Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O.O.C(O)(=O)C(O)=O>C(O)(C)C.CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][CH2:8][C:7]4[CH:16]=[CH:17][CH:18]=[CH:19][C:6]3=4)[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Yield: 32 %

Procedure:
A stirred mixture containing 4.5 gms. (0.017 mole) of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine, 3.4 gms (0.017 mole) of 4-(4-fluorobenzoyl)piperidine, 10.0 gms. of potassium carbonate and 75 ml. of dimethylformamide was heated at 90°-100°C. for 16 hours. The cooled suspension was filtered, the solvent removed at reduced pressure and the residual oil was taken up in ether and filtered to remove insoluble materials. The clear filtrate was treated with a solution of 2.1 gms. (0.017 mole) of oxalic acid dihydrate in isopropanol. The oxalate which separated on cooling was collected by filtration. The salt melted at 150°-155°C. and weighed 2.9 gms. (32% yield). After recrystallization from isopropanol the salt melted at 156°-159°C.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNC(=O)CCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of N-methyl-8-phenyloctanamide (25.2 g, 108.0 mmol, 1 eq) in THF (500 mL) cooled to 0° C. was added lithium aluminum hydride (12.3 g, 466.8 mmol, 4.3 eq) portionwise over 20 minutes. The cold bath was removed and the reaction was stirred at rt 3 hours. The reaction was then heated at reflux for 2 _hours. It was then cooled to rt and quenched by the slow addition of H2O (30 mL). EtOAc (300 mL) was added, followed by 2 M NaOH (40 mL). The solids were then filtered off and washed with EtOAc. The filtrate was dried over MgSO4 and concentrated in vacuo to afford N-methyl-N-(8-phenyloctyl)amine (19.7 g, 83%) as a light yellow oil. 1H NMR (CDCl3) δ 7.30-7.14 (m, 5H); 2.63-2.52 (m, 4H); 2.43 (s, 3H); 2.05 (s, 1H); 1.62 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:6]1[N:7]([CH3:25])[C:8](=[O:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:5].C([O-])(O)=O.[Na+]>C(OC(C)=O)(C)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([O:5][C:9]([CH3:14])([CH3:10])[CH3:8])[C:6]1[N:7]([CH3:25])[C:8](=[O:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C(O)c1c(-c2ccc(F)c(F)c2)c2ccccc2c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(F)c(F)c2)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a solution of [4-(3,4-Difluoro-phenyl)-2-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl]-hydroxy-acetic acid methyl ester (114 mg, 0.31 mmol) in t-BuOAc (10 ml) was added HClO4 (0.17 ml, 1.11 mmol). The reaction mixture was stirred at RT overnight. TLC showed most SM consumed, ended the reaction, added ice-water, adjusted to pH=6 by adding 1N aq NaHCO3, extracted with EA, washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by pre-TLC to afford title product. (m=57 mg, yield=43.2%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[OH-].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl.CC1CCCCC1>CC1CCCO1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: CC1CCCCC1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 32.5 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a solution of 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in 2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aqueous NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35° C. for 18 h. The suspension is poured into a mixture of ice-water (280 mL) and aqueous HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40° C. gave 216 g of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester as white crystalline solid. Yield: 99%, ES-MS: m/z 271 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.35 (2H, m), 1.54-1.63 (2H, m), 1.85-2.02 (1H, m), 2.45 (3H, s), 3.28-3.39 (2H, m), 3.86 (2H, d, J=6.60 Hz), 3.93 (2H, dd, J=11.37, 4.52 Hz), 7.35 (2H, d, J=9.29 Hz), 7.78 (2H, d, J=8.31 Hz)
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:14])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:14])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1ccn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn2ncnc(Oc3ccc(N)cc3F)c12
Reaction time: 7 h
Yield: 92.1 %

Procedure:
To a heterogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine (3.04 g, 10.55 mmol) in anhydrous methanol (60 mL) and anhydrous tetrahydrofuran (40 mL), at ambient temperature under nitrogen atmosphere, was added zinc dust (6.90 g, 105 mmol) and ammonium chloride (5.64 g, 105 mmol). The mixture was stirred for 7 h before the catalyst was filtered off and the filtrate was concentrated in vacuo to a pale yellow solid which was partitioned between chloroform and water. The aqueous layer was then extracted twice with chloroform. The combined chloroform layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (2.51 g, 92%) as a solid. 1H NMR (CDCl3) δ 7.86 (s, 1H), 7.64 (d, 1H, J=2.6 Hz); 7.08-7.03 (m, 1H), 6.61 (d, 1H, J=2.4 Hz), 6.55-6.45 (m, 2H), 3.78 (s, 2H), 2.60 (s, 3H); HRMS(ESI), 259.0995 (M+H)+ calc, 259.0997 (M+H)+ found.
Reaction SMILES: C(CCSSC1C=CC=CN=1)(O)=[O:2].[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[CH:23]1([NH:22][C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:2])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)CCSSc1ccccn1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 72 h

Procedure:
To a stirred solution of 6-(2-propenylhydrazone)nicotinamido-3-propanol (190 mg, 0.8 mmol) and 2-carboxyethyl-2-pyridyldisulphide (163 mg, 1.0 equiv) in THF (10 ml) at 0° C. was added dicyclohexyl-carbodiimide (157 mg, 1.0 equiv) and the mixture was stirred at 0°-5° C. for 72 hours during which time a white solid precipitated. The white solid was filtered off and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate and cooled, which gave a further precipitate of dicyclohexyl urea ("DCU"). This procedure was repeated once again until all of the urea had been removed. The desired product was purified by column chromatography on silica gel using 5% methanol in dichloromethane as eluent. Re-crystallisation in ethyl acetate/ether gave white solid (85 mg, 25%). 1H NMR (CDCl3) δ1.15 (t, 3H, J=7.5 Hz), 1.95 (pentet, 2H, J=6.0 Hz), 2.36 (dq, 2H, J=5.0, 7.6 Hz), 2.80 (t, 2H, J=7.0 Hz), 3.07 (t, 2H, J=7.0 Hz), 3.50 (m, 2H), 4.04 (t, 2H, J=6.0 Hz), 6.51 (broad triplet, 1H, D2O exchangeable), 7.07-7.12 (m, 1H, 7.17-7.21 (m, 2H), 7.60-7.72 (m, 2H), 7.95-7.99 (dd, 1H, J=8.8, 2.4 Hz), 8.22 (broad s, 1H, D2O exchangeable), 8.42-8.45 (m, 1H), 8.55 (d, 1H, J{32 2.4 Hz); mass spectrum (FAB); m/e relative intensity); 448 (100, M+1), 176 (45).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[C:2]([CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24])([OH:26])=[O:1]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C1c2cc(I)ccc2OC(Cc2ccccc2)CN1CCCO
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a magnetically stirred solution of 2-(3-hydroxypropyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one (0.75 grams, 1.7 mmol) in 5 mL dimethylformamide at room temperature was added a solution of pyridinium dichromate (2.58 grams, 6.86 mmol) in 5 mL dimethylformamde. The reaction mixture was stirred overnight, diluted with 75 mL water, washed 3×75 mL diethyl ether, made acidic to a pH of 2 with conc. HCl and extracted 3×75 mL diethyl ether. The combined organics were extracted 3×40 mL 1N sodium hydroxide. The combined aqueous layers were acidified to a pH of 2 with canc HCl and extracted 3×50 mL diethyl ether. These ether layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 0.557 grams (73%) of 2-(2-carboxyethyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.07 (1H, d, 4JHH=2 Hz, C9-H), 7.69 (1H, dd, 4JHH=2 Hz, 3JHH=8Hz, C7-H), 7.4-7.2 (5H, m, C6H5), 6.75 (1H, d, 3JHH=8 Hz, C6-H), 4.75 (1H, m, ArOCH), 3.89 (1H, dt, 2JHH=14 Hz, 3JHH=6 Hz, NCHHCH2 CO2), 3.69 (1H, dt, 2JHH=14 Hz, 3JHH=6 Hz, NCHHCH2 CO2), 3.44 (2H, d, 3JHH=3 Hz, CH2Ph), 3.07 (1H, dd, 2JHH=14 Hz, 3JHH=7 Hz, C3-H), 2.8-2.7 (3H, m, C3-H, CH2 CO2), 13C NMR (CDCl3), 176.1, 167.6, 164.4, 152.8, 141.7, 139.5, 136.4, 129.4, 129.1, 128.9, 128.8, 127.0, 124.7, 86.7, 84.7, 51.4, 45.0, 38.8, 33.0.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22].CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:37][O:36]2)(=O)=O)=CC=1>>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:34][C@H:35]4[CH2:37][O:36]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Product: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@H]1CO1
Yield: 16.8 %

Procedure:
The title compound (198 mg, 0.538 mmol, 16.8%) was obtained as light brown crystals from an 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product (1.00 g, 3.21 mmol) and (2R)-oxiran-2-ylmethyl 4-methyl-1-benzene sulfonate, by the same procedure as in Example 7.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:32](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN1CCCCC1)C=C2)CO)(C)([CH3:34])[CH3:33]>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]1[CH2:24][CH2:34][CH2:32][CH2:33][CH2:23]1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(CN3CCCCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid (9) of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)quinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD) δ 7.97 (s, 1H), 7.77 (d, 1H), 7.65-7.58 (m, 3H), 7.40-7.30 (m, 2H), 5.22 (s, 1H), 4.61 (s, 2H), 3.60-3.20 (m, 4H), 2.69 (s, 3H), 2.00-1.90 (m, 4H), 1.80-1.65 (m, 2H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C28H33ClN2O3: 482.0; Found: 481.3, 483.3.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[CH:12]1[C:22]2[CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][N:17]([C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=3)=[O:28])[C:16]=2[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH:12]1[C:22]2[CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][N:17]([C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:5][CH2:4][C:3]4[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=4[CH3:1])=[O:34])=[CH:36][CH:37]=3)=[O:28])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1CO
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1COC(=O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a mixture of 248 mg of 2-methylbenzyl alcohol in 4 ml of anhydrous tetrahydrofuran is added 80 mg of sodium hydride (60% in mineral oil) and the mixture stirred for 1 hour. To the mixture is added 430 mg of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)-carbonyl]benzoyl chloride and the mixture is stirred for 18 hours. The tetrahydrofuran is evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated and washed with 1N HCl, water, 1M NaHCO3, and brine. The organic layer is dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate and hexane added at the boil to give 170 mg of the desired product, m.p. 140°-142° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1)[O:9][C:8]([CH3:17])([CH3:16])[CH2:7][C:6]2([CH3:19])[CH3:18])#[CH:2].[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](I)[CH:27]=1)[CH3:21]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:12]=2)[O:9][C:8]([CH3:17])([CH3:16])[CH2:7][C:6]3([CH3:18])[CH3:19])[CH:27]=1)[CH3:21]
Reactant: C#Cc1cc(C(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: CCOC(=O)C=Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cccc(C#Cc2cc(C(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)c1

Procedure:
Following General Procedure B and using 6-ethynyl-8-isopropyl-2,2,4,4-tetramethylchroman (Intermediate 32, 0.05 g, 0.2 mmol), ethyl-3-iodo cinnamate (Reagent 6, 0.118 g, 0.39 mmol), triethyl amine (2 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained (0.058 g, 69%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CC#N>[CH3:16][N:17]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:10]=2)[N:7]=1
Reactant: CN[C@@H](C)c1ccccc1
Reactant: CCOC(=O)c1nnc2ccc(Cl)nn12
Solvent: CC#N
Product: CCOC(=O)c1nnc2ccc(N(C)[C@@H](C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 36 h
Yield: 32.6 %

Procedure:
A solution of ethyl 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (1.5 g, 6.6 mmol) and (S)-N-methyl-1-phenylethanamine (3.6 g, 26.4 mmol) in 20 mL of CH3CN was heated to reflux and stirred for 36 h. When cooled to room temperature, the reaction mixture was concentrated in vacuum, and the residue was purified by flash chromatography eluting with DCM/EA=5:1 to give product (S)-ethyl 6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate as a yellow oil (0.7 g, 32%). LRMS (M+H+) m/z: calcd 326.16; found 326. 1H NMR (300 MHz, CDCl3): δ 8.02-7.99 (d, J=9 Hz, 1H), 7.36-7.26 (m, 5H), 7.09-7.06 (d, J=9 Hz, 1H), 5.82-5.75 (q, 1H), 4.57-4.50 (q, 2H), 2.94 (s, 3H), 1.68-1.65 (d, 3H), 1.48-1.44 (t, 3H).
Reaction SMILES: [C:1]([N:9]1CCCC(C(OCC)=O)C1)(=O)[C:2]1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](Cl)=[O:35])[CH2:29]1)=[O:27].C(N(C(C)C)CC)(C)C.Cl.C(N)C>>[CH2:1]([NH:9][C:34]([CH:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:26](=[O:27])[CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH2:29]1)=[O:35])[CH3:2]
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: O=C(Cl)C1CCCN(C(=O)Cc2cccs2)C1
Agent: CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C1CCCN(C(=O)Cc2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with 1-(2-thiopheneacetyl)-3-piperidinecarbonyl chloride (609.8 mg; 2.25 mmol), diisopropylethylamine (920 μl; 5.28 mmol) and commercially available ethylamine hydochloride (204.8 mg; 2.51 mmol). The crude product was purified by chromatography on silica, eluting with 100% ethyl acetate, giving N-ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxamide (437.5 mg) as a thick, brown syrup. MS m/z (positive ion) 303 (M+Na+; 25), 281 (MH+; 100), 157 (25).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=[O:4].Cl[C:21]1[CH:22]=[CH:23][C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])=[C:25]([OH:27])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:43]>O1CCCC1.O>[Cl:43][C:22]1[CH:21]=[CH:26][C:25]([O:27][CH2:2][C:3]([C:5]2[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=2)=[O:4])=[C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[Cl:36])[CH:23]=1
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: Cl
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)COc2ccc(Cl)cc2Oc2ccc(Cl)cc2Cl)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 10.0 g (30.5 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone and the 8.8 g (30.5 mmol) of 5-chloro-2-(2,4-di-chloro-phenoxy)-phenol in 50 ml of tetrahydrofuran, 6.3 g (45.7 mmol) of potassium carbonate is added and the mixture is stirred for 4 days at room temperature. After addition of water and adjusting the pH to 5-6 by adding 32% HCl, the mixture is extracted with ethyl acetate. The combined extracts are washed with water, dried and evaporated. Crystallization of the crude product from methanol gives 15.4 g of compound 104, m.p. 111-114° C.
Reaction SMILES: C(N(CCCC)CC#CC#N)CCC.[CH2:15]([N:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:22][C:23]#[C:24][C:25]#[N:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(#N)C#CCCCCCCCCCCCC.NC1C=C(CN(CCCC)CCCC)[O:52][N:51]=1>>[NH2:26][C:25]1[CH:24]=[C:23]([CH2:22][N:21]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:52][N:51]=1
Reactant: CCCCCCN(CC#CC#N)CCCCCC
Reactant: CCCCN(CCCC)Cc1cc(N)no1
Agent: CCCCCCCCCCCCC#CC#N
Agent: CCCCN(CC#CC#N)CCCC
Product: CCCCCCN(CCCCCC)Cc1cc(N)no1

Procedure:
When in the procedure of Example 9(a) an appropriate amount of 4-dibutylamino-2-butynenitrile or 4-dihexylaminobutynenitrile was substituted for 2-pentadecynenitrile, 3-amino-5-dibutylaminomethylisoxazole, and 3-amino-5-dihexylaminomethylisoxazole were obtained respectively, and when each of these isoxazoles was substituted for 3-amino-5-dodecylisoxazole in the procedure of Example 9(b), the following compounds were obtained:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15](=[O:16])[NH:14][C:13]([CH:17]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH2:40][CH2:41][F:42])[C:32]=3[F:43])[NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[C:28]([CH3:30])[O:27][N:26]=4)=[CH:21][CH:20]=3)=[N:12]2)[N:6]=1)=[O:4].C1COCC1.[OH-].[Na+].C(O)(=O)C>CO>[F:43][C:32]1[C:33]([O:39][CH2:40][CH2:41][F:42])=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[CH:17]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[CH:21][CH:20]=1)[C:13]1[NH:14][C:15](=[O:16])[N:11]([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][CH:8]=2)[N:12]=1
Reactant: COC(=O)c1cccc(-n2nc(C(Nc3ccc(-c4noc(C)n4)cc3)c3cc(OC)cc(OCCF)c3F)[nH]c2=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3cccc(C(=O)O)n3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.7 %

Procedure:
After dissolving 167 mg of 6-(3-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)pyridine-2-carboxylic acid methyl ester in 6 ml of a methanol:THF=2:1 mixed solvent, there was added 562 μl of a 5N aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 15 hours. The mixture was adjusted to acidic with acetic acid and then concentrated under reduced pressure. The residue was dissolved in methanol, and the solution was filtered through celite and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give the title compound (81 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([C@:4]1([OH:25])[C@@:8]2([CH3:24])[CH2:9][C@H:10]([OH:23])[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:26]([O:23][C@H:10]1[CH2:9][C@@:8]2([CH3:24])[C@@H:7]([CH2:6][CH2:5][C@:4]2([OH:25])[C:2](=[O:3])[CH3:1])[C@H:12]2[C@H:11]1[C@:21]1([CH3:22])[C:15]([CH2:14][CH2:13]2)=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@]2(O)C(C)=O)[C@@H]2CCC3=CC(=O)CC[C@]3(C)[C@H]21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of 4-pregnene-11β,17α-diol-3,20-dione (2) (2 g), acetic anhydride (10 ml), pyridine (20 ml) and 4-dimethylaminopyridine (20 mg) was stirred for 6 hours at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with chloroform. The chloroform layer was sequentially washed with 10% HCl, a 5% aqueous NaHCO3 solution, and brine, dried over Na2SO4, and concentrated. The residue was subjected to column chromatography (silica gel, 150 g) using 70% chloroform/hexane as eluant, thereby obtaining an acetylated derivative (3) (2.24 g, 100%). Recrystallization from ethyl acetate/hexane afforded white crystals having a melting point of 159.5°-160° C.