Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[N:3]=[CH:4]2)=[CH:12][CH:13]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccc(F)cc1
Reactant: O=C(O)c1cccnc1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1Cc1ccc(F)cc1
Yield: 79 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.50 g (6.38 mmol) of 4-amino-1-(4-fluorobenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 58 and nicotinic acid instead of cyclopentylacetic acid to obtain 1.70 g of 1-(4-fluorobenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 79%).
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[N:16]=[CH:15][N:14]=[C:13]2[NH:12][C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: O=C=NCCc1ccccc1
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(NC(=O)NCCc3ccccc3)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 3, phenethyl isocyanate was reacted with 4-amino-6methoxy-7-(N-methylpiperidin4ylmethoxy)quinazoline to give the title compound; NMR Spectrum: (CDCl3) 1.48 (m, 2H), 1.98 (m, 5H), 2.29 (s, 3H), 2.91 (m, 4H), 3.7 (q, 2H), 4.02 (d, 5H), 7.28 (m, partially obscured by CHCl3 peak), 8.47 (s, 1H), 8.65 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:16]C)[C:11]=2[NH2:15])[CH2:6]1)[CH2:2][CH3:3].[BrH:18]>>[BrH:18].[CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=2[NH2:15])[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCNC1CCc2c(ccc(OC)c2N)C1
Agent: Br
Product: CCCNC1CCc2c(ccc(O)c2N)C1

Procedure:
50 ml of 48% hydrobromic acid containing 1.5 g of 2-propylamino-5-amino-6-methoxy-1,2,3,4-tetrahydronaphthalene are heated under reflux for 10 hours. 1.8 g of the dihydrobromide are then collected by concentrating the reaction medium. By following the procedure of Example 2(c), 1.19 g of the monohydrobromide are collected, melting at 280° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][CH2:13][C:14]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:15]=2[O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][C:27](OC)=[O:28])[N:21]=[CH:20]3)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:12][CH2:13][C:14]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:15]=2[O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH2:26][CH2:27][OH:28])[N:21]=[CH:20]3)=[O:36])[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)acetate (4.6 g, 7.87 mmol) in methanol (0.1M, 80 mL) was treated with sodium borohydride (893 mg, 23.6 mmol) in portions at room temperature. The mixture was stirred at room temperature for 18 hours, and the solvent evaporated in vacuo to a dark yellow residue. The residue was distributed between dichloromethane and saturated aqueous NH4Cl. The organic layer was filtered through 1PS paper, evaporated in vacuo and purified in Biotage eluting with 2-10% iPrOH/DCM. Desired fractions were evaporated in vacuo to a white foam, 2.97 g (68%). MS (APCI+) m/z 557 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H, J=9.1 Hz), 7.35 (s, 1H), 6.85-7.4 (m, 8H), 6.24 (s, 1H), 4.87 (t, 1H, J=5.4 Hz), 4.43 (t, 1H, J=5.6 Hz), 4.28 (d, 1H, J=5.9 Hz), 3.80 (q, 1H, J=5.5 Hz), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:23]([O:25][CH2:26]C)=[O:24])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>OS(O)(=O)=O.CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:23]([O:25][CH3:26])=[O:24])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following General Procedure E, ethyl 5-phenyl-6-(4-trifluoromethylphenyl)-pyridine-2-carboxylate (Compound 29, 103 mg, 0.28 mmol) and conc. H2SO4 (5 drops) in MeOH (5 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: COc1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2ccc(O)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a 0° C. mixture of 2-{[(2-chloro-4-methoxyphenyl)methyl]sulfanyl}-6-methyl-pyrimidin-4-ol (500 mg, 1.7 mmol) in anhydrous dichloromethane (20 mL) was added a solution of boron tribromide (1 M in THF, 2 mL, 2 mmol). The solution was stirred at room temperature overnight. Water (20 mL) and more dichloromethane (50 mL) were added to the mixture. The undissolved solid material was recovered by filtration, washed with diethyl ether (2×25 mL), and dried in vacuo. The crude product was purified by flash chromatography (0-10% MeOH/CH2Cl2), affording the title compound (65 mg, 13% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.37 (s, 2H), 6.00 (s (br), 1H), 6.70 (dd, 1H, J=2.3 Hz, 8.4 Hz), 6.84 (d, 1H, J=2.3 Hz), 7.40 (d, 1H, J=8.6 Hz), 9.96 (s, 1H); M+ 283; HPLC purity: 98.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[CH2:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2([OH:23])[CH2:19][CH2:18][N:17]([CH2:16][C:15]3[CH:24]=[CH:25][CH:26]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:22][CH2:21]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc([Mg]Br)cc1Cl
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(F)c(Cl)c3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To (3-chloro-4-fluorophenyl)magnesium bromide (6.8 ml of a 0.5 M solution in tetrahydrofuran, 3.4 mmol) was added a solution of 1-(3-methoxybenzyl)piperidin-4-one (500 mg, 2.28 mmol) from Step B of Example 12 in tetrahydrofuran (10 mL). The reaction mixture was stirred at ambient temperature for 3 h and then was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(3-chloro-4-fluorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (209 mg, 26%): 1H NMR (CDCl3, 500 MHz) δ 7.59-7.55 (m, 1H), 7.39-7.33 (m, 1H), 7.27-7.22 (m, 1H), 7.13-7.07 (m, 1H), 6.95-6.93 (m, 2H), 6.83-6.80 (m, 1H), 3.84 (s, 3H), 3.60-3.55 (m, 2H), 2.82-2.73 (m, 2H), 2.48-2.40 (m, 2H), 2.18-2.02 (m, 2H), 1.72-1.68 (m, 2H), 1.59-1.56 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23]Br)=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4].C([O-])=[O:35].[Na+]>CCO>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][OH:35])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4]
Reactant: COC(=O)c1c(Cc2ccc(C(=O)CBr)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(Cc2ccc(C(=O)CO)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 80 °C
Yield: 42.2 %

Procedure:
A mixture of 3-[4-(2-bromo-acetyl)-benzyl]-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (38 mg, 0.075 mmol) and sodium formate (25.5 mg, 5 eq.) in EtOH (15 mL) was heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and filtered. The crude residue was purified by preparative TLC (EtOAc/hexane, 60/40) to afford 14 mg of 3-[4-(2-hydroxy-acetyl)-benzyl]-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester as an off-white powder. MS=443 [M+H]+; MP=189.9-192.9° C.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:17][C@@H:12]2[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[OH:9][C@@H:10]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=3)[CH2:17][C@@H:12]2[CH2:11]1
Reactant: O=C(O[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A solution of 1.58 g (4.61 mmol) of (7S,8aS)-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-7-yl benzoate (Example 9) in 200 mL of methanol was treated with 50 mL of 15% aqueous sodium hydroxide. After 30 min, the solvent was removed and the residue partitioned between water and ethyl acetate. The layers were separated, the organic phase was dried (magnesium sulfate), filtered and evaporated to give 0.922 g (84%) of the title compound. 13C NMR (CDCl3): δ 39.4, 43.7, 49.0, 51.2, 62.2, 63.6, 69.9, 144.9, 145.2, 149.9, 153.2, 158.9. m/z (MH+) 239.
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:14])[CH:5]([CH:6]=[C:7]2[CH2:10][CH2:9][CH2:8]2)[CH:4]1[C:11]([OH:13])=[O:12].[F:15][C:16]1[C:21]([CH2:22]Br)=[C:20]([F:24])[C:19]([F:25])=[C:18]([F:26])[C:17]=1[F:27].O>CN(C)C=O>[CH3:2][C:3]1([CH3:14])[CH:5]([CH:6]=[C:7]2[CH2:10][CH2:9][CH2:8]2)[CH:4]1[C:11]([O:13][CH2:22][C:21]1[C:20]([F:24])=[C:19]([F:25])[C:18]([F:26])=[C:17]([F:27])[C:16]=1[F:15])=[O:12]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: CC1(C)C(C=C2CCC2)C1C(=O)O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(C=C2CCC2)C1C(=O)OCc1c(F)c(F)c(F)c(F)c1F
Yield: 67.1 %

Procedure:
3.6 g (0.0165 mol) of the potassium salt of 2,2-dimethyl-3-cyclobutylidenemethylcyclopropanecarboxylic acid were dissolved in 50 ml of dimethylformamide and the solution was heated to 110° C., together with 4.3 g (0.0165 mol) of pentafluorobenzyl bromide, for 3 hours. After the reaction had ended, the reaction mixture was poured into 150 ml of water and extracted twice with 100 ml of methylene chloride each time. The organic phase was then extracted by shaking twice with 100 ml of water each time and then dried over sodium sulphate. The solvent was stripped off in vacuo and last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 4.0 g (67.1% of theory) of pentafluorobenzyl 2,2-dimethyl-3-cyclobutylidenemethylcyclopropanecaboxylate were obtained as a brown oil with the refractive index nD30 :1.4850.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[Cl-].CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Treat a solution 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (5.79 g, 20.7 mmol) in dichloromethane (50 mL) at −78° C. with oxalyly chloride (1.99 mL, 22.8 mmol), DMSO (3.5 mL, 49.5 mmol), and triethylamine (8.6 mL, 62.1mmol). Stir at −78° C. for 30 min, warm to room temperature and stir for 1 h. Quench with ice and extract with dichloromethane (100 mL). Wash with saturated aqueous NaHCO3, saturated aqueous sodium chloride, dry (magnesium sulfate) concentrate and purify (silica gel chromatography, eluting with 40:60 to 50:50 ethyl acetate:hexanes) to give the title compound (4.53 g, 78%).
Reaction SMILES: N[C@H](C(O)=O)C(C)(C)C.[BH4-].[Na+].[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[NH:17][C:18](=[O:31])[C:19](=[O:30])[CH:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:21][C:15]=2[CH:14]=1.C(O)(=O)C.O1CCCC1>O1CCCC1>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[NH:17][C:18](=[O:31])[C@H:19]([OH:30])[C@H:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[S:21][C:15]=2[CH:14]=1
Reactant: COc1ccc(C2Sc3cc(Cl)ccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A mixture of L-tert-leucine (721 mg), sodium borohydride (189 mg) and tetrahydrofuran (50 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to -15° C., and thereto is added 8-chloro-2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (1113 mg). Each 0.38 ml of 25% acetic acid/tetrahydrofuran solution (1.67 mole as acetic acid) is added thereto at 20 minutes, and 2 hours 20 minutes after the beginning of the reaction, and the reaction solution is stirred at the same temperature for 19 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added 1N hydrochloric acid (70 ml). The precipitated crystal is collected by filtration, washed with water, and dried. The collected crystal is suspended in chloroform (50 ml), and the mixture is heated with stirring at 65° C. The mixture is cooled to 5° C., and allowed to stand overnight. The precipitated crystal is collected by filtration, and dried to give (2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (896 mg).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])\[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1/[C:15](/[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:10]
Reactant: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2ccccc2OC)cc1
Yield: 81.2 %

Procedure:
As before in Example 134, a solution of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.5 g) an 3-pyridinebutanamine (0.64 g) in tetrahydrofuran (15 mL) was stirred overnight at room temperature. After the usual workup. the crude product was crystallized from ethyl acetate to furnish 1.25 g of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 164°-165° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNCCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1
Yield: 61.2 %

Procedure:
1.6 g (4.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 48 hours with 3.6 ml (21 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 1.23 g (61%) of 7-chloro-3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 140°-142°, which was converted into the hydrochloride of m.p. 184°-187°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH3:15][NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27]>>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([NH:16][CH3:15])=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=2)[CH2:2]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: CNc1ccc(C(=O)N2CCCC(NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]

Procedure:
Prepared similarly to intermediate 20 from tert-butyl piperidin-3-ylcarbamate (available from, for example, Apollo Scientific Ltd) and 4-(methylamino)-3-nitrobenzoic acid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:15]1[CH:16]=[CH:17][C:18]2[CH2:25][CH:24]3[C:26]4([CH2:30][N:29]([CH2:31][C:32]([F:35])([F:34])[F:33])[S:28](=[O:37])(=[O:36])[NH:27]4)[CH:21]([CH2:22][CH2:23]3)[CH2:20][C:19]=2[CH:38]=1)(OC)=[O:12]>O1CCCC1>[OH:12][CH2:11][C:15]1[CH:16]=[CH:17][C:18]2[CH2:25][CH:24]3[C:26]4([CH2:30][N:29]([CH2:31][C:32]([F:35])([F:33])[F:34])[S:28](=[O:37])(=[O:36])[NH:27]4)[CH:21]([CH2:22][CH2:23]3)[CH2:20][C:19]=2[CH:38]=1
Reactant: COC(=O)c1ccc2c(c1)CC1CCC(C2)C12CN(CC(F)(F)F)S(=O)(=O)N2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(CO)ccc2C1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
Diisobutylaluminium hydride (1M in toluene, 49 mL, 49 mmol) was added slowly to a stirred solution of the product from Step 1 (5.1 g, 12.2 mmol) in dry tetrahydrofuran (100 mL) at −78° C. under nitrogen. After 30 minutes the reaction was allowed to warm to −10° C. and maintained at this temperature for 3 hours. The reaction was quenched with methanol and allowed to warm to room temperature. 1M Aqueous hydrochloric acid (100 mL) was added slowly. The mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to give a dark foam (5.2 g) which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[O:23]=[C:13]1[N:12]([CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 85 °C

Procedure:
To a solution of trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid methyl ester (15 g, 51.7 mmol) in a mixture of THF (240 mL) and H2O (60 mL), LiOH was added and the reaction was heated at 85° C. for 16 hours. The mixture was allowed to cool down to room temperature and the solvent removed under reduced pressure. The residue was dissolved in 100 mL of H2O and the solution acidified to pH 3. The precipitate formed was filtered and washed with 100 mL of CH3CN. The titled compound (11.9 g, 79%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:4]([C:12]1[S:13][C@H:14]2[O:20][C@H:19]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[C@@H:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C@H:17]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[C@H:15]2[N:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:4]([C:12]1[S:13][C@H:14]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C@H:17]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[C@H:15]2[N:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO)O[C@@H]2S1
Yield: 89.6 %

Procedure:
A solution of 147 (15 g, 21 mmol) in THF (100 mL) was treated with TBAF (8.4 g, 32 mmol) for 3 hours at room temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (2×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography with 10%-30% ethyl acetate in petroleum ether to afford 148 as a light yellow syrup (11.3 g, 90%). (ES, m/z): [M+H]+ 601.0; 1H NMR (300 MHz, CDCl3) δ 7.36-7.33 (m, 2H), 7.21-7.19 (m, 2H), 6.91-6.82 (m, 4H), 6.09 (d, J=6.6 Hz, 1H), 5.92-5.80 (m, 1H), 5.19-5.00 (m, 2H), 4.70-4.58 (m, 2H), 4.55-4.36 (m, 4H), 4.32-4.24 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 3.75-3.68 (m, 2H), 3.64-3.52 (m, 2H), 1.56 (s, 9H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.[F:23][C:24]([F:60])([F:59])[C:25]1[CH:26]=[C:27]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[C:28]([N:30]1[CH2:34][C@@:33]([CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[O:32][CH2:31]1)=[O:29].C(OCC)(=O)C>O1CCCC1>[F:59][C:24]([F:23])([F:60])[C:25]1[CH:26]=[C:27]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[C:28]([N:30]1[CH2:34][C@@:33]([CH2:42][CH2:43][OH:44])([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[O:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@]1(c2ccc(F)cc2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CO[C@](CCO)(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 508 mL) and acetic acid (70 mL, 1.27 mol) were added to a solution of the compound (131.76 g, 0.254 mol) obtained in Example 1b in tetrahydrofuran (500 mL), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (1000 mL) was added to the reaction mixture, washed with a saturated aqueous solution of sodium hydrogencarbonate, water, and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane, 30%→50%) to give the title compound (102.11 g; yield, 99%) as a colorless oily substance.