Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1(SCC)[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)[CH3:2]>C(C1C=CC=CC=1CC)C>[CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 190 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A suspension of 1.8 g of 17,17-bis(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4-dien-3-one in 120 ml of diethylbenzene is stirred at 190° C (oil bath temperature) for 1 hour. The solution is cooled to 0° C and the solid that precipitates is filtered. This is redissolved in 1:9 hexane-chloroform and chromatographed on a 60 g-silica gel column. Elution with 1:9 hexane-chloroform gives 1.35 g of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 680 mg of the title compound, melting point 282°-283° C (dec.), with consistent spectral data.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[NH:12][C:11]1=[O:21])(=O)=O.[C:22]1([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(OCC)(=O)C.O>[C:22]1([C:28]2[CH2:33][CH2:32][N:31]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[NH:12][C:11]3=[O:21])[CH2:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCCCn1c(=O)[nH]c(=O)c2ccccc21
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2ccccc12
Yield: 30.4 %

Procedure:
A mixture of 1-(4-methanesulfonyloxybutyl)-2,4(1H,3H)-quinazolinedione (312 mg), 4-phenyl-1,2,3,6-tetrahydropyridine (200 mg) and triethylamine (303 mg) was refluxed for 1.5 hours. The reaction mixture was poured into ethyl acetate-water, extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The crude residue was washed with hot methanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-2,4(1H,3H)-quinazolinedione (114 mg) as a powder.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:15]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C1C=CC=CC=1>>[Cl:14][C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:29][CH:28]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)c1ccccc1
Product: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Nc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 50.0 g of 2,6-dichloro-3-nitrobenzoic acid, 85.7 g of 4-benzyloxyaniline, and 115 ml of N,N-dimethylaniline was heated on a steam bath for 24 hours. The cooled mixture was triturated with 600 ml of chloroform and filtered. The precipitate was stirred in a mixture of 350 ml of chloroform and 350 ml of 1N aq NaOH. The red sodium salt was collected and stirred with a mixture of 300 ml of 1N hydrochloric acid and 1.5 l of chloroform. The chloroform layer was concentrated to provide the title compound as red crystals, mp 172°-174° C.
Reaction SMILES: CO[C:3](=NO)[C:4]1[C:5]2[C:6](C=O)=[CH:7][NH:8][C:9]=2[CH:10]=[CH:11][CH:12]=1.[H][H].C[O:20]C(C1C2C(CN)=CNC=2C=CC=1)=O.[OH-].[Na+]>C(O)(=O)C.O.[Pt]=O>[CH2:3]1[C:4]2[C:5]([C:9](=[O:20])[CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:7]=[N:8]1
Reactant: [H][H]
Reactant: COC(=O)c1cccc2[nH]cc(CN)c12
Reactant: COC(=NO)c1cccc2[nH]cc(C=O)c12
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=CC=C2CN=CC=C12

Procedure:
A mixture of 3-formylindole -4 -carboxylic acid methyl ester oxime (1.6 g), described in Example 2 and platinum oxide (120 mg) in 60 ml of acetic acid is stirred in a hydrogen atmosphere for 16 hr. Removal of the catalyst and concentration of the solution affords an oily residue [the acetic acid addition salt of 3-(aminomethyl)indole -4-carboxylic acid methyl ester] . The oil is suspended in water. The mixture is rendered alkaline with 10% NaOH. The solid is collected, triturated with 30% acetone in benzene and recrystallized from ethanol to afford the title compound, mp. 232°-234°C, νmaxCHCl3 1668 cm-1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:12]([C:14]2[N:18]=[CH:17][NH:16][N:15]=2)=[O:13])[CH:7]=[CH:6][N:5]=1.CI.[C:25](=O)([O-])O.[Na+]>CN(C)C=O.O>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:12]([C:14]2[N:18]=[CH:17][N:16]([CH3:25])[N:15]=2)=[O:13])[CH:7]=[CH:6][N:5]=1
Reactant: O=C([O-])O
Reactant: O=C(c1nc[nH]n1)N(Cc1ccnc(Br)c1)C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)N(Cc2ccnc(Br)c2)C2CCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (186 mg) was added to a solution of N-[(2-bromopyridin-4-yl)methyl]-N-cyclobutyl-1H-1,2,4-triazole-3-carboxamide (1.3 g) in dimethylformamide (10 mL), and the mixture was stirred at room temperature for 15 min. Methyl iodide (0.25 mL) was added thereto and the mixture was stirred at room temperature for 17.5 hr. Saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) to afford the title compound (748 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH2:22]([N:27]=[C:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:28](=[O:29])[NH:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: CCCCCN=C=O
Reactant: O=C1c2ccccc2SCCC1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCNC(=O)OCC1CCSc2ccccc2C1=O

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (264 mg, 1.27 mmol) in 16 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.2 ml, 1.4 mmol) and n-pentyl isocyanate (492 μl, 4.9 mmol). The mixture was heated under reflux for 15 hours, concentrated and purified by column chromatography on silica gel (eluent: 4:1 diisopropyl ether/hexane). The product was obtained in a yield of 145 mg (35%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)=[C:5]([CH3:25])[O:4][N:3]=1.[N:26]1C=CC=CC=1.O=S(Cl)Cl>C1COCC1>[NH2:26][C:10]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:25])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccc(F)cc1)C(=O)N2
Reactant: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(N)(c1ccc(F)cc1)C(=O)N2
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
Under N2, to a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)-3-hydroxyindolin-2-one (52 g, 154 mmol, 1.0 eq) in THF (500 mL) was added pyridine (40 mL, 496 mmol, 3.2 eq) and SOCl2 (16 mL, 219 mmol, 1.4 eq) slowly at −15° C.˜−20° C., the mixture was stirred for 20 min at −15° C.˜−20° C., quenched with brine, washed with brine (300 mL×2), to the THF layer was added NH3/H2O (100 mL), the mixture was stirred for 2 hours at room temperature, washed with brine, dried, concentrated, purified by silicon gel to give a crude product which was recrystallized from i-PrOH/toluene to give 14 g (yield 27%) product as white solid. 1H NMR (DMSO-d6) δH 10.57 (s, 1H), 7.40-7.44 (m, 2H), 7.22-7.24 (dd, 1H, J=8.0 Hz, 1.6 Hz), 7.11-7.16 (m, 3H), 6.98-7.00 (d, 1H, J=8.0 Hz), 2.75 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][NH:8][C:9]=1[NH2:10])=[O:4].[C:11]([CH:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)#[N:12].C(#N)C.C[O-].[Na+]>O.CN(C=O)C>[NH2:10][C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][N:7]([C:14]2([CH2:13][C:11]#[N:12])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: COC(=O)c1cn[nH]c1N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1N
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a flask containing 5-amino-1H-pyrazole-4-carboxylic acid methyl ester (2.0 g, 14 mmol) was added tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (6.3 g, 28 mmol), acetonitrile (57 mL), and DMF (25 mL), followed by the addition of catalytic NaOMe (0.10 g, 2.1 mmol). The mixture was heated to 70° C. and allowed to stir for 18 hours. The mixture was then allowed to cool to ambient temperature, diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound. LRMS (ESI) calc'd for C17H26N5O4 [M+H]+: 364. Found: 364.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1(S(OC)(=O)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[CH:8][C:7]1=[O:12]
Reactant: O=C1CCCCN1Cc1ccc(F)c(Cl)c1
Agent: COS(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C=CCCN1Cc1ccc(F)c(Cl)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1-(3-Chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) was dissolved in THF (5 L) and cooled to −20° C. under nitrogen. LHMDS (3.09 L, 3.09 mol, 1M in THF) was added over 40 minutes keeping the temperature at −20° C. and aged for 1 hr at −20° C. The methyl benzene sulfonate (231 mL, 1.69 mol) was added over 30 minutes, again keeping the internal temperature at −20° C. The reaction was aged for 30 minutes at −20° C. and LCMS showed the reaction complete. The reaction mixture was diluted with 4 L EtOAc and washed with four 2 L portions of distilled H2O. The organic layer was concentrated and the residue was dissolved in 4 L toluene. Na2CO3 (500 g) was added and the reaction heated to 100° C. for 1 hour. LCMS showed the reaction complete. The residue was diluted with 4 L EtOAc and washed with four 2 L portions of distilled water. The organic layer was concentrated and the residue purified by flash chromatography on silica eluting with a gradient of 0-60% EtOAc/heptane. The product was isolated as an oil.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][N:11]1[CH3:25])(=[O:9])[NH2:8]>C(Cl)Cl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:12][N+:11]1([CH3:6])[CH3:25])(=[O:9])[NH2:8]
Reactant: COS(=O)(=O)F
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)[N+](C)(C)C2)cc1
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.123 ml of methyl fluorosulfonate was added, whilst ice-cooling, to a solution of 320 mg of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (6) or (6a) above] dissolved in 7 ml of dry methylene chloride. The mixture was then stirred at the same temperature for 20 minutes and at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was repeatedly washed by decantation with diethyl ether and then dried under reduced pressure to afford 525 mg of the title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=O)[CH:2]=1.[CH3:19][Si:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][O:23][C:24]([NH:26][NH2:27])=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:19][Si:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][O:23][C:24](=[O:25])[NH:26][N:27]1[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=[C:10]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCOC(=O)NN
Reactant: O=C(CCC(=O)c1cccnc1)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)Nn1c(-c2cccnc2)ccc1-c1cccnc1
Temperature: 25 °C

Procedure:
A solution of 1,4-di-Pyridin-3-yl-butane-1,4-dione (1 g, 4.2 mmol) in toluene (40 mL) is treated with hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (888 mg, 5.0 mmol) and p-toluenesulfonic acid (30 mg). The reaction vessel is fitted with a Dean Stark trap, and the resulting solution is heated to reflux, with azeotropic removal of water until no starting materials are detected by TLC. The solution is cooled to rt, and washed with water. The organic layer is dried over Na2SO4, filtered and concentrated to afford (2,5-di-pyridin-3-yl-pyrrol-1-yl)-carbamic acid 2-trimethylsilanyl-ethyl ester, which is not purified further.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:13]2[CH:14]=[CH:15][O:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Nc1ccon1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1cccc(Nc2ccon2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.9 %

Procedure:
To a solution of 3-bromophenylboronic acid (2.00 g, 9.96 mmol) in CH2Cl2 (80 mls) was added Isoxazol-3-ylamine (0.84 g, 19.92 mmol), Cu(OAc)2 (0.9 g, 0.46 mmol) and triethylamine. (14 mls). The reaction mixture was stirred at room temperature for 18 h, filtered and the resulting precipitate purified by silica column chromatography (20-80% EtOAc in hexane) to afford the title compound (0.33 g). MS: [M+H]+=239, 241
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].B(F)(F)F.CCOCC.[CH:17]1[CH2:21][CH:20]=[CH:19][CH:18]=1.C1C2C3C=CC(C2C=C1)C3.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:20][CH2:21][CH:17]=[CH:18][CH3:19]
Reactant: C1=CCC=C1
Reactant: C=CC(=O)OCC
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: C1=CC2C3C=CC(C3)C2C1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC=CCCC(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Ethyl acrylate (200 g, 1.99 mol, commercially available at Aldrich Chemical Company, Inc.) was dissolved in 500 mL of toluene. The resulting solution was then cooled to 0° C. using a dry ice isopropanol bath. Boron trifluoride etherate (28 g, 0.19 mol, commercially available at Aldrich Chemical Company, Inc.) was added to the solution. Cyclopentadiene (197 g, 2.98 mol, freshly prepared by cracking dicyclopentadiene, which is commercially available at Aldrich Chemical Company, Inc.). was then added to the cold solution dropwise. After the feed was complete the reaction mixture was aged for 1 hr. The crude reaction mixture was poured onto 2 L of 10% sulfuric acid and wet ice. The organic layer was removed and then washed with sodium carbonate solution until basic. Fractional distillation afforded endo bicycle[2.2.1]hept5-ene-2-carboxylic acid, ethyl ester (300 g, 90% yield), which had a boiling point of 82° C. at a pressure of 10 mmHg
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example E.16) (0.90 g, 1.86 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.491 g, 2.23 mmol) according to the general procedure VI. Obtained as a yellow solid (0.290 g, 34%). MS (ISP) 451.1 [(M+H)+]; mp 262° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1.O>C1COCC1.CCCCCC>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]2=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]2[CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc4ccccc4c3)C2=N1
Yield: 71.8 %

Procedure:
To a suspension of 60% sodium hydride (0.79 g) in THF (20 ml) was added 2-chloroethanesulfonyl chloride (1.93 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min. Then, a solution of 3-(naphthalen-2-yl)pyridin-2-amine (0.87 g) in THF (20 mL) was added. The reaction mixture was stirred at room temperature overnight and at 50° C. for 1 hr, and water and hexane were added under ice-cooling. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound (0.88 g).
Reaction SMILES: [O:1]1[C:5]2([C@@H:9]([NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH:27][C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(CC)CC>C1COCC1>[OH:27][C:28]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:29][CH2:30][CH:31]([N:7]2[CH2:8][C@H:9]([NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)[C:5]3([O:1][CH2:2][CH2:3][CH2:4]3)[CH2:6]2)[CH2:32][CH2:33]1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CNCC12CCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCC(O)(c3ccccc3)CC2)CC12CCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the amine of step H (90 mg, 0.243 mmol) and 4-hydroxy-4-phenyl-cyclohexanone (43 mg, 0.226 mmol) in THF (5 mL) was added sodium triacetoxyborohydride (129 mg, 0.61 mmol) followed by Et3N (0.29 ml, 2 mmol). The mixture was stirred at room temperature overnight. Solvent was removed under vacuum. The residue was taken up in EtOAc/NaHCO3 aqueous solution. The two phases were separated and the water layer was extracted with EtOAc twice. The combined organic phase was dried (Na2SO4) and concentrated. Purification by prep-HPLC provided two isomers. MS: 546.4 (M+1)+.
Reaction SMILES: O[CH:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([C:10]1[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=1)[CH2:6]2.CC1(C)[O:35][C:33](=[O:34])[CH2:32][C:30](=[O:31])[O:29]1.N1CCCCC1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([CH:5]3[CH2:4][CH:3]4[CH:2]([CH:32]([C:33]([OH:35])=[O:34])[C:30]([OH:31])=[O:29])[CH:7]([CH2:8][CH2:9]4)[CH2:6]3)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4O)nc2n(CCC)c1=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4C(C(=O)O)C(=O)O)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8-(8-Hydroxy-bicyclo[3.2.1]oct-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (30 mg) taken in CHCl3 (5 ml). To this solution Meldrum's acid (58 mg), piperidine (10 mg) were added and heated to reflux overnight. The next day, after cooling to room temperature, diluted with ethyl acetate, washed with 1N HCl, sat NaHCO3, brine, and dried. The solvent was removed under reduced pressure, the crude residue was taken up in MeOH, cooled to 0° C., NaBH4 (30 mg) was added, the mixture was stirred for 15 min. The reaction was diluted with 1N HCl, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was taken up in THF (5 ml) and 4N HCl (5 ml) was added and stirred for 1 day. The reaction mixture was extracted with ethyl acetate, washed with brine, and concentrated. The crude product was purified by HPLC. Yield (6 mg). Mass (ES+ 447).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C(N(CC)CC)C.[CH2:20]=[C:21]([C:26](OS(F)(=O)=O)([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]>C(OCC)C>[CH2:20]=[C:21]([C:26]([O:8][C:7]1[C:6]([F:9])=[C:5]([F:10])[C:4]([F:11])=[C:3]([F:12])[C:2]=1[F:1])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C(F)(F)F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Pentafluorophenol (7.5 g, 0.040 mole) and triethylamine (4.5 g, 0.044 mole) in dry ethyl ether (7 ml) are added gradually to CH2═C(CF3)CF2OSO2F (11 g, 0.045 mole) in ethyl ether (14 ml) at 20° C. The reaction mixture is agitated at 20° C. for 30 minutes and washed in turn with water, dilute aqueous HCl, water, sodium bicarbonate solution, and water and the resulting ether solution is dried over MgSO4. Distillation of the dried mixture gives CH2═C(CF3)CF2OC6F5 (9.8 g, 73% yield, b.pt. 86–88° C. at 20 mm Hg).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:9](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>>[C:3]1([CH:2]2[CH2:12][CH:11]2[NH2:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:3]1([CH:2]2[CH2:1][CH:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)C1CC1c1ccccc1
Product: NC1CC1c1ccccc1

Procedure:
Generally, the trans isomer of 2-phenylcyclopropylamine is prepared by reacting styrene with ethyl diazoacetate and forming the ester, ethyl 2-phenylcyclopropanecarboxylate. The resulting ester is hydrolyzed to the 2-phenylcyclopropanecarboxylic acid. At this stage there are 3 to 4 parts of the trans isomer to 1 part of the cis isomer. A complete separation is accomplished by recrystallizing the acid from hot water. The pure trans isomer comes out as crystalline material while the cis isomer stays in solution. The trans 2-phenylcyclopropanecarboxylic acid is then reacted with thionyl chloride to form the acid chloride which is then successively treated with sodium azide and subjected to the curtius degradation. The isocyanate formed by this procedure is hydrolyzed readily to the (+) (-) 2-phenylcyclopropylamine.