Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:5].[OH2:17].[OH-].[Na+]>CO>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]1[CH2:8][CH:6]1[C:4]([OH:17])=[O:5]
Reactant: CON(C)C(=O)C1CC1c1ccccc1F
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1ccccc1F
Temperature: 25 °C

Procedure:
A mixture of 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (8.92 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7 g).
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]([CH3:15])=[N:11][NH:12][C:13]=1[CH3:14]>O.C(O)C>[ClH:5].[Cl:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]([CH3:14])=[N:12][N:11]([C:2]([NH2:3])=[NH:1])[C:10]=1[CH3:15]
Reactant: N#CN
Reactant: Cc1n[nH]c(C)c1CCCCl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(C(=N)N)c(C)c1CCCCl
Temperature: 80 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
A solution of 0.17 g of cyanamide in 0.3 ml of water was added to a solution of 0.46 g of 4-(3-chloropropyl)-3,5-dimethyl-1H-pyrazole hydrochloride in 5 ml of ethanol, and the reaction mixture was stirred for one day at 80° C. the solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from isopropanol-diisopropylether to obtain 0.13 g of 4-(3-chloropropyl)-3,5-dimethyl-1H-pyrazole-1-carboxamidine hydrochloride.
Reaction SMILES: O.[CH3:2][C:3]1[C:4]([CH2:15][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].ClC1C=CC=C(C(OO)=[O:34])C=1.C(N(CC)CC)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN1CCCC1=O.O>[CH3:2][C:3]1[C:4]([CH2:15][S:16]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:34])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:13])([F:12])[F:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 2.5 °C
Yield: 105.7 %

Procedure:
20 g (0.0538 mole) of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole hydrate was dissolved at room temperature in 60 ml of 1-methyl-2-pyrrolidone (NMP) and the reaction mixture was cooled to a temperature of from 0 to 5° C. 12.07 g (0.070 mole) of 3-chloroperbenzoic acid were suspended (optionally per partes) and the reaction was carried out at a temperature of from 0 to 10° C. for half an hour, then at 10-15° C. until the reaction was completed. At the end of the reaction 0.5 ml of triethylamine and a solution of 11.36 g sodium thiosulphate pentahydrate in 12 ml of water were added. The product was precipitated with water (120 ml at 20±5° C.) and filtered off to obtain 21 g of wet lansoprazole.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:34]([O:38][C:39]([NH:41][C:42](N1C=CC=N1)=[N:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]/[C:42](/[NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])=[N:43]/[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
2-(Acetylamino)-4-[2-(4-aminophenyl)ethyl]-1,3-thiazole-5-carboxylic acid (106 mg) was suspended in THF (2 ml) under N2 atmosphere. Bis(trimethylsilyl)acetamide (0.253 ml) was added to the suspension at r.t., and the mixture was stirred at r.t. for 15 minutes. Then, N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (119 mg) was added to the solution at r.t. The reaction mixture was stirred at r.t. for 20 hours, and concentrated in vacuo. The residue was dissolved in CHCl3. The organic solution was washed with 1N-HCl, water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was washed with ethyl ether to give 2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino](tert-butoxycarbonyl)iminomethyl}amino)phenyl]ethyl}-1,3-thiazole-5-carboxylic acid (115.8 mg) as a pale brown solid.
Reaction SMILES: Cl.C(=[N:15][C:16]1[CH:17]=[C:18]([C:22]2([CH3:32])[N:27]=[C:26]([NH2:28])[CH2:25][N:24]3[N:29]=[CH:30][CH:31]=[C:23]23)[CH:19]=[CH:20][CH:21]=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>O.C(O)(C)C>[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2([CH3:32])[N:27]=[C:26]([NH2:28])[CH2:25][N:24]3[N:29]=[CH:30][CH:31]=[C:23]23)[CH:19]=[CH:20][CH:21]=1
Reactant: CC1(c2cccc(N=C(c3ccccc3)c3ccccc3)c2)N=C(N)Cn2nccc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: CC1(c2cccc(N)c2)N=C(N)Cn2nccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Hydrochloric acid 37% in H2O (0.14 mL) was added to a solution of rac-4-[3-(benzhydrylidene-amino)-phenyl]-4-methyl-4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine (0.37 g, 0.9 mmol) in isopropanol (10 mL). The mixture was stirred at room temperature for 3 hours. Et2O was added and the mixture was stirred for 15 minutes. The solid precipitated was filtered, washed with Et2O and dried in vacuo. The residue was suspended in DCM and washed with NaHCO3 (aq. sat. solution). The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield (0.21 g, 97% yield) as a white solid which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:13](O)[CH3:14]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:13]([C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6])=[CH2:14]
Reactant: COc1c(Br)ccc(F)c1C#N
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(F)c(C#N)c1OC

Procedure:
3-bromo-6-fluoro-2-methoxybenzonitrile (4.40 g, 19.1 mmol), potassium vinyl trifluoroborate (5.12 g, 38.3 mmol), PdCl2(dppf)-CH2Cl2 Adduct (0.7 g, 1 mmol) and TEA (5.33 mL, 38.3 mmol) were added to 80 mL ethanol in a 200 mL flask. The reaction mixture was degassed and heated to reflux for 4 h. The reaction mixture was cooled and then most of the ETOH was removed. The residue was diluted with ethyl acetate. The mixture was washed with brine twice. The organic layer was separated and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified thru a 330 g RediSep column and eluted with 10% ETOAc/hexane solvent system to yield the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[CH3:26]O>>[F:12][C:13]1[CH:18]=[C:17]2[C:16](=[CH:15][CH:14]=1)[NH:19][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:26])=[O:9])[CH2:4][C:3]2=1
Reactant: NNc1ccc(F)cc1
Reactant: CO
Reactant: O=C1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 120 °C
Yield: 100 %

Procedure:
A stirred mixture of 96.2 mg (0.68 mmol) of 4-oxocyclohexanecarboxylic acid, 100 mg (0.62 mmol) of (4-fluorophenyl)hydrazine hydrochloride, 3 mL of methanol and 80 μL of concentrated sulfuric acid in a 5 mL microwave process vial was heated for 10 min at 120° C. under argon in a microwave. The alcoholic solution was concentrated to about one-third of the original volume and then externally cooled (ice bath). An off-white product precipitate formed, which could be filtered off and thereby was carefully washed with a little cold water. Alternatively the reaction mixture was poured onto chopped ice and water and the precipitate collected by filtration to afford the title compound in 100% yield (152 mg). C14H14FNO2, Mr=247.26; 1H NMR (400 MHz, DMSO-d6) d: 1.84-1.92 (m, 1H), 2.16-2.20 (m, 1H), 2.66-2.85 (m, 4H), 2.90 (dd, J=4.8/14.6 Hz, 1H), 3.65 (s, 3H), 6.80 (td, J=2.8/9.2 Hz, 1H), 7.10 (dd, J=2.8/10.0 Hz, 1H), 7.20 (dd, J=4.6/8.6 Hz, 1H) 10.80 (bs, 1H); LCMS (ESI) tR: 2.54 min (>99%, UV254, ELSD), m/z: 248.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=4)[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccc(C(F)(F)F)c3)CC12
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 3-(trifluoromethyl)phenylacetic acid (1.43 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(3-(trifluoromethyl)phenyl)acetyl]-4-perhydroisoindolone (2 g) is obtained in the form of white crystals melting at 184° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:5]([CH3:15])=[N:6][CH:7]=[C:8]([CH:14]=1)[C:9]([O:11]CC)=[O:10]>C(O)C>[Br:3][C:4]1[C:5]([CH3:15])=[N:6][CH:7]=[C:8]([CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1cnc(C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C(=O)O)cc1Br
Reaction time: 3 h
Yield: 43.6 %

Procedure:
2M Aqueous sodium hydroxide solution (1.91 mL, 3.8 mmol) was added to a stirred solution of ethyl 5-bromo-6-methylnicotinate (preparation 47c, 0.41 g, 1.7 mmol) in ethanol (14 mL) at room temperature. After 3 hours, the solvent was evaporated and water was added to the residue. The pH was adjusted to 4-5 with concentrated hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated to give the title compound (0.16 g, 43%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][CH2:29][CH2:30][CH2:31][NH2:32]>C(O)(C)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:22]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(C)c1NCCCN
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NCCCNCC(O)COc1ccc(OCc2ccccc2)cc1

Procedure:
4.23 g. 4-Benzyloxyphenyl glycidyl ether, 5.9 g. N-(2,6-dimethylphenyl)-1,3-diaminopropane and 5 ml. isopropyl alcohol are stirred for 24 hours at ambient temperature. The reaction mixture is worked up by chromatography on silica gel.
Reaction SMILES: I[CH3:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15](=[S:28])[NH:14][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1.[OH-].[NH4+]>O.C(O)C.C(Cl)(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:15]([S:28][CH3:2])=[N:14][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CSc1nc2cnc3cc(Br)ccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Iodomethane (0.89 mL, 14 mmol) was added to a suspension of tert-butyl 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (4 g, 9 mmol) in deionized water (25 mL), ethanol (25 mL), and ammonium hydroxide (5 mL), and the reaction was stirred for two hours at room temperature and then diluted with chloroform and water. The aqueous layer was separated and extracted four times with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was dried under high vacuum to provide 2.7 g of tert-butyl 3-(7-bromo-2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: Cc1onc(-c2ccncn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a solution of (5-methyl-3-pyrimidin-4-yl-isoxazol-4-yl)-methanol (313 mg, 1.63 mmol) in THF (20 mL) was added methyl 6-hydroxynicotinate (276 mg, 1.8 mmol) and triphenylphosphine (644 mg, 2.5 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (−40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (95 mg, 18%) as a white solid. MS: m/e=327.3 [M+H]+.
Reaction SMILES: C(OC1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Se:13][C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)=[CH:7][CH:6]=1)(=O)C.[C:28](=[O:31])([O-])[O-].[K+].[K+].[CH2:34](OCC)C.O>CO>[CH3:34][C:23]1[C:14]([Se:13][C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:28]([OH:31])=[CH:6][CH:7]=2)=[CH:15][C:16]2[C:17]([CH3:27])([CH3:26])[CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]=2[CH:22]=1
Reactant: CCOCC
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Oc1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1[Se]C#Cc1ccc(O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A mixture of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)phenyl acetate (500 mg, 1.1 mmol) and potassium carbonate (160 mg, 1.1 mmol) in methanol (20 ml) is stirred for 24 h at room temperature and is then treated with ethyl ether and water. The organic phase is washed twice with water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified on a column of silica (ethyl acetate 20/heptane 80). 300 mg (66%) of a clear oil are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[N:23]([C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]=[O:25]>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:28]1[CH:34]=[CH:35][CH:36]=[C:26]([NH:23][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=3[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=2)=[O:25])[CH:27]=1)[CH3:33]
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: CCCc1c(OCc2ccc(N)cc2)ccc(C(C)=O)c1O
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(NC(=O)Nc3cccc(C(=O)OCC)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-[4-(4-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (980 mg, 30% pure by LC-MS) in anhydrous CH2Cl2 (4 mL) is added ethyl 3-isocyanatobenzoate (0.18 mL) at room temperature under Ar gas. The reaction mixture is stirred at room temperature overnight. The resulting white precipitate is filtered to give the title compound (215 mg). LC-MS (m/e): 491 (M+1).
Reaction SMILES: C([C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:15])[CH:10]=2)[N:5]=1)(O)=O>C(Cl)(Cl)Cl>[Br:15][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:13]=[C:12]2[OH:14]
Reactant: O=C(O)c1cc(O)c2cc(Br)ccc2n1
Solvent: ClC(Cl)Cl
Product: Oc1ccnc2ccc(Br)cc12

Procedure:
The 2-carboxy-4-hydroxy-6-bromoquinoline (5.42 g, 20 mmol) was slurried in 250 ml of light mineral oil and heated to 270°-295° C. for 10-15 minutes. The mixture was allowed to cool overnight, diluted with chloroform and filtered, and then washed with adequate amounts of chloroform, yielding 6-bromo-4-hydroxyquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C:16](=[O:21])[CH2:17][CH2:18]OC)[CH2:13][C:12]2=[O:22])[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[OH:21][CH:16]([C@H:14]1[CH2:15][N:11]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:10])[C:12](=[O:22])[CH2:13]1)[CH2:17][CH3:18]
Reactant: COCCC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-(3-methoxypropanoyl)pyrrolidin-2-one 1.20 (12 g, 39.30 mmol, 1.00 equiv), ethanol (100 mL), followed by the addition of NaBH4 (3.35 g, 88.16 mmol, 2.50 equiv) in several batches with stifling at 0° C. The resulting solution was stirred at 0° C. for 2 h, quenched by the addition of 100 mL of water/ice and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane: methanol (200:1-80:1) to afford (4R)-4-(1-hydroxypropyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one as a mixture of diastereomers. The diastereomers were separated by chiral HPLC (CHIRALPAK IC), and the later eluting diastereomer was collected to afford (R)-4-((R)-1-hydroxy-3-methoxypropyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.21. This compound is the later eluting diastereomer under RP-HPLC conditions (Gemini column, water/acetonitrile/TFA).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1.Br[C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=1[CH3:29]>>[CH3:29][C:23]1[CH:24]=[C:25]([C:27]#[N:28])[S:26][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1(c2ccccc2)OCC(=O)Nc2ccc(Br)cc21
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2

Procedure:
Prepared from 7-bromo-5-methyl-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methyl-thiophene-2-carbonitrile using the coupling procedures of examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.15 (s, 1H), 7.85 (s, 1H), 7.49 (m, 1H), 7.38-7.21 (m, 7H), 4.29 (d, J=15.19 Hz, 1H), 4.04 (d, J=15.05 Hz, 1H), 2.22, (s, 3H), 1.93 (s, 3H); MS (ES) m/z 375 ([M+H]+, 100%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]O)[C:6]=1[O:13][CH2:14][CH2:15][F:16].P(Br)(Br)[Br:18]>C(OCC)C>[Br:18][CH2:11][C:7]1[C:6]([O:13][CH2:14][CH2:15][F:16])=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:10]=[CH:9][CH:8]=1
Reactant: OCc1cccc(OCCF)c1OCCF
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: FCCOc1cccc(CBr)c1OCCF
Yield: 243.5 %

Procedure:
In a manner similar to that described by Noller et al. (Organic Synthesis, Vol. II. p 358-360), 2.0 grams (0.086 mole) of 1,2-di(2-fluoroethoxy)-3-hydroxymethylbenzene and 1.1 ml (0.0032 mole) of phosphorus tribromide were reacted in 90 ml of cold (0° C.) diethyl ether. The reaction mixture was partitioned between water and diethyl ether. The organic phase was washed with an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 2.3 grams of 3-bromomethyl-1,2-di(2fluoroethoxy)benzene as a solid, mp 99°-100° C.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:15]([C:17]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20])[CH3:16]>>[CH2:15]([C:17]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:18]=1[C:19]([NH:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:20])[CH3:16]
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=369.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-ethyl-4-(trifluoromethyl)-benzoic acid (CAS 854531-63-8).
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:14](Br)[CH:15]=C.[CH2:18](Cl)Cl.CCCCCC>CN(C=O)C>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=[CH:7][C:8]=1[O:13][CH3:18])[CH:14]=[CH2:15]
Reactant: ClCCl
Reactant: C=CCBr
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCOc1cc([N+](=O)[O-])ccc1OC
Temperature: 65 °C

Procedure:
97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolved in one liter of DMF and 1.5 equivalentsof allyl bromide added. The reaction was heated to 65° C. for two hours, after which time much of the dark color had discharged and tic (1:1 CH2Cl2/hexane) indicated loss of starting material. The solvent was concentrated in vacuum and the residue washed with water. The product was isolated by filtration and dried in a vacuum. This gave 112 g of pale yellow solid. A sample recrystallized from methanol, gave m.p. 93-94° C.