Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH2:6][C:5]2=[O:22].Br[Zn][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH2:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH2:6][C:5]2=[O:22])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccc(Br)cc21
Reactant: CC(C)(C)C[Zn]Br
Product: CC(C)(C)Cc1ccc2c(c1)C(=O)CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzyl 6-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3.10 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.35 g) were combined in a round bottom flask. The mixture was put under high vacuum and purged with nitrogen. A 0.5 M solution of bromo(neopentyl)zinc (55 mL) prepared using the procedure of Negishi et al. Tet Lett. 1983, 24, 3823-3824, was added to the mixture and was stirred at room temperature for two days. The reaction had not gone to completion, so an additional 10 mL of bromo(neopentyl)zinc solution was added and the mixture was stirred for one additional day. The mixture was then partitioned between ethyl acetate and aqueous ammonium chloride, dried with magnesium sulfate, filtered, and concentrated. Silica gel chromatography using a 20% ethyl acetate in heptane solvent solution gave 2.17 g of the title compound. MS (ESI+) for C22H25NO3 m/z 353.17 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.C(N(CC)CC)C>CO>[F:1][C:2]([F:7])([F:6])[C:3](=[N:5][NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)[NH2:4]
Reactant: N=C(N)C(F)(F)F
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reaction time: 6 h
Yield: 108.3 %

Procedure:
To a solution of trifluoroacetoamidine (4.24 g, 37.8 mmol) in methanol (20 mL), were added 4-methoxyphenylhydrazine hydrochloride (4.72 g, 27 mmol) and then triethylamine (3.77 mL, 27 mmol) at room temperature. The mixture was stirred for 6 hours. The solvent was removed under reduced pressure. 20 mL of water and 50 mL of ethyl acetate-tetrahydrofuran (9:1) were added to the residue and the organic layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate-tetrahydrofuran (9:1). A combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (6.82 g, 108.2% yield). The residue was used for the next reaction without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[C:37]1([C@H:47]([NH2:49])[CH3:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([NH:49][C@@H:47]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)[CH3:48])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=C(O)C1COCC(=O)N1Cc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@@H](NC(=O)C1COCC(=O)N1Cc1ccccc1)c1cccc2ccccc12
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a stirred solution of 4-benzyl-5-oxomorpholine-3-carboxylic acid (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580) (500 mg, 2.12 mmole) in dichloromethane (15 mL), HOBt (430 mg, 3.19 mmole) and DIPC (287 μL, 3.19 mmole) were added at room temperature. The reaction mixture was stirred for 15 min, then (R)-1-(naphthalen-1-yl)ethanamine (400 μL, 2.57 mmole) was added to the reaction mixture and stirred overnight. Solid separated out was filtered, washed with dichloromethane (2×15 mL), filtrate collected and washed with brine solution (2×15 mL) and DM water. The organic layer was concentrated to get crude amide and which was further purified by flash chromatography (n-Hexane:ethyl acetate, 8:3) to get title compound (500 mg). m/z 389.2
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(OCCBr)cc1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-4-fluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1 H), 7.80 (d, J=8.7 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), −7.11-6.97 (m, 2H), 6.83-6.71 (m, 2H), 4.64 (t, 2H), 4.20 (t, 2H), 2.88 (t, 2H), 1.70-1.58 (m, 2H), 0.94 (t, J=7.3 Hz, 3H); MS (ES) m/z 357 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[O:25][N:24]=[C:23]([OH:26])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:15]1([C:21]2[O:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[C:23](=[O:26])[CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Oc1cc(-c2ccccc2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(-c2ccccc2)on1-c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 80.9 %

Procedure:
After mixing 22.6 g of 4-chloro-3-nitrobenzotrifluoride, 19.3 g of 5-phenyl-3-hydroxyisoxazole, 16.8 g of potassium carbonate, and 150 ml of dimethyl sulfoxide, the reaction was performed for 3 hours at 70° C. After the reaction was over, the reaction mixture was cooled and poured into water. Crystals thus deposited were recovered by filtration and recrystallized from a mixture of dimethylformamide and methanol to provide 28.4 g of the desired product with a yield of 95.0%. The melting point thereof was 185° C. to 187° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([CH3:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[C:20]([C:15]1[S:14][C:13]([CH2:12][CH:11]([O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH3:18])=[CH:17][CH:16]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cc2cccs2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CC(C)OS(=O)(=O)c2ccc(C)cc2)s1

Procedure:
2-(p-Toluenesulphonyloxy)-propylthiophene was reacted with acetyl chloride and aluminium trichloride in methylene chloride to give 5-acetyl-2-(p-toluenesulphonyloxy)-propylthiophene. With sodium azide in DMSO there was obtained therefrom 5-(3-azidopropyl)-2-thienyl methyl ketone. Oxidation with sodium hydrobromite gave 5-(3-azidopropyl)-2-thiophenecarboxylic acid, m.p. 71°-72°. Reaction of this acid with thionyl chloride and subsequent treatment with conc. ammonia yielded 5-(3-azidopropyl)-2-thiophenecarboxamide, m.p. 85°-87°. There was obtained therefrom after treatment with triphenylphosphine and hydrolysis 5-(3-aminopropyl)-2-thiophenecarboxamide, m.p. 143.5°-144° (from water).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH:24]=[O:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][OH:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CO)s2)c1
Yield: 86.5 %

Procedure:
To 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carbaldehyde (Example 88, Step 1, 0.15 g, 0.41 mmol) was added methanol (4 mL) and sodium borohydride (0.016 g, 0.41 mmol). Once complete, the reaction was diluted with ethyl acetate, washed carefully with aqueous saturated ammonium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to yield [5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol (0.13 g, 85%). MS ESI: [M+H]+ m/z 366.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=4.8, 1H), 7.98 (s, 2H), 7.45 (s, 1H), 7.28 (d, J=4.9, 1H), 7.17 (s, 1H), 6.10 (t, J=5.8, 1H), 4.71 (d, J=5.8, 2H), 2.31 (s, 3H). rhSYK activity=+++
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)([Cl:12])=O>>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1
Product: O=C(Cl)c1cccnc1

Procedure:
Thionyl chloride (10 mL) was added to nicotinic acid (370 mg, 3.0 mmol) and the mixture was stirred under reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried in vacuum to yield nicotinoyl chloride. Methyl 2-amino-3-hydroxybenzoate (167 mg, 1.0 mmol) and pyridine (240 mg, 3.0 mmol) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. Then nicotinoyl chloride (420 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 30 min then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20: to 5:1) to obtain methyl 2-hydroxy-3-(nicotinamido)benzoate as a solid (215 mg, yield 79%). LC-MS (ESI) m/z 273 [M+1]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH2:66])[CH:61]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:61]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 86% yield: LCMS (ESI) m/z 432 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:47]1([C@H:53]([NH2:55])[CH3:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:55][C@@H:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C[C@@H](N)c1ccccc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(+)-1-phenylethylamine (Aldrich) to give the title product. LC-MS (ES+) 768 [(M+H)+].
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[C:23]([C:27]1[CH:67]=[CH:66][C:30]([C:31]([NH:33][C@@H:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([NH:48][NH:49][C:50](=O)[C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:53][CH:52]=3)=O)=[CH:42][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([C:27]1[CH:67]=[CH:66][C:30]([C:31]([NH:33][C@@H:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]3[S:10][C:50]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:53][CH:52]=4)=[N:49][N:48]=3)=[CH:42][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2nnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)s2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
Prepared using INT-3: To a stirring solution of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (65.7 mg, 0.16 mmol) in THF (3 mL) was added (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbonyl)phenyl)propanoate INT-3 (100.0 mg, 0.16 mmol) and the mixture heated to 65° C. After 1 h, the reaction mixture was concentrated and purified by column chromatography (10-100% EA in iso-hexanes) to afford 37.0 mg (29%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoate as a yellow solid. LCMS-ESI (m/z) calculated for C36H43N3O4S: 613.8; no ion observed, tR=3.31 min. (Method 4).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH2:19][CH3:20])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[CH:1]([N:14]1[CH2:17][C:16]([CH2:19][CH3:20])([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(OC)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
To a DMF (50 mL) solution of 1-benzhydryl-3-ethylazetidin-3-ol (2.18 g, 8.15 mmol), methyl iodide (0.51 mL, 8.15 mmol) and 60% sodium hydride (0.65 g, 16.31 mmol) were added at 0° C. under a nitrogen stream, and the mixture was stirred for 1.5 hours at the same temperature. This reaction liquor was poured onto ice water, and the mixture was extracted with ethyl acetate. The extract was washed with ice water and saturated brine in this order, and then dried over anhydrous sodium sulfate. Sodium sulfate was separated by filtration, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 25S, ethyl acetate/n-hexane=1/9-4/6), to obtain the title compound (1.18 g, 52%) as an oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:9][CH:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([F:20])[C:15]([F:19])=[C:16]([F:18])[CH:17]=2)[CH3:11])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC(NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)c(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1cc(F)c(F)c(F)c1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 2.71 g of N-[(4-chlorophenyl)-(3-nitrophenyl)methyl]-N-[1-(3,4,5-trifluorophenyl)ethyl]amine [prepared as described in step (a) above], 3.06 g of nickel chloride hexahydrate and 973 mg of sodium borohydride were reacted, to obtain 946 mg of isomer A and 691 mg of isomer B of the title compound as a colorless oil and white solid, respectively.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].[OH-].[Na+].C(OCC)(=O)C.S([O-])(O)(=O)=O.[Na+]>CO>[CH2:1]([C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)ccc(C(=O)OC)c1OCOC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCc1c(OC)ccc(C(=O)O)c1OCOC
Yield: 95.2 %

Procedure:
1.32 g of methyl 3-allyl-4-methoxy-2-(methoxymethoxy)benzoate was dissolved in 12 ml of methanol, and the obtained mixture was then stirred while cooling on ice. Thereafter, 2.97 ml of a 5 N sodium hydroxide aqueous solution was added to the reaction mixture, and the obtained mixture was then stirred at room temperature overnight. The reaction solution was cooled on ice, and ethyl acetate was added thereto. Then, the obtained mixture was adjusted to be approximately pH 5 with addition of a 5% sodium hydrogen sulfate aqueous solution. An organic layer was separated, and a water layer was extracted with ethyl acetate. The obtained organic layers were gathered. The combined organic layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, so as to obtain 1.19 g of the subject compound. This compound was used in the following reaction without further purification.
Reaction SMILES: [OH-].[Na+].C([O:10][C:11]1[CH:47]=[CH:46][C:45]([O:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)=[CH:44][C:12]=1[C:13]([NH:15][C:16]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:34][C:17]=1[C:18]([O:20]C1CCN(C(OC(C)(C)C)=O)CC1)=[O:19])=[O:14])C1C=CC=CC=1>CO.O1CCOCC1>[C:58]([O:57][C:55]([N:52]1[CH2:53][CH2:54][CH:49]([O:48][C:45]2[CH:46]=[CH:47][C:11]([OH:10])=[C:12]([CH:44]=2)[C:13]([NH:15][C:16]2[CH:37]=[C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:35]=[CH:34][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])[CH2:50][CH2:51]1)=[O:56])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc(-c3ccccc3)cc2NC(=O)c2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc2OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.13 mL) was added to a solution mixture of the obtained tert-butyl 4-(2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzamido)-4-phenylbenzoyloxy)piperidine-1-carboxylate (0.072 g) in methanol (1 mL) and dioxane (1 mL), followed by stirring at room temperature for 1 hour. A 2 mol/L aqueous solution of sodium hydroxide (0.089 mL) was added to the reaction mixture, followed by heating to reflux for 20 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 3.5 with a 10% aqueous solution of citric acid, ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution mixture of the obtained residue, 10% palladium-carbon (0.039 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.024 g of 2-(5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]=4[N:11]3[CH2:10][CH2:9]2)=[C:4]([Cl:26])[CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>O1CCCC1>[Cl:26][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[C:12]2=[N:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]=3[N:11]2[CH2:10][CH2:9]1)[CH:34]=[O:35]
Reactant: CN(C)C=O
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(C=O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromo-2-chlorophenyl)-8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (204.6 mg, 0.451 mmol) in tetrahydrofuran (3.0 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.34 mL, 0.542 mmol) at −78° C. The reaction mixture was stirred at same temperature for 1 hr, to the mixture was added N,N-dimethylformamide (0.17 mL, 2.255 mmol). The reaction mixture was allowed to warm to 0° C. and stirred for 1 hr. The reaction mixture was quenched with aqueous saturated ammonium chloride at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow amorphous (89.5 mg, 0.156 mmol, 49%).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:8]([Mg]Br)[CH2:9][CH:10]=[CH2:11]>C1COCC1>[CH2:5]=[CH:4][CH2:3][CH2:2][C:1](=[O:6])[CH2:11][CH2:10][CH:9]=[CH2:8]
Reactant: C=CCC[Mg]Br
Reactant: C=CCCC(=O)Cl
Solvent: C1CCOC1
Product: C=CCCC(=O)CCC=C
Temperature: -78 °C

Procedure:
In an oven-dried 500 mL round-bottomed flask (t=g) was added 4-Pentenoyl chloride (6.04 mL, 54.7 mmol) in THF (80 mL) to give a tan solution. After cooling to −78° C., 3-Butenylmagnesium bromide (115 mL, 57.5 mmol) was added via syringe over 90 min. After warming to room temperature for 3 hours, the reaction was quenched with saturated NH4Cl solution. THF was stripped off and the remaining was extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4, and concentrated to a slightly yellow oil. Purification (two batches) by FCC up to 40% Et2O/hexane afforded the product as a colorless oil: (5.13 g, 68%). 1H NMR (400 MHz, CDCl3) δ 5.84-5.68 (m, 2H), 5.05-4.90 (m, 4H), 2.49 (t, J=7.4 Hz, 4H), 2.35-2.20 (m, 4H).