Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]([C:10](=[O:28])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]=1[NH2:27])[CH:7]1[CH2:9][CH2:8]1)C.[OH-].[Na+]>CO>[C:20]([C:16]1[C:15]([NH2:27])=[C:14]([CH2:13][CH2:12][CH2:11][C:10]([N:6]([CH:7]2[CH2:9][CH2:8]2)[CH2:5][C:4]([OH:29])=[O:3])=[O:28])[CH:19]=[CH:18][N:17]=1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CCOC(=O)CN(C(=O)CCCc1ccnc(C(=O)OC(C)(C)C)c1N)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)c1nccc(CCCC(=O)N(CC(=O)O)C2CC2)c1N
Reaction time: 8 h

Procedure:
Ester 7-3 (1.07 g, 2.64 mmol) was dissolved in 26 mL MeOH, then treated with 1 N NaOH (6.6 mL, 6.6 mmol). After stirring overnight the reaction was concentrated, redissolved in water, the pH was, adjusted to 1 with 10% KHSO4, then extracted with EtOAc (5×). The aqueous phase was adjusted to pH 3 with aq. NaOH, then reextracted with EtOAc (2×). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated, providing 7-4 as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[H-].[Na+].[C:22](O)(=[O:24])[CH3:23]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18][O:24][CH2:22][CH3:23])=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1oc(C2(Br)CCCCC2)nc1CBr
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1nc(C2CCCCC2)oc1C(=O)OCC
Temperature: 65 °C
Reaction time: 1 h

Procedure:
1.25 g 2-(1-Bromo-cyclohexyl)-4-bromomethyl-oxazole-5-carboxylic acid ethyl ester was dissolved in 15 ml ethanol. 176 mg sodium hydride were added and the reaction mixture stirred at 65° C. for one hour. The cooled reaction mixture was neutralized by the addition of acetic acid (pH˜6). 50 mg palladium on charcoal (10%) were added and the reaction mixture was stirred under an atmosphere of hydrogen for one hour. The catalyst was filtered off through a pad of celite, the filtrate was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 370 mg 2-Cyclohexyl-4-ethoxymethyl-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]([Br:17])=[CH:15][N:16]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+].CO>C1COCC1.O>[Br:17][C:14]1[N:13]2[N:18]=[CH:19][N:20]=[C:12]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=2)=[N:16][CH:15]=1
Reactant: COC(=O)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
4-(5-Bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-benzoic acid methyl ester (460 mg, 1.32 mmol) is suspended in THF (11 mL) and a solution of lithium hydroxide monohydrate (554 mg, 13.2 mmol) in water (11 mL) is added. The reaction mixture is stirred at room temperature for 4 hours then methanol (11 mL) is added and the mixture is stirred at 50° C. for 24 hours. The mixture is partitioned between water and DCM, the aqueous phase is acidified with 2M HCl (pH 2) and a yellow precipitate is formed. The precipitate is collected by filtration, washed with water and diethyl ether and dried to afford the title compound (215 mg, 49%).
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])C)\[CH3:8])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:8])[CH2:9][CH2:10][CH:11]1[O:23][CH:12]1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C=C(\C)CCC=C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC1OC1C
Temperature: -20 °C

Procedure:
To a solution of geranyl acetate (1.5 g) in CH2Cl2 (30 ml) is added m-chloroperbenzoic acid (1.3 g) under stirring at -20° C. The mixture is stirred for 90 minutes, at the end of which time it is concentrated under reduced pressure and the residue is dissolved in hexane. The insoluble matter is filtered off, the filtrate evaporated to dryness under reduced pressures and the residue purified by column chromatography on silica gel (30 g) with CCl4 -ethyl acetate (10:1). The above procedure provides a colorless oil of 1-acetoxy-3-methyl-6,7-epoxy-2-octene. A solution of the above product (780 mg) in ether (10 ml) is added to a solution of LiAlH4 (290 mg) in ether (30 ml) under ice-cooling and stirring. The mixture is stirred for 30 minutes, at the end of which time the excess LiAlH4 is decomposed with cold water. To this reaction mixture is added a saturated aqueous solution of sodium hydrogen carbonate (5 ml), the ether layer is separated, and the water layer is extracted with ethyl acetate. The ether layer and the extract are pooled and worked up in the conventional manner. The residue is purified by column chromatography on silica gel (15 g) with CCl4 -acetone (3:1) as the eluent. The procedure yields a colorless oil of 3,7-dimethyl-2-octene-1,7-diol (XI, n=O). 2,3-Dimethoxy-5-methyl-1,4-benzoquinone (336 mg) is reduced with Na2S2O4 (4 g) and the resultant VI (R=H3CO, X=Y=OH) (309 mg) and XI (309 mg) are dissolved in dioxane (10 ml). Under stirring in nitrogen gas stream and at room temperature, a solution of BF3 -ether (1.5 ml) in dioxane (2 ml) is added. The mixture is stirred for 2 hours, whereupon IIId (R=H3CO, X=Y=OH, n=O, m=3) is obtained.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)(=[O:12])[CH3:11].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[C:10]([O:13][CH2:14][CH2:15][CH2:16][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCCCBr
Reactant: c1ccc2[nH]cnc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1cnc2ccccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
In a nitrogen atmosphere, a mixture of 118 g of benzimidazole, 181 g of 3-bromopropyl acetate, 111 g of triethylamine, 2 g of sodium iodide, and 500 g of N,N-dimethylformamide was heated and stirred at 80° C. for 16 hours. The reaction mixture was subjected to conventional aqueous work-up and then purified by column chromatography, obtaining 3-(1H-benzimidazol-1-yl)propyl acetate (yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][C:20]([O:22]C)=[O:21])[NH:12][C:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[C:10]1[C:38]([O:40][CH3:41])=[O:39].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:10]([C:38]([O:40][CH3:41])=[O:39])=[C:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[NH:12][C:13]([CH2:19][C:20]([OH:22])=[O:21])=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2CCCN(C)C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)C1=C(CCc2ccccc2CCCN(C)C)NC(CC(=O)O)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.2 %

Procedure:
To a solution of dimethyl 4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenyl}ethyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate (4.31 g, 7.14 mmol) in 1,4-dioxane (61 ml) was added 2N NaOH. The reaction mixture was stirred at room temperature for 2.5 h. The residual 1,4-dioxane was removed by evaporation in vacuo. The residue was diluted with water (19 ml) and washed with diethyl ether (50 ml×2) and AcOEt (20 ml). The water phase was then acidified with aq. NaH2PO4 to about pH 5. The whole was extracted with CH2Cl2 (300 ml×3). The combined extract was washed with brine, dried over MgSO4, and concentrated to afford the desired acid (4.30 g, 90% yield) as a yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:44]([N:41]([CH2:42][CH3:43])[C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)[CH3:45]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCN(CC)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-diethylaminophenyl borate (123 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 7 hours, cooled, extracted with ethyl acetate/THF (1:1), washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were recrystallized from ethanol to give yellow crystals of 7-(4-diethylaminophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 54) (198 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:20]([N:22]([CH2:36][CH3:37])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH3:21].Cl>C(=S)=S.C(Cl)Cl.C(=S)=S>[CH2:36]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[S:12][C:11]=2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:32])=[CH:34][CH:35]=1)[CH3:37]
Reactant: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2cc3ccccc3s2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: S=C=S
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)sc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of 4.0 g. (0.03 mol.) of anhydrous aluminum chloride in 30 ml. of carbon disulfide under a nitrogen atmosphere at 5° is added a mixture of 2.1 g. (0.01 mol.) of 2-phenylbenzothiophene in 40 ml. of 1:1 carbon disulfide-methylene chloride containing 3.06 g. (0.01 mol.) of 4-(3-diethylaminopropoxy)benzoyl chloride. After addition, the reaction mixture is warmed to ambient temperature and stirred for 16 hours. Dilute aqueous hydrochloric acid is added to the mixture and the layers are separated. The aqueous phase is re-extracted with chloroform and the organic layers are combined and concentrated to give a residue which is treated with ethereal hydrochloric acid and chromatographed on silica gel with methanol-chloroform as eluant to give the title compound as the corresponding hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:38])(C[Si](OC(C)C)(C)C)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:18][CH:17]=2)[C:12]1=[O:29])[CH3:10].[C:39](=O)([O-])[OH:40].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:38])([CH2:39][OH:40])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:20][CH:21]=2)[C:12]1=[O:29])[CH3:10]
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccccc1F)[C@@H](C)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Yield: 60.3 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (5.5 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 50 ml), to which 10 ml of 30% aqueous hydrogen peroxide and 0.82 g of sodium hydrogencarbonate were added. The mixture was heated at 80° to 85° C. for 2 hours. The reaction solution was cooled and extracted with 200 ml of ethyl acetate. The extract was washed with 100 ml of water, an aqueous solution of Na2S2O3 (100 ml×2) and 100 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from a mixture of methanol and diisopropyl ether to give 2.7 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 60%) as colorless powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[S:5][CH:6]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=2)[O:8][CH:14]=1
Reactant: NC(=O)c1cc(Cl)cs1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2cc(Cl)cs2)n1
Yield: 48 %

Procedure:
In substantially the same manner as in Reference Example 47, 4-chloro-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(4-chloro-2-thienyl)oxazole. The yield was 48%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 72-73° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([C:25]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(B(O)O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
Dissolve 4-aminomethylphenyl boronic acid hydrochloride (1.0 g, 5.34 mmol) in DCM (50 mL), add triethylamine (1.64 mL, 11.74 mmol) and cool the mixture to 0° C. Add cyclopentanecarbonyl chloride (778 mg, 5.78 mmol) and warm to room temperature. Stir the reaction mixture for 18 h, filter and wash the solid with DCM (10 mL) to give the title compound as a fine white powder (1.1 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[Br:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:17]1[CH:18]=[C:14]([Br:13])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16]1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1n[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(Br)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 59.6 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.77 g), 4-bromo-3-trifluoromethyl-1H-pyrazole (0.90 g) and potassium carbonate (0.57 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-bromo-3-trifluoromethyl-1H-pyrazole (0.9 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=N[OH:39])C.[Cl-].[In+3].[Cl-].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[C:25]([C:32]([NH2:33])=[O:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC=NO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cccnc54)c3CO)ncc2c1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5cccnc54)c3CO)ncc2c1
Reaction time: 3 h
Yield: 17.4 %

Procedure:
A stirred solution of 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (610 mg, 783 μmol, Eq: 1.00), acetaldoxime (139 mg, 143 μl, 2.35 mmol, Eq: 3) and indium (III) chloride (8.66 mg, 39.1 μmol, Eq: 0.05) in toluene (25.2 ml) was heated to 110° C. and stirred for 3 h. The reaction mixture was poured into 15 mL EtOAc and extracted with sat NH4Cl (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. After removal of solvent and residue was separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes) gave 66 mgs of desired product with impurity. This material was re-purified by preparative reverphase HPLC in TFA. The desired product was neutralized with NaHCO3 (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo., extracted with ethyl acetate/methanol (9:1) to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (43 mgs, 12%) as white solid. 1H NMR (DMSO-d6) δ: 8.64 (dd, J=7.9, 1.6 Hz, 1H), 8.60 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 8.36 (dd, J=4.8, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.82 (dd, J=13.2, 1.6 Hz, 1H), 7.66-7.78 (m, 3H), 7.63 (dd, J=7.3, 2.3 Hz, 1H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 7.18 (br. s., 1H), 4.72 (t, J=5.4 Hz, 1H), 4.11-4.34 (m, 2H), 1.44 (s, 9H). MS m/e 486.6 (M+H+).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([C:20]3[O:21][C:22]4[C:28]([C:29]([O:31]C)=O)=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH4+:33]>CO>[C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([C:20]3[O:21][C:22]4[C:28]([C:29]([NH2:33])=[O:31])=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cccc(C(=O)N4CCN(C(=O)C(C)C)CC4)c3)oc12
Solvent: CO
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(-c3nc4cccc(C(N)=O)c4o3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
Methyl 2-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxylate (150 mg, 0.34 mmol) was added to ammonium in methanol (10 mL) in a sealing tube and stirred at 25° C. for 3 days. The solvent was removed under reduced pressure. The crude product was purified by pre-HPLC to obtain 2-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (20 mg, yield 14%). 1H-NMR (400 MHz, CD3OD) δ: 1.12-1.13 (d, J=6 Hz, 6H), 2.97 (brs, 1H), 3.55-3.85 (m, 8H), 7.50-7.54 (t, J=8.0 Hz, 1H), 7.71-7.75 (m, 2H), 7.91-7.95 (m, 2H), 8.41-8.45 (m, 2H); LC-MS (ESI) m/z: 421 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:6]1=[O:41].[BH4-].[Na+]>CO.C1COCC1>[F:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:25][CH:26]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][CH:35]([OH:40])[C:36]([CH3:37])([CH3:38])[CH3:39])[C:6]1=[O:41]
Reactant: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(=O)C(C)(C)C)c(=O)n2Cc1c(F)cccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(O)C(C)(C)C)c(=O)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a mixed solution of compound (120 mg, 0.182 mmol) obtained in Example 63 in methanol (6 ml) and THF (4 ml) was added sodium borohydride (6.9 mg, 0.182 mmol) under ice cooling. The reaction liquid was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue was distributed between water and ethyl acetate, and the organic layer was extracted. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH-silica gel (Produced by Fuji Silysia Chemical Ltd.) column chromatography (eluent; ethyl acetate), and recrystallized from ethyl acetate and diethylether to give the title compound (81.1 mg, 68%) as colorless crystals.
Reaction SMILES: C1[CH:6]([CH2:7][CH:8]2CC[CH:11]([N:14]=C=O)[CH2:10][CH2:9]2)[CH2:5][CH2:4]C(N=C=O)C1.C1(N=C=O)CCCCC1>C1COCC1>[CH2:11]([NH2:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1
Agent: O=C=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCCCCCN
Yield: 220 %

Procedure:
According to the procedure described in Example 1, starting from 10 g (38.12 mmol) of methylene-bis(4-cyclohexylisocyanate), alias 4,4A′-methylene-bis(cyclohexyl isocyanate, into 200 ml of THF and 10.82 g (83.86 mmol) of octylamine into 100 ml of THF, 16.30 g of a white solid are obtained.
Reaction SMILES: C(C(CCCC)C[OH:5])C.C(N(CC)CC)C.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([CH2:23][C:24]([OH:25])=[O:5])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC(CC)CO
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Mix 2-ethyl-1-hexanol (6.5 g, 5 mol), triethylamine (50.5 g, 0.5 mol) and methylene chloride (50 mL). Add, by dropwise addition, 2-phenylacetyl chloride (5 mol) and warm to 50° C. Stir at room temperature overnight, filter and wash the filtercake with methylene chloride (50 mL). Combine the organic phases and wash with 5% aqueous hydrochloric acid (50 mL) and water. Dry (MgSO4), evaporate the solvent in vacuo and purify by distillation to give 2-phenylacetic acid, 2-(2-ethylhexy)1 ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:5][CH:4]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=2)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[CH:8][CH:7]=1)=[O:18]
Reactant: C#Cc1ccc(NC(=O)c2ccccc2C)cc1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)cc1
Yield: 74.9 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-2-methyl-benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound (109 mg, 75%).