Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:18]([C:19]([NH:21][CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[N:25]=2)[CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:32])[N:10]1[C@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:39][S:40]([CH3:43])(=[O:42])=[O:41].C(N(CC)CC)C.[C:51](OC(=O)C)(=[O:53])[CH3:52]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[C:51]([O:31][CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:22]([NH:21][C:19]([C@@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:32])[N:10]([C@H:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]3[NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[C@H:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[O:20])[CH3:23])[N:25]=1)(=[O:53])[CH3:52]
Reactant: CC(=O)OC(C)=O
Reactant: CC(NC(=O)[C@@H]1c2ccccc2C(=O)N([C@H]2CCCC[C@@H]2NS(C)(=O)=O)[C@H]1c1ccc(Cl)cc1Cl)c1cccc(CO)n1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cccc(C(C)NC(=O)[C@@H]2c3ccccc3C(=O)N([C@H]3CCCC[C@@H]3NS(C)(=O)=O)[C@H]2c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 714 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 14.3 ml of chloroform was cooled to 0° C., and 0.23 ml of triethylamine, 0.16 ml of acetic anhydride, and 6.8 mg of DMAP were added thereto in this order, followed by stirring at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate-water was added thereto for liquid separation, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}methyl acetate.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8].[CH3:20][C@H:21]1[CH2:23][C@@H:22]1[CH2:24]Br.O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C[C@H]1C[C@@H]1CBr>[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([CH2:20][C@H:21]2[CH2:23][C@@H:22]2[CH3:24])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: C[C@H]1C[C@@H]1CBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Potassium tert-butoxide (3.94 g, 35.1 mmol) was added to a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5.79 g, 31.9 mmol) and 18-crown-6 (0.41 g, 1.55 mmol) in tetrahydrofuran (130 ml) and the mixture was stirred at room temperature for 1 hour. After dropwise addition over 30 minutes of (1S,2S)-2-methylcyclopropylmethyl bromide (5.71 g, 38.3 mmol) to the reaction mixture at 50° C., the mixture was heated under reflux for 3 hours. Potassium tert-butoxide (0.36 g, 3.22 mmol) and (1S,2S)-2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol) was further added to the mixture and this mixture was heated for 1 hour. The reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to afford the desired compound (8.26 g, 100%) as a pale brown oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH2:9](I)[CH2:10][CH3:11]>CN(C)C=O.[Ag]=O>[CH2:9]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH3:11]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCCI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCCO[C@@H](C)C(=O)OCC
Yield: 73.7 %

Procedure:
Twenty grams of ethyl (S)-lactate, 45.0 g of propyl iodide, and 30.0 g of silver oxide were stirred in 100 ml of dimethylformamide for 40 hours. Any insoluble matter was removed by filtration, and water was added to the filtrate. The filtrate was extracted three times with hexane. The hexane layer was dehydrated, and the organic solvent was removed therefrom by distillation under reduced pressure to obtain 20.0 g of ethyl (S)-2-propoxypropionate (b.p.=78° C./50 mmHg). Eighteen grams of the product was stirred in 100 ml of a 5N sodium hydroxide aqueous solution for 6 hours, and adjusted to a pH of 3 to 4 with dilute sulfuric acid under ice-cooling. The reaction mixture was extracted with diethyl ether several times, and the extract was dehydrated and distilled to remove the diethyl ether to obtain 10.2 g of (S)-2-propoxypropionic acid. To the whole quantity of the product were added 20 ml of thionyl chloride and 0.5 ml of pyridine, followed by stirring at reflux for 2 hours. The excess thionyl chloride was removed from the reaction mixture by distillation under reduced pressure. The residue was dissolved in benzene, and any insoluble matter was separated by filtration. The benzene was removed from the filtrate by distillation to obtain 10.5 g of (S)-2-propoxypropanoyl chloride as an oily substance.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Br:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[N:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C(O)C>[Br:5][C:6]1[C:7]([O:1][CH2:2][CH3:3])=[N:8][CH:9]=[N:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CC[O-]
Reactant: FC(F)(F)c1ncnc(Cl)c1Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncnc(C(F)(F)F)c1Br
Yield: 78.4 %

Procedure:
0.94 g (13.77 mmoles) of sodium ethoxide was added, at room temperature, to a solution of 3.00 g (11.48 mmoles) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 50 ml of ethanol. The mixture was stirred to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 2.44 g (yield: 82.9%) of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:17][C:18](=[O:22])[C:19]([O-])=[O:20])[CH2:14][CH2:15][CH3:16]>>[CH3:16][CH2:15][CH2:14][CH2:13][O:17][C:18]([C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[N:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:22]
Reactant: CCCCOC(=O)C(=O)[O-]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: CCCCOC(=O)C(=O)Nc1cccc(-c2nn[nH]n2)c1
Yield: 75 %

Procedure:
5-(3-Aminophenyl)tetrazole (1.7 g) was added to 12 ml of n-butyloxalate and reacted at a bath temperature of 165° to 175° C. for 1.5 hr while stirring. After cooling, the precipitated crystals were filtered off and recrystallized from acetone-n-hexane, to give 2.3 g (yield: 75%) of 5-(3-n-butyloxalylaminophenyl)tetrazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)C=Cc1ccc(N)cc1
Temperature: 75 °C

Procedure:
A mixture of 3-(4-nitro-phenyl)-acrylic acid methyl ester (72) (39.54 g, 0.191 mol) and SnCl2.2H2O (220 g, 0.98 mol) in anhydrous ethanol (300 ml) was heated at 50° C. for 1 hour and at 75° C. for 1 hour. The reaction mixture was allowed to cool to 10° C., treated with 20% NaOH solution to pH 8–9, and extracted with ethyl acetate (3×200 ml). The organic extract was washed with saturated NaCl (3×150 ml), dried (MgSO4), and evaporated under reduced pressure. Recrystallization from isopropanol (180 ml) afforded pure title compound in a form of yellowish crystals (17.938 g, 53%). 1H NMR (DMSO-d6, HMDSO), δ: 3.64 (3H, s); 5.73 (2H, s); 6.22 (1H, d, J=16.0 Hz); 6.57 (2H, d, J=8.0 Hz); 7.38 (2H, d, J=8.0 Hz); 7.50 (1H, d, J=16.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Br:17]Br.C([O-])(=O)C.[Na+]>>[NH2:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([N:8]2[CH:9]=[N:10][N:11]=[CH:12]2)=[CH:6][C:7]=1[Br:17]
Reactant: Nc1ccc(-n2cnnc2)cc1C(F)(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Nc1c(Br)cc(-n2cnnc2)cc1C(F)(F)F

Procedure:
The following compound, m.p. 202°-3°, was prepared similarly to the previous Preparation using 4-(4-amino-3-trifluoromethylphenyl)-1,2,4-triazole, bromine, and sodium acetate (in place of hydrogen bromide and acetic acid) as the starting materials: ##STR146##
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:20][C:19]1[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:4]=2[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])[N:1]=[C:23]([CH3:25])[C:22]=1[C:21]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCNC(=O)C(C)(C)COc1cccc2nc(C)c(C(=O)OCC)c(N)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221, 1.38 g, 5.0 mmol) and ethyl acetoacetate (0.66 g, 5.0 mmol) in dry toluene (150 mL) was added SnCl4 (2.61 g, 10.0 mmol) dropwise via syringe at room temperature under nitrogen. After 1 hr at room temperature, the reaction mixture was refluxed for an additional 5 hrs. The solution was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with EtOAc, and aqueous NaOH (2N) was added at room temperature to pH>8. The solution was filtered and the organic layer separated. The aqueous layer was extracted with EtOAc (5×). The combined organic layers was washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel (0.5% MeOH in EtOAc) to give the title compound as an off-white solid (1.63 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 0.73 (t, J=7.6 Hz, 3H), 1.25 (s, 6H), 1.32 (t, J=7.4 Hz, 3H), 1.35-1.42 (m, 2H), 2.54 (s, 3H), 3.00-3.05 (m, 2H), 4.12 (s, 2H), 4.31 (q, J=7.4 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 8.08 (s, 2H). MS 388 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[C:7](Br)=[N:8][CH:9]=1)=[O:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[C:7]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[N:8][CH:9]=1)=[O:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cnc(Br)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)n1C
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To 2-bromo-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (800 mg) were added 4-(trifluoromethyl)phenylboronic acid (1.04 g), and tetrakis(triphenylphosphine)palladium(0) (422 mg), and tetrahydrofuran (9 ml), saturated sodium carbonate water (3 ml), and water (1.5 ml) as solvents, and stirred at 120° C. for 30 minutes under microwave radiation. After completion of the reaction, to the reaction solution 6 was added water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 3-methyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazole-4-carboxylic acid methyl ester (980 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:10][O:11][CH3:12])[C:8]=1[OH:9])[NH2:5].C(N(CC)C1C=CC=CC=1)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[C:7]([CH2:10][O:11][CH3:12])[C:8]=1[OH:9]
Reactant: COCc1cc(N)cc(Cl)c1O
Reactant: CC(C)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: COCc1cc(NC(=O)OC(C)C)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
3-Chloro-4-hydroxy-5-methoxymethylaniline (52.8 g) and N,N-diethylaniline (42.0 g) were dissolved in ethyl acetate (300 ml). To the resultant solution was dropwise added isopropyl chloroformate (34.6 g) in 15 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water. The organic layer was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g). Sodium hydride (9.60 g, 60% dispersion in mineral oil) was added to dimethylformamide (240 ml). To the resultant mixture was added isopropyl N-(3-chloro-4-hydroxy-5-methoxymethylphenyl)carbamate (65.6 g) under 5° C. The resulting solution was stirred at a temperature of 20° C. for 30 minutes, and chloroacetonitrile (19.0 g) was added thereto in 5 minutes. The mixture was heated at 90° C. for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-cyanomethoxy-5-methoxymethylphenyl)carbamate (Compound No. 5) (67.5 g) in a yield of 76.8%. M.P., 58.5°-60.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])O)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH:34]([O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=4)[CH:11]=3)[P:36]([O:38][CH2:39][CH3:40])([O:41][CH2:42][CH3:43])=[O:37])=[CH:32][CH:33]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:16])([CH3:17])[CH3:15]
Reactant: N#Cc1ccc2ccc(O)cc2c1
Reactant: CCOP(=O)(OCC)C(O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Oc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.2 %

Procedure:
A solution of 1.50 g (0.0088 mol) 7-hydroxy-naphthalene-2-carbonitrile, 3.93 g (0.0088 mol) 4-{4-[(diethoxy-phosphoryl)-hydroxy-methyl]-phenoxy}-piperidine-1-carboxylic acid tert.-butyl ester and 3.73 g (0.0142 mol) triphenylphosphine in 150 ml tetrahydrofuran is admixed at 5° C. with 2.23 ml (0.0142 mol) azodicarboxylic acid diethyl ester and stirred for 96 h at room temperature. After concentration the residue is purified by chromatography on a silica gel column (mobile solvent: ethyl acetate/methanol 19:1). After concentrating the appropriate column fractions one obtains 2.47 g (47%) of the title compound as a viscous, yellow oil. 31P-NMR: δ=19.0 ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]1([C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)O)[OH:28].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:23][C:22]([F:24])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:28][C:27]3[CH:29]=[CH:31][CH:32]=[CH:33][C:34]=3[O:26]2)=[CH:20][CH:19]=1
Reactant: Oc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: FC(F)(F)Oc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 71.2 %

Procedure:
A solution of 4-(4-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 247) (373 mg, 1.0 mmol), catechol (440 mg, 4.0 mmol) and p-TsOH.H2O (380 mg, 2.0 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 44 hours. Standard work-up and purification gave 4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (260 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[CH3:14])[CH:5]=[C:4]([CH3:15])[N:3]=1.CN(C)CCN(C)C1N=C(C2SC(N[C:33](=[O:35])[CH3:34])=NC=2C)C=C(C)N=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:33](=[O:35])[CH3:34])=[N:10][C:9]=2[CH3:14])[CH:5]=[C:4]([CH3:15])[N:3]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(C)nc(N(C)CCN(C)C)n2)s1
Reactant: Cc1cc(-c2sc(N)nc2C)nc(C)n1
Product: CC(=O)Nc1nc(C)c(-c2cc(C)nc(C)n2)s1

Procedure:
This is prepared by acylating 5-(2,6-dimethyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (intermediate AF) using the procedure described for N-(5-{2-[(2-dimethylamino-ethyl)-methyl-amino]-6-methyl-pyrimidin-4-yl}-4-methyl-thiazol-2-yl)-acetamide (Example 39, step 2).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:14]([CH:24]=1)[C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16].O>C1COCC1>[OH:23][C:20]1([CH3:4])[CH2:19][CH2:18][N:17]([C:15]([C:14]2[CH:24]=[C:10]([CH3:9])[CH:11]=[CH:12][C:13]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(=O)CC2)c1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(C)(O)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 M methylmagnesium bromide-diethyl ether solution (0.84 mL) was added to a solution of 1-(5-methyl-2-(pyridin-4-yl)benzoyl)piperidin-4-one (0.37 g) in THF (10 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.19 g).
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3)(=O)=O.[OH-].[Na+]>C(O)C>[CH2:2]([S:9][C@@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccccc1

Procedure:
To 2.25 gm. of sodium metal dissolved in 185 ml. of ethanol is added 8.2 ml. of benzyl mercaptan followed by 3 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3-one. The reactants are heated to reflux for 48 hours. Pour the reaction mixture into 5% NaOH solution and extract with ethyl acetate. Wash the ethyl acetate extracts with water, dry over Na2SO4, and evaporate to a residue. The residue is purified on a 300 gm. silica gel column eluting with chloroform/ethyl acetate (2:1) to obtain the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:26][CH2:27][C@H:28]([OH:38])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:38][C@H:28]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH2:27][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 230) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.85(t, J=7.0 Hz, 3 H), 1.15–1.45 (m, 12 H), 1.50–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.92 (brt, J=6.7 Hz, 2 H), 3.54 (brd, J=12.3 Hz, 2 H), 3.70–3.90 (m, 3 H), 6.66 (d, J=6.7 Hz, 2 H), 6.75 (d, J=8.3 Hz, 1 H), 6.88 (d, J=9.0 Hz, 2 H), 7.04 (d, J=9.0 Hz, 2 H), 8.89 (brs, 1 H), 9.28 (brs, 1 H); MS (ES) m/z: 534.1 (MH+); HRMS Calcd. for C28H44N3O5S (MH+): 534.3002. Found: 534.3017.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1[N:22]([CH2:26][CH2:27][O:28][CH3:29])[C:23](=[O:25])[CH3:24].C(OCC)(=O)C>C1C=CC=CC=1>[CH2:1]([NH:8][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1[N:22]([CH2:26][CH2:27][O:28][CH3:29])[C:23](=[O:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COCCN(C(C)=O)C1=C(NCc2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzylamine (0.5 ml) was added to a solution of N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (0.5 g) in benzene (15 ml) and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution and the mixture was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethyl acetate-hexane to give N-(3-benzylamino-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (0.51 g) as a red powder.