Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1>C(O)C.[Pt].[H][H]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:9][CH:10]=1
Reactant: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CN1CCCC1Cc1ccc(N)cc1

Procedure:
Reduce 8.5 g of 1-methyl-2-(4-nitrobenzylidene)pyrrolidine in ethanol with platinum/hydrogen. Remove the catalyst and solvent and recrystallize from n-hexane to obtain 3.6 g (49% of theory) of title compound (m.p. 59° to 61°).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:18])C(C#N)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[C:23]([C:22]([OH:25])=[O:24])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Agent: Cl
Product: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Temperature: 120 °C
Yield: 45.7 %

Procedure:
Intermediate f (8.2 g, 0.035 mol) was added to a mixed solvent of glacial acetic acid (100 mL) and HCl (72 mL, 0.86 mmol). The mixture was warmed up to 120° C. and reacted under reflux for 4 h. The solvent was evaporated off. To the obtained fraction was added water (200 mL). The mixture was filtered by suction and dried to produce Intermediate g (3.7 g) in a yield of 45.7%.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[O:9][N:8]=1)C>Cl.C1COCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[O:9][N:8]=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[N:11]=2)=[CH:17][CH:16]=1
Reactant: CCOC(CCc1noc(-c2ccc(OC)cc2)n1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CCC=O)no2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3,3-diethoxypropyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole (1.0 g, 3.0 mmol) in 2N HCl (10 mL) and THF (10 mL) was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc (3×). The organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give the desired product. LCMS calculated for C12H13N2O3 (M+H): 233.1. found: 233.1.
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[CH:22]1(B(O)O)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1.O.CCOC(C)=O.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>[CH:22]1([C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
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: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a stirred solution of compound (iii) (3 g, 10.9 mmol) in toluene (75 mL) was added a solution of sodium carbonate (2.29 g, 21.8 mmol) in water (15 mL) and the mixture was purged with nitrogen for 10 min. Cyclopropyl boronic acid (1.4 g, 16.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) were added and the reaction mixture was heated at reflux for 6 h (monitored by TLC). The reaction was then cooled to RT and diluted with EtOAc. The aqueous and organic layers were separated. Concentration of the solvent gave the crude product which was purified by column chromatography to give 5-cyclopropyl-2,4-dinitrobenzaldehyde (iv) (2 g, 78%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2ccc3ccccc3n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccc3ccccc3n2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.51 g), sodium hydrogen carbonate (0.75 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(quinolin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.49 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL), N,N′-carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.20 g, 38%).
Reaction SMILES: O1CCC[CH2:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:10]#[N:11].CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([CH3:2])[C:14]=1[O:15][CH3:16])[C:10]#[N:11]
Reactant: COc1cc(C#N)cc(Br)c1OC
Reactant: C1CCOC1
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C#N)cc(C)c1OC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
50 mg [1,1″-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) and 5 mL tetrahydrofuran was stirred for 10 min at ambient temperature before 500 mg 3-bromo-4,5 dimethoxybenzonitrile, 0.1 mL trimethylboroxine and 0.85 g cesium carbonate as a solution in 1 mL water were added. The suspension was stirred at 100° C. for 4 h and then diluted with water and ethyl acetate. The phases were separated and the water phase was extracted with additional ethyl acetate (×2). The organic phases were combined, dried over magnesium sulfate and concentrated. The residue was purified with silica gel chromatography (SiO2:cyclohexane/ethyl acetate 9:1 to 7:3) to provide 4.17.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][C:5](=[O:21])[N:6]2[C:12]=1[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[O:9][C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]2=1.[H][H].F[C:25]1[CH:26]=[C:27]([Cl:31])[CH:28]=[CH:29][CH:30]=1>O.CN(C)C=O>[Cl:31][C:27]1[CH:26]=[C:25]([N:4]2[C:5](=[O:21])[N:6]3[C:7]4[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=4[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[C:12]3=[N:3]2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=c1[nH]nc2n1-c1ccccc1Oc1ccccc1-2
Reactant: [H][H]
Reactant: Fc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(-c2cccc(Cl)c2)nc2n1-c1ccccc1Oc1ccccc1-2
Reaction time: 3 h

Procedure:
To a stirred suspension of 1.12 g. (0.025 mole) of a 57% mineral oil dispersion of sodium hydride in 20 ml. of dry dimethylformamide is added a solution of 4.25 g. (0.017 mole) of dibenzo[b,f][1,2,4]triazolo[4,3-d][1,4]-oxazepin-3(2H)-one in 10 ml. of dry dimethylformamide at a rate so as to maintain the temperature of the reaction mixture at Ca. 32°-35° and to maintain a steady evolution of H2. After the addition is complete, the mixture is heated to about 50° until the evolution of hydrogen ceases. 2.76 g. (0.021 mole) of 3-fluoro-chlorobenzene is added to the reaction mixture at a rate so as to maintain a temperature of 50°-60°. After the addition is complete, the reaction mixture is stirred at 60°-70° for 3 hours and then at 35° for an additional 12 hours. The reaction mixture is cooled, diluted with a large excess of water and extracted with methylene chloride. The solvent is evaporated to give the crude title compound which is purified by chromatography as described in Example 1c.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[OH:1][CH:3]([CH2:4][NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Reactant: CC(C)(C)N
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)(C)C)cc3)n(C)c(=O)c2c1

Procedure:
1.7 gm (5 mmols) of the epoxide obtained in (a) were heated in a steel cylinder with 17 ml of tert. butylamine at 120° C. for 3 hours. Thereafter, the excess amine was distilled off in vacuo, and the oily residue was recrystallized from acetone/ether.
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][CH:14]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:15][CH2:16][O:17][CH2:18][C:19]#N.CC[O:29]CC>>[CH3:13][CH:14]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:15][CH2:16][O:17][CH2:18][C:19]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[O:29]
Reactant: CC(C)=CCCC(C)CCOCC#N
Reactant: CCOCC
Reactant: Brc1ccc2ccccc2c1
Agent: [Mg]
Product: CC(C)=CCCC(C)CCOCC(=O)c1ccc2ccccc2c1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.24 g of magnesium in ether, a solution of 19.09 g 2-bromonaphthalene in 80 ml of ether was dropped. The mixture was heated to reflux. After refluxing for one hour, the mixture was cooled to 0-5° C. and a solution of 15.00 g (3,7-dimethyl-oct-6-enyloxy)-acetonitrile (Kulka, K. et al., Perfumer & Flavorist Vol. 3 (1978), p.39) in 20 ml of ether was dropped in at this temperature. After stirring at room temperature for 3 hours, the mixture was quenched with water and aqueous sulfuric acid. After extracting with ether, the combined organic phases were washed with saturated sodium bicarbonate and water, dried, filtered, and evaporated to dryness. The resulting dark oil was purified by chromatography to yield 15.22 g of a yellow oil.
Reaction SMILES: CN(C)[CH:3]=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[NH2:23][CH2:24][CH:25]([C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([NH2:34])=[C:29]([Cl:35])[CH:28]=1)[OH:26]>C(OCC)(=O)C.CO.C(N(CC)CC)C>[C:3]([OH:4])(=[O:26])/[CH:17]=[CH:16]/[C:15]([OH:14])=[O:22].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:23][CH2:24][CH:25]([C:27]1[CH:28]=[C:29]([Cl:35])[C:30]([NH2:34])=[C:31]([Cl:33])[CH:32]=1)[OH:26].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:23][CH2:24][CH:25]([OH:26])[C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([NH2:34])=[C:29]([Cl:35])[CH:28]=1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=C(CCCCCBr)OCCc1ccccn1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1c(Cl)cc(C(O)CNCCCCCC(=O)OCCc2ccccn2)cc1Cl
Product: O=C(O)/C=C/C(=O)O

Procedure:
According to method I (dimethylformamide, 1 hour at 90° C.) from {2-(2-pyridyl)ethyl}6-bromohexanoate and 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol. Working up by means of chromatography (ethyl acetate/methanol/triethylamine 20:2:1). Recrystallized as the hemifumarate from acetone. Melting point: 75°-76° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H](C(O)=O)CC(C)C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:21]1[CH2:26][CH2:25][O:24]CC1.[CH2:27](OC(Cl)=O)[CH:28]([CH3:30])[CH3:29].N.CO>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C:25](=[O:24])[C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:21])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(phenylmethoxy)carbonyl]-L-leucine (3 g., 11.3 mmol.) in 60 mL of methylene chloride at -20° under argon was added N-methylmorpholine (1.24 mL, 11.3 mmol.) followed by isobutylchloroformate (1.47 mL, 11.3 mmol.). The resulting suspension was stirred at -20° C. for 15 minutes at which time a solution of ammonia/methanol (about 5.6M, 20 mL, 113 mmol.) was added. After 30 minutes at -20° C., the reaction was quenched with water and warmed to room temperature. The layers were separated and the aqueous layer was extracted with methylene chloride (2×). The combined organic extracts were dried (MgSO4) and evaporated to give 2.82 g. of the title A compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[H-].[Na+].[Br:11][C:12]1[S:16][C:15]([C:17](O)=[O:18])=[CH:14][CH:13]=1.C(Cl)(=O)C(Cl)=O>CN(C=O)C.C(Cl)Cl>[Br:11][C:12]1[S:16][C:15]([C:17]([NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])=[O:18])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cc1cnccc1N
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnccc1NC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of 3-methylpyridine-4-amine (1.23 g, 11.37 mmol, 1.2 eq) in DMF (5 mL) at 0° C. was added solid sodium hydride (60% suspension in mineral oil, 0.44 g, 18.49 mmol, 2.0 eq) and stirred for 1 h at room temperature. In a separate flask, to a solution of 5-bromothiophene-2-carboxylic acid (1.91 g, 9.25 mmol, 1.0 eq) in DCM (10 mL) was added oxalyl chloride (4.0 mL, 46.2 mmol, 5.0 eq) at 0° C. and then stirred at the same temperature for 2 h. The solvent and excess of oxalyl chloride were removed by evaporation under vacuum. The residue was dissolved in DMF (2 mL) and added to the above mixture at 0° C. and the resulting mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction followed by ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and purified by column chromatography (silica gel, DCM:MeOH system) to afford 1.0 g of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.39 (d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.05 (d, J=5.5 Hz, 1H), 7.87 (s, 1H, D2O exchangeable), 7.40 (d, J=4.0 Hz, 1H), 7.09 (d, J=4.0 Hz, 1H), 2.29 (s, 3H); ESI-MS (m/z) 297, 299 [(MH)+ Br79,81].
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](O)(=O)[CH3:17]>O1CCCC1.C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH2:16][CH3:17])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.1 g of 3-phenoxybenzaldehyde in 23 ml of an anhydrous tetrahydrofuran is added dropwise to 60 ml of 3-N-ethylmagnesium bromide in ethyl ether, cooled in an ice bath under a nitrogen atmosphere, over a period of about 11/2 hours. The reaction mixture is stirred overnight and warmed to room temperature, after which time it is poured over ice containing 12 ml of acetic acid. The organic and aqueous phases are separated and the aqueous phases extracted twice with ethyl ether. The ethereal extracts are combined and washed with a solution prepared from 3 g of sodium carbonate and 40 ml of water. The aqueous wash layers are extracted further with ethyl ether and the combined ethereal extracts are dried over anhydrous sodium sulfate and filtered. The ether is removed under reduced pressure to yield 29.45 g of 1-(3-phenoxyphenyl)propan-1-ol.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>O>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])#[N:2]
Reactant: COC(=O)CCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCCCC#N
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
7.5 g (154 mmol) of sodium cyanide was added to 80 mL of dimethyl sulfoxide, and dissolved therein under heat at 90° C. 25.0 g (128 mmol) of methyl 5-bromovalerate was dropwise added to the solution at an inner temperature of 130° C. or lower, and stirred at 100° C. for 2 hours. After cooled to room temperature, 50 mL of water was added to this, which was then extracted with 60 mL of ethyl acetate. The organic layer was dried with magnesium sulfate, and the solvent was evaporated away under reduced pressure to give 18.0 g (yield 99%) of methyl 5-cyanovalerate.
Reaction SMILES: [C:1]12([C:11](=[O:12])OC(C)(C)[O:6][C:4]1=[O:5])[CH2:3][CH2:2]2.Cl.[CH3:14][O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18].C(N(CC)CC)C.S(=O)(=O)(O)O>CN(C=O)C.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([N:18]1[CH2:2][CH2:3][CH:1]([C:4]([OH:6])=[O:5])[C:11]1=[O:12])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N1CCC(C(=O)O)C1=O
Temperature: 25 °C

Procedure:
2(S)(3-carboxy-2-oxo-1-pyrrolidinyl)-4-methyl pentanoic acid methyl ester was prepared according to the method of R. M. Freidinger, J.Org.Chem., 1985, 50 (19):3631-3633. A solution of isopropylidene cyclopropane-1,1-dicarboxylate (5.0 g, 29.30 mmol), leucine methyl ester hydrochloride (5.31 g, 29.3 mmol), and triethylamine (2.97 g, 29.3 mmol) in degassed DMF (50 mL) was heated at 65° C. for 1 hour. The solution was cooled to ambient temperature and poured into a mixture of 10% aqueous sulfuric acid (H2SO4) (100 mL) and ethyl acetate (100 mL). The organic layer was separated. After drying with Na2SO4, the solvent was removed in vacuo to yield 7.55 g of a brown oil. To the crude oil (7.55 g) in degassed DMF (50 mL) were added 3-(dimethylaminomethyl)indole (gramine) methiodide (13.2 g, 42.94 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5.16 g, 33.90 mmol). The mixture was heated at 85° C. for 18 hours and cooled to ambient temperature. The mixture was poured into ethyl acetate (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous phase was separated, acidified to pH 3-4 with 10% aqueous H2SO4, and extracted with ethyl acetate (3×). After drying with Na2SO4, the solvent was removed in vacuo and the residue chromatographed (eluting with 1% acetic acid/ethyl acetate) to yield 1.56 g of the title compound as a white solid; MS(FAB+) m/e 387 (M+H)+. 1H NMR(DMSO-d6, 300 MHz) δ0.65 (m, 6H), 1.23-1.80 (m, 3H), 1.90 (m, 1H), 2.12 (m, 1H), 2.77-3.48 (m, 6H), 3.51 (m, 3H), 4.98 (m, 1H), 6.92 (m, 3 H), 7.28 (d, 1H), 7.97 (d, 1H), 10.90 (br s, 1H), 12.70 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)CCC2)cc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CCC2)cc1
Yield: 85.5 %

Procedure:
Following a synthetic procedure which was similar to the one outlined in Step 3 of Example 1, 270 mg (0.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylsulfonyl)benzene (Step 1) was reacted with 300 mg (1.8 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1). Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (4:1) gave 265 mg (86%) of 1-[2-(4-methylthiophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene as a colorless solid: mp 138°-139° C.; NMR (CDCl3) d 2.08 (m, J=7 Hz, 2H), 2.47 (s, 3H), 2.90 (t, J=7 Hz, 4H), 3.04 (s, 3H), 7.06 (d, J=8 Hz, 2H), 7.11 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H); MS (EI) m/e (rel intensity) 344 (100), 297 (4), 218 (33); HRMS. Calc'd for C19H20O2S2 : 344.0905. Found: 344.0907. Anal. Calc'd for C19H20O2S2 : C, 66.24; H, 5.85; S, 18.16. Found: C, 66.28; H, 5.81; S, 18.95.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:10][C@@H:9]1[CH2:20][CH2:21][CH2:22][CH3:23])=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:38]([C:40]1[CH:53]=[CH:52][C:43]([CH2:44][N:45]2[C:49](C=O)=[CH:48][N:47]=[CH:46]2)=[CH:42][CH:41]=1)#[N:39].C(=O)(O)[O-].[Na+].C(Cl)[Cl:60]>FC(F)(F)C(O)=O>[ClH:60].[ClH:60].[CH2:20]([C@H:9]1[CH2:10][N:11]([CH2:15][C:16]([F:17])([F:18])[F:19])[C:12](=[O:14])[CH2:13][N:8]1[CH2:6][C:49]1[N:45]([CH2:44][C:43]2[CH:52]=[CH:53][C:40]([C:38]#[N:39])=[CH:41][CH:42]=2)[CH:46]=[N:47][CH:48]=1)[CH2:21][CH2:22][CH3:23]
Reactant: ClCCl
Reactant: CCCC[C@H]1CN(CC(F)(F)F)C(=O)CN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H]1CN(CC(F)(F)F)C(=O)CN1Cc1cncn1Cc1ccc(C#N)cc1
Product: Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of the product from Step D (0.578 g, 1.71 mmol) was stirred in 30% trifluoroacetic acid in methylene chloride for 1 h. The volatiles were removed in vacuo, and the residue dissolved in dichloroethane (5 mL). The pH was adjusted to 5-6 with N-methylmorpholine. Sodium triacetoxyborohydride (0.544 g, 2.57 mmol) and 1-(4-cyanobenzyl)imidazolyl-5-carboxaldehyde from Step I (0.361 g, 1.71 mmol) was added. The reaction was stirred overnight at 20° C. then poured into saturated sodium bicarbonate solution. The organic phase was washed with saturated brine and dried over magnesium sulfate. The crude product was purified by preparative HPLC on a 40×100 mm Waters PrepPak® reverse phase HPLC column (Delta-Pak™ C18 15 μm, 100 Å) using a gradient elution of 25% (0.1% TFA in acetonitrile), 75% (0.1% TFA in water) progressing to 45% (0.1% TFA in acetonitrile), 55% (0.1% TFA in water) over 50 min. Pure fractions were combined, concentrated, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate. The purified product was converted to the hydrochloride salt with HCl in dichloromethane. The title compound was obtained as a white solid. FAB ms (m+1) 434. Anal. Calc. for C22H26F3N5O·2.0 HCl: C, 52.18; H, 5.57; N, 13.83. Found: C, 52.41; H, 5.60; N, 13.65.