Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:13]=[N:12]2)[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:39])[CH3:41])[N:33]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2N2CCOCC2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3N3CCOCC3)cc2=O)n1
Yield: 51 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2-morpholin-4-yl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 53) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-morpholin-4-yl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (0.61 g, 51%); ES+-HRMS m/e calcd for C29H38N6O5 [M+H+] 551.2977 found 551.2976. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.24-1.76 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 2.83-3.05 (m, 4H), 3.46-3.59 (m, 4H), 3.89 (s, 2H), 4.67 (s, 1H), 5.51 (dd, J=4.1, J=11.0 Hz, 1H), 5.74 (d, J=3.0 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.09-7.18 (m, 2H), 7.25 (dd, Jo=7.8 Hz, Jm=1.5 Hz, 1H), 7.27-7.37 (m, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.02 (d, J=3.0 Hz, 1H), 10.77 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[NH:6][C:7](=O)[C:8]=1[CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[CH3:2].P(Cl)(Cl)([Cl:26])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:26][C:7]1[C:8]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:3]([CH2:1][CH3:2])[N:4]=[C:5]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1
Reactant: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1CC

Procedure:
To a suspension of methyl 2-(4-ethyl-6-oxo-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoate (2.53 g; 7.86 mmol) in dry toluene (15 mL) under nitrogen atmosphere were 5carefully added phosphorus oxychloride (7.30 mL; 79 mmol) and dimethylaniline (0.794 mL; 6.29 mmol) and the reaction mixture was heated under reflux for 3 h. The volatiles were removed under reduced pressure (while the reaction mixture was still at elevated temperature), the residue was cooled in an ice-bath and quenched by adding crushed ice and a saturated solution of sodium hydrogen carbonate until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were collected, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.352 g (8.6%, over 3 last steps) of the title compound as a yellow oil.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH3:11])(=O)C.[CH3:19][Si:20]([CH3:34])([CH3:33])[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH:24]=[C:23]1[O:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>>[CH2:16]([O:15][C:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([C@@H:24]2[CH2:25][CH2:26][CH2:27][C@@H:22]([O:21][Si:20]([CH3:33])([CH3:19])[CH3:34])[C:23]2=[O:28])[NH:8][C:7]1=[O:9])[CH3:11])=[O:14])[CH:17]=[CH2:18].[CH2:16]([O:15][C:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([C@H:27]2[CH2:26][CH2:25][CH2:24][C@H:23]([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:22]2=[O:21])[NH:8][C:7]1=[O:9])[CH3:11])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1OC(C)=O
Reactant: C[Si](C)(C)OC1=CCCCC1O[Si](C)(C)C
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H]1CCC[C@@H](O[Si](C)(C)C)C1=O
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@H]1CCC[C@H](O[Si](C)(C)C)C1=O

Procedure:
Using (3R,4R)-4-acetoxy-3-[(R)-1-(allyloxycarbonyloxy)ethyl]azetidin-2-one and 1,2-bis(trimethylsilyloxy)-2-cyclohexene, the procedure of Reference Example 3 was otherwise repeated to give (3S,4R)-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-4-[(1S,3R)-2-oxo-3-trimethylsilyloxycyclohexan-1-yl]azetidin-2-one (S-compound) and (3S,4R)-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-4-[(1R,3S)-2-oxo-3-trimethylsilyloxycyclohexan-1-yl]azetidin-2-one (R-compound), each as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[N:24]([CH2:25][CH3:26])[NH:23][C:22](=[O:27])[CH:21]=1>>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:22](=[O:27])[NH:23][N:24]([CH2:25][CH3:26])[C:20]=3[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: CCn1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C1COCC(=O)C1
Product: CCn1[nH]c(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Yield: 24.5 %

Procedure:
2H-Pyran-3,5(4H,6H)-dione (0.11 g, 1 mmol), 3bromo-4-fluoro-benzaldehyde (0.2 g, 1 mmol), and 5-amino-1-ethyl-1,2-dihydropyrazol-3-one (0.12 g, 1 mmol) were processed as described in Example 26C to provide 0.1 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.2 (t, 3H), 3.82 (q, 2H), 3.99 (s, 2H), 4.52 (q, 2H), 4.96 (s, 1H), 7.18 (m, 1H), 7.21 (t, 1H), 7.39 (dd, 1H), 9.65 (bs, 1H), 10.52 (s, 1H); MS (ESI) m/z 406 (M−H)−; Anal. calcd for C17H15N3BrFO3.0.5 C2H5OH: C, 50.13; H, 4.21; N, 9.74. Found: C, 49.94; H, 3.96; N, 9.21.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:19]([C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([N+]([O-])=O)[C:23]=1[C:24]#[N:25])([O-:21])=[O:20]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:26]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[C:23]=2[C:24]#[N:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cccc([N+](=O)[O-])c2C#N)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a suspension of tert-butyl-4-(2-hydroxyethyl)piperidine-1-carboxylate (769 μL, 3.50 mmol) and NaH (118 mg, 3.50 mmol, 60% dispersion in mineral oil) in dry DMF (5 mL) at 0° C., was added a solution of 2,6-dinitrobenzonitrile (614 mg, 3.18 mmol) in dry DMF (4 mL). The reaction was stirred under N2, warming to rt. Upon completion, the reaction was quenched with H2O (50 mL), and the precipitate was collected by vacuum filtration to provide tert-butyl-4-(2-(2-cyano-3-nitrophenoxy)ethyl)piperidine-1-carboxylate (955 mg, 80%) as a tan solid 1H NMR (400 MHz, CDCl3) δ 1.09 (m, 2H), 1.40 (s, 9H), 1.73 (m, 5H), 2.70 (m, 2H), 3.94 (m, 2H), 4.32 (t, J=6.8 Hz, 2H), 7.75 (m, 1H), 7.92 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:32]([O-])=O)[C:5]([NH:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[C:14]([O:30][CH3:31])[CH:13]=2)[CH2:10][CH3:11])=[N:6][CH:7]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[I:1][C:2]1[CH:3]=[C:4]([NH2:32])[C:5]([NH:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=3)=[C:14]([O:30][CH3:31])[CH:13]=2)[CH2:10][CH3:11])=[N:6][CH:7]=1
Reactant: CCC(Nc1ncc(I)cc1[N+](=O)[O-])c1ccc(OCc2ccc(C(F)(F)F)nc2)c(OC)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(Nc1ncc(I)cc1N)c1ccc(OCc2ccc(C(F)(F)F)nc2)c(OC)c1
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a stirred suspension of 5-iodo-N-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-3-nitropyridin-2-amine (1.25 g, 2.12 mmol) in acetic acid (20 mL) was added iron (0.714 g, 12.77 mmol). The yellow mixture was heated to 125° C. As the mixture was heated, the yellow color faded and a gray suspension formed. After 10 min, the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (75 mL). The suspension was filtered through Celite with the aid of ethyl acetate (50 mL). The filtrate was washed with water (2×30 mL) and then with concentrated ammonium hydroxide (2×30 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 1.20 g (>100%) of 5-iodo-N2-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)pyridine-2,3-diamine as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH:13]([O:16][Si](C)(C)C)[C:14]#N)[N:3]=1.S(=O)(=O)(O)O.O.C([O-])([O-])=[O:28].[Na+].[Na+].[CH3:33][CH2:34][OH:35]>>[CH2:34]([O:35][C:14](=[O:28])[CH:13]([OH:16])[C:4]1[N:3]=[C:2]([CH3:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)[CH3:33]
Reactant: Cc1nc(C(C#N)O[Si](C)(C)C)nn1-c1ccccc1
Reactant: CCO
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(O)c1nc(C)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of the crude (RS)-(5-methyl-1-phenyl-1H-[1,2,4]triazol-3-yl)-trimethylsilanyloxy-acetonitrile (2.47 g) in EtOH (20 ml) was added concentrated sulfuric acid (1.73 ml). The mixture was heated to reflux and stirring was continued for 17 h. After cooling to r.t., the mixture (light red clear solution) was poured into 50 ml of water. The solution was brought to pH˜8 by the addition of saturated Na2CO3. It was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The product was isolated by chromatography (silica gel, gradient cyclohexane=>EtOAc) to give (RS)-hydroxy-(5-methyl-1-phenyl-1H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester (1.17 g) as off-white solid. MS 262.2 ([M+H]+)
Reaction SMILES: [Na].[CH2:2]([N:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][C:11]([C:13]1[CH:21]=[C:17]([C:18]([NH2:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[O:32]([CH2:39][CH2:40]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH2:23]([N:9]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:40][CH2:39][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:17]([CH:21]=1)[C:18]([NH2:20])=[O:19])=[O:12])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCOc1ccccc1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCCOc1ccccc1

Procedure:
A solution of the sodium salt from 5-(N,N-dibenzylglycyl)-salicylamide (10 g) and sodium hydride (0.7 g) in dimethylformamide (50 ml) was heated at 100° for 2 hours with 2-phenoxyethyl bromide (6 g. ). The solution was evaporated under reduced pressure gave a yellow residue that was dissolved in ethyl acetate and water. The organic solution was washed three times with water, dried (MgSO4) and evaporated to leave the crude ether as a yellow oily solid, which was recrystallised from ethanol (150 ml) to give colourless plates (4.6 g) m.p. 146°-147°.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1.O[O:18][S:19]([O-:21])=O.[K+].[C:23]([O-])(O)=O.[Na+]>C1COCC1.CO.O>[CH3:23][S:19]([C:3]1[N:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1)(=[O:21])=[O:18]
Reactant: O=C([O-])O
Reactant: O=S([O-])OO
Reactant: CSc1nccc(OCc2ccccc2)n1
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1nccc(OCc2ccccc2)n1

Procedure:
To a solution of 2-(methylthio)-4-[(phenylmethyl)oxy]pyrimidine (P9, 245 mg) in THF/MeOH 1/1 (15.6 mL) was added a solution of Oxone® (2.6 g) in water (14 mL). After 40 min a saturated NaHCO3 solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (10 g) eluting with dichloromethane/methanol from 100/0 to 99/1 to give the title compound as a white solid (230 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:13]([N:15]([CH2:26][CH3:27])[C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[N:24]=1)[C:19](O)=O)[CH3:14]>>[CH2:26]([N:15]([CH2:13][CH3:14])[C:16]1[CH:17]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[CH:8][CH:9]=3)[N:12]=2)[CH:22]=[C:23]([CH3:25])[N:24]=1)[CH3:27]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: N=C(NO)c1ccc(CO)cc1
Product: CCN(CC)c1cc(-c2nc(-c3ccc(CO)cc3)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-hydroxy-4-hydroxymethyl-benzamidine and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.76 min; [M+1]+=339.11.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O)[CH3:2].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Br:16])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1c(CO)cccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1c(CBr)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a mixture of the compound (3.13 g) obtained in Example 417b, carbon tetrabromide (5.26 g) and methylene chloride (100 ml), triphenylphosphine (4.16 g) was added under ice cooling. The reaction mixture was stirred under ice cooling for 30 min and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate: n-hexane=1:9) to give 3.59 g of the titled compound (yield, 87%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[Br:17][C:18]1[CH:26]=[CH:25]C=C[C:19]=1[C:20]([Cl:22])=O.[O:27]1[CH2:32][CH2:31]OCC1>>[ClH:22].[Br:17][C:18]1[CH:26]=[CH:25][C:31]([C:32]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[N:4]=2)=[O:27])=[CH:20][CH:19]=1
Reactant: C1COCCO1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccccc1Br
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccc(Br)cc3)n2)CC1
Product: Cl
Yield: 84 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 2-bromobenzoyl chloride (142 L, 1.09 mmol), and 1,4-dioxane (10 mL) to yield 335 mg (84%) of the title compound: mass spectrum (ion spray): m/z=404.3 (M+1); Analysis Calculated for C19H24N4ObrCl.1.1H2O: C, 49.65; H, 5.75; N, 12.19. Found: C, 49.39; H, 5.51; N, 12.46; mp 121-3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[OH:19])[CH2:14][CH2:13]2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:41])([F:39])[F:40])=[CH:35][CH:36]=3)([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:24][CH:25]=3)[OH:19])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)N2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a stirred solution of 0.50 gram (0.0008 mole) of N-(3-chloro-4-methoxyphenylcarbonyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 5 mL of tetrahydrofuran was slowly added 0.42 mL (0.0040 mole) of borane-methyl sulfide complex (10M in BH3). Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was then cooled in an ice-bath, and 20 mL of methanol was added slowly to quench the reaction. The reaction mixture was then concentrated under reduced pressure to a residue. Another 20 mL of methanol was stirred with the residue, and this was concentrated under reduced pressure to the residue. The process of adding 20 mL of methanol and concentrating the solution to the residue was repeated once more. The residue was partitioned between ethyl acetate and water, and the mixture was stirred for 15 minutes. The organic layer was separated, washed with an aqueous solution saturated with sodium chloride, and then dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of ethyl acetate in hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.13 gram of N-(3-chloro-4-methoxyphenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:11]([N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:18])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(NC2CCCC2)c1Br
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C2CCCC2)c1Br
Temperature: 80 °C
Yield: 75.1 %

Procedure:
To a stirred solution of methyl 2-bromo-3-(cyclopentylamino)benzoate (1.4 g, 4.69 mmol) in acetonitrile (10 mL), cesium carbonate (3 g, 9.2 mmol) and methyl iodide (3.38 g, 23.3 mmol) were added and the resulting reaction mixture heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered and the residue was washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to afford methyl 2-bromo-3-(cyclopentyl(methyl)amino)benzoate (1.1 g, 75%).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])N>>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][N:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[N:2]1
Reactant: CN(C)CCNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CN(C)CCn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2-hydrazino-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=6.2 Hz, 2 H), 8.22 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.7 Hz, 1H), 7.85 (m, 2 H), 7.73 (m 2H), 7.57 (t, J=7.1 Hz, 1H), 7.23 (m, 2H), 7.17 (d, J=9.1 Hz, 2H) 7.00 (d, J=6.2 Hz, 2H), 5.42 (s, 2H), 4.05 (t, J=6.6 Hz, 2H), 2.66 (t, J=7.1 Hz, 2H), 2.10 (s, 6H); MS: (M+H m/z=450.4).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:20]1[N:34]=[C:33]([F:35])[CH:32]=[CH:31][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[O:23].CCCCCC.CC(=O)OCC>CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[N:34]=[C:33]([F:35])[CH:32]=[CH:31][C:21]=2[C:22]([NH:24][CH2:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[O:23])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(CCS)c1ccccc1
Reactant: O=C(NCc1cccs1)c1ccc(F)nc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1cccs1)c1ccc(F)nc1SCCS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
258 mg (2.3 mmol) of potassium tert-butoxide were added at 0° C. to a solution of 465 mg (2.3 mmol) of 2-(phenylsulfonyl)ethanethiol in DMF (7 ml). After stirring for 10 min at 0° C., 381 mg (1.5 mmol) of 2,6-difluoro-N-(thiophen-2-ylmethyl)nicotinamide were added and the mixture was then heated for 16 hours at 50° C. Dilution with EA and washing with brine were then carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 298 mg (0.68 mmol, 45%) of 2-[2-(benzenesulfonyl)ethylthio]-6-fluoro-N-(2-thienylmethyl)-nicotinamide. MS: m/z 437.0 [M+H]+
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[CH:11]=[O:12].[S:21](=O)(=O)(O)O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]([C:1]2[S:21][CH:4]=[CH:3][CH:2]=2)[OH:12])[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17]
Reactant: [Li]CCCC
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cccs2)cc([N+](=O)[O-])c1OC
Reaction time: 0.5 h

Procedure:
18.8 ml of n-butyllithium solution (1.6M in hexane) are added dropwise at -50° within 10 minutes to 4.03 g of thiophone dissolved in 40 ml of tetrahydrofuran. After stirring at -50° for 30 minutes 6.3 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 100 ml of tetrahydrofuran are added dropwise within 30 minutes. The reaction mixture is stirred at -50° for 1 hour at 0° for 30 minutes and poured into 100 ml of 2N sulphuric acid. The mixture is extracted three times with 100 ml of ether each time; the combined ether phases are washed with sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenemethanol of m.p. 79°-81° (from methylene chloride/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:14]1[O:18][C:17]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([NH:26][C:27](=[O:29])[CH3:28])[CH:20]=2)=[CH:16][C:15]=1[C:30]1[N:34]=[CH:33][N:32](COCC[Si](C)(C)C)[N:31]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:14]1[O:18][C:17]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([NH:26][C:27](=[O:29])[CH3:28])[CH:20]=2)=[CH:16][C:15]=1[C:30]1[NH:34][CH:33]=[N:32][N:31]=1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(CN4CCCC4)ccc3Cl)o2)c(C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cc(-c3nnc[nH]3)c(-c3cc(CN4CCCC4)ccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of N-(4-{5-[2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.20 g, 0.34 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was purified by column chromatography to give N-(4-{5-[2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]-4-(4H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.14 g, 81%). LCMS (FA): m/z=477.6 (M+H).