Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C(C)C(O)=O)=CC=1Cl.N([O-])=O.[Na+].S([O-])(O)=O.[Na+].ClC1C=C(C(C)C(O)=O)C=CC=1NN.C(OC(OCC)CC(OCC)OCC)C.[OH-].[Na+].C([O:56][C:57](=[O:72])[CH:58]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH:70]=[CH:69][CH:68]=[N:67]2)=[C:62]([Cl:71])[CH:61]=1)[CH3:59])C>Cl.O>[Cl:71][C:62]1[CH:61]=[C:60]([CH:58]([CH3:59])[C:57]([OH:72])=[O:56])[CH:65]=[CH:64][C:63]=1[N:66]1[CH:70]=[CH:69][CH:68]=[N:67]1
Reactant: CCOC(=O)C(C)c1ccc(-n2cccn2)c(Cl)c1
Agent: CC(C(=O)O)c1ccc(N)c(Cl)c1
Agent: CC(C(=O)O)c1ccc(NN)c(Cl)c1
Agent: CCOC(CC(OCC)OCC)OCC
Solvent: O
Product: CC(C(=O)O)c1ccc(-n2cccn2)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
20 g (100 mmoles) of 2-(4-amino-3-chlorophenyl) propionic acid are dissolved in 20 ml of concentrated hydrochloric acid and diazotized with 6.9 g of sodium nitrite in 20 ml of water at from -2° to -6° C. The solution is thereafter stirred for a further hour and subsequently stirred into 100 ml of a freshly-prepared, ice-cold, 5.5 N solution of sodium hydrogen sulfite. Heating is then effected slowly to a temperature of from 60° to 70° C. After one hour, acidification is effected with concentrated hydrochloric acid, and the resulting reaction mixture is left at 70° C. for a further 12 hours. 2-(3-chloro-4-hydrazinophenyl)propionic acid forms therein. 22 g (100 mmoles) of 1,1,3,3-tetraethoxypropane are then added thereto. After three hours' heating to 100° C., the reaction mixture is cooled, rendered alkaline with 35% strength sodium hydroxide solution and, in order to saponify the 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid ethyl ester which is formed in addition to the acid, reheated for one hour. After cooling, impurities are extracted by shaking with benzene; the aqueous phase is acidified with concentrated hydrochloric acid; the product is extracted with diethyl ether; and the ether phase is washed with water, dried and concentrated in a vacuum. 24 g (96% of theory) of 2-[3-chloro-4-(pyrazol-1-yl)phenyl]propionic acid, m.p. 83° to 85° C., are thus obtained.
Reaction SMILES: [B:1](OC1CCC(C)C(C)C1)([O:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH3:19])[CH2:13]1)[O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]([CH3:10])[CH2:4]1.[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:34]=1[OH:44])([CH3:32])([CH3:31])[CH3:30]>>[B:1]([O:44][C:34]1[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:38][C:37]([CH3:39])=[CH:36][C:35]=1[C:40]([CH3:43])([CH3:42])[CH3:41])([O:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([CH3:19])[CH2:13]1)[O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]([CH3:10])[CH2:4]1
Reactant: CC1CCC(OB(OC2CCC(C)C(C)C2)OC2CCC(C)C(C)C2)CC1C
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: Cc1cc(C(C)(C)C)c(OB(OC2CCC(C)C(C)C2)OC2CCC(C)C(C)C2)c(C(C)(C)C)c1

Procedure:
Bis(3,4-dimethylcyclohexyl) 2,6-di-t-butyl-4-methylphenyl borate was prepared by transesterification of tri(3,4-dimethylcyclohexyl) borate (1.5 mole) with 2,6-di-t-butyl-4-methylphenol (0.5 mole). The reaction mixture was slowly distilled to remove 3,4-dimethylcyclohexanol and the product was obtained as a viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=3[N:8]=2)[CH:2]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=3[N:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3cccnc3)nc3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(-c3cccnc3)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(3-pyridyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6]1.[BH4-].[Na+].Cl>CO>[CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6]1
Reactant: CN(CCc1ccccc1)C(=O)Cn1ccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(CCc1ccccc1)C(=O)Cn1ccc(CO)c1
Reaction time: 0.75 h

Procedure:
To a solution of N-methyl-N-phenethyl-2-[3-formylpyrrol-1-yl]acetamide in methanol, stirred in an ice bath, is added in portions 5 molar equivalents of sodium borohydride. The mixture is stirred in the cooling bath for an additional 45 minutes and 1N aqueous HCl solution is added dropwise until the pH of the mixture is approximately 6-7. The resulting mixture is concentration in vacuo and the residue obtained is partitioned between ethyl acetate and water. The organic layer is dried over MgSO4 and concentrated in vacuo to give N-methyl-N-phenethyl-2-[3-hydroxymethylpyrrol-1-yl]acetamide. This material is used without further purification in the next step.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH:13]=O)=[CH:5][C:6]2[CH2:10][CH2:9][O:8][C:7]=2[C:11]=1[CH3:12].C(O)(=O)C>[Zn].O>[CH3:13][C:4]1[C:3]([CH3:2])=[C:11]([CH3:12])[C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1
Reactant: Cc1c(C=O)cc2c(c1C)OCC2
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(c(C)c1C)OCC2
Reaction time: 12 h
Yield: 79 %

Procedure:
Zinc amalgum [prepared by heating a mixture of zinc dust (7.0 g), mercuric chloride (0.70 g), concentrated hydrochloric acid (0.5 ml) and water (30 ml) for 5 minutes and then decanting the aqueous solution] was added to a mixture of 2,3-dihydro-6,7-dimethylbenzo[b]furan-5-carboxaldehyde (6.93 g, 39 mmol), acetic acid (50 ml), water (50 ml), and concentrated hydrochloric acid (100 ml). The mixture was heated at reflux with vigorous stirring for 12 hours. After cooling, the mixture was poured into water. The dried (Na2SO4) ether extract was evaporated and the residue was purified by column chromatography over silica with hexane elution to give 2,3-dihydro-5,6,7-trimethylbenzo[b]furan (5.00 g, 78%) as a white solid, mp <50° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:31]=[CH:30][C:20]([CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:19][CH:18]=4)[N:15]=3)[NH:10][C:9]2=[O:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1N=C2N(CC3CCCCC3)C(=O)NC2=NC=1.C(NCC1C=CC(B(O)O)=CC=1)(OC(C)(C)C)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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]>[NH2:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:15]=[C:16]3[N:8]([CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9](=[O:32])[NH:10][C:11]3=[N:12][CH:13]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: NCc1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1

Procedure:
tert-Butyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzylcarbamate. 6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 55.B) (200 mg, 0.64 mmol), [4-(N-boc-aminomethyl)phenyl]boronic acid (195 mg, 0.77 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (53 mg, 0.06 mmol) and potassium phosphate (550 mg, 2.58 mmol) in DMF (15 mL) and water (1 mL) were reacted according to General Procedure B. The product was purified by reverse-phase semi-preparatory HPLC (30-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The desired fractions were concentrated to approximately one third the original volume and treated with potassium carbonate (1.75 M). The desired product was collected by vacuum filtration, washed with water and dried under high vacuum to provide the title compound. The product was used directly in the next step without further purification or characterization. MS (ESI) m/z 438.1 [M+1]+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].CS(O[CH2:27][CH2:28][O:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[N:33][C:34]([CH3:40])=[N:35]2)(=O)=O>>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:27][CH2:28][O:29][C:30]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:31]=4[CH:32]=[N:33][C:34]([CH3:40])=[N:35]5)[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Reactant: CS(=O)(=O)N1CCOc2ccc(CN3CCNCC3)cc21
Product: Cc1ncc2c(OCCN3CCN(Cc4ccc5c(c4)N(S(C)(=O)=O)CCO5)CC3)cccc2n1

Procedure:
The title compound was prepared from 4-methanesulfonyl-6-(piperazin-1-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazine and 5-(2-(methanesulfonyloxy)ethoxy)-2-methylquinazoline following the method of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13](=O)[CH2:14]Br)[CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(F)cc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cc(F)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-fluoro-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-fluoro-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [F:1][C:2]([F:14])([C:5]([F:13])([F:12])[C:6]([F:11])([F:10])[CH:7]([F:9])[F:8])[CH2:3][OH:4].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[N:28]=1>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:4][CH2:3][C:2]([F:14])([F:1])[C:5]([F:12])([F:13])[C:6]([F:10])([F:11])[CH:7]([F:8])[F:9])[N:28]=1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A reaction flask was loaded with 2,2,3,3,4,4,5,5-octafluoropentanol (16.1 g), DMF (42 ml), anhydrous potassium carbonate (9.6 g), followed by stirring at room temperature for one hour. To this mixture, 2,6-difluoropyridine (8.0 g) was dropwise added. The temperature was raised to 60° C., and the mixture was stirred for four hours. The heating was stopped, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was condensed by an evaporator to give 2-fluoro-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-pyridine (20 g).
Reaction SMILES: ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:13]1[C:18]([NH2:19])=[C:17](Cl)[C:16]([Cl:21])=[C:15](Cl)[C:14]=1[Cl:23].C1(O)C=CC=CC=1.II>[Ta].O>[Cl:21][C:16]1[CH:17]=[C:18]([CH:13]=[C:14]([Cl:23])[CH:15]=1)[NH2:19]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Ta]
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: II
Solvent: Oc1ccccc1
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1
Temperature: 165 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
131 parts of tetrachloroaniline/pentachloroaniline mixture corresponding to the data in Example 3, 200 parts of phenol, 5.7 parts of iodine and 33 parts of a 5% strength ruthenium-on-charcoal catalyst which is moist with water (23 parts dry) are brought to reaction in a tantalum autoclave, whilst stirring, during the course of 4 hours, at 165° C. and under a maximum hydrogen pressure of 50 bars. After the usual working up, 87 parts of 98% strength 3,5-dichloroaniline are obtained (93% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCC(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCC(=O)Cl)cc1
Temperature: 65 °C

Procedure:
To a suspension of 3-(4-methoxyphenyl)propionic acid (10 g) in 150 ml of toluene are added 8 ml of thionyl chloride and the mixture is heated to 65° C. for 4 hours. The solvent is evaporated off under reduced pressure and the residue is redissolved in toluene and concentrated to dryness. Such steo is repeated twice. 11 g of the product are obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH2:28].ClCCl>CCCCCC>[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH:28][C:10](=[O:12])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH3:13]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-3-nitro-phenyl)-propionic acid (0.60 g, 2.70 mmol), SOC2 (0.96 mL, 13.0 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (0.77 g, 3.50 mmol). After normal workup, the pure objective compound (0.98 g, 82%) was obtained as white solid by recrystallization (dichloromethane:n-hexane=1:3): m.p 122° C.; 1H NMR (200 MHz, CDCl3) δ 1.60 (d, J=7.2 Hz, 3H, CH3), 3.65-3.84 (m, 4H, CO2CH3 & CH), 7.55 (dd, J=8.8, 2.2 Hz, 1H, ArH), 7.84 (d, J=2.2 Hz, 1H, ArH), 8.44 (d, J=2.0 Hz, 1H, ArH), 9.51 (br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH:17]1(/[CH:23]=[CH:24]/[C:25]([Cl:27])=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:27].[CH:17]1(/[CH:23]=[CH:24]/[C:25]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:6]3[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-Cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate-hexane yielded the titled compound. MW: 369.90; mp: 168.0-169.0° C.; 1H-NMR (DMSO) δ: 8.80-8.76 (1H, m), 8.24 (1H, td, J=7.7, 1.8 Hz), 7.82-7.71 (2H, m), 7.46 (1H, d, J=9.2 Hz), 7.34-7.25 (2H, m), 7.09 (1H, dd, J=9.2, 2.6 Hz), 6.42 (1H, dd, J=15.8, 1.1 Hz), 3.56 (3H, s), 2.40-2.20 (1H, m), 1.80-1.55 (5H, m), 1.40-1.05 (5H, m).
Reaction SMILES: [CH2:1]([C:8]1=[N:9][NH:10][C:11](=[O:24])/[C:12]/1=[C:13]1\[NH:14][C:15]2[C:20]([C:21](Cl)=[CH:22]\1)=[CH:19][CH:18]=[CH:17][CH:16]=2)C1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1>>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14]/[C:13](=[C:12]3/[C:8]([CH3:1])=[N:9][NH:10][C:11]/3=[O:24])/[CH:22]=2)=[CH:28][CH:27]=1
Reactant: O=C1NN=C(Cc2ccccc2)/C1=C1\C=C(Cl)c2ccccc2N1
Reactant: Nc1ccc(S)cc1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-3-benzyl-4-(4-chloroquinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one and 4-aminothiophenol under conditions similar to those described in Example 6. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.81 (s, 2H) 6.77-6.79 (m, 3H) 7.23-7.30 (m, 3H) 7.33 (d, J=8.34 Hz, 2H) 7.40-7.48 (m, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H); ESI-MS: m/z calc'd for C25H20N4OS 424.14. found 424.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:47])[CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[C:57]1([NH2:64])[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.C(#N)C>[NH2:63][C:60]1[CH:61]=[CH:62][C:57]([NH:64][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:40]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]2[C:25]3([CH2:24][CH2:23][N:22]([CH2:21][CH2:20][C@:11]4([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:48]=[C:49]([C:51]([F:53])([F:54])[F:52])[CH:50]=[C:3]([C:2]([F:1])([F:55])[F:56])[CH:4]=5)[CH2:12]4)[CH2:27][CH2:26]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[CH3:47])=[CH:58][CH:59]=1
Reactant: CN(CCCC(=O)O)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: Nc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CCCC(=O)Nc1ccc(N)cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
The compound (163 mg, 0.206 mmol) obtained in Example 63e and benzene-1,4-diamine (111 mg, 1.03 mmol) were suspended in a mixed solvent of dichloromethane (8 mL) and acetonitrile (8 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59.0 mg, 0.309 mmol) and triethylamine (0.057 mL, 0.41 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59.0 mg, 0.309 mmol) and 4-N,N-dimethylaminopyridine (0.5 mg, 0.004 mmol) were further added, and the mixture was stirred at room temperature for 13 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and dichloromethane was added (×2) to separate the layers. The resulting organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→0:1, v/v) to give the title compound (141 mg; yield, 78%) as a light pink solid.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[S:25][C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: Clc1nc2ccccc2s1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nc4ccccc4s3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-benzothiazole. MS (ESI) mass calcd. for C26H23N3OS, 425.56; m/z found, 426.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([OH:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC=C)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]1([CH:7]([OH:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH:7]([O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=COC(=O)CCCCC
Agent: CCOC(=O)CC(O)c1ccccc1
Product: CCCCCC(=O)OC(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 35 h

Procedure:
The mixture of 5.0 g (25.7 mmol) of ethyl 3-phenyl-3-hydroxypropionate, 1.83 g (13 mmol) of vinyl caproate and 1.0 g of lipase PS was stirred at room temperature for 35 hours. After the lipase was removed by filtration, the filtrate was eluted by column chromatography (eluting solution; 9/1 of toluene/ethyl acetate) to obtain 2.2 g (>99%ee) of (-)-ethyl 3-phenyl-3-hydroxypropionate and 4.1 g (about 90%ee) of (+)-ethyl 3-phenyl-3-hexanoyloxypropionate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH:17]1([C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)[CH2:19][CH2:18]1
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Oc2ccc(C3CC3)cn2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A mixture of the compound (5.00 g) obtained in step (1) above, cyclopropylboronic acid (2.01 g), palladium(II) acetate (201 mg), tripotassium phosphate (13.4 g), tricyclohexylphosphine (0.6 mol/L, solution in toluene, 30.0 mL), toluene (95.0 mL) and water (5.0 mL) was stirred at 100° C. for 3 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter the crude product was adsorbed on diatomaceous earth, with the solvents being distilled off under reduced pressure. The crude product adsorbed on the diatomaceous earth was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-63:37) to give the titled compound as a yellow oil (3.89 g).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[N:16]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>CN(C=O)C>[F:55][C:56]([F:60])([F:59])[CH2:57][NH:58][C:18]([C:14]1[N:15]([CH3:17])[N:16]=[C:12]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH2:21][OH:22])[CH:13]=1)=[O:20]
Reactant: CCCCc1noc(CO)c1COc1cc(C(=O)O)n(C)n1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1noc(CO)c1COc1cc(C(=O)NCC(F)(F)F)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 5-(3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.16 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (57 mg, 0.18 mmol), N,N-diisopropyl ethyl amine (138 μL, 0.8 mmol) and 2,2,2-trifluoroethylamine HCl (24 mg, 0.18 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (47 mg, 75%) as a colorless oil. MS: m/e=391.2 [M+H]+.\