Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)[CH:47]=[CH:46][C:4]=1[CH2:5][NH:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1.C(N(CC)CC)C.ClCCCC(Cl)=[O:64].[OH-].[Na+]>ClCCl>[NH2:17][C:12]1[C:11]2[C:10]3[C:9](=[N:34][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:32]=2)[CH2:8][CH:7]([N:6]2[CH2:47][CH2:46][CH2:4][C:5]2=[O:64])[C:16]=3[CH2:15][S:14][N:13]=1
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(CN2N=C3CC(N4CCCC4=O)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture composed of di-tert-butyl {8-[(2,4-dimethoxybenzyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 42 (47 mg), triethylamine (36 μl), dichloromethane (1 ml) and 4-chlorobutyryl chloride (14 μl) was stirred at room temperature for 12 hours. A 0.1 N sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dehydrated dichloromethane (1.5 ml). 1,3-Dimethoxybenzene (16 μl) and trifluoroacetic acid (1.5 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a 0.1 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dimethylformamide (1 ml) and potassium tert-butoxide (15 mg) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was separated with water and chloroform. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (13 mg, 46%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([N:49]5[CH2:53][CH2:52][CH2:51][CH2:50]5)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCNC1
Reactant: OC1CCN(c2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: Fc1ccc(Nc2ncnc3cnc(N4CCC(N5CCCC5)CC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-hydroxy-1-piperidinyl]pyrimido[5,4-d]pyrimidine by oxidation with Dess-Martin reagent and subsequent reductive amination with pyrrolidine and sodium cyanoborohydride. Melting point: 202°-204° C.; Rf : 0.58 (alumina; petroleum ether/ethyl acetate/methanol=10:10:1)
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]3[N:17]=[C:18]([NH:21][CH2:22][CH3:23])[N:19]=[CH:20][C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([NH:21][C:18]1[N:19]=[CH:20][C:9]2[C:8](=[O:24])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)=[CH:26][CH:25]=3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:17]=1)[CH3:23]
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(Cc1ccc(N)cc1)C2=O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(NC(=O)c3cccnc3)cc1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
Compound 6 (80.0 mg, 0.227 mmol) obtained in Example 6 was dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1.5 hours after adding nicotinoyl chloride.hydrochloride (61.0 mg, 0.340 mmol) and triethylamine (0.095 mL, 0.340 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by silica gel column chromatography to give the title compound (Compound 7) (54.3 mg, 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1
Reactant: Fc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2ccncc2)cc1-c1nc(-c2ccccn2)no1
Yield: 4.1 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmole), 4-pyridylboronic acid (76.7 mg,0.6265 mmol) and Pd(PPh3)4 (36.1 mg, 0.03123 mmol) in a solution of 2M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) was heated overnight at 105° C. Standard work up, afforded 4.1 mg (4%) of 3-(2-pyridyl)-5-[2-fluoro-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:16][CH2:15][CH2:14][C:13]3[C:9]2=[CH:10][N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:12]=3)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:13]([CH2:14][CH2:15][CH:16]=2)=[N:12][N:11]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCCC3(O)c2ccc(Cl)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC=C3c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
4-(4-Chlorophenyl)-2-(p-tolylsulfonyl)-6,7-dihydro-5H-indazol-4-ol (0.76 g, 1.89 mmol) is added to dichloromethane (20.0 mL), triethylsilane (6.04 mL, 37.7 mmol), and TFA (0.16 mL, 2.07 mmol) and stirred at room temperature for 2.0 h. The reaction is quenched with saturated NaHCO3, separated, the organics washed with brine dried over Na2SO4, filtered, and evaporated to dryness to give the title compound (0.622 g, 86%). 1H NMR (CDCl3) δ 2.42 (s, 3H), 2.55 (m, 2H), 2.82 (t, 2H), 5.98 (t, 1H), 7.37-7.31 (m, 6H), 7.81 (s, 1H), 7.87 (d, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 96.7 %

Procedure:
To a solution of 1.2 g (6.0 mmol) 4-amino-1-t-butoxycarbonylpiperidine from Step B in 40 mL of methylene chloride was added 3.15 mL (18 mmol) of DIPEA and 1.03 mL (7.2 mmol) of benzyl chloroformate while cooled in an ice bath. After 0.5 h the reaction was quenched with aqueous sodium carbonate and extracted three times with methylene chloride. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 25% ethyl acetate in hexanes to afford 1.94 g of title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[C:9]1[N:14]=[C:13]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[N:1]1([C:9]2[N:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Brc1cccc(COC2CCCCO2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(COC2CCCCO2)nc(-n2ccnc2)c1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 7.4 %

Procedure:
Imidazole (500 mg, 74 mmol) was added to a stirred mixture of sodium hydride (300 mg of a 60% dispersion in oil, 75 mmol) and dimethylformamide (20 ml), at room temperature under nitrogen. After 0.75 h, 6-bromo-2-[(tetrahydropyran-2-yl)oxymethyl]pyridine (400 mg 14.6 mmol) prepared following the procedure given for Example 11 part a in dimethylformamide (5 ml) was added. The mixture was heated at 80° C. for 24 h then in a sealed tube at 120° C. for 4 h. The solvent was evaporated in vacuo and the residue partitioned between water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate (×3). The combined extracts were dried (MgSO4), and evaporated in vacuo and the residue flash chromatographed on silica gel, eluting with 5% methanol/dichloromethane to give the title-compound (280 mg, 73%), 1H NMR (250 MHz, CDCl3), δ 1.5-1.8 (6H, m, 3 of CH2), 3.58 (1H, m, CH2O), 3.93 (1H, m, CH2O), 4.66 (1H, d, J=14.1 Hz, CH2O), 4.82 (1H, d, CH), 4.90 (1H, d, J=14.1 Hz, CH2O), 7.19 (1H, br s, Ar—H), 7.24 (1H, d, J=8.2 Hz, Ar—H), 7.43 (1H, dd, J=7.6 Hz and 7.1 Hz, Ar—H), 7.64 (H, t, J=1.2 Hz, Ar—H), 7.83 (1H, t, J=7.9 Hz, Ar—H), 8.35 (1H, s, Ar—H); MS (ES+) m/e 260 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C.Cl[C:24]1[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:25]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:24]2[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[N:25]=2)[CH2:12][CH2:11]1
Reactant: COc1ccccc1NC1CCNCC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC1CCN(c2nc(-c3ccncc3)cc(=O)n2C)CC1
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 4-(2-methoxyphenylamino)-piperidine (0.8 g, 3.87 mmol) and triethylamine (1.3 g, 12.8 mmol) in tetrahydrofuran (20 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.8 g, 3.61 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 2-(4-(2-methoxyphenylamino)-piperidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.2 g, 3.07 mmol, 85%) as white crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:73])=[O:74])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([C@@H:20]1[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(S(=O)(=O)N2CCOCC2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(S(=O)(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Yield: 16 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.37 g, 1.6 mmol), then reacted with 2-methoxy-4-(morpholinosulfonyl)aniline (Matrix) (0.16 g, 0.59 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(morpholine-4-sulfonyl)-phenyl]-amide as a white solid (Yield 0.06 g, 17%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([S:11][CH3:12])=[N:10][C:3]=12.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=4[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[C:9]([S:11][CH3:12])=[N:10][C:3]=12
Reactant: CSc1nc2c(C)ccnc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(SC)nc3c(C)ccnc32)cc1
Reaction time: 0.5 h

Procedure:
200 mg of 7-methyl-2-methylthio-3H-imidazo[4,5-b]pyridine and 370 mg of methyl 2-(4-bromomethylphenyl)benzoate was dissolved in dimethylformamide, and 48 mg of sodium hydride was added at room temperature to the solution under stirring. The reaction was allowed to proceed for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (benzene:ethyl acetate=10:1→3:2) to prepare the intended product as a colorless oleaginous substance. The yield was 60 mg.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24]O)[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1.C(N(S(F)(F)[F:34])CC)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][F:34])[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3F)cn2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](CF)OC4=O)cc3F)cn2)n1
Reaction time: 24 h
Yield: 75.5 %

Procedure:
In 5 ml of methylenechloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([OH:36])=O)(=[O:31])[CH3:30].[CH:40]1[C:48]2[C:47]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:46]=3[O:45][C:44]=2[CH:43]=[CH:42][C:41]=1[NH2:54]>>[C:29]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([NH:54][C:41]1[CH:42]=[CH:43][C:44]2[O:45][C:46]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:47]=3[C:48]=2[CH:40]=1)=[O:36])(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]1C(=O)Nc1ccc2oc3c(c2c1)CCCCC3

Procedure:
Following the procedure of Example 30, triethylamine (0.21 mL, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.15 g, 0.78 mmol), N-hydroxybenzotriazole (0.11 g, 0.78 mmol), N-acetyl-L-proline (0.094 g, 0.60 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.12 g, 0.60 mmol) 1-acetyl-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-prolinamide (0.13 g). MS (ESI) m/z 341 ([M+H]+); MS (ESI) m/z 339.1 ([M−H]−); HRMS: calcd for C20H24N2O3+H+, 341.18597; found (ESI, [M+H]+), 341.1863.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[S:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.36 g) in methanol (10 ml) was added a solution of 1-[5-fluoro-2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 1 (0.58 g) and triethylamine (0.65 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.17 g).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:15]([O-])([O-])=[O:16].[Cs+].[Cs+].I[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].CO>[Cu]I.C1(C)C=CC=CC=1>[CH3:15][O:16][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 41.7 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 1,10-phenanthroline (36 mg, 0.20 mmol, 20 mol %), Cs2CO3 (652 mg, 2.0 mmol), 3-iodobenzonitrile (229 mg, 1.0 5 mmol), methanol (162 μL, 4.0 mmol) and toluene (1 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with diethyl ether. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane/diethyl ether 5:1) provided 111 mg (84% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@H:43]([NH2:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[C:46](O)(=[O:48])[CH3:47]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@H:43]([NH:45][C:46](=[O:48])[CH3:47])[CH3:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)N)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)NC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 80 mg of (R)-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1-methyl-ethylamine are reacted with acetic acid to afford the title compound as a brown oil. Rf=0.17 (EtOAc-heptane 5:1); Rt=4.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27](B5OC(C)(C)C(C)(C)O5)[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1.Br[C:43]1[CH:44]=[N:45][CH:46]=[C:47]([CH:51]=1)[C:48]([NH2:50])=[O:49].O1CCOCC1>C(Cl)(Cl)Cl.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:43]5[CH:44]=[N:45][CH:46]=[C:47]([CH:51]=5)[C:48]([NH2:50])=[O:49])[CH:28]=4)[O:23]3)[CH2:21][CH2:22]2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2O3)nc2c(OC)cccc12
Reactant: NC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(N)=O)c4)ccc2O3)nc2c(OC)cccc12
Reaction time: 21 h

Procedure:
350 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-2,4′-piperidin]-4-one, 151 mg of 5-bromonicotinamide, 72.5 mg of Pd(PPh3)4 and 1.4 mL of 2M Na2CO3aq were heated with 1,4-dioxane at 100° C. and stirred for 21 hours. The reaction solution was diluted with CHCl3, filtered through Celite, and the filtrate was dried with magnesium sulfate and concentrated. The residue was purified through silica gel thin-layer chromatography (CHCl3/MeOH=9/1) to obtain the intended compound. 1H-NMR (400 MHz, CDCl3) δ: 8.90-9.00 (2H, m), 8.36 (1H, s), 8.15 (1H, s), 7.70-7.80 (2H, m), 7.40-7.55 (1H, m), 7.19 (1H, s), 7.17 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=7.8 Hz), 6.3-6.5 (1H, br), 5.7-6.1 (1H, br), 4.50-4.60 (1H, m), 4.10-4.15 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.55-3.70 (1H, m), 3.35-3.50 (1H, m), 2.88 (1H, d, J=16.6 Hz), 2.82 (1H, d, J=16.6 Hz), 2.20-2.30 (1H, m), 2.05-2.15 (1H, m), 1.80-2.05 (2H, m). MS [M+H]+=553.