Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([OH:30])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(=O)C(C)(C)C.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCC(O[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(NCCCCC(O[PH](=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
An acetonitrile (29.7 ml) solution of the benzyl 6-benzyloxycarbonylamino-2-((hydroxyphosphinoyl)oxy)hexanoate (2.97 g) obtained in the above step (a) was added with benzyl alcohol (3.53 ml) and a pyridine (11.9 ml)-acetonitrile (11.9 ml) mixed solution of pivaloyl chloride (4.20 ml), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction system, and the organic substances were extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and pyridine was removed by azeotropic distillation using toluene. The residue was roughly purified by silica gel (Kanto Kagaku Co., 60 N, spherical, neutral) chromatography (300 g, hexane:ethyl acetate=3:2) to obtain crude benzyl 6-benzyloxycarbonylamino-2-((benzyloxyphosphinoyl)oxy)hexanoate (2.45 g, 68%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:17])[C:7]([CH2:10][N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])=[N:8][CH:9]=1)=[O:4].O.O.[OH-].[Li+:21].[ClH:22]>CO>[CH3:16][O:15][CH2:14][CH2:13][N:11]([CH2:10][C:7]1[N:6]([CH3:17])[C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=1)[CH3:12].[Cl-:22].[Li+:21]
Reactant: Cl
Reactant: COCCN(C)Cc1ncc(C(=O)OC)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCN(C)Cc1ncc(C(=O)O)n1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (380 mg, 1.58 mmol) were dissolved in methanol (4.5 ml) and treated with water (0.39 ml) and lithium hydroxide monohydrate (80 mg, 1.89 mmol) and stirred for 18 h at ambient temperature. The reaction mixture is the carefully acidified at 0° C. with 1N hydrochloric acid and evaporated to dryness. The title compound was obtained as mixture with lithium chloride and used without further purification. Light brown solid (>98% yield by 1H-NMR). MS: m/e=226(M−H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:19])=[C:5]([CH:14]=[C:15]([F:18])[C:16]=1[Cl:17])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])#[N:2].[CH:20](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[C:1]([C:3]1[C:4]([Cl:19])=[C:5]([CH:14]=[C:15]([F:18])[C:16]=1[Cl:17])[C:6]([C:8](=[CH:20][NH:40][CH:37]1[CH2:39][CH2:38]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])#[N:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)c(C#N)c1Cl
Reactant: CCOC(OCC)OCC
Reactant: NC1CC1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)c(C#N)c1Cl
Reaction time: 2 h
Yield: 70 %

Procedure:
76.0 g of ethyl 3-cyano-2,4-dichloro-5-fluorobenzoylacetate (0.25 mol), 66.6 g of triethyl orthoformate (0.45 mol) and 77.4 g of diacetyl oxide (0.72 mol) were stirred at 150° C. for 2.5 hours. Fractions having a lower boiling point were evaporated under reduced pressure. To the residue was added 250 ml of anhydrous ethanol. 14.5 g of cyclopropylamine (0.25 mol) was added to the solution and the reaction was then carried out for 2 hours. The resulting mixture was filtered under suction. The residue was recrystallized from a mixture of petroleum ether and cyclohexane to yield 65.0 g (0.175 mol) of ethyl 2-(3-cyano-2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate in 70.1% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]2[N:18]=[CH:19][CH:20]=[CH:21][C:6]1=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=4[O:9][CH2:8][C:7]4[N:18]=[CH:19][CH:20]=[CH:21][C:6]3=4)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution the product of step 2 (1.1 g) in DMF (15 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (0.81 g) and potassium carbonate (0.53 g) and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound as major regioisomer (0.86 g) and minor one (0.05 g).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:21])([F:20])[C:10]1[C:11]([C:15]([O:17]CC)=[O:16])=[CH:12][NH:13][CH:14]=1.I[CH2:23][CH3:24]>O>[CH2:23]([N:13]1[CH:14]=[C:10]([C:9]([F:8])([F:20])[F:21])[C:11]([C:15]([OH:17])=[O:16])=[CH:12]1)[CH3:24]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a mixture of 60% sodium hydride (212 mg, 5.31 mmol) and N,N-dimethylformamide (25 mL) was added with stirring at 0° C. ethyl 4-(trifluoromethyl)-1H-pyrrole-3-carboxylate (1.00 g, 4.83 mmol), and the mixture was stirred at room temperature for 30 min. Iodoethane (581 μL, 7.24 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (4 mL) and 8N aqueous sodium hydroxide solution (2 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr and at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give the title compound (710 mg, 71%) as a white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[O:12])=O)(C)(C)C.Cl.NCCCC(OC1C(C)=CC=CC=1C)=O>>[NH2:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Oc1ccc(OC(F)(F)F)cc1
Agent: Cc1cccc(C)c1OC(=O)CCCN
Agent: Cl
Product: NCCC(=O)Oc1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared from 4-(trifluoromethoxy)phenyl N-(tert-butoxycarbonyl)-β-alaninate in a similar manner as described for 2,6-dimethylphenyl 4-aminobutanoate hydrochloride. Mass Spectrum M+H+ 251.10
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:17]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[Na].O>C(O)C>[CH2:1]([CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]([O:25][CH2:26][CH3:27])=[O:24])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(=O)OCC
Yield: 59 %

Procedure:
Then, 501 g of farnesyl bromide as mentioned above and 285 g of diethyl malonate in 1,500 ml of ethanol were subjected to a condensation reaction in the presence of 37.1 g of metallic sodium. The reaction mixture was poured into water and extracted with ether. The organic layer was dried over anhydrous sodium sulfate. After removing the solvent, the residue was fractionated in vacuo to give 378 g of diethyl farnesylmalonate, b.p. 155° - 160° C. (0.2 mmHg). This product was saponified and decarboxylated in 1,000 ml of ethanol with 204 g of potassium hydroxide. The reaction mixture was neutralized with hydrochloric acid and extracted with ether. After removing the solvent, the residue was fractionated in vacuo to give 218 g of farnesylacetic acid, b.p. 142° - 150° C. (0.2 mmHg). The gas chromatographic analysis using 5% of polyethylene glycol 20 M (PGE-20M. for short) on kieselguhr (60- 80 mesh) at 180° C. of the column temperature, indicated that the substance was a mixture of stereo-isomers, 16% of Δ4,8 -cis-isomer, 48% of Δ4 -cis-Δ 8 -trans- and Δ4 -trans-Δ 8 -cis-isomers, and 36% of Δ4 -trans-Δ 8 -trans-isomer. By further fractionation through a rectifying column with 40 theoretical plates, was obtained 56.5 g of Δ4,8 -trans-farnesylacetic acid, b.p. 147° - 149° C. (0.2 mmHg). This showed that the Δ4,8 -trans-isomer was recovered in a yield of 72% based on the amount contained in the mixture. Subsequently, 150 g of farnesylacetic acid, which was obtained as the first distillate, was isomerized by heating with 0.15 g of acetylacetonatoruthenium RU (AA)3 at 200° C. in a nitrogenous atmosphere. By gas chromatographic analysis, the ratio of Δ4,8 -cis-isomer, Δ4 -cis-Δ 8 -trans-isomer+ Δ4 -trans-Δ 8 -cis-isomer and Δ4,8 -trans-isomer was 23.3:69.7:7.0 in the starting farnesylacetic acid and was 17.7:52.9:29.4 after isomerization.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.Cl.[NH2:21][CH:22]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH2:25][N:24]([C:38]([N:40]2[CH2:49][CH2:48][C:43]3([O:47][CH2:46][CH2:45][O:44]3)[CH2:42][CH2:41]2)=[O:39])[CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([NH:21][CH:22]2[CH2:27][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)[CH2:25][N:24]([C:38]([N:40]3[CH2:41][CH2:42][C:43]4([O:47][CH2:46][CH2:45][O:44]4)[CH2:48][CH2:49]3)=[O:39])[CH2:23]2)=[O:16])[CH:17]=[CH:18][CH:19]=1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.59 ml (3.38 mmol) of N,N′-diisopropylethylamine and 248 mg (1.58 mmol) of 3-chlorobenzoic acid were added to a solution of the compound from Example 62A (500 mg, 1.06 mmol) in N,N′-dimethylformamide (18 ml). After addition of 522 mg (1.37 mmol) of HATU, the mixture was stirred at RT overnight. The reaction mixture was purified directly by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 414 mg (67% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([N+:21]([O-])=O)[CH:12]=3)=[CH:10][N:4]2[N:3]=1.CC(O)=O>[Fe].CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[C:13]([CH:12]=3)[NH2:21])=[CH:10][N:4]2[N:3]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 96.9 %

Procedure:
Iron (0.489 g) is added to a mixture of 6-chloro-2-[3-nitro-4-(trifluoromethyl)phenyl]imidazo[2,1-f]pyridazine (0.600 g, 1.75 mmol), HOAc (0.802 mL), EtOH-water (10 mL, 4:1). The mixture is heated at 80° C. for 2 hours, then cooled, concentrated, taken into sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (2×50 mL). Organic is dried and concentrated to give the title compound (530 mg), which is used without further purification. LCMS m/z=313.4 [M+H]+, tR=2.82 min.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2.[C:17](=[O:19])=[O:18].O>CCCCCC.C1COCC1>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([C:17]([OH:19])=[O:18])[C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2
Reactant: Fc1cc2cc[nH]c2cc1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Temperature: -75 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
1.25 ml (2 mmol) of a 1.6 M butyl lithium solution in hexane were diluted with 4 ml THF at −78° C. under nitrogen. 224 mg (2 mmol) of potassium-tert-butylate and then 156 mg (1 mmol) of 5,6-difluoro-1H-indol were added. The reaction was exothermal and an orange solution was obtained, which was stirred for 2 h at −75° C. Solid carbon dioxide was added at that temperature and the reaction mixture was allowed to warm to rt within 30 min. Water was added and the reaction mixture was extracted three times with diethyl ether. The aqueous layer was acidified with 1N aqueous HCl solution and extracted three times with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was stirred with n-hexane and a trace of diethyl ether for 15 min and filtered to yield 100 mg (51%) product as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): 13.6 (br, 1H), 11.2 (br, 1H), 7.85 (dd, 1H), 7.42 (s, 1H), 6.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]([O:20][CH2:21]Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:21][O:20][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]nc(I)c2c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (3.00 g, 9.26 mmol) was dissolved in N,N-dimethylformamide (150 ml) at 4° C. To the solution was added sodium hydride (60%, 519 mg, 12.98 mmol) in small portions. The flask was warmed to room temperature and stirred for 1 hour. To the mixture was added chloromethyl pivalate (2.29 ml, 15.78 mmol). The reaction mixture was stirred for 2 hours at room temperature, and quenched with methanol. Saturated ammonium chloride solution was added, and the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, and the organic layer was washed four times with. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in acetone. The solution was filtered and the solid material collected was discarded. The filtrate was concentrated in vacuo. The crude material was re-crystallized in ether to give 2.80 g (69%) of 2,2-dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. 1H-NMR (250 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.20 (s, 1H), 6.43 (s, 2H), 1.14 (s, 9H); MS m/z 437.8, 439.8 (M+H+).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1>>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 16.3 %

Procedure:
Using cyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methanol (0.14 g) synthesized in Example 17(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.15 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.04 g, 23%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:20](Cl)(Cl)[Cl:21].[CH3:24][CH:25]([CH3:49])[CH2:26][NH:27][C@H:28]1[CH2:33][C@@H:32]([C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:35])[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]1.C(=O)([O-])[O-:51].[K+].[K+]>C(#N)C.O>[ClH:21].[ClH:21].[CH3:24][CH:25]([CH3:49])[CH2:26][N:27]([C@H:28]1[CH2:33][C@@H:32]([C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:35])[CH2:31][NH:30][CH2:29]1)[C:20]([CH:8]1[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9]1)=[O:51]
Reactant: COCCCCn1c(C(Cl)(Cl)Cl)nc2cccc(C(=O)OC)c21
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCCN1c2c(cccc2C(=O)OC)NC1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Product: Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 2.5 %

Procedure:
Methyl 1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole-7-carboxylate (0.44 g) and tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (0.3 g) were dissolved in acetonitrile (5.0 ml) and water (5.0 ml), potassium carbonate (2.4 g) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10→10:0) was concentrated under reduced pressure, and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was dissolved in 4N hydrochloric acid-ethyl acetate solution, and the mixture was stirred for 30 min. The reaction mixture was concentrated, purified by HPLC, and the object fraction was concentrated, diluted with aqueous calcium carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and converted to hydrochloride with 4N hydrochloric acid-ethyl acetate solution to give the object product (9.3 mg).
Reaction SMILES: NCN[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.C[CH2:14][N:15](C(C)C)C(C)C.C([Si](C)(C)Cl)(C)(C)C.Cl[C:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=[O:32]>C1COCC1>[CH3:40][O:39][C:37]([C:36]1[CH:41]=[CH:42][C:33]([C:31]([NH:15][CH2:14][C:4]2[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=2)=[O:32])=[CH:34][CH:35]=1)=[O:38]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCNc1ccc(C(=O)O)cc1
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
Into a solution of 4-(aminomethyl)amino benzoic acid (5.0 g, 33.1 mmol) in anhydrous THF (200 mL) were added DIEA (12.45 mL, 72.7 mmol) and tert-butyl dimethyl chlorosilane (5.48 g, 36.4 mmol). The resulting mixture was allowed to stir at rt for 1 hr and methyl 4-(chlorocarbonyl)benzoate (7.23 g, 36.4 mmol) was added neat. After overnight stirring at rt, the reaction mixture was quenched with HCl (0.1N, 250 mL) until pH=1. Extraction with EtOAc/THF (400 mL), drying over MgSO4, evaporation under vacuo gave the title compound as a white powder (7.0 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[OH:19])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: NCC(O)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC(O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-amino-1-phenyl-ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(OC)(C)C>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound 2 (614.5 g, 3.33 mol) in DMF (3.5 L) was added K2CO3 (953 g, 6.90 mol) and benzyl chloride (480 g, 3.80 mol). The mixture was heated to 90° C. and left stirring for 3 hours. The suspension was cooled to room temperature, then MTBE (2 L) was added, followed by water (12 L). The mixture was then stirred for 10 minutes and the aqueous layer was separated and extracted with MTBE (2 L×3). The organic layers were combined and washed with water (2 L×2) and brine (1.5 L×1) and concentrated to give compound 3 as a light-yellow solid. 1H NMR (DMSO-d6; 400 MHz) δ 10.42 (s), δ 7.71 (m), δ 7.51 (m), δ 7.43 (m), δ 7.35 (m), δ 7.24 (m), δ 5.27 (s), δ 1.26 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].[C:16](O)(=[O:18])[CH3:17]>>[CH3:10][C:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]([CH3:17])=[O:18])=[CH:4][CH:3]=1)=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OC(C)=O)cc1
Temperature: 20 °C

Procedure:
A 500 mL, 3-neck flask fitted with mechanical stirrer, an inert gas inlet topped reflux condenser, and a thermocouple was charged with acetic acid (32 mL) and 4-aminophenol (10.9 g, 0.10 mol). Acetic anhydride (30.2 g, 0.30 mol) was added in one portion and the brown, clear solution was heated to 100°-110° C. and maintained at that temperature for 16 hours. Heating was stopped and the reaction mixture was allowed to cool slowly with stirring (under argon). After approximately 1 hour the mixture had cooled to 20° C. and precipitation began. The mixture was cooled to ~0° C. (ice-salt bath) and maintained at that temperature for 6 hours and was then filtered. The pale-pink solid was dried in vacuum to yield 16.1 g, 0.08 mol of 4-acetoxyacetanilide (mp 140°-142° C.). The molecular structure was confirmed by IR and 1H NMR analyses.