Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5](=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:22]([Br:23])=[C:21]([N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]3[N:41]=[CH:42][C:43]([C:44]4[CH:45]=[N:46][C:47]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[CH:48][CH:49]=4)=[C:19]3[N:18]=2)[CH2:13][CH2:12]1)[C:6]([O:8]CC)=[O:7])(=O)C.C1COCC1.[Li+].[OH-].Cl>O>[CH3:30][Si:29]([CH3:32])([CH3:31])[CH2:28][CH2:27][O:26][CH2:25][N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:21]1[N:20]2[N:41]=[CH:42][C:43]([C:44]3[CH:45]=[N:46][C:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[CH:48][CH:49]=3)=[C:19]2[N:18]=[C:17]([CH:14]2[CH2:13][CH2:12][CH:11]([C:5](=[O:4])[C:6]([OH:8])=[O:7])[CH2:16][CH2:15]2)[C:22]=1[Br:23]
Reactant: CCOC(=O)C(OC(C)=O)=C1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(C(=O)C(=O)O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 50 mL roundbottom flask was charged ethyl 2-acetoxy-2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate (0.47 mmol, 400 mg), a solution of 2:1 THF:H2O (15 mL), and 1N LiOH(aq) (1.18 mmol, 1.18 mL). The resulting solution was stirred at room temperature for 18 hours. After 18 hours, the reaction was quenched with 1N HCl(aq) (1.18 mmol, 1.18 mL) and the solvent removed in vacuo. The resulting residue was taken on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:17]=1.C(Cl)Cl.C(#N)C.I([O-])(=O)(=O)=[O:39].[Na+]>[Ru](Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:39])=[O:9])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=2)[N:17]=1
Reactant: CC(C)(C)S(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)S(=O)(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-methylpropane-2-sulfinamide (Intermediate-144, 0.075 g, 0.158 mmol) in mixture of DCM:acetonitrile:water (0.2 ml:0.2 mL:0.3 mL), sodium periodate (0.050 g, 0.238 mmol) and ruthenium chloride (0.001 g, 0.003 mmol) were added and the reaction mass was stirred at RT for 4 h. After completion of the reaction the reaction mass was filtered through celite bed and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained product was purified with column chromatography on neutral alumina eluting with 10% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.30 (s, 9H), 4.31 (d, J=6.0 Hz, 2H), 7.55-7.71 (m, 4H), 7.86 (d, J=8.7 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H), 12.71 (s, 1H). MS (m/z): 489.04 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1)=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21](=[S:23])[NH2:22]>>[Br:12][C:7]1[CH:6]=[C:5]([C:3]2[N:22]=[C:21]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[C:14]([F:25])([F:13])[F:24])[S:23][CH:2]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(CBr)c1ccc(F)c(Br)c1
Reactant: NC(=S)c1cnccc1C(F)(F)F
Product: Fc1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1Br
Yield: 41 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(3-bromo-4-fluorophenyl)ethanone (3.10 g) and 4-trifluoromethylpyridine-3-thiocarboxamide (1.87 g), the title compound (1.50 g) was obtained as brown needle crystals.
Reaction SMILES: [OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].C(OC(COC1C=CC(F)=CC=1)CCCN(CC#CCCCC(OC)=O)S(C)(=O)=O)(=O)C.[OH-].[Na+]>>[OH:1][CH:2]([CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CCOC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Agent: COC(=O)CCCC#CCN(CCCC(COc1ccc(F)cc1)OC(C)=O)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)N(CC#CCCCC(=O)O)CCCC(O)COc1ccc(F)cc1

Procedure:
The synthesis of this compound is carried out as described in Example 1, Step E except that the ethyl 7-{N-[4-hydroxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido} -heptanoate is replaced by an equimolar amount of methyl 7-{N-[4-acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}-hept- 5-ynoate and the amount of sodium hydroxide is doubled. The product of this reaction is the subject compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35](=[O:37])[CH3:36].CC(C)=O>C(Cl)Cl>[CH3:26][C:6]1[C:5]2[C:10](=[C:11]([CH3:12])[C:2]([O:1][CH2:34][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=2)[O:9][C:8](=[O:13])[C:7]=1[CH2:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20]
Reactant: CC(=O)CCl
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (4.00 g, 11.5 mmol), potassium carbonate (4.5 g, 36.9 mmol), chloroacetone (1 mL, 11.5 mmol) and acetone (200 mL) were refluxed overnight. After the solution was allowed to cool to room temperature, CH2Cl2 (200 mL) was added and the resulting solid was filtered off. The remaining solution was cold decolorized with charcoal and the solvent evaporated. The resulting solid was stirred with water, vacuum filtered, and washed with water. After air drying, 4,8-dimethyl-7-(2-oxo)propyloxy-3-(phthalimidomethyl)coumarin (4.06 g, 87.1% ) was obtained as an off-white solid. 1H NMR (CDCl3): δ 7.66-7.83 (m, 4H), 7.48 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.91 (s, 2H), 4.62 (s, 2H), 2.59 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:13](=[O:14])[O:15][CH3:16])=[CH:5][CH:4]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 15 ml of pyridine was dissolved 3.00 g of 6-(trifluoromethyl)pyridin-3-amine, and then 2.1 ml of methyl chloroformate was added thereto under ice-cooling, followed by 2 hours of stirring at room temperature. Under ice-cooling, 30 ml of a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by 1 hour of stirring. Thereafter, the precipitated crystals were filtrated and, after washing with water, dried under reduced pressure to obtain 3.88 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([O-])=O.[H][H]>C1(C)C=CC=CC=1.[Pt]>[O:27]([C:5]1[C:4]([NH2:1])=[C:13]([NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Nc1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Reaction time: 4 h
Yield: 74 %

Procedure:
A 500 mL Parr bottle was charged with a solution of 3-nitro-2-phenoxy-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine in toluene (150 mL) and 5% Pt/C catalyst (1.1 g), placed on Parr apparatus and charged with hydrogen (˜54 psi, 3.8 Kg/cm2). The reaction was allowed to shake for 4 hours, at which time the reaction was monitored by HPLC. The reaction was not complete. An additional 1.0 g 5% Pt/C catalyst was added to the Parr bottle, it was recharged with hydrogen and shaken overnight. The reaction was then complete. The mixture was filtered through Celite and washed with toluene (500 mL). The filtrate was concentrated to provide 2-phenoxy-N4-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine as a yellow syrup (8.2 g, 74%). TLC (10% MeOH/CH2Cl2, Rf=0.48). Mass-spec M+1=419.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:7]([O:8][CH3:9])[C:4]=1[O:5][CH3:6].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][C:12]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(OC)c1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OC)c1OC
Yield: 78.7 %

Procedure:
Pyrogallol trimethyl ether (5.1 g) was suspended in CCl4 (60 mL) and N-bromosuccinimide (6.5 g, 1.2 eq.) was added. The reaction mixture was heated at reflux for 20 hours. The succinimide was collected and the filtrate concentrated in vacuo to a brown oil. The oil was separated by gravity column chromatography (hexane-ethyl acetate, 19: 1) and yielded the title compound as a yellow oil (5.9 g, 78%): EIMS m/z 234 ((M+ —CH3, 81Br), 232 (M+ —CH3, 79Br), 107, 95, 69, 58, 44; 1H NMR (CDCl3, 300 MHZ) δ 7.21 (1H, d, J=9.0 Hz, H6), 6.58 (1H, d, J=9.0 Hz, H5), 3.91 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.85 (3H, s, OCH3).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([CH2:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.C(OCC)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:14][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)CC(=O)C=Cc1ccc(O)c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
A mixture of 4-hydroxy-3-nitrobenzaldehyde (43.5 g), acetylacetone (26 g), acetic acid (3.12 g) and piperidine (1.03 ml) in benzene (26 ml) was refluxed for 1 hours under azeotropic dehydration. To the reaction mixture was added 100 ml of diethyl ether. The mixture was washed with water (100 ml) and a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate and evaporated in vacuo to afford 2-(4-hydroxy-3-nitrobenzylidene)acetylacetone (55.0 g).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[N:3]=1.P(Br)(Br)([Br:24])=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O>[Br:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)c1ccc(-n2nc(O)c3ccccc3c2=O)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Product: CC(C)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
4-Hydroxy-2-(4-isopropylphenyl)-2H-phthalazin-1-one (0.10 g, 0.36 mmol), phosphorus oxybromide (0.41 g, 1.4 mmol) and 2,6-di-tert-butyl-4-methylphenol (0.02 g, 0.09 mmol) were stirred at 150° C. for 30 min. H2O (100 ml) was added after cooling to RT. Extraction with DCM, drying of the combined organic phases over Na2SO4 and evaporation of the solvent yielded the desired compound (0.05 g, 41%) which was used without any further characterization.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][N:8]([CH2:10][CH2:11][OH:12])[CH2:7][N:6]([CH2:13][CH2:14][OH:15])[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O.C(Cl)Cl>[C:22]([O:12][CH2:11][CH2:10][N:8]1[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][N:6]([CH2:13][CH2:14][OH:15])[CH2:7]1)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: OCCN1CN(CCO)CN(CCO)C1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN1CN(CCO)CN(CCO)C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1,3,5-tris(2-Hydroxyethyl)perhydro-s-triazine (21.6 g, 0.1 mole) and potassium carbonate (35 g) are combined in a mixture of 50 ml of water and 150 ml of methylene chloride at 0° C. Oleic acid chloride (30 g, 0.1 mole) in 50 ml of methylene chloride is added at a rate such that the reaction mixture is retained at a temperature below about 10° C. After complete addition, the mixture is stirred at 0° C. for 15 hours and then at about 25° C. for an additional 16 hours. The organic layer is separated, dried over magnesium sulfate and concentrated to a yellow oil. Analysis by infrared spectroscopy and nuclear magnetic resonance spectroscopy identify the product as 1,3,5-triazine-1,3,5-(2H,4H,6H)triethanol monooleate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N.C(=O)([O-])[O-].[K+].[K+]>C(#N)CC.O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: OCCN1CCC(O)CC1
Agent: C[P+](C)(C)CC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CCC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCN2CCC(O)CC2)CC1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester 3 (5 g, 25 mmol), 1-(2-Hydroxy-ethyl)-piperidin-4-ol 22 (4 g, 27.5 mmol) and DIEA (5.6 ml, 32.5 mmol) are suspended in 25 ml of propionitril. Cyanomethyl-trimethyl-phosphonium iodide (4 g, 30 mmol) is added and the reaction mixture is refluxed. Additional portions of cyanomethyl-trimethyl-phosphonium iodide (1.5 g, 11.25 mmol) are added after 90 minutes and after 3 hours. After cooling to room temperature, a solution of potassium carbonate (4 g) in 250 ml of water is added and the product is isolated by extraction with DCM. Evaporation under reduced pressure gave 6.9 g of a red oil which could be crystallized from ether.
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:32]([NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCc1nc2cnc3ccccc3c2n1CCCCN
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 87.4 %

Procedure:
Using the general method of Example 146 Part B, 4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine (4.0 g, 12.3 mmol) was reacted with phenyl isocyanate (1.34 mL, 12.3 mmol) to provide 4.77 g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][C:10]1[N:11]=[C:12](N)[S:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[ClH:25]>CC#N.[Cu](Cl)Cl>[Cl:25][C:12]1[S:13][C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:10]([CH3:9])[N:11]=1
Reactant: Cc1nc(N)sc1-c1ccc([N+](=O)[O-])cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1nc(Cl)sc1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isoamyl nitrite (3.5 ml, 25 mmol) is added to a stirred suspension/solution of anhydrous copper (II) chloride (2.75 g, 20 mmol) in dry methylcyanide (50 ml). 4-Methyl-5-(4-nitro-phenyl)-thiazol-2-ylamine (25a) (4.0 g, 17 mmol) is then added over 30 minutes. The resulting slurry is stirred at room temperature for 1 hour then heated at 70° C. for 30 minutes. After cooling to room temperature the black solution is poured into 4M hydrochloric acid (200 ml). The product is extracted with ethyl acetate, dried (MgSO4) and the solvent removed to give the title compound as an orange powder (3.13 g). MH+ (TOF, ES+): 255.0
Reaction SMILES: [C:1]([CH:4]1[CH:9]([C:10](O)=[O:11])[CH2:8][CH2:7][CH:6]=[CH:5]1)(O)=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O>C1COCC1.C1C=CC=CC=1>[OH:2][CH2:1][C@H:4]1[C@@H:9]([CH2:10][OH:11])[CH2:8][CH:7]=[CH:6][CH2:5]1
Reactant: O=C(O)C1C=CCCC1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: OC[C@@H]1CC=CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 18 h
Yield: 102 %

Procedure:
A solution of the anhydride of 3,4-dicarboxycyclohex-1-ene (25.8 g) in THF (150 ml) is added with cooling to a stirred suspension of LiAlH4 (9 g) in THF (200 ml) under N2 at a rate such as to maintain the temperature at 0° C. After stirring for 18 hours at room temperature the mixture is gently refluxed for one hour and cooled in ice. The excess lithium aluminium hydride is decomposed by the careful addition of 1:1 THF-H2O mixture (100 ml). After dilution with chloroform (150 ml) the resulting mixture is filtered and the solid is washed with chloroform (3×25 ml). Concentration of the filtrate under reduced pressure yields an oily residue which is dissolved in benzene, dried over (MgSO4) and reconcentrated in vacuo to give the title compound as an oil (22 g, ca. 90%), νmax (film) 3350 cm-1.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([O:16]CC)=O)[CH:8]=2)[NH:3]1.O.[NH2:20][NH2:21]>C(O)C>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([NH:20][NH2:21])=[O:16])[CH:8]=2)[NH:3]1
Reactant: NN
Reactant: CCOC(=O)COc1ccc2c(c1)CCC(=O)N2
Solvent: CCO
Solvent: O
Product: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetate (0.4 g, 1.7 mmol) in ethanol (10 mL), hydrazine hydrate (0.9 g, 17 mmol) was added and the reaction was heated at 80° C. for two hours. The solid which formed was filtered and dried. 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetohydrazide was obtained as a white solid (0.25 g, 66%) and was used in the next step without further purification. 1H NMR: 400 MHZ, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.83 (t, J=8.40 Hz, 2H), 4.31 (d, J=4.00 Hz, 2H), 4.41 (s, 1H), 6.76 (d, J=2.00 Hz, 2H), 6.82 (s, 1H), 9.26 (s, 1H), 9.91 (s, 1H). LCMS: RT 0.607 min. LCMS (ES-API), m/z 236.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:40][CH:37]4[CH2:39][CH2:38]4)[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: O=CC1CC1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CC4CC4)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using cyclopropanecarboxaldehyde instead of acetone and was obtained as a light brown oil. MS m/e: 578.2 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:40])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[C:25]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NN(CCO)C=2)=CC=1.C(N1CCCC[C@@H]1C(O)=O)(OC(C)(C)C)=O.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14](=[O:40])[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]2[C:25]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=2)=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Agent: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Yield: 95.2 %

Procedure:
Using the same procedure for the preparation of compound 4A, reaction of compound 2A (2.17 g, 6.13 mmol) and N-Boc-2(S)-piperidinecarboxylic acid (3A) (5.63 g, 24.55 mmol) in the presence of DMAP (0.30 g, 2.46 mmol) and (DIPC, 3.80 mL, 24.54 mmol) in anhydrous THF (40 mL) provided the title compound (9A, 3.30 g) as a foam-like powder in 95.2% yield. The 1H NMR and LCMS data are exactly same with those of compound 4A.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[O-]CC.[Na+].C[O:19][C:20](=O)[CH2:21][C:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([C:22]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[NH:6][C:20](=[O:19])[CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: N=C(N)c1ccccc1C(F)(F)F
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Yield: 32.4 %

Procedure:
A mixture of 2-trifluoromethylbenzamidine (1.12 g, 5 mmol), sodium ethoxide (1.02 g, 15 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid methyl ester (0.80 mL, 5 mmol) in ethanol (50 mL) and was heated at reflux for 16 hours. The reaction was cooled, concentrated, diluted with water and acidified with 2 N hydrochloric acid. This solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.48 g, 32% yield) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) δ 12.8 (br s, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.78 (m, 2H), 7.71 (d, J=7.4 Hz, 1H), 6.24 (s, 1H), 1.20 (s, 9H) ppm; LC-MS 297.03 (M+H); Rt (Method A) 3.30 minutes.