Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:30]=[C:11]3[N:12]=[C:13]([CH3:29])[C:14]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.[B]1OC2C(=CC=CC=2)O1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:30]=[C:11]3[N:12]=[C:13]([CH3:29])[C:14]([C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a stirred solution of methyl 2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.083 g, 0.196 mmol) in toluene (5 mL) was added 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.039 ml, 0.039 mmol) and cooled to −35° C. To this was added dropwise 1M catecholborane/THF (0.294 ml, 0.294 mmol) over 10 min and stirred for additional 20 min. Then, the reaction was slowly warmed to −15 C over 30 min, diluted with EtOAc (10 ml) and quenched with sat. Na2CO3 (5 mL). The resulting mixture was vigorously stirred for 30 min, aq. larer removed and organic layer washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated to yellow residue which was purified by prep-HPLC to afford (S)-methyl 2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.08 g, 0.184 mmol, 94% yield) as solid. 1H NMR (500 MHz, CDCl3) δ: 7.82 (s, 1H), 7.75-7.68 (m, 1H), 7.68-7.58 (m, 2H), 7.34-7.24 (m, 4H), 6.88 (s, 1H), 5.16 (s, 1H), 3.78 (s, 3H), 3.69-3.34 (br.s., 1H), 2.58 (s, 3H). LCMS (M+H) calcd for C22H18ClFN3O3: 426.1. found: 426.2.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:12]1([CH:11]([NH:24][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(CNC(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of para-cyanobenzyl bromide (13.72 g, 70 mmol), benzhydrylamine (13.79 g, 70 mmol) and potassium carbonate (16.8 g, 70 mmol) in ethanol (200 ml) was stirred under reflux for 5 hours. The mixture was allowed to cool, the resulting precipitate filtered off and the filtrate evaporated under reduced pressure. The residue was recrystallised from 80-100 petrol/isopropanol to give the title compound as an oil, 14.5 g.
Reaction SMILES: [OH-].[Li+].C([O:6][CH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[N:11]=[N:10][N:9]=1)(=O)C>C(O)C.O>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([CH2:7][OH:6])=[N:9][N:10]=[N:11]2)=[N:14][CH:15]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Lithium hydroxide (0.30 g, 12.5 mmol) was added at 0° C. to a solution of {1-[5-(trifluoromethyl)-2-pyridinyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 57, 1.80 g, 6.27 mmol) in a mixture of ethanol and water (2:1). The reaction mixture was stirred for 3 hr at room temperature. The ethanol was removed under reduced pressure. The residue was diluted with DCM and washed with ice-water, saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (60-120 mesh silica gel), eluting with 30% ethyl acetate/pet ether, to give the title compound (0.90 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A mixture of (2S)-2-tert-Butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid (12.65 g, 40.5 mmol) and 0.5 g of 10% Pd/C in 100 ml of MeOH under hydrogen at 1 atmosphere was stirred for 4 h. The solution was filtered through Celite 545 and the filtrate evaporated in vacuo to afford the 11.95 g of the title compound in quantitative yield as a dark brown solid that was used without purification: 1H NMR (CD3OD) δ 6.75-6.70 (3H,m), 6.65-6.58 (1H, m), 4.35-4.3 (1H, m), 3.6-3.38 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:45]=[CH:44][C:20]([C:21]([N:23]([CH3:43])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]#[C:31][CH2:32][NH:33][C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[O:35])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)C>O1CCCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:45]=[CH:44][C:20]([C:21]([N:23]([CH3:43])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][CH2:31][CH2:32][NH:33][C:34]([N:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)=[O:35])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C#CCNC(=O)N3CCN(C)CC3)cc2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CCCNC(=O)N3CCN(C)CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To an ice cooled mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[3-(4-methylpiperazin-1-yl)carbonylamino-(1-propyn-1-yl)]phenyl]benzamide (250 mg) and nickel chloride hexahydrate (297 mg) in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml) was added sodium borohydride in small portions and the mixture was stirred at the same temperature for 1 hour. The mixture was filtered through bed of Celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform (20 ml) and washed with water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a syrup. The residue was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[3-(4-methylpiperazin-1-ylcarbonyl)aminoprop-1-yl]phenyl]benzamide (75.0 mg) as a powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)ccc3F)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 110.1 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (450 mg, 0.86 mmol, 1.00 equiv) in dichloromethane (40 mL). This was followed by the addition of CF3COOH (10 mL) dropwise with stirring at 25° C. over 5 min. The resulting solution was stirred for 3 h at 25° C. and then concentrated under vacuum. The residue was diluted with dichloromethane and the resulting mixture was washed with aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate and concentrated under vacuum to give 400 mg (99%) of 3-[4-(2,5-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][NH:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: COc1ccc(CCN)cc1OC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CCNC=C2C(=O)Nc3cc(OC)c(OC)cc32)cc1OC

Procedure:
5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 6.00 g. of 2(3,4-dimethoxyphenyl)ethylamine and 2.20 acetic acid in 40 ml. benzene was reacted as described in Example 5 to give 6.30 g. product, m.p. 164°-166° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([S:17][CH3:18])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.ClC1C=C2C(=CC=1SC)NC(=O)C(C(F)(F)F)=N2.CN(C1C=CC=CN=1)C.O=P(Cl)(Cl)Cl.[SH:51][C:52]1[S:53][C:54]([CH3:57])=[N:55][N:56]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[S:17][CH3:18])[N:3]=[C:2]([S:51][C:52]1[S:53][C:54]([CH3:57])=[N:55][N:56]=1)[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: CSc1cc2nc(Cl)c(C(F)(F)F)nc2cc1Cl
Reactant: Cc1nnc(S)s1
Agent: CN(C)c1ccccn1
Agent: CSc1cc2[nH]c(=O)c(C(F)(F)F)nc2cc1Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1cc2nc(Sc3nnc(C)s3)c(C(F)(F)F)nc2cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
2,6-Dichloro-7-methylsulfanyl-3-trifluoromethylquinoxaline (116 mg, 0.37 mmol, prepared similarly as described above from 6-chloro-7-methylsulfanyl-3-trifluoromethyl-1H-quinoxaline-2-one, dimethylaminopyridine and POCl3) and 2-mercapto-5-methyl-1,3,4-thiadiazole (146 mg, 1.1 mmol) was dissolved in DMF (3.3 ml). Potassium carbonate (20 mg) was added and the reaction mixture was stirred at 50° C. for 2 hours. The cooled mixture was partitioned between diethyl ether and water. The organic layer separated, evaporated and the residue recrystallised from ethanol to afford 80 mg (50%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[C:7]3[N:8]([C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[C:7]3[N:8]([C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnc2c(-c3cnco3)cc(C3CC3)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnc2c(-c3cnco3)cc(C3CC3)cn12
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 103.1 %

Procedure:
To a mixture of ethyl 6-cyclopropyl-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (150 mg) in a mixed solvent of THF (3 mL) and ethanol (1.2 mL) was added 8N aqueous sodium hydroxide solution (95 μL), and the mixture was stirred at 70° C. for 50 min. The reaction mixture was neutralized with 6N hydrochloric acid in an ice bath, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title Compound (140 mg).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH2:15]([NH2:27])[CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.O>S1(CCCC1)(=O)=O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][NH:27][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:2]=2[I:1])[CH:26]=[CH:25][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(I)c(OCC2CO2)c1
Reactant: COc1ccc(CCN)cc1OC
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccc(I)c(OCC(O)CNCCc2ccc(OC)c(OC)c2)c1
Yield: 89.8 %

Procedure:
A solution of 5.0 g (0.016 mole) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane, the product of Example 5b. and 3.25 g (0.0179 mole) of homoveratrylamine in 10 ml of sulfolane was heated at 60°-70° C. for 18 hr. Water was added and the precipitate which formed was collected by filtration. It was recrystallized from acetonitrile to give 7.0 g (87% yield) of crystalline 1-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-(2-iodo-5-methoxyphenoxy)-2-propanol, mp 83°-88° C.
Reaction SMILES: [Na].[CH2:2]([N:9]1[C:17](Br)=[N:16][C:15]2[C:10]1=[N:11][C:12]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:13][C:14]=2[NH2:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C[OH:28]>>[CH2:2]([N:9]1[C:17]([OH:28])=[N:16][C:15]2[C:10]1=[N:11][C:12]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:13][C:14]=2[NH2:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)COc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COC(=O)COc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1

Procedure:
After sodium (0.30 g, 13.04 mmol) was dissolved in methanol (30 ml), thereto was added 9-benzyl-8-bromo-2-methoxycarbonylmethoxyadenine (0.10 g, 0.25 mmol) obtained by Reference example 21, and the mixture was refluxed for 7 hours under stirring. After being allowed to cool, the solution was neutralized with concentrated hydrochloric acid and concentrated. After the residue was dissolved in methanol (30 ml), thereto was added sulfuric acid (2 ml) and the solution was stirred for 7 hours. After being neutralized in an ice bath with saturated sodium hydrogencarbonate solution, the solution was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜30/1) and the obtained compound was washed with methanol to give the captioned compound (62 mg, 0.19 mmol) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:9][C:10]=1[C:11]([CH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1)=[O:12].ClC1C=CC=C(C(OO)=[O:35])C=1.O>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[S:9][C:10]=1[C:11]([CH:13]1[CH2:14][CH2:15][S:16](=[O:35])[CH2:17][CH2:18]1)=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCSCC2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCS(=O)CC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Compound 587 (500 mg, 1.27 mmol) was dissolved in chloroform (13 mL), and m-chloroperbenzoic acid (219 mg, 1.27 mmol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 591 (359 mg, 69%).
Reaction SMILES: [I-].[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:28]([O:32][C:33]([NH:35][C@@:36]([CH2:48][CH3:49])([CH2:39][O:40][C:41](=[O:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:37]=O)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([NH:35][C@:36]([CH2:48][CH3:49])([CH:37]=[CH:8][C:4]1[N:3]([CH3:2])[CH:7]=[CH:6][CH:5]=1)[CH2:39][O:40][C:41](=[O:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CCCCCC(=O)OC[C@](C=O)(CC)NC(=O)OC(C)(C)C
Reactant: Cn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CCCCCC(=O)OC[C@](C=Cc1cccn1C)(CC)NC(=O)OC(C)(C)C
Yield: 69 %

Procedure:
The reaction was carried out in the similar manner to Reference example 1 (1d) using (1-methylpyrrol-2-yl)methyltriphenylphosphonium iodide obtained in Reference example 1 (1c) and (2S)-2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanal obtained in Reference example 2 (2b) as starting materials to obtain the title compound (yield: 69%).
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:19]1([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]2[CH2:29][C@H:28]([NH2:30])[C@@H:27]2[CH2:31][CH3:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl.C(OCC)(=O)C>[C:4]([O:3][C:1]([NH:30][C@H:28]1[CH2:29][N:26]([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:27]1[CH2:31][CH3:32])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CC[C@H]1[C@@H](N)CN1C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@H]1[C@@H](NC(=O)OC(C)(C)C)CN1C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 57.1 %

Procedure:
tert-Butyl dicarbonate (202 mg, 0.93 mmol) and triethylamine (0.27 mL, 1.93 mmol) were added to a solution of cis(±)-1-(diphenylmethyl)-2-ethylazetidin-3-amine obtained in Example (235d) (206 mg, 0.77 mmol) in dichloromethane (4 mL), followed by stirring for two hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1) to obtain 161 mg of the title compound as a colorless oily substance (57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl:19]CC1C=CC2OC(C3C=CC=C(F)C=3)=NC=2C=1>>[Cl:19][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: OCc1ccc2oc(-c3ccc(F)cc3)nc2c1
Reactant: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Product: Fc1ccc(-c2nc3cc(CCl)ccc3o2)cc1

Procedure:
Compound 74B was reacted in a manner analogous to Compound 69C to give the title product. 400 MHz 1H NMR (DMSO-d6) δ □ ppm 4.9 (s, 2H) 7.4 (t, J=9.0 Hz, 2H) 7.5 (dd, J=8.4, 1.8 Hz, 1H) 7.7 (d, J=9.0 Hz, 1H) 7.8 (d, J=1.2 Hz, 1H) 8.2 (dd, J=9.0, 5.4 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([OH:14])=[N:12][CH:13]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1.CC(=O)OCC>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11](=[O:14])[N:12]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:13]=1
Reactant: BrCC1CC1
Reactant: Cc1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cn(CC2CC2)c1=O
Temperature: 70 °C
Yield: 66 %

Procedure:
Potassium carbonate (1.32 g, 9.57 mmol) was added to 5-bromo-3-methyl-2-hydroxypyridine (600 mg, 3.19 mmol) and bromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 mL). After heating at 70° C. for 3 h, EA extractive work up and silca gel chromatography (PE:EA=30:110:1), the title compound (510 mg, yield: 66.0%) was obtained as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.39 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 3.77 (d, J=6.8 Hz, 2H), 2.15 (s, 3H), 0.65-0.60 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 242.1; 244.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(-n2cccc2)c1
Yield: 81.5 %

Procedure:
Ethyl m-aminobenzoate (1.6 g) was dissolved in 10 ml of glacial acetic acid, and 1.3 g of 2,5-dimethoxytetrahydrofuran was added. The mixture was refluxed for 2 hours, and the solvent was evaporated. The residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, and then worked up in a customary manner. Finally, recrystallization from hexane gave 1.7 g (yield 82%) of ethyl 3-(1-pyrrolyl)benzoate as colorless needles having a melting point of 64° to 65° C. The resulting pyrrolyl compound (1.1 g) was dissolved in 30 ml of ethyl ether, and with stirring under ice cooling, 0.2 g of lithium aluminum hydride was added. The mixture was stirred for 1 hour. The reaction mixture was extracted by adding water and ethyl ether. The extract was worked up in a customary manner. Recrystallization from a mixture of ethyl acetate and hexane gave 0.80 g (yield 91%) of 3-(1-pyrrolyl)benzyl alcohol as colorless needles having a melting point of 66° to 68° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-])=O>CCO.[Pd]>[F:14][C:11]([F:12])([F:13])[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccnc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a stirred solution of 4-nitro-2-trifluoromethyl-pyridine 1-oxide (0.4 g, 1.90 mmol) in EtOH (15 mL) is added 10% Pd—C (0.04 g) under nitrogen atmosphere. Hydrogenation is performed in a Parr shaker at 30 psi for 3 h at room temperature. After completion of reaction it is filtered through diatomaceous earth and washed with EtOH. Filtrate is concentrated to give 2-trifluoromethyl-pyridin-4-ylamine as a thick liquid (0.23 g, 74%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>O1CCOCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NCCCCO
Solvent: C1COCCO1
Product: O=C(NCCCCO)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
43 mmol (8.2 g) naphthalen-2-carboxylic acid chloride is dissolved in 50 mL dioxane and dropwise added to a solution of 112 mmol (10.0 g) 4-amino-butan-1-ol in 100 mL dioxane and stirred overnight at room temperature. The mixture is then poured into 200 mL of ice water and filtrated. The white solid separated is dried under vacuum.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Reactant: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
3-Hydroxy-2-methyl-4-quinoline carboxylic acid (549 mg), 6-benzyloxy-4-chloro-7-methoxyquinoline (810 mg), and 4-(N,N-dimethylamino)-pyridine (990 mg) were dissolved in 1,2-dichlorobenzene (40 ml) to prepare a solution. The mixture was stirred at 150° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (718 mg, yield 63%).