Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.[OH:16][C@H:17]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([N:23]2[CH2:22][CH2:21][N:20]([C:18](=[O:19])[C@H:17]([OH:16])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:24]2)[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(Cl)nc3cc(C(=O)O)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2,4-dichloroquinazoline-7-carboxylic acid (0.45 g, 1.9 mmol) in CH2Cl2 (20 mL) was added (R)-2-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one (0.37 g, 1.9 mmol) and triethylamine (0.52 mL, 3.7 mmol). The reaction mixture was stirred overnight at room temperature and then purified via silica gel chromatography using 0-10% MeOH/CH2Cl2 to obtain 2-chloro-4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-quinazoline-7-carboxylic acid (0.58 g, 77%). LC/MS: m/z 407.3 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[C@H:28]1[N:36]2[C@@H:31]([CH2:32][CH2:33][CH:34](P(=O)(OCC)OCC)[C:35]2=[O:37])[CH2:30][CH2:29]1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[C@H:28]1[N:36]2[C@@H:31]([CH2:32][CH2:33]/[C:34](=[CH:8]\[C:7]3[CH:10]=[CH:11][C:12]([N:13]4[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]4)=[C:5]([O:4][CH3:3])[CH:6]=3)/[C:35]2=[O:37])[CH2:30][CH2:29]1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cc(F)c(F)cc3F)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cc(F)c(F)cc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
Lithium hydroxide (0.265 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.60 g) and diethyl [(3S,8aR)-3-(2,4,5-trifluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (2.0 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.97 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.CS(O[CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][CH2:25][N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[N+:17]([O-:19])=[O:18])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1[N+](=O)[O-]
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCCCN(C(=O)OC(C)(C)C)c1cccc(OC)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
tert-Butyl (3-methoxy-2-nitrophenyl)carbamate (3.00 g) and 4-methoxybutyl methanesulfonate (3.06 g) were dissolved in dimethylformamide (40 ml), cesium carbonate (7.30 g) was added, and the mixture was stirred at 65° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-7:3) was concentrated under reduced pressure to give the object product (2.11 g).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].Cl>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Agent: Cl
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 54 %

Procedure:
Treat dl-13-ethyl-3-methoxygona-2,5(10)-dien-17-one with hydrochloric acid in aqueous methanol to obtain dl-13-ethylgon-4-ene-3,17-dione (25.6, 54% from dl-13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol), m.p. 156°-157.5°; ultraviolet absorption peak in 95% ethanol at 240.5 mμ (15,900), infrared maxima (potassium bromide) at 5.77 μ, 5.98 μ. Recrystallize dl-13-ethylgon-4-ene-3,17-dione (1.0 g) three times from ethyl acetate to obtain 484 mg., 157°-159.5°; ultraviolet absorption peak (95% ethanol) at 240 mμ (ε17,200), infrared maxima (potassium bromide) at 5.77 μ, 5.98 μ.
Reaction SMILES: C1(C[O:8][CH2:9][C@H:10]2[O:30][C@H:29]([C@@H:31]([CH2:40][O:41]CC3C=CC=CC=3)[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:11]2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.B(F)(F)F.CCOCC>C(OC(=O)C)(=O)C>[C:14]1([CH2:13][O:12][C@H:11]2[C@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:29]([C@@H:31]([CH2:40][OH:41])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:30][C@@H:10]2[CH2:9][OH:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COC[C@@H](OCc2ccccc2)[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: OC[C@@H](OCc1ccccc1)[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
In accordance with Flowchart D, 2,5-anhydro-D-mannose 26 is treated with acetyl chloride in methanol at reflux, then neutralized with lead carbonate, giving 2,5-anhydro-D-mannose, dimethyl acetal 27. which is treated with sodium hydride and benzyl bromide in dimethylformamide, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose, dimethyl acetal 28. Compound 28 is then treated with tetrafluoroboric acid in acetonitrile, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 29 which is then treated with Tebbe's reagent in ether at -40° C., then neutralized with sodium hydroxide, giving 3,6-anhydro-1,2-dideoxy-4,5,7-tris-O-(phenylmethyl)-D-manno-hept-1-enitol 30. Compound 30 is treated with osmium tetroxide in pyridine, giving 2,5-anhydro-1,3,4-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol 31, which is treated with sodium hydride in dimethylformamide, followed by treatment with benzyl bromide, giving 2,5-anhydro-1,3,4,6,7-pentakis-O-(phenylmethyl)-D-glycero-D-manno-heptitol 32. Compound 32 is treated with borontrifluoride etherate in acetic anhydride, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)D-glycero-D-manno-heptitol, 1,7-diacetate 33, which is treated with sodium ethoxide in ethanol, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol 34. Compound 34 is treated with diethyl phosphorochloridate in pyridine at reduced temperature, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol, 1,7-bis(diethyl phosphate) 35. Substituting other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 35 is treated with bromotrimethyl silane in chloroform at reduced temperature, under an inert atmosphere, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol, 1,7-bis(dihydrogen phosphate) 36, which is then hydrogenated over palladium on carbon in methanol, giving the product of Formula I, where R', R", R'" and R"" are hydrogen,
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[NH2:5].F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([NH:5][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: CC(C)C[C@H](N)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Temperature: 107.5 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
A mixture of crude (S)-3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butan-1-amine (66.34 g, 192.4 mmol), methyl 6-fluoronicotinate (32.8 g, 212 mmol), and freshly pulverized and dried (150 C, vacuum oven, 12 h) tripotassium phosphate (75.6 g, 356 mmol) was purged with dry nitrogen then diluted with N,N-dimethylacetamide (320 ml). The mixture was heated to 110° C. (107-108° C. internal temperature) for 24 hours. The reaction was diluted with water (˜1.5 L) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous portion was decanted, leaving behind a thick amorphous solid. This material was washed with water (2×1 L). The resulting solid was dissolved in ethyl acetate and the remaining water was removed via azeotropic distillation (rotary evaporator, approximately 2×1 L ethyl acetate). The combined aqueous layers were stirred vigorously for 12 hours resulting in the precipitation of an additional aliquot (approximately 500 mg) of the crude product that was combined with the originally recovered material. The crude material was purified via ISCO MPLC (SiO2, 0-75% ethyl acetate in heptane) to yield the product (53.0 g, 62%) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.93 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.97 (dd, J=8.5, 2.1 Hz, 1H), 7.92 (dd, J=8.9, 2.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 6.25 (d, J=8.8 Hz, 1H), 5.79 (d, J 6.5 Hz, 1H), 4.73-4.85 (m, 1H), 3.84 (s, 3H), 1.77-1.86 (m, 1H), 1.65-1.77 (m, 2H), 1.01 (d, J=6.1 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H). MS (M+1): 444.5.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[N:13][C:12]=1[CH3:18])C>C1COCC1>[CH3:18][C:12]1[C:11]([CH2:10][OH:9])=[C:16]([CH3:17])[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)c1c(C)ccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccnc(C)c1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium aluminum hydride in THF (1.0 M, 40 mL, 40 mmol) placed in a 100-mL round bottom flask equipped with a magnetic stirring bar was cooled in an ice bath and cautiously treated with a solution of 2,4-dimethyl-nicotinic acid ethyl ester (5.4 g, 30 mmol) in anhydrous THF (10 mL) over 5 min period. After the addition was complete the cold bath was removed and the mixture was allowed to stir at room temperature for 2 h. The reaction mixture was then cooled in an ice bath and the excess LAH was quenched by drop wise addition of water until gas evolution stopped. The reaction mixture was then basified with 2M NaOH to pH 9-10. Ether (100 mL) was added the mixture was washed with 1 M NaOH, water and brine. The organic layer was dried over MgSO4 and the solvent was evaporated to yield (2,4-dimethyl-pyridin-3-yl)-methanol as a white solid. MS: (M+H)/z=138.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH:19]([CH3:21])[CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH:19]([CH3:21])[CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCCC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl butanoate (602 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 43 (513 mg, 75% yield) as a white powder after work-up and mass-guided preparative HPLC purification. NMR (400 MHz, DMSO-d6): δ=0.83-0.95 (br. m, 11H), 1.17-1.38 (br. m, 3H), 1.48-1.58 (m, 2H), 1.65-1.73 (br. m, 2H), 1.83-1.98 (br. m, 3H), 2.10 (tt, J=12.0, 3.2 Hz, 1H), 2.21-2.32 (br. m, 2H), 2.75-2.87 (br. m, 2H), 6.44 (d, J=5.6 Hz, 1H), 7.40 (t, J=6.0 Hz), 11.97 (br. s, 1H). MS (EST) m/z 366.21 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19].CO.C(=O)(O)[O-].[Na+]>ClCCl.O>[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cc1ccccc1Oc1cccc(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccccc1Oc1cccc(O)c1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Boron tribromide (12.89 g, 0.051 mol) was dissolved in dichloromethane (50 ml) and cooled to 0°-5° C. A solution of methyl 2-(3-methoxyphenoxy)phenylacetate (7.0 g; 0,026 mol) in dichloromethane (80 ml) was added dropwise, with stirring over 1 hour. After stirring at 0°-5° C. for 20 minutes the mixture was added dropwise, with stirring to absolute methanol (100 ml) maintaining the temperature at 0°-5° C. The resulting solution was poured into water (250 ml) containing sodium bicarbonate (12 g), and the resulting mixture was extracted with ether (500 mls). The organic phase was washed with water (3×200 ml) and saturated brine (150 ml). After drying and filtration, evaporation of the ether solution gave methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (6.12 g, 92.3% yield) as a brown gum. This material was suitable for use in subsequent steps without further purification. However, chromatography using mixtures of ether and hexane as eluant gave material of higher purity as a viscous golden oil which rapidly darkened on exposure to air.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:28])=[CH:17][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]2[C@H:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@@H]5CCOC5)cc4C)ccc3OCc3ccccc3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1ccc(OCc2ccccc2)c(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 2 h
Yield: 15.5 %

Procedure:
The crude methyl 2-((S)-6-((4-(benzyloxy)-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 36b (1 g, 1.69 mmol) was dissolved in 50 mL of a mixed solvent of methanol and tetrahydrofuran (V/V=1:4), followed by addition of 1M aqueous lithium hydroxide solution (20 mL, 20 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 150 mL of water and 30 mL of ethyl acetate, 1M hydrochloric acid was added dropwise to adjust the pH to 2˜3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 2-((S)-6-((4-(benzyloxy)-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 36c (152 mg) as a brown oil, which was directly used in the next step without further purification.
Reaction SMILES: CNC(=O)C1C=CC(N2CCC(=O)N(C3C=CC(C#N)=C(C(F)(F)F)C=3)C2=O)=CC=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].C1CCN2C(=NCCC2)CC1.[NH2:49][C:50]1[CH:59]=[CH:58][C:53]([C:54]([NH:56][CH3:57])=[O:55])=[C:52]([F:60])[CH:51]=1>CS(C)=O>[CH3:57][NH:56][C:54]([C:53]1[CH:58]=[CH:59][C:50]([NH:49][CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:51][C:52]=1[F:60])=[O:55]
Reactant: CNC(=O)c1ccc(N)cc1F
Reactant: C=CC(=O)OCC
Agent: CNC(=O)c1ccc(N2CCC(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C2=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCOC(=O)CCNc1ccc(C(=O)NC)c(F)c1
Reaction time: 24 h

Procedure:
Synthesis of N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2(1), (X═O, R1=CH3). Ethyl acrylate (8 g, 80 mmol) and DBU (0.81 g, 5.4 mmol) were added to a solution of 4-amino-N-methyl-2-fluorobenzamide (9 g, 53.6 mmol) in DMSO (90 ml) and stirring was continued for 24 h at 70° C. (LCMS control). The reaction mixture was subjected to lyophilization, the residue was recrystallized from aqueous alcohol. It gave ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate 5. LCMS (M+H)+ 269. 1H NMR (DMSO-d6, 400 MHz) δ 7.57 (br. s, 1H), 7.48 (t, J=8.8 Hz, 1H), 6.47 (br. s, 1H), 6.42 (d, J=8.8 Hz, 1H), 6.33 (d, J=14.8 Hz, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.32 (br. m, 2H), 2.73 (d, J=4.4 Hz, 3H), 2.55 (t, J=6.4 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H). The solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (425 mg, 1.87 mmol) 3.1 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (500 mg, 1.87 mmol) 5 (R1=CH3) in CH2Cl2 (10 ml) was stirred for 5 h. The reaction mixture was evaporated in vacuo, and the product was isolated by colomn chromatography on SiO2 (eluent—n-hexane:AcOEt:Et3N=1:1:0.03). It gave ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate 6(1) (R1=CH3, X═O). LCMS (M+H)+ 481. HCl (2.5 ml) was added to the solution of ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate (500 mg, 1.04 mmol) 6(1) in AcOH (5 ml) and the resultant mixture was stirred for 15 h. The reaction mixture was poured into water, the product was extracted with EtOAc. Organic layer was dried over Na2SO4, evaporated in vacuo and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:1) N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2, (X═O, R1=CH3) was isolated; Ki1.3.2(1)=85.6 nM, LCMS (M+H)+ 435. 1H NMR (DMSO-d6, 400 MHz): δ 8.29 (d, J=7.6 Hz, 1H), 8.23 (br. m, 1H), 8.11 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 2.77 (d, J=4.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:18])([C:15](O)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:18])([C:15]([Cl:21])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C(=O)O)CCC(OCc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Product: CC1(C(=O)Cl)CCC(OCc2ccccc2)CC1
Yield: 99 %

Procedure:
A solution of 4-benzyloxy-1-methyl-cyclohexanecarboxylic acid (1.71 g, 6.89 mmol) in thionyl chloride (10 ml) was refluxed for 2 hours. The reaction mixture was concentrated on high vacuum giving 1.84 g (99%) of 4-benzyloxy-1-methyl-cyclohexanecarbonyl chloride as a yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:29](=[O:31])[CH3:30])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc(N)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(n1cncc1C(=O)OC(C)C)CCC2
Reaction time: 2.5 h

Procedure:
To a solution of 3-(7-amino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester (0.180 g, 0.602 mmol) and pyridine (0.052 g, 0.662 mmol) in dichloromethane (2 mL) is added acetyl chloride (0.052 g, 0.662 mmol) at 0° C. and the reaction is stirred for 2.5 hours. The solution is then washed with 10% aqueous HCl and water and the combined aqueous phases are extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, and concentrated to give a residue, which is purified by silica gel chromatography (dichloromethane-methanol mixtures) to give 3-(7-acetylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 342.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.39 (d, J=6.3 Hz, 3 H), 1.40 (d, J=6.3 Hz, 3 H), 1.78-1.92 (m, 2 H), 2.08 (s, 3 H), 2.16-2.31 (m, 2 H), 2.81-2.89 (m, 1 H), 2.98 (dt, J=16.9, 6.1 Hz, 1 H), 5.25 (sept, J=6.3 Hz, 1 H), 6.32 (t, J=5.4 Hz, 1 H), 7.17 (br. s, 1 H), 7.22 (d, J=8.3 Hz, 1 H), 7.43 (s, 1 H), 7.50 (dd, J=8.3, 2.1 Hz, 1 H), 7.74 (d, J=1.0 Hz, 1 H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([NH:28][NH2:29])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.[C:30]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([NH:28][NH:29][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)NNC(=O)CCCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
IPEA (2.5 mL) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide (500 mg) in methylene chloride (12 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. 4-benzoylbutyric acid (334 mg) and BOPCl (442 mg) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for four hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (692 mg). Imidazole (494 mg), carbon tetrabromide (2.36 g) and triphenylphosphine (559 mg) were added to a suspension of 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (634 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 515 mg of the title compound. The property value of the compound is as follows.