Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:20])([C:8]1[C:12]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.[Fe]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]2[S:10][N:9]=[C:8]([C:2]([CH3:20])([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]=2[CH:13]=1
Reactant: CCOC(=O)C(C)(C)c1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)c1nsc2ccc(N)cc12
Temperature: 56 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl α,α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetate (0.714 g, 2.42 mmol), iron powder (0.500 g), 10% acetic acid (23.0 mL) and ethyl acetate (23.0 mL) is stirred at 54-58° C. for one hour, cooled, and poured into saturated sodium hydrogen carbonate solution. The resultant aqueous mixture is extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and a 10% ethyl acetate in methylene chloride solution gives the title product as a light brown oil which is identified by NMR spectral analysis.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+:6].[Na+].[Na+].[C:9]([NH:12][CH2:13][CH2:14][S:15][C:16]1[CH2:22][C@H:21]2[N:18]([C:19](=[O:40])[C@H:20]2[C:23]([CH3:39])([O:25]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:24])[C:17]=1[C:41]([O:43]CC1C=CC([N+]([O-])=O)=CC=1)=[O:42])(=[O:11])[CH3:10].C(=O)(O)[O-].[Na+]>[Pd].O1CCOCC1>[C:9]([NH:12][CH2:13][CH2:14][S:15][C:16]1[CH2:22][C@H:21]2[N:18]([C:19](=[O:40])[C@H:20]2[C:23]([OH:25])([CH3:24])[CH3:39])[C:17]=1[C:41]([O-:43])=[O:42])(=[O:11])[CH3:10].[Na+:6]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)NCCSC1=C(C(=O)[O-])N2C(=O)[C@@H](C(C)(C)O)[C@H]2C1
Temperature: 25 °C

Procedure:
A mixture of 5% palladium on activated carbon (175 mg), dioxane (12.5 ml) and 1/30M sodium phosphate buffer (pH 7.0, 5.5 ml) was shaken for an hour under a hydrogen atmosphere (40 psi) at ambient temperature. A solution of 4-nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (175 mg) in a mixture of dioxane (12 ml) and 1/30M sodium phosphate buffer (pH7.0, 5 ml) was added to the mixture at 0° C. and the resulting mixture was shaken under a hydrogen atmosphere (40 psi) for an hour, during which time the reaction temperature rose to ambient temperature. 1% Aqueous solution of sodium bicarbonate (2.29 ml) was added therein at 0° C. and the mixture was filtered through cellulose powder. The filter-cake was washed with water (3×20 ml). The combined filtrates were concentrated to a half volume, washed with ethyl acetate (3×50 ml), and evaporated in vacuo. The residue was dissolved in water (220 ml) containing sodium chloride (6.6 g) and chromatographed on Diaion non-ionic adsorption resin, HP-20 AG (trade mark, made by Mitsubishi Chemical Industries) (150-300μ, φ2.2×36 cm) eluting with water (360 ml) and a mixture of water and acetone (10:0 to 7:3, 600 ml). The fractions, whose UV spectra showed λmax 300 nm, were combined and lyophilized to give sodium (5R,6R)-3-(2-acetamidoethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (46.5 mg) as white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)NC1CCNCC1
Temperature: 2 °C
Yield: 93.6 %

Procedure:
The crude solution containing 130 g of 4-(t-butoxycarbonylamino)-1-benzylpiperidine (0.448 mol) was hydrogenated at 45 psi, room temperature in the presence of 10% Pd/C (52 g, 50% wet) and stopped when theoretical amount of H2 was consumed (23.5 h, TLC). The mixture was filtered from the catalyst and the cake was washed with ethanol (500 mL). The filtrate was concentrated to about 100 mL, redissolved in ethanol and reconcentrated. The mixture was solvent switched to heptane (200 mL final volume) and cooled to 2° C. The slurry was filtered and the solid was washed with heptane (200 mL). The solid was dried in a vacuum oven overnight to give 84 g of the title compound as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:14]=2)[C:9](=[O:21])[N:8]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]=1[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][CH2:3][CH3:4].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([NH2:39])=[O:19])[CH:14]=2)[C:9](=[O:21])[N:8]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:7]=1[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)O)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(N)=O)cc12
Yield: 85.3 %

Procedure:
A solution of (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.34 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.29 g, 87.9%) as crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([N:5](C)[C:6](=O)OCC)[CH3:4].C(O)C.[OH-].[K+].[ClH:19]>O>[ClH:19].[F:1][C:2]([F:13])([F:12])[CH:3]([NH:5][CH3:6])[CH3:4]
Reactant: CCOC(=O)N(C)C(C)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNC(C)C(F)(F)F
Temperature: 40 °C
Reaction time: 66 h

Procedure:
A mixture of 1000 mg of ethyl N-(2,2,2-trifluoro-1-methylethyl)-N-methylcarbamate, 20 ml of ethanol and 20 ml of water is admixed with 1070 mg of powdered potassium hydroxide and the mixture is stirred at 40° C. for 66 hours. The reaction mixture is then diluted with water and extracted with three times 20 ml of a mixture consisting of equal parts of methylene chloride and diethyl ether. The combined organic phases are dried over sodium sulphate and then concentrated under slightly reduced pressure at room temperature. The solution obtained is admixed with ethereal hydrochloric acid, with ice cooling, and is stirred at room temperature for 60 hours. Concentration under reduced pressure gives 280 mg of N-(2,2,2-trifluoro-1-methylethyl)-N-methylamine hydrochloride. The yield was calculated accordingly to be 34% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:10]([CH:11]([OH:14])[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:10]([C:11](=[O:14])[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)c1c(-c2ccco2)nn2c(Cl)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C#CC(=O)c1c(-c2ccco2)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (3.63 g, 13.3 mmol) was dissolved in dichloromethane (200 mL) and manganese dioxide (34.7 g, 399 mmol) was added. This slurry was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration and the filtrate was concentrated to a solid, 1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.99 g, 55%). 1H NMR (CDCl3): δ 8.54 (d, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.49 (t, 1H), 7.21 (d, 1H), 6.58 (m, 1H), 3.35 (s, 1H). MS m/z 271 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13][C:12]1=[O:22].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[Cl:43]>ClCCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[Cl:43])[CH3:34])=[O:8])=[CH:4][C:3]=1[N:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13][C:12]1=[O:22]
Reactant: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(C(=O)O)ccc1Cl
Reactant: CNc1cccc(F)c1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(C(=O)N(C)c2cccc(F)c2Cl)ccc1Cl
Reaction time: 0.67 h
Yield: 25.1 %

Procedure:
To a stirred solution of 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid (50 mg, 0.151 mmol) in anhydrous 1,2-dichloroethane (0.5 mL) at room temperature was added oxalyl chloride (23 mg, 0.181 mmol) followed by a catalytic amount of DMF. After stirring for 40 mins, a solution of N-methyl-2-chloro-3-fluoroaniline 29-1 (30 mg, 0.188 mmol) in 1,2-dichloroethane (0.5 mL), followed by 4-(dimethylamino)pyridine (22 mg, 0.179 mmol) were added and the mixture was stirred for 12 h. Direct purification via reverse phase preparative LCMS gave 4-chloro-N-(2-chloro-3-fluoro-phenyl)-N-methyl-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzamide 30-1 (18 mg, 25%) as a colorless solid. MS: 350.5, tR=8.75 min (method 3); 1H NMR (CDCl3) δ 7.50 (1H, m), 7.44 (1H, dd, J=8.4, 1.8 Hz), 7.31 (1H, m), 7.26 (1H, s), 6.95 (1H, dd, J=9, 2.1 Hz), 6.79 (1H, m), 6.55 (1H, s), 3.46 (3H, s), 1.93 (3H, s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:19][C:18]([CH2:20][CH3:21])=[N:17][C:16]=3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:5]1([N:8]([C:9]2[CH:14]=[C:13]([C:15]3[S:19][C:18]([CH2:20][CH3:21])=[N:17][C:16]=3[C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:12]=[CH:11][N:10]=2)[C:1](=[O:3])[CH3:2])[CH2:7][CH2:6]1
Reactant: CC(=O)Cl
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(NC3CC3)c2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(N(C(C)=O)C3CC3)c2)s1
Reaction time: 4 h

Procedure:
At 40° C., 35 mg (0.44) mmol of acetyl chloride are added dropwise to a solution of 100 mg (0.29 mmol) of N-cyclopropyl-4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine-2-amine and 80 mg (0.58 mmol) of potassium carbonate in 5 ml acetonitrile. After 4 h, 30 ml of water are added, and the reaction mixture is extracted with ethyl acetate (3×25 ml). The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 39 mg (31%) of the desired product; 1H-NMR(MeCN-d3) δ: 8.40 (d, 1H), 7.49 (m, 2H), 7.16 (d, 1H), 7.108 (m, 3H), 3.05 (q, 2H), 2.99 (m, 1H), 2.07 (s, 3H), 1.40 (t, 3H), 0.79 (m, 2H), 0.44 (m, 2H).
Reaction SMILES: [N:1](=[C:3]([C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13])[C:4]1[CH:9]=[CH:8][C:7](OC)=[CH:6][CH:5]=1)[OH:2].COC1C=CC(CC(C2C=NC=CC=2)=O)=CC=1>>[OH:2][N:1]=[C:3]([C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=NO)C(=O)c2cccnc2)cc1
Agent: COc1ccc(CC(=O)c2cccnc2)cc1
Product: O=C(C(=NO)c1ccccc1)c1cccnc1

Procedure:
(α-hydroximino-p-methoxybenzyl)-(3-pyridyl)-ketone (m.p. 183°-186°C), starting from 11.3 g (p-methoxybenzyl)-(3-pyridyl)-ketone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][NH:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH3:14].C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:21]([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[CH:29][CH:28]=2)[CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(CNCc2ccco2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1ccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C#N)cc2)cc1
Reaction time: 2 h
Yield: 57.8 %

Procedure:
4-cyanobenzene-1-sulfonyl chloride (600 mg, 2.9 mmol) was added to a stirring solution of N-(4-ethoxybenzyl)-1-(furan-2-yl)methanamine (Example 5-3b) (685 mg, 2.9 mmol) and triethylamine (455 mg, 4.5 mmol) in DCM (100 mL) and the reaction was stirred for 2 hours. The reaction was diluted with H2O (200 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromatography (10% ethyl acetate in hexanes) to afford 4-cyano-N-(4-ethoxybenzyl)-N-(furan-2-ylmethyl)benzenesulfonamide (665 mg, 68%) as an off white solid. NMR (DMSO-d6, 400 MHz): δ 1.29 (t, J=7.2 Hz, 3H), 3.97 (q, J=6.8 Hz, 2H), 4.23 (s, 2H), 4.27 (s, 2H), 6.15 (d, J=3.2 Hz, 1H), 6.27 (m, 1H), 6.84 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 7.39 (m, 1H), 7.92 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.C([N+](CC)(CC)CC)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=S)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:43][N:44]([CH3:51])[CH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH2:48]>O1CCCC1>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:48][CH2:47][C:46]([CH3:50])([CH3:49])[CH2:45][N:44]([CH3:51])[CH3:43])=[N:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)CC(C)(C)CN
Reactant: CC(C)CCNC(=S)Nc1ccc(OCc2ccccc2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)CCN=C(NCC(C)(C)CN(C)C)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.9 %

Procedure:
Benzyltriethylammonium permanganate (0.281 g; 1.5 eq.) is added, at 5° C. and portionwise, to a solution of N-(4-benzyloxyphenyl)-N′-(3-methylbutyl)thiourea (0.200 g) and 3-dimethylamino-2,2-dimethylpropylamine (0.156 g; 2 eq.) in tetrahydrofuran (THF; 2.2 ml). The reaction medium is stirred for three days at room temperature. After filtration and concentration, the product is purified by chromatography on silica (eluent: methanol +0.1% acetic acid). The product, dissolved in dichloromethane, is washed with 1N sodium hydroxide. After drying and concentration, 0.067 g of N-(4-benzyloxyphenyl)-N′-(3-dimethylamino-2,2-dimethylpropyl)-N″-(3-methylbutyl)guanidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N([C:36](=[O:39])NN=2)N=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]2[N:12]([C:36](=[O:39])[NH:15][N:14]=2)[CH:13]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Yield: 88 %

Procedure:
The title compound (190 mg, 88% yield) as a yellow foam was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (200 mg, 0.61 mmol) in a manner analogous to that in which 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 1G) was prepared. HPLC/MS: retention time=3.83 min, [M+H]+=356.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][N:11]([CH:13]([N:16](C)C)[O:14]C)C.NC(N)=O>>[N:7]1[CH:8]=[CH:9][C:4]([C:1]2[CH:2]=[CH:10][NH:11][C:13](=[O:14])[N:16]=2)=[CH:5][CH:6]=1
Reactant: COC(N(C)C)N(C)C
Reactant: CC(=O)c1ccncc1
Agent: NC(N)=O
Product: O=c1nc(-c2ccncc2)cc[nH]1
Temperature: 85 °C

Procedure:
A mixture of 4-acetylpyridine (25 ml, 226.0 mmol) and bis(dimethylamino)methoxymethane (44 ml, 293.8 mmol) was heated at 85° C. for 30 min followed by evaporation to dryness to recover a solid of 3-(dimethylamino)-1-(4-pyridyl)-3-propen-1-one. Its ethanolic solution (200 ml) was transferred into ethanolic 1.13 N sodium ethoxide (200 ml) containing urea (16.3 g, 271 mmol). The mixture was heated to reflux overnight, then cooled down to ice-bath temperature. The precipitate was filtered, dissolved in a minimal amount of water and the aqueous solution was washed with dichloromethane. The title compound was precipitated from the aqueous solution by neutralization with 6N hydrochloric acid and filtered. More material was obtained from the original reaction filtrate which was concentrated, diluted with a minimal amount of water and washed with dichloromethane. The aqueous solution was neutralized with 6N hydrochloric acid and the precipitate filtered. MS (m/z): 174.1 (M+H)+; C9H7N3O requir. 173.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:14][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([CH2:8][O:9][CH3:10])[N:4]=1)=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COCc1ccc(Br)c(C(=O)O)n1
Solvent: c1ccccc1
Solvent: CO
Product: COCc1ccc(Br)c(C(=O)OC)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 3-bromo-6-methoxymethyl-pyridine-2-carboxylic acid (200 mg, 0.81 mmol) in benzene (4 ml) and MeOH (1 ml) was slowly added trimethylsilyl-diazomethane (0.41 ml, 0.81 mmol) at ambient temperature, and the reaction mixture was stirred for 2 hours. The solvents were removed and the residue was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered, and evaporated. The crude product was purified by silica gel chromatography using an ethyl acetate/hexane eluent to yield 158 mg (75%) of the title compound as light yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][C:20]#[N:21])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:7]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][NH2:21])=[CH:22][CH:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCOc1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
3.4 g of lithium aluminum hydride was suspended in 100 ml of anhydrous tetrahydrofuran and to the suspension was gradually added 10.0 g of (4-benzylphenoxy)acetonitrile under ice cooling in nitrogen stream. After stirring at room temperature for 1 hour and ice cooling, to the reaction mixture were carefully added 3.4 ml of water, then 3.4 ml of 5N aqueous sodium hydroxide solution and finally 10 ml of water, followed by stirring for a while. Undesired matters were removed by filtration with cerite and the filtrate was concentrated under reduced pressure to obtain 9.8 g of 2-(4-benzylphenoxy)ethylamine. This was used for the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1.[H][H]>CO.[C].[Pd]>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Reaction time: 16 h

Procedure:
0.05 g of 10% palladium-carbon was added to a solution of 1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 79) in 60 ml of methanol. Under normal-pressure hydrogen gas, the solution was vigorously stirred. After 16 hours, the reaction was ceased, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 0.94 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-(4-hydroxy-3-methoxyphenyl)propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](=[O:29])SC2C=CC=CN=2)=[CH:3]1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH2:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:41][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]2)[CH2:5][CH2:6]4)=[O:29])([CH3:39])[CH3:40])=[CH:34][CH:33]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: COc1ccc(C(C)(C)N)cc1
Solvent: ClCCl
Product: COc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
610 mg of S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [prepared as described in step (a) above] were dissolved in 1 ml of dry methylene chloride, and 630 mg of 1-(4-methoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10a) were added to the resulting solution. The mixture was then stirred at room temperature for 3 days. At the end of this time, the reaction mixture was subjected, without further treatment, to silica gel column chromatography using a gradient elution method, with mixtures of methylene chloride and acetone in ratios ranging from 3:2 to 1:1 by volume as the eluent, and the product was recrystallized from diisopropyl ether, to give 670 mg of the title compound as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][CH2:24][CH2:25][C:26](O)=[O:27].COC1C=CC(C(O)=O)=CC=1>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:26](=[O:27])[CH2:25][CH2:24][O:23][CH3:22])[CH2:20][CH2:21]2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: COCCC(=O)O
Agent: COc1ccc(C(=O)O)cc1
Product: COCCC(=O)N1CCC(CN2CCC(NC(=O)OC(C)(C)C)CC2)CC1

Procedure:
Similar procedures as Example 60 are repeated except that 4-(t-butoxycarbonylamino)-1-(4-piperidinylmethyl)piperidine, and 3-methoxypropionic acid are used instead of 4-methoxybenzoic acid in Example 60 as described below to give 4-(t-butoxycarbonylamino)-1-[1-(3-methoxypropionyl)-4-piperidinylmethyl]piperidine.