Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:43]=[CH:42][C:16]([CH2:17]/[C:18](=[C:23](\[C@H:28]2[CH2:33][CH2:32][C@@H:31]([O:34][Si](C(C)(C)C)(C)C)[CH2:30][CH2:29]2)/[C:24]([O:26][CH3:27])=[O:25])/[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1)=O)(C)(C)C>C(O)C>[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17]/[C:18](=[C:23](\[C@H:28]2[CH2:33][CH2:32][C@@H:31]([OH:34])[CH2:30][CH2:29]2)/[C:24]([O:26][CH3:27])=[O:25])/[C:19]([O:21][CH3:22])=[O:20])=[CH:42][CH:43]=1
Reactant: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: COC(=O)/C(Cc1ccc(OCCN)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O)CC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Concentrated hydrochloric acid (catalytic amount) was added to a solution of dimethyl 2-(4-(2-((tert-butoxycarbonyl)amino)ethoxy)benzyl)-3-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)maleate (20 mg, 0.033 mmol) in ethanol (1.0 ml) at room temperature, and the mixture was stirred at 50° C. for 15 hr. This mixture was concentrated, and sodium bicarbonate water was added to the residue, followed by extraction with dichloromethane. The organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The residue was chromatographed on silica gel column (methanol:dichloromethane=1:9) to give the title compound as an oil (10 mg, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[CH:16]=[CH:15][CH:14]=1)[CH3:12].[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[C:25]=1[NH2:26])[CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19](=[N:26][C:25]2[C:27]([CH2:31][CH3:32])=[CH:28][CH:29]=[CH:30][C:24]=2[CH2:22][CH3:23])[CH3:20])[N:18]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Reactant: CCc1cccc(CC)c1N
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Yield: 12.1 %

Procedure:
1.00 g of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)-ethyl]pyridin-2-yl}ethanone (3.3 mol), 0.99 g of 2,6-diethylaniline (6.6 mmol) and 1.0 g of Sicapent were heated under reflux under argon in 50 ml of tetrahydrofuran for 2 h. A further portion of Sicapent (0.5 g) was added and the mixture was heated under reflux under argon for a further 1.5 h. A further portion of Sicapent (0.5 g) and 0.50 g of 2,6-diethylaniline (3.3 mmol) were added and the mixture was heated under reflux under argon for a further 15 h and then cooled to room temperature. The reaction mixture was filtered and the residue on the filter was washed with 10 ml of tetrahydrofuran. The filtrate was topped up to 125 ml with tetrahydrofuran, 4 g of Sicapent were added and the mixture was heated again under reflux under argon for 2.5 h and then cooled to room temperature. It was filtered and the residue on the filter was washed with 10 ml of tetrahydrofuran. The solvent was then distilled off completely and the residue was stirred with 10 ml of methanol. The precipitate formed was filtered off and washed twice with methanol. After drying in vacuo, 0.36 g (0.8 mmol) of 2-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-6-[1-(2,6-diethylphenylimino)ethyl]pyridine was obtained in a yield of 25%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:29]1([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:8]34[CH2:13][CH2:12][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:14][CH2:15]3)[CH2:10][O:9]4)[CH:5]=[CH:6][CH:7]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(O)COCCC12CCC(c3cccc(OCC4CCC4)c3)(CC1)OC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A mixture of tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (7F; 15 mg, 0.041 mmol), (bromomethyl)cyclobutane (9.25 mg, 0.062 mmol) and Cs2CO3 (41 mg, 0.124 mmol) in MeCN (1.0 mL) was heated to ˜60° C. for 10 h. The reaction was then cooled to rt, filtered and the filtrates were concentrated in vacuo. The crude alkylated phenol ester product was dissolved in THF/MeOH (1 mL of a 1:1 mixture) and aq. NaOH (90 μL of a 1 N solution, 0.090 mmol) and the mixture was stirred at rt for 3 h, then was concentrated in vacuo. The residue was dissolved in EtOAc (3 mL) and washed with 1 N aq. HCl, water, brine, then dried (MgSO4), and concentrated in vacuo. The crude product was purified by preparative HPLC/MS (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:water with 0.1% HCO2H; Mobile Phase B: 95:5 MeCN:water with 0.1% HCO2H; Gradient: 45-85% B over 20 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (7.7 mg, 67% yield; 99% purity by LC/MS) as a light yellow oil. LCMS [M−H]−=373; 1H NMR (500 MHz, DMSO-d6) δ 7.18 (t, J=8.3 Hz, 1H), 6.97-6.86 (m, 2H), 6.75 (dd, J=8.1, 1.2 Hz, 1H), 3.95 (s, 2H), 3.92 (d, J=6.6 Hz, 2H), 3.77 (s, 2H), 3.53-3.48 (m, 2H), 2.74-2.65 (m, 1H), 2.14-1.98 (m, 4H), 1.97-1.74 (m, 6H), 1.72-1.58 (m, 4H), 1.41 (t, J=6.6 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:56]([O:60][CH3:61])(=[O:59])[CH:57]=[CH2:58]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C)C=O>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2](/[CH:58]=[CH:57]/[C:56]([O:60][CH3:61])=[O:59])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CC(=O)OC
Reactant: COc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)c(OC)c1
Temperature: 115 °C
Reaction time: 15 h
Yield: 85.5 %

Procedure:
To a 2 ml N,N-dimethylformamide solution of 150 mg (0.36 mmol) of the compound obtained in Example 15, 8 mg (0.036 mmol) of palladium acetate, 22 mg (0.072 mmol) of tri-o-tolylphosphine, 0.15 ml (1.08 mmol) of triethylamine, and 97 μl (1.08 mmol) of methyl acrylate were added, and the mixture was stirred at 115° C. in a sealed tube for 15 hours. Then, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 130 mg (85%) of the captioned compound.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([OH:23])[CH2:20][NH:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(Cl)Cl.[C:28](Cl)(=[O:30])[CH3:29]>C(N(CC)CC)C>[C:28]([N:21]([CH3:22])[CH2:20][CH:19]([OH:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:30])[CH3:29]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CNC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOCC(O)CN(C)C(C)=O
Reaction time: 8 h

Procedure:
5 g of 1-hexadecyloxy-3-methylamino-propan-2-ol are dissolved in 30 cc. of anhydrous chloroform. At first 3 g of triethylamine and separately thereafter 2.4 g of acetylchloride are added dropwise with cooling and the mixture is stirred for 8 hours. The chloroform solution is washed with 2% hydrochloric acid and water, is evaporated and the residue is dissolved in 100 cc. of methanol. A solution of 0.6 g of sodium hydroxide in a little methanol is added to the methanol solution and the mixture is stirred at room temperature for one hour. The solvent is evaporated in a vacuo and the residue is triturated in chloroform. The chloroform solution is washed with 2% hydrochloric acid and water, is dried over sodium sulfate and is evaporated.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C@@H:15]1[CH2:19][C@H:18]([Cl:20])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O>C1COCC1>[C:24]([O:23][C:21]([N:16]1[CH2:17][C@@H:18]([Cl:20])[CH2:19][C@H:15]1[CH:13]=[O:12])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Cl)C[C@H]1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
57 ml (57 mmol, 1.2 M soltion in toluene) of diisobutylaluminium hydride (DIBAH) was added during 40 min to a cold solution (-78° C.) of 6 g (22.7 mmol) (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 180 ml THF. The reaction was stirred for 2 h at −78° C. and quenched with a suspension of 23 g silica gel/23 g MgSO4.7H2O in 70 ml aqueous 10% KHSO4. The suspension was stirred for 15 min at room temperature, filtered and washed with THF. After evaporation of the THF, the residue was taken up in CH2Cl2, dried over Na2SO4 and evaporated to give 5.88 g crude (2S,4S)-4-Chloro-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester. Preparation of ketones and alcohols:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:9]2[C:10]([CH3:16])=[CH:11][C:12]([OH:15])=[C:13]([CH3:14])[C:8]=2[O:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:9]2[C:10]([CH3:16])=[CH:11][C:12]([O:15][CH2:27][C:26]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:25]=3[Cl:24])=[C:13]([CH3:14])[C:8]=2[O:7][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1coc2c(C)c(O)cc(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1coc2c(C)c(OCc3ccc(Cl)cc3Cl)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl(6-hydroxy-4,7-dimethyl-1-benzofuran-3-yl)acetate (150 mg) and DMF (dry) (6.4 mL) were added K2CO3 (133 mg) and 2,4-dichlorobenzyl chloride (0.107 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water. The precipitate was collected by filtration and washed with water and hexane to give the title compound (176.5 mg).
Reaction SMILES: ON1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.[CH:9]1[CH2:16]CCCC[CH2:11][CH:10]=1.C(=O)=O.O=O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH:11]12[O:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:16][CH2:9][CH2:10]2
Reactant: O=C1CCC(=O)N1O
Reactant: C1=CCCCCCC1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C=O
Solvent: O
Solvent: CC(=O)O
Product: C1CCCC2OC2CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
This reaction was performed with a solution of 0.1191 g (1.03 mmol) of N-hydroxysuccinimide, 2.0868 g (18.9 mmol) of cyclooctene and 0.1330 g (0.53 mmol) of cobalt acetate tetrahydrate in 40 ml of acetic acid was heated to 40° C. in a Parr Hastelloy reactor with temperature and pressure transducer. After the temperature reached 40° C., 745 psi of CO2 was introduced into the reactor, then 120 psi of O2 was added slowly to the reactor. The mixture was stirred under pressure for six hours at 40° C., then the pressure was released, and the mixture was cooled to room temperature. The mixture solution was extracted with ethyl acetate then washed with a saturated NaCl solution in water and, dried over Na2SO4 to give cyclooctene oxide, the only product 5% with 5% conversion analyzed by GC-MS.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18]>>[N:15](=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8])[NH:16][C:17]([NH2:19])=[O:18]
Reactant: NNC(N)=O
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: NC(=O)NN=c1c(=O)c2ccccc2c1=O

Procedure:
ninhydrin, semicarbazide hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.O=[C:10]1[CH2:17]C(C)(C)C[C:12](C)=[CH:11]1>>[CH3:17][C:10]1[CH2:11][CH2:12][CH:7]2[C:2]([CH:1]=1)=[CH:3][C:4](=[O:8])[CH2:5][CH2:6]2
Reactant: CC1=CC(=O)CCC1
Reactant: CC1=CC(=O)CC(C)(C)C1
Product: CC1=CC2=CC(=O)CCC2CC1

Procedure:
This material is prepared according to the procedure for Preparation 1 wherein 3-methyl-2-cyclohexenone is substituted for isophorone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)([O-])[O-].[K+].[K+].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1/[CH:23]=[CH:24]/[S:25]([NH2:28])(=[O:27])=[O:26].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][S:25](/[CH:24]=[CH:23]/[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])=[O:5]
Reactant: NS(=O)(=O)/C=C/c1cccs1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)/C=C/c1cccs1)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 29 %

Procedure:
2,4-Dichlorobenzoyl chloride (53 μL, 0.375 mmol) was added to a mixture of potassium carbonate (69 mg, 0.5 mmol) and (E)-2-thiophen-2-yl-ethenesulfonic acid amide (47 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) at ambient temperature. The mixture was heated at 80° C. for 16 hours then allowed to cool to room temperature whereupon 1N HCl (2 mL) was added in one portion. The mixture was extracted with ethyl acetate (2 mL) and the organics were dried with MgSO4, filtered and concentrated in vacuo. The resultant residue was purified by preparative HPLC to afford (E)-2-thiophen-2-yl-ethenesulfonic acid 2,4-dichloro-benzoylamide (26.3 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[C:20]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Product: CCC(=O)n1c2ccccc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-Propionyl-3-methylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]quinazolin-12(6H)one and propionyl chloride.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[C@@H:8]([CH2:20][CH2:21][CH:22]([OH:30])[C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6]1)(=O)C.[OH-].[Na+]>C(O)C>[F:29][C:23]([F:28])([CH2:24][CH2:25][CH2:26][CH3:27])[CH:22]([OH:30])[CH2:21][CH2:20][C@H:8]1[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6][C@H:5]([OH:4])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C

Procedure:
A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (16) (70.62 g, 132.1 mmol) in ethanol (213 ml) was cooled on ice, and an 8N-sodium hydroxide aqueous solution (132 ml, 1056 mmol) was added thereto drop wise. After stirring at room temperature for approximately hours, the reaction mixture was concentrated under reduced pressure. The residue was supplemented with water (280 ml) and t-butyl methyl ether (141 ml), and cooled on ice. After 6N-hydrochloric acid was added drop wise to adjust to pH 3 to 4, the solution was extracted three times with ethyl acetate (280 ml). The organic layers were combined and sequentially washed with water (280 ml) twice and saturated aqueous sodium chloride (336 ml). After drying with anhydrous magnesium sulfate (50 g), the solution was concentrated under reduced pressure to give crude 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (17) as white solid. The entire amount was used in the following step without purification.
Reaction SMILES: Br[C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]([C:26]#[N:27])=[CH:15][CH:14]=2)[C:6]1=[O:28].[NH2:34]C1C=CC=CC=1CN1C(C)(C)C(=O)N(C2C=CC(C#N)=C(C(F)(F)F)C=2)C1=O.C(=N)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:34][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]([C:26]#[N:27])=[CH:15][CH:14]=2)[C:6]1=[O:28]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C(=O)N1Cc1ccc(F)cc1Br
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1N
Agent: N=C(c1ccccc1)c1ccccc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C(=O)N1Cc1ccc(F)cc1N

Procedure:
Compound 253.2 (5-[3-(2-bromo-4-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-4′-fluorobiphenyl-2-carbonitrile) was, as described for the preparation of 61.2, reacted with benzophenone imine to obtain 264.1. Molecular weight 446.15 (C25H20F2N4O2); retention time Rt=2.78 min. [E]; MS (ESI): 447.12 (MH+).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][C:7]#[N:8].[C:12](OCC)(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15]>C(O)C>[CH3:2][C:3]1[CH:4]=[C:5]([CH:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]#[N:8])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)C
Reactant: Cc1cccc(CC#N)c1
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(C(C#N)C(=O)CC(C)C)c1
Temperature: 112 °C
Yield: 95.8 %

Procedure:
To a solution of 2.99 g (0.13 g. atm) of sodium in 50 ml of absolute ethanol, heated to 60° C., was added 11.81 g (0.09 m) of 3-methyl-benzyl cyanide followed by the slow addition, over a period of 20 minutes of 31.27 g (0.24 m) of ethyl isovalerate. The reaction mixture was heated under reflux overnight (18 hrs.). During this period the color of the solution turned from yellow to dark orange. After approximately 70 ml of solvent and excess of ethyl valerate was removed by distillation, 75 ml of toluene was added and additional 30 ml of the solvent was removed by heating the mixture to 112° C. The reaction mixture was cooled, diluted with 100 ml of toluene and was washed twice with water. The aqueous extracts were combined and acidified with 6N hydrochloric acid. The product was extracted in 300 ml of methylene chloride. The organic extract was washed with water, dried over magnesium sulfate and was concentrated under vacuum to afford 18.56 g of orange colored oil. Crystallization from ethyl acetate hexane solution afforded 14.0 g. of a white solid. m.p. 46.5°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]([OH:15])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cnccc1-c1ccc(Cl)cc1F
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (0.12 g, 0.509 mmol) (prepared as in Example 5, Part B) in anhydrous THF (15 mL) was added methyl magnesium bromide (3.0 M in diethyl ether) (0.364 g, 3.06 mmol) at −60° C. dropwise. After complete addition the solution was stirred at −60° C. for 10 min. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (15 mL). The organics were extracted with ethyl acetate (3×20 mL) and washed with water (1×15 mL) and brine (1×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via preparative TLC (20% ethyl acetate in hexane) to afford 1-(4-(4-chloro-2-fluorophenyl)pyridin-3-yl)ethanol (40 mg, 0.159 mmol, 31% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.50 (s, 1H), 7.15-7.26 (m, 3H), 7.07 (d, J=3.8 Hz, 1H), 4.82 (q, J=6.3 Hz, 1H), 3.06 (bs, 1H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:6][N:5]([C:8]([C@@:10]2([CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1>Cl.CCOCC.CO>[NH2:15][C@@H:12]1[CH2:13][CH2:14][C@@:10]([C:8]([N:5]2[CH2:4][CH2:3][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([OH:1])[CH2:7][CH2:6]2)=[O:9])([CH:23]([CH3:24])[CH3:25])[CH2:11]1
Reactant: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](N)C1
Reaction time: 3.5 h

Procedure:
tert-Butyl {(1R,3S)-3-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]-3-isopropyl-cyclopentyl}carbamate (0.30 g, 0.70 mmol) was dissolved in a 2.0 M solution of HCl in ether (10 mL). After being stirred for 3.5 h, a few drops of MeOH was added to get a clear solution. The mixture was concentrated to give an oil. The crude product was used in the next reaction without purification. MS calculated for C20H30N2O2: (M+H) 331; found 331.2.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:28])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:21]3[CH:25]=[CH:24][NH:23][N:22]=3)=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:21]3[CH:25]=[CH:24][NH:23][N:22]=3)=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCc1cc[nH]n1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCc1cc[nH]n1

Procedure:
Using 0.1 g of N-(trans-4-methylcyclohexyl )-4-(2-pyrazolylethoxy) -3-methoxycinnamamide (Example 180), 0.007 g of 10% palladium-carbon, and 30 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.05 g of N-(trans-4-methylcyclohexyl) -3-[4-(2-pyrazolylethoxy)-3methoxyphenyl]propionamide (a compound of the present invention) was obtained as light-yellowish brown crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:20](Br)[CH:21]=[CH2:22].C(=O)(O)[O-].[Na+].[I-].[Li+]>CN(C)C=O>[CH2:22]([N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
To a solution of 5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione (258 mg, 1.0 mmol) and allyl bromide(121 mg, 1.0 mmol) dissolved in dimethylformamide(5 ml), sodium bicarbonate(126 mg, 1.50 mmol) and lithium iodide(13.0 mg, 0.10 mmol) were added and stirred at 90° C. for 24 hours. The resulting product was distilled under the reduced pressure to remove dimethylformamide and purified by column chromatography to obtain the titled compound as a white solid(157 mg, yield: 52.3%).