Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][F:24])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)[OH:4].Br[CH2:26][C:27](Br)=[O:28].[Br-].[N-:31]=[N+:32]=[N-:33].[Na+]>C(OC(=O)C)C.CN(C)C=O.O>[N:31]([CH2:26][C:27]([NH:1][C@H:2]([CH2:23][F:24])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:28])=[N+:32]=[N-:33]
Reactant: O=C(Br)CBr
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)CN=[N+]=[N-])cc2)cn1
Temperature: 50 °C
Yield: 30.4 %

Procedure:
To a slurry of N-((5-(4-((1R,2S)-2-amino-3-fluoro-1-hydroxypropyl) phenyl) pyridin-2-yl) methyl)methanesulfonamide (800 mg, 2.26 mmol) in ethylacetate/aqueous NaHCO3 (1:1) (10 mL) is slowly added bromoacetyl bromide (900 mg, 4.5 mmol) over a period of 20 minutes. Organic layer is separated and aqueous layer extracted with ethyl acetate (3×10 mL). Combined extract is dried over Na2SO4 and concentrated to get crude product. m/z (CI) M+H 474. A mixture of crude bromide (500 mg) and sodium azide (470 mg, 7.0 mmol) in dimethylformamide (6 mL) is heated for 30 min at 50° C. Reaction is cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Combined extract is dried over Na2SO4, concentrated under vacuum and then obtained crude product purified on silica gel column using 0 to 5% methanol/CH2Cl2 to give the title compound (300 mg): 1H NMR (400 MHz, DMSO-d6) 2.95 (s, 3H), 3.71-3.87 (m, 2H), 4.22-4.42 (m, 4H), 4.47-4.58 (m, 0.5H), 4.50-4.70 (m, 0.5H), 4.83-4.93 (m, 1H), 5.83-5.93 (m, 1H), 7.47 (d, 2H), 7.54 (d, 1H), 7.64-7.77 (m, 3H), 8.06-8.20 (m, 2H), 8.83 (d, 1H). m/z (CI) M+H 437.
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:17]1=[O:29])(C(C)(C)C)(C)C>ClCCl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([OH:15])[C:17]2=[O:29])=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(Cl)cc2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1[C@@H](O)CCN1Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 102.3 %

Procedure:
A solution of 4 M HCl in dioxane (4.93 ml, 19.7 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one (1.34 g, 3.94 mmol) in dichloromethane (4 mL) at RT. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to afford (S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one (910 mg, 4.03 mmol, quantitative yield): LC-MS (M+H)+ 226.1; 1H NMR (500 MHz, methanol-d4) δ 7.37-7.33 (m, J=8.5 Hz, 2H), 7.27-7.23 (m, J=8.5 Hz, 2H), 4.52-4.37 (m, 2H), 4.34 (t, J=8.2 Hz, 1H), 3.30-3.18 (m, 2H), 1.84 (dq, J=12.8, 8.5 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][C:9]#[N:10])#[N:2].C[O-].[Na+].C(O)(=O)C>CN(C)C=O>[NH2:10][C:9]1[CH2:8][O:7][C:6]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:5]=2[S:4][C:3]=1[C:1]#[N:2]
Reactant: COc1ccc(OCC#N)c(SCC#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)SC(C#N)=C(N)CO2
Temperature: 0 °C

Procedure:
In 120 ml of N,N-dimethylformamide is dissolved 30 g of 2-cyanomethylthio-4-methoxyphenoxyacetonitrile, and 30 g of 28% sodium methoxide is added dropwise to the solution under ice-cooling and under a nitrogen gas stream with stirring, followed by stirring for 2 hours. The reaction mixture is poured in ice-cold water containing 12 g of acetic acid, and the precipitate is collected by filtration, washed with water and recrystallized from chloroform to give colorless prisms of 3-amino-7-methoxy-2H-1,5-benzoxathiepin-4-carbonitrile. Yield of 19.5 g, m.p. of 203°-205° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13](O)=[O:14])=[CH:9][CH:8]=1)#[N:6]>>[C:5]([C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([Cl:3])=[O:14])=[CH:9][CH:8]=1)#[N:6]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(C=CC(=O)O)cc1
Product: N#Cc1ccc(C=CC(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.2mol of p-cyanobenzaldehyde and 0.3mol of malonic acid were dissolved in 80ml of pyridine at room temperature, and 30 drops of piperidine were added thereto. The mixture was heated and stirred for 4 hours at about 100° C. After the reaction, the solution was poured slowly into dilute hydrochloric acid (250ml hydrochloric acid/250g water). Then, the resulting white precipitate was separated by filtering and washed with dilute hydrochloric acid and water, and was recrystallized by use of glacial acetic acid to obtain p-cyanocinnamic acid. 0.3mol of thionyl chloride was added to 0.1mol of the p-cyanocinnamic acid and the mixture was heated and stirred at about 80° C for 3 hours. An excess thionyl chloride was then removed under reduced pressure to obtain p-cyanocinnamic acid chloride.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:9].C(N(CC)C(C)C)(C)C.[I-].ClC1C=CC=C[N+]=1C.Cl.[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62](=[O:69])[NH:63][CH2:64][CH2:65][CH2:66][NH:67][CH3:68])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([NH:63][CH2:64][CH2:65][CH2:66][N:67]([CH3:68])[C:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:16][CH2:15]3)=[O:20])=[O:69])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CNCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a stirred mixture of 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]-propionic acid (2.8 g, 7.6 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) in DMF (31 mL) was added 2-chloro-1-methylpyridinium iodide (3.9 g, 15 mmol). Once the solids had dissolved, (3-methylaminopropyl)carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride salt (2.63 g, 7.58 mmol) was added and the resulting mixture was stirred at room temperature until essentially complete by HPLC and LCMS. The mixture was then concentrated under reduced pressure to remove most of the DMF and the residue was dissolved in DCM (30 mL). This mixture was washed with water (3×20 mL) and brine (3×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% MeOH in DCM) to give the title compound (5.0 g, 97% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH:2]=[CH2:3].N1C=CC=CC=1.P(Br)(Br)[Br:21].[Br-].[Na+]>CCOCC>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][Br:21])[CH:2]=[CH2:3]
Reactant: BrP(Br)Br
Reactant: C=CCOCCOCCOCCO
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CCOCCOCCOCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a stirred solution of alcohol (15) (3.83 g, 20.1 mmol, 1.0 equiv.) and pyridine (0.16 mL, 2.00 mmol, 0.1 equiv.) in Et2O (20 mL) was added dropwise phosphorus tribromide (0.74 mL, 7.60 mmol, 0.36 equiv.) at 0° C. After 30 min, the reaction was allowed to warm to room temperature. As the reaction was not completed after 12 h, pyridine (1.60 mL, 20.0 mmol, 1.0 equiv.) and sodium bromide (4.14 g, 40.2 mmol, 2.0 equiv.) were successively added. After 12 h of reflux, the resulting solution was submitted to a EtOAc/NH4Cl-saturated aqueous solution extraction. The combined organic phases were dried over anhydrous Na2SO4, filtered then evaporated under reduced pressure. Purification was achieved by column chromatography (Hexanes/EtOAc gradient) to afford bromide (16) (0.90 g, 18%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 5.93 (ddt, J=17.3, 10.5, 5.7 Hz, 1H), 5.28 (dq, J=17.3, 1.5 Hz, 1H), 5.19 (dq, J=10.5, 1.5 Hz, 1H), 4.03 (dt, J=5.7, 1.5 Hz, 2H), 3.82 (t, J=6.3 Hz, 2H), 3.71-3.65 (m, 6H), 3.64-3.59 (m, 2H), 3.48 (t, J=6.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 134.9, 117.4, 72.5, 71.4, 70.9, 70.8, 70.7, 69.6, 30.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[H][H]>[Pt].CO>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: [H][H]
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: NCCCCCCN
Agent: [Pt]
Solvent: CO
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reaction time: 4.5 h
Yield: 90.1 %

Procedure:
In a 5 liter autoclave were charged 981 g (6.32 mols) of 2,2,6,6-tetramethyl-4-piperidone, 350 g (3.01 mols) of hexamethylenediamine, 1500 g of methanol and 5.0 g of 5% platinum on carbon with keeping the temperature at 45°-55° C. The inside of the autoclave was pressurized to 40 bars with hydrogen and heated to 70°-80° C. to carry out hydrogenation. The hydrogenation was completed after 4-5 hours. The catalyst was removed by filtration at 70°-80° C. under 2-3 bars and 1070 g of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,6-hexanediamine was obtained by distillation. Yield: 90%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=2)[CH2:11][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2cccc(Br)c2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2cccc(Br)c2)CC1)c1ccccc1
Yield: 53.4 %

Procedure:
0.108 g (0.0004 mol) of 1-(3-bromo-benzyl)-piperidin-4-ol and 0.12 ml (0.00085 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.08 g (53.5%) of 1-(3-bromo-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([O:11]C)=O)#[N:2].[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>O1CCCC1.O>[NH2:2][C:1]1[C:3]2[C:4]3[CH:8]=[CH:7][S:6][C:5]=3[C:9](=[O:11])[N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20]=2[S:21][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CBr
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)c1sccc1CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc2c(c1N)c1ccsc1c(=O)n2-c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 1.81 g of methyl 3-cyanomethylthiophene-2-carboxylate and 1.62 g of phenyl isothiocyanate in 30 ml of tetrahydrofuran was added 480 mg of a 60% sodium hydride with stirring at 0° C. in a stream of nitrogen, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 1.14 ml of methyl bromoacetate at room temperature, and the mixture was stirred for 3 hours. To the reaction mixture was added 480 mg of a 60% sodium hydride, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 100 ml of water, and precipitates were collected by a filtration. The precipitates were successively washed with water, benzene and n-hexane, and dried over to obtain 3.06 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:30].[Mg+2]>C(Cl)Cl.CO.C([O-])(O)=O.[Na+]>[CH3:1][S:2]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:25])[F:24])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)=[O:30]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CSc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(methylthio)-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (1.62 g, 4.39 mmol) in CH2Cl2/MeOH (2:1, 22 mL) was added magnesium monoperoxyphthalate (1.3 g, 2.2 mmol). The mixture was stirred at room temperature for 18 h. Additional magnesium monoperoxyphthalate (300 mg) was added and after 1 h, the mixture was diluted with saturated aqueous NaHCO3 (50 mL), extracted with (3×20 mL) of EtOAc and dried over Na2SO4. Evaporation of the solvent followed by purification by Combiflash chromatography (SiO2, eluant 5% MeOH/EtOAc) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.92-1.98 (m, 2H), 2.14-2.18 (m, 2H), 2.84 (s, 3H), 3.90-4.08 (m, 5H), 5.01-5.03 (m, 1H), 7.11 (t, 1H), 7.38 (d, 1H), 7.51 (d, 1H), 7.61-7.67 (m, 2H), 7.82 (d, 1H). MS (+ESI) m/z 386 (MH+).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O>ClCCl>[C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([O:16][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cn1nccc1[C@H]1CC[C@H](O)C[C@@H]1OC(=O)c1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Yield: 81.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 162e by using the (1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (290 mg, 0.966 mmol) prepared in Example 163d, 2,6-lutidine (0.136 mL, 1.17 mmol), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.269 mL, 1.17 mmol) and dichloromethane (5.0 mL), to yield the title compound (327 mg, 82%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:28].[NH2:39][CH2:40][CH2:41][OH:42].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(=O)([O-])O.[Na+]>[OH:42][CH2:41][CH2:40][NH:39][C:36]([C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:31][CH2:32]1)=[O:37]
Reactant: COc1c(C(=O)N[C@H]2CC[C@H](C(=O)O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: NCCO
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)N[C@H]2CC[C@H](C(=O)NCCO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the compound of Example 537 (215 mg, 0.417 mmol), 2-aminoethanol (32.5 μL, 0.542 mmol) and HOBt (84.6 mg, 0.626 mmol) in DMF (5 mL) was added WSCD (120 mg, 0.626 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=10/0-8/2). Recrystallization of the obtained solid from ethyl acetate-THF gave the title compound (131 mg, 56%) as a white powder.
Reaction SMILES: C([S:20]/[CH:21]=[CH:22]\[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.[N+]([O-])([O-])=O.[Ag+:39]>O1CCCC1.CO>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23](/[CH:22]=[CH:21]\[S:20][Ag:39])[CH:24]=1
Reactant: C(=C\c1cccnc1)\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: [Ag]S/C=C\c1cccnc1
Temperature: 40 °C
Yield: 109.8 %

Procedure:
To a solution of 3-[(Z)-2-(tritylthio)vinyl]pyridine (690 mg) in a mixture of tetrahydrofuran (3 ml), methanol (5 ml) and pyridine (0.147 ml) was dropwise added a solution of silver nitrate (371 mg) in methanol (20 ml) at ambient temperature. The reaction mixture was stirred at 40° C. in dark. The precipitate was collected, washed with methanol and dried over phosphorus pentoxide to give [(Z)-2-(3-pyridyl)vinylthio]silver (487 mg).
Reaction SMILES: CCN(CC)CC.[C:8]([O:11][CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)=O)(=[O:10])[CH3:9].[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl>CCO>[C:8]([O:11][CH2:12][C:13]1[N:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:30]=[C:16]2[C:15]=1[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:10])[CH3:9]
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)OCC(=O)C1CCCCC1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c2c(nn1-c1ccc(F)cc1)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
Et3N (0.717 mL, 0.520 g, 5.14 mmol) was added to a stirring suspension of 1.00 g (5.04 mmol) of 2-acetoxyacetylcyclohexanone (Dolmazon, R.; Gelin, S. J. Heterocyclic Chem., 1982, 19, 117-121) and 0.820 g (5.04 mmol) of 4-fluorophenylhydrazine.HCl in 20 mL of absolute EtOH. The resulting solution was stirred under N2 for 4 h at room temperature and refluxed for 6 h. The mixture was concentrated and the residue was partitioned between 100 mL of Et2O and 50 mL of dilute aqueous HCl. The Et2O layer was washed with water, saturated aqueous NaHCO3, and brine. After drying over Na2SO4, the solution was concentrated to give 1.43 g of light brown solid. Recrystallization from EtOAc:hexanes afforded 0.753 g (52%) of the title compound as a white solid, m.p. 128.5°-129.5° C.; 1H NMR (CDCl3, 400 MHz) 1.85 (m, 4), 2.07 (s, 3), 2.60 (t, 2, J=6 Hz), 2.73 (t, 2, J=6 Hz), 5.00 (s, 2), 7.15 (t, 2, J=9 Hz), 7.45 (dd, 2, J=5, 9 Hz); IR (KBr) 1740, 1220 cm-1 ; MS (DCI) m/z 289 (base), 228 . Anal. Calcd. for C16H17FN2O2 : C, 66.65; H, 5.94; N, 9.72. Found: C, 66.74; H, 5.89; N, 9.61.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:19]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:18]=1.[NH4+].[Cl-]>CO.C1COCC1.O.[Fe]>[NH2:19][C:3]1[C:2]([Br:1])=[CH:18][C:6]2[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]3[CH2:12][CH2:11]3)[O:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1c(C2CC2)oc2cc([N+](=O)[O-])c(Br)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Yield: 86.4 %

Procedure:
A mixture of crude compound ethyl 5-bromo-2-cyclopropyl-6-nitrobenzofuran-3-carboxylate (8.5 g, 25 mmol), iron filings (4.1 g, 75 mmol) and NH4Cl (8 g, 150 mmol) in MeOH-THF—H2O (2:2:1, 100 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish the pure product of ethyl 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylate (7.00 g, yield: 91%). 1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 6.75 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.11 (s, 2H), 2.94˜2.99 (m, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.19˜1.21 (m, 2H), 1.12˜1.15 (m, 2H). MS (M+H)+: 324/326.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[OH:15].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=1.CC(C)([O-])C.[K+].O>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=1
Reactant: COCCOc1cc2[nH]ccc2cc1O
Reactant: CC(=O)Nc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Temperature: 150 °C
Reaction time: 13 h
Yield: 53 %

Procedure:
6-(2-Methoxyethoxy)-1H-indol-5-ol described in Production Example 20-4 (3.94 g, 19.0 mmol) and N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (3.25 g, 19.0 mmol) were dissolved in dimethylsulfoxide (25 mL), then 97% potassium tert-butoxide (2.20 g, 19.0 mmol) was added at room temperature, and the mixture was heated and stirred at 150° C. for 13 hours. Water and ethyl acetate were added to the reaction liquid at mom temperature for partition. The aqueous layer was extracted with ethyl acetate three times and the combined organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under vacuum, and then the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1-ethyl acetate:methanol=49:1-9:1). The target fraction was concentrated under vacuum to obtain the title compound (3.45 g, 53%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:17][CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16][CH2:17]2)=[O:13])=[C:5]3[NH:18][CH:19]2[CH2:20][CH2:21][CH:22]([CH2:25][N:26]([CH3:27])[CH3:28])[CH2:23][CH2:24]2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CN(C)CC1CCC(Nc2c(C(=O)C3CCC3)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CC1CCC(Nc2c(C(=O)C3CCC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)CC1
Yield: 88.1 %

Procedure:
Following general procedure II, (6-chloro-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)(cyclobutyl)methanone (65 mg, 0.16 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.24 mmol) to afford the desired product (72 mg, 77%) as light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J=11.5, 2.0 Hz, 1H), 5.74-5.64 (m, 1H), 4.29-4.19 (m, 1H), 3.12-3.07 (m, 2H), 2.95 (s, 6H), 2.52-2.41 (m, 4H), 2.39-2.34 (m, 2H), 2.24-2.12 (m, 1H), 2.09-1.98 (m, 2H), 1.98-1.89 (m, 1H), 1.78-1.66 (m, 2H), 1.49-1.35 (m, 2H); ESI MS m/z 511 [M+H]+; HPLC>99% (AUC), tR=10.52 min.