OH:9]>C(O)C>[CH2:4]([CH:3]([CH2:6][CH3:7])[CH2:2][NH:11][CH2:10][CH2:8][OH:9])[CH3:5]
Reactant: CCC(CC)CBr
Reactant: NCCO
Solvent: CCO
Product: CCC(CC)CNCCO
Temperature: 75 °C
Yield: 92.7 %

Procedure:
A mixture of 3-bromomethyl-pentane (6.0 g, 36.4 mmol) and ethanolamine (13 mL, 218 mmol) in ethanol (45 mL) was heated at 75° C. for 16 h. The reaction mixture was concentrated and the resulting residue was diluted with DCM (70 mL). The organic layer was partitioned with water (70 mL) and the aqueous layer extracted with DCM. Combined organic layers, dried over magnesium sulfate, filtered, and concentrated to give the title compound as an oil (4.90 g). 1H NMR (d6-DMSO, 400 MHz) δ (ppm): 3.44 (t, J=5.6 Hz, 2H), 2.54 (t, J=6.0 Hz, 2H), 2.40 (d, J=5.6 Hz, 2H), 1.31-1.25 (m, 5H), 0.83 (t, J=6.8 Hz, 6H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:18]([CH:15]1[CH2:17][CH2:16]1)=[O:19]
Reactant: OCCCCCCCCCCCCBr
Reactant: O=C(Cl)C1CC1
Product: O=C(OCCCCCCCCCCCCBr)C1CC1

Procedure:
In an analogous manner to that described in Example 2, from 12-bromododecan-1-ol and cyclopropane carboxylic acid chloride there is obtained cyclopropane carboxylic acid 12-bromododecyl ester of melting point 29°-31° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14](Cl)(Cl)=[O:15].CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[C:31]([CH3:38])[N:32]=[CH:33]2>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:14]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[C:31]([CH3:38])[N:32]=[CH:33]3)=[O:15])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: NCc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(F)c(C(F)(F)F)c3)cccc2cn1
Temperature: 25 °C

Procedure:
4-Fluoro-3-(trifluoromethyl)benzylamine (0.8 g, 4.15 mmol) in toluene (20 mL) was refluxed with 20% w/v phosgene solution in toluene (2.1 mL) overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was again taken up in toluene (25 mL) and was stirred overnight at 80° C. with DIEA (2 mL, 11.5 mmol) and 5-amino-3-methylisoquinoline (500 mg, 3.16 mmol). The mixture was cooled to room temperature, concentrated in vacuo, and the residue was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH, eluant) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.72 (s, 1H), 8.16 (d, 1H, J=7.8 Hz), 7.70-7.77 (m, 4H), 7.48-7.54 (m, 3H), 7.14 (t, 1H, J=5.9 Hz), 4.42 (d, 2H, J=6.1 Hz), 2.64 (s, 3H); MS (ESI+) m/z 378 (M+H).
Reaction SMILES: [CH3:1][S-:2].[Na+].C(O)(=O)C.[O:8]1[CH:13]2[CH:9]1[C:10](=O)[CH2:11][C:12]2([O:25][Si](C)(C)C)[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>CO.C(N(CC)CC)C>[CH3:1][S:2][C:10]1[C:9](=[O:8])[CH2:13][C:12]([OH:25])([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1
Reactant: C[S-]
Reactant: C[Si](C)(C)OC1(CCCCOc2ccccc2)CC(=O)C2OC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC1=CC(O)(CCCCOc2ccccc2)CC1=O
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a solution of 25 mg of sodium thiomethoxide dissolved in methanol, 51 μl of acetic acid was added, and the mixture was stirred for 10 minutes. Triethylamine (170 μl) was then added, and after the mixture was stirred for 10 minutes, a solution of 16 mg of 2,3-epoxy-4-trimethylsilyloxy-4-(4-phenoxybutyl)cyclopentanone obtained in Example 549 in 3 ml of methanol was added and the mixture was stirred for 5 hours. Then saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to obtain 7.1 mg (yield 51%) of 2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cnccn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 95.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (200 mg, 0.545 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.129 ml, 0.739 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration and washed with water. This was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (190 mg, 95.4%) as a solid. mp 134-135° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[C:19]([C:22](=O)[C:23]4[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[CH3:31])[CH:20]=[CH:21][C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=O)[CH:8]=[CH:7][C:6]1=2)[CH3:2].[Cl-].[OH:47][NH3+:48].[OH2:49]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[C:19]([C:22](=[O:49])[C:23]4[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[CH3:31])[CH:20]=[CH:21][C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=[N:48][OH:47])[CH:8]=[CH:7][C:6]1=2)[CH3:2]
Reactant: O
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3C)cc2c2c3ccc(C(=O)c4c(C)cc(C)cc4C)cc3ccc21
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c2ccc(C(=NO)c3ccccc3C)cc2c2c3ccc(C(=O)c4c(C)cc(C)cc4C)cc3ccc21
Temperature: 130 °C
Reaction time: 6 h

Procedure:
To [7-(2-ethyl-hexyl)-3-(2,4,6-trimethylbenzoyl)-7H-benzo[c]carbazole-10-yl]-o-tolyl-methanone (0.25 g, 0.42 mmol) in pyridine (2 ml) is added hydroxylammonium chloride (59 mg, 0.84 mmol). The mixture is heated at 130° C., and then it is stirred for 6 hours. After the reaction mixture is cooled to room temperature, it is poured into water, and then the crude product is extracted with CH2Cl2 and washed with water and brine. After drying over MgSO4 and concentration, the desired product is obtained as a pale yellow solid (0.23 g, 90%). It is composed of an isomeric mixture, and the structure is confirmed by 1H-NMR spectrum (CDCl3) δ [ppm]: 0.84 (t), 0.92 (t), 1.23-1.40 (m), 2.05-2.07 (m), 2.10 (s), 2.18 (s), 2.20 (s), 2.40 (s), 4.32 (dd), 6.97 (s), 7.19 (dd), 7.34-7.38 (m), 7.42 (dd), 7.51 (dd), 7.62 (dd), 7.84 (d), 7.97 (d), 8.12 (dd), 8.61 (br), 9.06 (br).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:23][CH2:22]2)[CH:16]=1)=[O:14])([O-])=O.CO.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:25][CH2:26]2)[CH:16]=1)=[O:14]
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc2c1CCN2C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
Under a hydrogen atmosphere 130 mg (0.27 mmol) 1-{1-[6-(4-nitro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 25 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixture methanol:THF (15 mL of each) at RT and 3 bar hydrogen pressure. Then the catalyst was eliminated by suction filtering and the residue was washed with 50 mL DMF. The filtrate was evaporated down i. vac., the residue was stirred with methanol and suction filtered. The solid was dried at 50° C. in the CAD.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][NH2:29])=[CH:7][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]([CH2:17][C:18]([OH:20])([CH3:21])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][NH:29][C:41]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:42])=[CH:7][C:6]=2[N:5]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC(C)(C)O
Reactant: CC(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCNC(=O)NC(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 0.17 h

Procedure:
1-[4-Amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol dihydrochloride (prepared as described in Part A of Example 654, 0.466 g, 1.00 mmol), dichloromethane (10 mL), and triethylamine (0.418 mL, 3.0 mmol) were combined. The mixture was stirred for 10 minutes. Isopropyl isocyanate (0.097 mL, 1.00 mmol) was added and the reaction was stirred for 16 hours. Saturated aqueous sodium carbonate (˜8 mL) was added and the layers were separated. The organic layer was concentrated and purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform). The fractions containing product were combined and concentrated. Trituration of the product in dichloromethane, followed by filtration provided 0.319 g of N-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylurea as an off-white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:15][O:16][CH:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH2:31])[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].Cl[CH2:33]Cl>>[CH3:15][O:16][CH:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH:31][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=2)[CH:24]=1)[C:18]([O:20][CH2:21][CH3:33])=[O:19]
Reactant: COC(=O)C(Cc1ccc(OC)c(N)c1)OC
Reactant: ClCCl
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(Cc1ccc(OC)c(NC(=O)Cc2ccc(C(F)(F)F)cc2)c1)OC
Temperature: 25 °C
Reaction time: 30.5 h

Procedure:
4-Trifluoromethylphenylacetic acid (316 mg, 1.50 mmol) and methyl 2-methoxy-3-(3-amino-4-methoxyphenyl)propanoate (253 mg, 0.999 mmol) were dissolved in dichloromethane (10 mL) and, after N-cyclohexyl-carbodiimido-N′-methyl polystyrene (1.46 g, 2.26 mmol) was added, the mixture was stirred for 30.5 hours at room temperature. The insolubles were removed by filtration and the filtrate was concentrated under reduced pressure to afford the title product quantitatively as brown crystals.
Reaction SMILES: [C:1]([N:4]([CH:23]1[CH2:25][CH2:24]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([NH2:22])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)C.[F:29][B-:30]([F:33])([F:32])[F:31].[H+].[N:35]([O-])=O.[Na+]>O.CCOCC>[F:29][B-:30]([F:33])([F:32])[F:31].[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]2[C:8]([N+:22]#[N:35])=[CH:7][CH:6]=[C:5]([N:4]([C:1](=[O:3])[CH3:2])[CH:23]3[CH2:24][CH2:25]3)[N:10]=2)[CH2:12][CH2:13]1)=[O:18])[CH3:21]
Reactant: O=N[O-]
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2N)CC1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+]#N)CC1
Reaction time: 1 h

Procedure:
A solution of 20.8 g (60 mmole) of 4-[6-(acetylcyclopropylamino)-3-amino-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 44 ml of ethanol and 27 ml of 48% tetrafluoroboric acid was cooled to 0° C. and treated dropwise with a solution of 4.56 g (66 mmol) of sodium nitrite in 8 ml of water under a nitrogen atmosphere keeping the temperature 0°-5° C. After the addition was complete, the reaction was stirred at 0°-5° C. for one hour and treated with 150 ml of anhydrous ether keeping the temperature below 10° C. The solid was removed by filtration, the precipitate was washed with ethanol/ether (1:1), ether and dried in vacuo to give 24.5 g of the title compound, mp 100°-105° C. (dec.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)cc1

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-227 using 4-fluoro-nitrobenzene and cyclohexanol (heat 1.5 hours at 55° C.). Purify the material by silica gel chromatography (Prep.2000) eluting with methylene chloride/hexane 1:1 to provide the title compound as an oil. Mass spectrum (m/e): 221.1 (M*). (Bruker 300) 1H NMR (CDCl3) δ 8.13-8.18 (2H, d), 6.90-6.93 (2H, d), 4.31-4.39 (1H, m), 1.92-2.02 (2H, m), 1.75-1.85 (2H, m), 1.50-1.62 (3H, m), 1.28-1.44 (3H, m).