Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[OH:28][CH2:29][C@H:30]1[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@H:30]([CH2:29][OH:28])[CH2:31][CH2:32][C:33]4=[O:35])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 63.8 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.53 g) described in Preparation Example 112 and (S)-5-hydroxymethylpyrrolidin-2-one (428 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.05 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:25][C@H:26]([N:28]([CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH2:46][C:47]([F:50])([F:49])[F:48])C(OC(C)(C)C)=O)[CH3:27])=[CH:19][C:20]=2[C:22]([NH2:24])=[O:23])[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:25][C@H:26]([NH:28][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[CH3:27])=[CH:19][C:20]=2[C:22]([NH2:24])=[O:23])[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCCOCc1ccccc1)CC2)N(CCOc1ccccc1OCC(F)(F)F)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCCOCc1ccccc1)CC2)NCCOc1ccccc1OCC(F)(F)F
Yield: 86.6 %

Procedure:
To a solution of (R)-(-)-1-(4-benzyloxybutyl)-5-[2-[N-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide (523 mg) in methylene chloride (7.5 ml) was added dropwise trifluoroacetic acid (1.5 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of chloroform and methanol (10/1) as eluent to give 388 mg of (R)-(-)-1-(4-benzyloxybutyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide melting at 101°-102° C.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[CH:31][C:32](O)=[N:33][C:34]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[CH:31][C:32]([O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:33][C:34]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Reactant: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
To a solution of, ethyl 2-(3-(((methylsulfonyl)oxy)methyl)phenoxy)acetate (100 mg) and 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-ol (100 mg) in DMF (3.0 mL) was added potassium carbonate (72 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, 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 the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (77 mg) as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH2:14][C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CN=[N+]=[N-]
Temperature: 55 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of Example 220A (365 mg, 1.021 mmol) in N,N-dimethylformamide (5 mL) was added sodium azide (531 mg, 8.17 mmol). The reaction mixture was stirred at 55° C. for 8 hours. Chromatography on a 12 g silica gel column eluted with 5% ethyl acetate/hexanes for 3 minutes followed by a gradient to 100% ethyl acetate over 20 minutes provided the title compound (135 mg, 0.557 mmol, 54.6% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.65 (d, J=3.5 Hz, 1H), 4.24 (d, J=3.5 Hz, 1H), 3.97 (ddd, J=10.2, 7.6, 3.1 Hz, 1H), 3.64 (dd, J=12.3, 5.5 Hz, 1H), 3.39-3.22 (m, 3H), 2.01-1.80 (m, 2H), 1.42 (s, 9H); MS (DCI) m/z 243 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=[O:17])C=1C#N)#N.O1CCOCC1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH:11]=[O:17])=[CH:5][CH:4]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCc1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(C=CC=O)cc1
Yield: 68 %

Procedure:
A mixture of 4-methoxy phenylpropane (2 g), silica gel (0.5-0.8 g), DDQ (7.5 g) and dioxane (5-8 ml) was taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was placed inside a microwave oven operating at medium power (600 W) and irradiated for 2-8 minutes. After completion of the reaction (monitored by TLC), the contents of the flask were poured into chloroform and passed through a bed of Celite and further washed with chloroform. The filtrate and washing were combined and the chloroform layers were washed with an aqueous NaOH (15%, 3×15 ml). The combined aqueous layers were further extracted with chloroform (3×15 ml). The chloroform layers were then combined and washed with saturated sodium chloride (3×15 m), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude product which was loaded on silica column and the column was first eluted with hexane (70-80 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 4-methoxy cinnamaldehyde in 68% yield as a solid; mp 57-58° C.; (lit. mp 58° C.). The physical and spectral data was found to similar as reported.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(C=O)cc1
Reactant: NCc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 55 %

Procedure:
At room temperature, a solution of 1.00 g (3.81 mmol) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate (Example I-3) and 0.37 g (3.81 mmol) of furfurylamine in 10 ml of dichloroethane is stirred for 30 min, 1.21 g (5.72 mmol) of sodium triacetoxyborohydride are added and the mixture is then stirred at room temperature for 22 h. 6 ml of sat. NaHCO3 solution and 10 ml of ethyl acetate are then added, the phases are separated, the aqueous phase is extracted 2× with ethyl acetate and the combined organic phases are dried over sodium sulphate. The solvent is removed under reduced pressure, and chromatographic purification on silica gel (cyclohexane→cyclohexane/ethyl acetate 10:1→2:1) then gives 720 mg (55%) of tert-butyl 3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1.[CH3:46][O:47][CH2:48][CH2:49][CH2:50][C:51](Cl)=[O:52]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14][CH:13]2[O:12][CH2:11][CH:2]2[CH2:3][N:4]([C:51](=[O:52])[CH2:50][CH2:49][CH2:48][O:47][CH3:46])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]2)=[CH:20][CH:21]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CNc3ccccc3O2)cc1
Reactant: COCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COCCCC(=O)N1CC(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)Oc2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 0.33 g of tert-butyl 3-(3,4-dihydro-2H-benzo[1,4]oxazin-2(R,S)-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 40 ml of chloroform and 0.23 ml of triethylamine is admixed at room temperature with 0.23 g of 4-methoxybutyryl chloride and stirred over 30 minutes. The reaction mixture is washed successively with 1N HCl and 1N NaOH, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.27 (1:1.5 EtOAc-heptane); Rt=6.05.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][C@H:38]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37]5)=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)OCC32C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.4 %

Procedure:
To a solution of 1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.45 g, 1.07 mol), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (0.60 g, 3.22 mmol) and triphenylphosphine (0.70 g, 2.68 mmol) in tetrahydrofuran (50 mL) was added diethyl azodicarboxylate (0.42 mL, 2.68 mmol) slowly at 0° C. The mixture was stirred to 16 h at ambient temperature, then concentrated in vaccuo. The residue was purified by column chromatography (ethyl acetate/hexanes-1:2) to afford tert-butyl (3S)-3-{[1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylate as an oil (0.52 g, 83%): 1H NMR (300 MHz, CDCl3) δ7.43-7.25 (m, 10H), 7.16-7.06 (m, 1H), 7.07-6.91 (m, 3H), 6.58-6.43 (m, 3H), 6.38-6.25 (m, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.80 (s, 1H), 4.73 (d, J=9.0 Hz, 1H), 3.65-3.36 (m, 4H), 2.22-1.95 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 611.3 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetic acid (156 mg, 0.501 mmol, described in Intermediate 22), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (145 mg, 0.577 mmol, described in Intermediate 9), HOBT (95 mg, 0.620 mmol), and EDC (123 mg, 0.642 mmol) in DMF (2 mL) was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between H2O (60 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 90:10, to give the title compound. MS: m/z=545 (M+1). HRMS: m/z=545.2025; calculated m/z=545.1995 for C30H27F2N4O4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.B.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[O:27])[CH:17]=[CH:18][CH:19]=1>O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[OH:27])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(CCCCCCC=O)c1
Reactant: c1cocn1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CCCCCCC(O)c2ncco2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
Under an atmosphere of argon, oxazole (0.0567 g, 0.822 mmol) was taken in dry tetrahydrofuran then treated with a 1 M borane-tetrahydrofuran complex solution (0.896 mL, 0.896 mmol) and allowed to stir for 1 hour at ambient temperature. This clear solution was then cooled to −78° C. and a 2.6 M n-butyllithium solution in hexanes (0.411 mL, 1.07 mmol) was added. Upon addition of the n-butyllithium, the reaction solution changed from a clear solution to a clear yellow or dark green solution indicating lithiation of the borane-complexed oxazole. Stirring continued for 40 minutes before the addition of 7-(3-Methoxyphenyl)heptanal (0.181 g, 0.822 mmol, dissolved in 5 mL tetrahydrofuran). After 2 hours, the reaction solution was allowed to warm to ambient temperature and the reaction was quenched with a 5% solution of acetic acid in ethanol (excess) and stirred for 16 hours. The solvent was removed under reduced pressure and the residue re-dissolved in ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate, then brine and then dried over sodium sulfate. The solvent was removed under reduced pressure and flash column chromatography with silica gel (20%-50% ethyl acetate:hexanes gradient elution) gave the title compound as a light yellow oil (69%, 0.165 g): 1H NMR (600 MHz, CDCl3) δ 7.57 (s, 1H), 7.18 (t, 1H), 7.02 (s, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.71 (m, 2H), 4.78 (t, 1H), 4.75 (bs, 1H), 3.78 (s, 3H), 2.57 (t, 2H), 1.89-1.91 (m, 2H), 1.57-1.62 (m, 2H), 1.42-1.45 (m, 1H), 1.30-1.40 (m, 5H); 13C NMR (150 MHz, CDCl3) δ 166.21, 159.36, 144.21, 138.49, 128.97, 126.26, 120.65, 113.98, 110.65, 67.11, 54.88, 35.77, 35.17, 31.07, 28.97, 28.94, 24.82.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12]>O1CCCC1>[OH:3][C:1]([CH:12]1[CH2:16][CH2:15][O:14][C:11]1=[O:13])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)C1CCOC1=O
Reaction time: 4 h
Yield: 62.5 %

Procedure:
Under argon atmosphere, 39.7 mL (4.43 mmol, 1.5 equivalents) of the solution of 2-bromozinc-γ-butyrolactone in tetrahydrofuran obtained in Example 61 was added dropwise to a solution of 1.25 mL (10.7 mmol) of acetophenone in 10 mL of THF at 6˜8° C. The mixture was stirred at 4˜6° C. for 4 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL of 1N hydrochloric acid, 10 mL of water, 20 ml, 15 mL and 10 mL of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2, 1/1) afforded 1.88 g of the desired product (NMR yield 62.5%; internal standard dioxane). 0.92 g of the desired product was obtained as crystals (yield 42%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[O:11][C:12]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][C:13]=3[CH:14]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][C:13]=2[CH:14]=1
Reactant: CCOC(=O)c1ccc2cc(CCCCN3C(=O)c4ccccc4C3=O)oc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2cc(CCCCN)oc2c1

Procedure:
A solution of ethyl 2-(4-phthalimidobutyl)-benzofuran-6-carboxylate (3.9 g., 0.01 mole) and hydrazine hydrate (0.55 g., 0.011 mole) in ethanol (20 ml.) is heated at 60° C. for 8 hours. The solvent is evaporated at reduced pressure. The solid residue is treated with water and 5 N sodium hydroxide solution and then is extracted with chloroform. The evaporation of the solvent from the organic extract provides ethyl 2-(4-aminobutyl)benzofuran-6-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-(+)-1-amino-2-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.93 (m, 1H), 3.39 (m, 2H), 2.20 (s, 3H), 1.18 (d, 3H, J=6.4 Hz). ESHRMS m/z 464.1154 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:23]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C2CCCCC2)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4cnn(C)c4)cc3c2C)C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 38.9 %

Procedure:
To a solution (15 mL) of ethyl 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (0.59 g) synthesized in Example A174(3) in N,N-dimethylacetamide were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.44 g), potassium carbonate (0.29 g) and tetrakistriphenylphosphine palladium (0.06 g), and the mixture was stirred at 70° C. for 24 hr under argon atmosphere. The reaction mixture was cooled to room temperature, and filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.23 g, 39%) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.04 g, 16%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:13]=2)[N:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:13]=2)[N:8]=1
Reactant: [H][H]
Reactant: COc1ccccc1CNc1ccc2cc(/C=C/c3ccncc3)ccc2n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CNc1ccc2cc(CCc3ccncc3)ccc2n1

Procedure:
(2-Methoxy-benzyl)-[6-((E)-2-pyridin-4-yl-vinyl)-quinolin-2-yl]-amine (example 2, 51 mg, 0.139 mmol) was dissolved in 20 mL ethanol. Palladium on charcoal (10%, 15 mg, 0.014 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a yellow oil (40 mg, 78%), MS: m/e=370.1 (M+H+).