Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:26][CH:27]=[CH2:28])[CH2:10][C:11]([N:13]2[C@@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][O:15][C:14]2=[O:25])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C([C@@H](C=CC)CC(O)=O)C=CC=1Cl.C([C@H]1COC(=O)N1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CC(C1C=C(C(C)C)C(S([N:83]=[N+:84]=[N-:85])(=O)=O)=C(C(C)C)C=1)C>C1COCC1.O.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:26][CH:27]=[CH2:28])[C@H:10]([N:83]=[N+:84]=[N-:85])[C:11]([N:13]2[C@@H:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:16][O:15][C:14]2=[O:25])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: C=CC[C@@H](CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: CC=C[C@@H](CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1N[C@@H](Cc2ccccc2)CO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.03 h
Yield: 81 %

Procedure:
A solution of 3-(3(S)-(3,4-dichlorophenyl)-1-oxo-5-hexenyl)-4(S)-benzyl-2-oxazolidinone (190 mg, 0.45 mmol; prepared from 3-(R)-(3,4-dichlorophenyl)-hex-4-enoic acid (from Step B above) and 4(S)-benzyl-2-oxazolidinone according to the procedure of Evans, D. A.; et. al. J. Am. Chem. Soc. 1990, 112, 4011-4030) in THF (2.5 mL) was added to a solution of KHMDS (1.0 mL of 0.5M in PhCH3, 0.50 mmol), and THF (1.5 mL) at -78° C. The reaction was maintained at -78° C. for 30 min whereupon a solution of trisyl azide (177 mg, 0.57 mmol) and THF (1.5 mL) was added. The mixture was stirred for 2 min and HOAc (0.13 mL, 4.6 mmoL) was added. The reaction mixture was stirred 1 h in a 30° C. water bath, whereupon it was diluted with H2O (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were washed with sat. aq. NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, 15-25% EtOAc/hexanes) to afford the title compound (169 mg, 81%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(N(C)C)[CH2:8][CH2:7][C:6](F)(F)[CH2:5][CH2:4]1.C([O:21]C1(OC)C=CC(C(O)=O)=CC1OC)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]([NH2:1])(=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C1(CN)CCC(F)(F)CC1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-(aminomethyl)-4,4-difluoro-N,N-dimethylcyclohexanamine represented by Formula 105 (190 mg, 0.99 mmol) was slowly added to a solution of 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (327.66 mg, 1.14 mmol) and diisopropylethylamine (0.70 mL, 3.95 mmol) in DMF (7 mL) at room temperature. The reaction mixture was cooled to 0° C. and, after adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 375.75 mg, 0.99 mmol) thereto, agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (20 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in an alkalinized benzamide compound represented by Formula 11. HCl in MeOH (1.25 M, 0.75 mL, 0.93 mmol) was added to the alkalinized benzamide compound (360 mg, 0.78 mmol) in MeOH (5 mL) at room temperature. The reaction mixture was agitated at room temperature for 3 hours, the reaction solvent was removed under reduced pressure, and the remaining solids were filtered and washed with hexane to produce a benzamide salt compound represented by Formula 15 as a desired product (VVZ-016; 370 mg, 75% yield).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:24]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:24]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[O:25])[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C

Procedure:
2.43 Grams of Z-Asn-Leu-Gln-NHNHBoc was suspended in 80 ml of methanol, a small amount of palladium black was added to the suspension, and the suspension was stirred for 18 hours under the condition of introducing hydrogen gas. After completion of the reaction, the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure to remove the solvent, the residue obtained was dried under a reduced pressure in a desiccator to obtain the desired product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][CH:36]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:12](=[O:14])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([C:22]([F:23])([F:25])[F:24])[CH:7]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[N:37][CH:36]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCCO2)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A solution of 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared as in Example 12, 300 mg, 0.79 mmol) in methylene chloride (6 mL) was treated with N,N-dimethylformamide (7 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.48 mL, 0.95 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (6 mL) and was treated dropwise with a solution of 6-aminonicotinic acid methyl ester (252 mg, 1.67 mmol) in tetrahydrofuran (5 mL) and 2,6-lutidine (0.48 mL, 3.95 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (100 mL) and extracted with methylene chloride 3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 7/3 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (227 mg, 55%) as a white foam: EI-HRMS m/e calcd for C23H25F3N2O6S (M+H)+ 537.1277. found 537.1284.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH:21]([CH3:23])[CH3:22]>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH:21]([CH3:23])[CH3:22])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: CC(C)C(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Agent: Cl
Product: CC(C)c1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 60 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and isobutyramidine hydrochloride. Yield: 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5]P(=O)([O-])[O-].[Li]CCCC.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)CCCC#C>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([CH:5]=[CH:23][CH2:22][CH2:21][CH2:20][C:19]#[CH:18])[CH:3]=1
Reactant: CCCCCC
Reactant: O=P([O-])([O-])Cc1cccc(Cl)c1
Agent: C#CCCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCC=Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
An oven-dried 250 mL three-necked round-bottomed flask under a nitrogen atmosphere was charged with 3-chlorobenzylphosphonate (4.74 g, 18 mmol) and dry THF (60 mL). The solution was cooled to 0° C. in an ice bath for 15 min, then n-BuLi (12 mL of a 1.6 M n-hexane solution, 19 mmol) was added dropwise over 10 min, via syringe. The mixture was stirred at 0° C. for 30 min, then 5-hexynal (1.0 g, 10 mmol) in dry THF (40 mL) was added. The solution was warmed to room temperature and was stirred for 3 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:9). The reaction was quenched by adding saturated aqueous ammonium chloride solution (70 mL). The layers were separated and the aqueous phase was extracted with ether (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, gravity filtered and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 0.5:9.5, to provide 1.9 g of the title compound as a colorless oil in a 93% yield.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[C:12]1(/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccccc1)N[C@@H]1CN2CCC1CC2

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-phenylpropenoic acid; MS (ES+) 257 (MH+).
Reaction SMILES: C(S(C1C=CC(C2N=C(C3OC(C4SC(CNC)=CC=4)=NN=3)C(N)=NC=2)=CC=1)(=O)=O)(C)C.C(S(C1C=CC(C2N=C(C3OC(C4SC=C(CNC)C=4)=NN=3)C(N)=NC=2)=CC=1)(=O)=O)(C)C.F[CH:66](F)[CH2:67][NH:68][CH2:69][C:70]1[S:74][C:73]([C:75]2[O:79][C:78]([C:80]3[C:81]([NH2:98])=[N:82][CH:83]=[C:84]([C:86]4[CH:91]=[CH:90][C:89]([S:92]([CH:95]([CH3:97])[CH3:96])(=[O:94])=[O:93])=[CH:88][CH:87]=4)[N:85]=3)=[N:77][N:76]=2)=[CH:72][CH:71]=1.C(NCC1SC(C2OC(C3C(N)=NC=C(C4C=CC(S(C(C)C)(=O)=O)=CC=4)N=3)=NN=2)=CC=1)(C)C>>[CH2:67]([NH:68][CH2:69][C:70]1[S:74][C:73]([C:75]2[O:79][C:78]([C:80]3[C:81]([NH2:98])=[N:82][CH:83]=[C:84]([C:86]4[CH:91]=[CH:90][C:89]([S:92]([CH:95]([CH3:97])[CH3:96])(=[O:94])=[O:93])=[CH:88][CH:87]=4)[N:85]=3)=[N:77][N:76]=2)=[CH:72][CH:71]=1)[CH3:66]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CNCC(F)F)s4)o3)n2)cc1
Agent: CC(C)NCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)s1
Agent: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)s1
Agent: CNCc1csc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)c1
Product: CCNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)s1

Procedure:
Compound IA-140 5-(4-isopropylsulfonylphenyl)-3-[5-[5-(methylaminomethyl)-2-thienyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine 1H NMR (400 MHz, DMSO) d 1.22 (d, 6H), 2.65 (s, 3H), 3.42-3.46 (m, 1H), 4.5 (s, 2H), 7.5 (d, 1H), 8.0 (d, 1H), 8.05 (d, 1H), 8.4 (d, 1H), 9.05 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 471.3 Compound IA-226 5-(4-isopropylsulfonylphenyl)-3-[5-[4-(methylaminomethyl)-2-thienyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine 1H NMR (400 MHz, MeOD) d 1.4 (d, 6H), 2.8 (s, 3H), 4.4 (s, 2H), 3.3-3.4 (m, 1H), 8.0-8.1 (m, 3H), 8.12 (s, 1H), 8.35 (d, 2H) and 9.0 (s, 1H) ppm; MS (ES+) 471.3 Compound IA-236 3-[5-[5-[(2,2-difluoroethylamino)methyl]-2-thienyl]-1,3,4-oxadiazol-2-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine 1H NMR (400 MHz, DMSO) d 1.25 (d, 6H), 3.4-3.6 (m, 3H), 4.55 (s, 2H), 6.2-6.5 (m, 1H), 7.5 (d, 1H), 7.8-8.1 (m, 4H), 8.45 (d, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 521.3 Compound IA-248 3-[5-[5-[(isopropylamino)methyl]-2-thienyl]-1,3,4-oxadiazol-2-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine 1H NMR (400 MHz, DMSO) d 1.25 (m, 6H), 1.35 (d, 6H), 3.4-3.6 (m, 2H), 4.6 (s, 2H), 7.5 (d, 1H), 7.95-8.1 (m, 4H), 8.45 (d, 2H), 8.9-9.0 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 499.4
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][NH:4]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:26][C:25]([F:27])([F:28])[C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:4]2[CH2:5][CH2:6][N:7]([S:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)(=[O:11])=[O:10])[CH2:8][C@@H:3]2[CH3:2])=[CH:23][CH:22]=1)([OH:30])[CH3:29]
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 85.8 %

Procedure:
A 100 mL round-bottomed flask was charged with (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (10.0 g, 35.4 mmol), 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (16.7 g, 61.9 mmol, Example 27, step 1), sodium tert-butoxide (13.6 g, 141 mmol) and 20 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.98 g, 4.24 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (1.94 g, 0.265 mmol, Strem Chemical Inc, Newburyport, Mass.). The mixture was heated at 100° C. for 12 h. After that time, the reaction was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined extracts were dried (MgSO4) and concentrated and purified by column chromatography (330 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (13.20 g) as a mixture of two isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:18]([C:23]1[CH:24]=[CH:25][C:26]([O:14][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)=[CH:27][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 99.9 %

Procedure:
To 150 mL of methylene chloride, 12.6 g (55.0 mmol) of 4-benzyloxy-benzoic acid, 8.2 g (50.0 mmol) of 4-pentylphenol, and 0.61 g (5.0 mmol) of 4-dimethylaminopyridine were added. Then, 11.4 g (55.0 mmol) of dicyclohexylcarbodiimide was added while stirring the mixture under argon. After being stirred for 6 hours under argon, the mixture was filtered and the filtered liquid was concentrated. The residue was purified by silica-gel column chromatography. As a result, 18.7 g of a white solid was obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:15]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.FC(F)(F)C1C=CN=C(OC)C=1.BrC1C(C(F)(F)F)=C([Li])C(OC)=NC=1.FC(F)(F)C1C=CN=C(OC)C=1[Li].[CH3:65][O:66][C:67]1[C:74]([O:75][CH3:76])=[C:73]([O:77][CH3:78])[CH:72]=[C:71]([CH3:79])[C:68]=1[CH:69]=[O:70]>O1CCCC1.O>[CH3:65][O:66][C:67]1[C:74]([O:75][CH3:76])=[C:73]([O:77][CH3:78])[CH:72]=[C:71]([CH3:79])[C:68]=1[CH:69]([C:16]1[C:17]([O:20][CH3:21])=[N:18][CH:19]=[C:14]([Br:13])[C:15]=1[C:22]([F:25])([F:23])[F:24])[OH:70]
Reactant: COc1cc(C(F)(F)F)c(Br)cn1
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: COc1cc(C(F)(F)F)ccn1
Agent: [Li]CCCC
Agent: [Li]c1c(C(F)(F)F)ccnc1OC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1cc(C)c(C(O)c2c(OC)ncc(Br)c2C(F)(F)F)c(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
17.1 ml of n-butyllithium (1.57 mol/l hexane solution) was dropwise added at 0° C. to a solution having 3.80 ml (27.1 mmol) of diisopropylamine dissolved in 50 ml of tetrahydrofuran, followed by stirring for 30 minutes. The solution was cooled to −78° C., and a solution having 5.81 g of the mixture of 5-bromo-4-trifluoromethyl-2-methoxypyridine and 4-trifluoromethyl-2-methoxypyridine (molar ratio 55:45) obtained in Step (c) dissolved in 10 ml of tetrahydrofuran was added, followed by stirring for 45 minutes to prepare a mixture of 5-bromo-4-trifluoromethyl-2-methoxy-3-pyridyllithium and 4-trifluoromethyl-2-methoxy-3-pyridyllithium. A solution having 5.51 g (26.2 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 15 ml of tetrahydrofuran was added, followed by stirring for 1 hour. Water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 5.02 g of (2,3,4-trimethoxy-6-methylphenyl)(5-bromo-4-trifluoromethyl-2-methoxy-3-pyridyl)methanol.
Reaction SMILES: C(O)C.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[CH:9]([N:12]([CH:57]([CH3:59])[CH3:58])[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C:25]([OH:56])([C:32]1[N:33]=[CH:34][N:35]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:36]=1)[CH2:26][C:27](OCC)=[O:28])[CH:19]=[CH:18]2)=[O:14])([CH3:11])[CH3:10]>O.C1COCC1>[OH:56][C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:13]([N:12]([CH:57]([CH3:59])[CH3:58])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH:24]=[CH:23]2)([C:32]1[N:33]=[CH:34][N:35]([C:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=1)[CH2:26][CH2:27][OH:28]
Reactant: CCOC(=O)CC(O)(c1ccc2cc(C(=O)N(C(C)C)C(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc2cc(C(O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1)C(C)C
Reaction time: 0.42 h
Yield: 89 %

Procedure:
1.5 mL of ethanol and 1.5 mL of THF were added to 0.11 g (2.94 mmol, 8 eq) of sodium borohydride. 0.16 g (1.47 mmol, 4 eq) of calcium chloride was added at 0° C., and the mixture was stirred at 0˜3° C. for 25 minutes. 0.25 g (0.37 mmol) of ethyl 3-{6-[(diisopropylamino)carbonyl]-2-naphthyl}-3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate was added at 0° C. The mixture was stirred at 20˜23° C. for 8 hours and 15 minutes. 13 mL of water was added dropwise, and the mixture was stirred at 25° C. for 15 minutes. Crystals were filtered, and washed with water. Vacuum drying (50° C.) to a constant weight afforded 0.21 g of 6-[1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N,N-diisopropyl-2-naphthamide (yield 90%).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH:13]([F:15])[F:14])=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:9]2[CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:34][CH:35]1[C:43]2[C:38](=[CH:39][C:40](B(O)O)=[CH:41][CH:42]=2)[CH2:37][N:36]1[C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[CH:16]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:40]4[CH:39]=[C:38]5[C:43](=[CH:42][CH:41]=4)[CH:35]([CH3:34])[N:36]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:37]5)[C:11]=3[O:12][CH:13]([F:15])[F:14])[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)[CH2:18][CH2:17]1
Reactant: CC1c2ccc(B(O)O)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(Br)ccc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C4C)ccc2c1=O
Yield: 59.4 %

Procedure:
In 7 ml of toluene was suspended 0.70 g of ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate, followed by adding thereto 3 ml of ethanol, 1.74 ml of a 2 M aqueous sodium carbonate solution, 0.80 g of (+)-1-methyl-2-trityliso-indoline-5-boronic acid and 0.05 g of bis(triphenyl-phosphine)palladium(II) chloride, and the resulting mixture was heated under reflux for 2 hours under a nitrogen atmosphere. The reaction mixture was added to a mixed solvent of 10 ml of ethyl acetate and 10 ml of water, and the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=1:1) to obtain 0.72 g of ethyl (+)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2-trityliso-indolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate as colorless crystals.