Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[C:27]([O:31][C:32](NCC(O)=O)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(OC(C)C)(C)C>>[C:27]([O:31][C:32](=[O:33])[NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide hydrochloride (Example 73) and N-(tert-butoxycarbonyl)-glycine (Aldrich) according to the method described in Example 94. Melting Point: 177-179° C. (diisopropylether)
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([C:20]2[C:25]([O:26][CH3:27])=[N:24][C:23]([CH3:28])=[CH:22][N:21]=2)[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C1(C)C=CC=CC=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.O.C(O)C>[CH3:27][O:26][C:25]1[C:20]([N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[S:8]([C:7]2[C:2]([C:34]3[CH:35]=[CH:36][C:31]([S:30][CH3:29])=[CH:32][CH:33]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[N:21][CH:22]=[C:23]([CH3:28])[N:24]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1Cl
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1-c1ccc(SC)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.022 g) was added to a deoxygenated mixture of 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.405 g), 4-methylthiophenylboronic acid (obtained by the procedure described in Tetrahedron Lett., 1993, 34, 8237) (0.148 g), toluene (4.5 ml), ethanol (2.5 ml) and 2M sodium carbonate solution (7 ml) and the mixture was stirred and heated under reflux for 18 hours. Water was added and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-35% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylthiophenyl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.415 g) as an oil; 1H NMR (CDCl3): 0.0 (s, 9H), 0.8 (t, 2H), 2.5 (s, 3H), 2.55 (s, 3H), 3.6 (t, 2H), 3.9 (s, 3H), 4.8 (s, 2H), 7.3-7.5 (m, 3H), 7.6-7.7 (m, 2H), 7.8 (s, 1H), 8.7 (dd, 1H), 8.8 (dd, 1H); mass spectrum (+ve ESP): 533 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1([CH3:32])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[NH:6][C:5]1=[O:31])[CH:2]=[CH2:3].Br[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.C([O-])(=O)C.[K+]>CN(C=O)C.CCOC(C)=O.[Cu]>[CH2:1]([C:4]1([CH3:32])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C(=O)Nc2ccccc2N(CC(=O)N(c2ccc(OC)cc2)C(C)C)C1=O
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCC1(C)C(=O)N(CC(=O)N(c2ccc(OC)cc2)C(C)C)c2ccccc2N(c2cccnc2)C1=O
Temperature: 125 °C
Yield: 53 %

Procedure:
To a stirring solution of 2.5 g (5.74 mmol) of 2-(3-Allyl-3-methyl-2,4-dioxo-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl) acetamide, prepared as in Part A, in 25 mL of DMF is added 1.81 g (11.5 mmol, 2 equiv.) of 3-bromopyridine, 1.12 g (11.5 mmol, 2 equiv.) of potassium acetate, and 364 mg (11.5 mmol) of copper powder. The suspension is heated to 125° C. for 4 h and then cooled to RT. It is diluted with 350 mL EtOAc and filtered through a bed of celite. The filtrate is washed with H2O (2×300 mL), conc. NH4OH (2×150 mL) and then dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 1.56 g of 2-(3-Allyl-3-methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-[4-methoxyphenyl]acetamide as an oil: 1H NMR (CDCl3, 300 MHz) δ8.51 (m, 2H), 7.68 (d, 1H, J=9), 7.39-6.93 (m, 8H), 6.71 (d, 1H, J=8), 5.78-5.64 (m, 1H), 5.08-5.00 (m, 2H), 4.72 (d, 1H, J=16), 4.39 (d, 1H, J=17), 4.08 (m, 1H), 3.85 (s, 3H), 3.81-3.79 (m, 1H), 2.11 (d, 1H, J=8), 1.77 (s, 1H), 1.60 (s, 2H), 1.21-1.07 (m, 6H).
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=CC=1.Cl.O[C@H](COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C2C(=CC=CC=2)C=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:84][CH:85]([CH2:100][O:101][C:102]1[CH:107]=[CH:106][C:105]([O:108][CH3:109])=[CH:104][CH:103]=1)[CH2:86][NH:87][C:88]([CH3:99])([CH3:98])[CH2:89][C:90]1[CH:95]=[CH:94][C:93]([O:96][CH3:97])=[CH:92][CH:91]=1>>[ClH:1].[OH:84][CH:85]([CH2:100][O:101][C:102]1[CH:107]=[CH:106][C:105]([O:108][CH3:109])=[C:104]([O:2][CH3:3])[CH:103]=1)[CH2:86][NH:87][C:88]([CH3:99])([CH3:98])[CH2:89][C:90]1[CH:91]=[CH:92][C:93]([O:96][CH3:97])=[CH:94][CH:95]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)c(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 390 (M+, 0.0), 269 (17), 268 (100), 163 (6), 153 (5), 121 (21), 114 (17), 77 (5), 71 (19), 70 (17), 58 (7).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]=[O:12])[CH2:7][CH2:6]1.[C-:13]#[N:14].[Na+]>C(O)C>[C:13]([CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)#[N:14]
Reactant: [C-]#N
Reactant: O=CN1CCC(CCCBr)CC1
Agent: [Na+]
Solvent: CCO
Product: N#CCCCC1CCN(C=O)CC1
Yield: 61.5 %

Procedure:
4-(3-Bromopropyl)-1-piperidinecarboxaldehyde (60 g, 0.256M) and NaCN (25 g) in ethanol (600 ml) was refluxed for 7 hours, Solvent was removed, added water (300-400 ml) and extracted with CH2Cl2 (4×200 ml). The extracts, dried over Na2SO4 was stripped to dryness which was purified on silica gel columns, eluted with ethylacetate-hexane (8:2 parts by volume) to yield 4-(3-cyanopropyl)-1-piperidinecarboxaldehyde (28.4 g, 61% yield).
Reaction SMILES: [C:1]([C:4]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[N+:19]([O-])([O-:21])=[O:20].[K+]>OS(O)(=O)=O>[N+:19]([C:12]1[CH:11]=[C:10]2[C:15]([NH:16][C:17]3[C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]2=[O:18])=[CH:14][CH:13]=1)([O-:21])=[O:20]
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3[nH]c12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cccc2c(=O)c3cc([N+](=O)[O-])ccc3[nH]c12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A stirred solution of 4-carboxyacridanone (10.0 g) in c.H2SO4 (50 ml) was treated portionwise at below 5° C. with powdered KNO3 (4.6 g), then stirred for 30 min at 20° C. and poured into ice water. The precipitate was collected, washed, dried and crystallized from DMF/MeOH and then DMF to give pure product of m.p. about 375° C. (65% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:12])[C:4]=2[O:3]1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:28])=S.[Na+].[Na+]>C(OCC)(=O)C>[O:28]1[C@H:6]2[C@@H:7]1[C:2]([CH3:16])([CH3:1])[O:3][C:4]1[C:11]([CH3:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][C:5]=12
Reactant: O=S([O-])([O-])=S
Reactant: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)C=C2
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)[C@@H]1O[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution (50 mL) of ethyl acetate containing 2,2,8-trimethyl-7-nitro-2H-1-benzopyran (3.32 g, 15.1 mmol), N-methyl imidazole (0.482 mL, 6.05 mmol) and (R,R,S,S)-Ph,Ph salen manganese complex (XY) (142 mg, 0.151 mmol) were added at room temperature, and sodium hypochlorite aqueous solution (34.1 mL, 1.776 mol/kg, 60.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting solution was filtered through celite. The resulting filtrate extracted with ethyl acetate. The organic phase was washed with water and sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=7/1) and the aimed product was obtained as pale yellow crystal (yield: 78%, optical purity: 99% ee).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([NH2:16])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])C2C=CC=CC=2N=N1>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([NH:16][C:36](=[O:37])[O:38][CH2:39][CH:40]=[CH2:41])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: C=CCOC(=O)n1nnc2ccccc21
Reactant: Nc1cc(-c2ccc3cnccc3c2)on1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)Nc1cc(-c2ccc3cnccc3c2)on1
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
To a solution of 5-(isoquinolin-6-yl)isoxazol-3-amine (0.10 g, 0.47 mmol) in 4 mL of DMF at 0° C. was added LiHMDS (0.57 mL, 1.0 M in THF). The mixture was stirred for 20 minutes. Allyl 1H-benzo[d][1,2,3]triazole-1-carboxylate (0.14 g, 0.71 mmol) (prepared as described by Katritzky, A. et al. J. Phys. Org. Chem. 1993, 6(10), 567-73 which is hereby incorporated by reference for all purposes as if specifically set forth herein) was added to the mixture. The mixture was stirred for 20 minutes. The reaction was quenched with 5 mL of aqueous NH4Cl. The mixture was extracted three times with 10 mL of EtOAc, and the combined organic extracts were washed with 20 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc/hexanes) afforded allyl 5-(isoquinolin-6-yl)isoxazol-3-ylcarbamate (0.075 g, 0.25 mmol, 54% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 9.39 (s, 1H), 8.59 (d, J=5.7 Hz, 1H), 8.57 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.45 (s, 1H), 6.03-5.95 (m, 1H), 5.39 (dd, J=1.4 Hz, 17.1 Hz, 1H), 5.27 (d, J=10.5 Hz, 1H), 4.68 (d, J=5.5 Hz, 2H).
Reaction SMILES: C(OC([NH:8]C1C=CN=CC=1B(O)O)=O)(C)(C)C.[CH2:18]([N:22]1[C:34]([CH2:35][CH:36]([CH3:38])[CH3:37])=[C:33]2[C:24]([C:25]([NH2:39])=[N:26][C:27]3[CH:28]=[CH:29]C=[CH:31][C:32]=32)=[N:23]1)[CH2:19][CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:18]([N:22]1[C:34]([CH2:35][CH:36]([CH3:38])[CH3:37])=[C:33]2[C:24]([C:25]([NH2:39])=[N:26][C:27]3[CH:28]=[CH:29][N:8]=[CH:31][C:32]=32)=[N:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCn1nc2c(N)nc3ccccc3c2c1CC(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccncc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCn1nc2c(N)nc3ccncc3c2c1CC(C)C
Temperature: 100 °C
Yield: 1.5 %

Procedure:
2-Butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,6-naphthyridin-4-amine was synthesized from 4-[(tert-butoxycarbonyl)amino]pyridin-3-ylboronic acid (2.48 g, 10.4 mmol) and 4-bromo-1-butyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (prepared as described in Parts A-F of Example 4, 1.56 g, 5.49 mmol) according to the reaction conditions described in Examples 52-54. Additional palladium (II) acetate (50 mg) and triphenylphosphine (170 mg) were added after the reaction had been heated for 23 hours. After the addition, the flask was placed under vacuum and back-filled with nitrogen twice. The solution was heated at 100° C. for an additional 29 hours. The reaction was worked-up and purified as described in Example 54, but was not recrystallized from acetonitrile, to provide 25 mg of 2-butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,6-naphthyridin-4-amine as an off-white solid.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([CH3:13])([NH2:12])[CH3:11])[CH2:4][CH2:3]1.[C:15](ON1C(=O)CCC1=O)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1COCC1>[F:14][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]([NH:12][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:11])[CH3:13])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)CCN1CCC(F)(F)CC1
Solvent: C1CCOC1
Product: CC(C)(CCN1CCC(F)(F)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
Crude 4-(4,4-difluoropiperidin-1-yl)-2-methylbutan-2-amine (6.56 g, 31.8 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (7.93 g, 1 equiv, 31.8 mmol) in one portion. The reaction was left to stir at room temperature for 1 d. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (100 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1M HCl (50 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a colorless oil which solidified on standing. The crude solid was purified on an ISCO purification system with gradient elution from 0-6% methanol. The desired fractions were collected and concentrated to give a white solid (7.54 g, 69.7%). 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 6H), 1.68-1.72 (t, J=6.8, 4H), 1.92-2.05 (m, 4H), 2.16-2.20 (m, 2H), 2.48-2.52 (t, J=6.8, 4H), 2.53-2.58 (m, 4H), 5.04 (s, 2H), 6.70 (s, 1H), 7.27-7.40 (m, 5H). LRMS (ESI+) for C18H26F2N2O2 (340.1); Found: 341 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:34].[Cl-].[NH4+]>C(CC(=O)C)(=O)C.[Cu+2].CN1C(=O)CCC1>[NH2:34][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: N
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)CC(C)=O
Solvent: CN1CCCC1=O
Product: CCSc1ccccc1-c1nc2cc(N)cnc2n1C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a pressure-resistant reaction container, 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (1.74 g), copper (II) acetylacetone (0.26 g), acetylacetone (0.50 g), cesium carbonate (3.25 g), NMP (9 ml), and 28% of aqueous ammonia (4 ml) were added, and stirred at 120° C. for 6 hours. The mixture was cooled to room temperature, and then saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.20 g of 6-amino-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 125).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:26])[F:25])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:44])[CH3:45])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: C1CCNC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 29.2 %

Procedure:
With 350 mg of the compound obtained in Example 219 and 75 mg of pyrrolidine as starting materials, 110 mg of the title compound (pale orange amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[C:27]([CH:33]5[CH2:35][CH2:34]5)[N:28]4[CH2:31][CH3:32])=[C:24]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]4[CH3:42])[N:23]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:33]1([C:27]2[N:28]([CH2:31][CH3:32])[C:29]3[C:25]([N:26]=2)=[C:24]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]2[CH3:42])[N:23]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:21][CH:20]=2)[N:30]=3)[CH2:34][CH2:35]1
Reactant: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(Nc4cccc(OCc5ccccc5)n4)cc3)nc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(Nc4cccc(=O)[nH]4)cc3)nc21
Reaction time: 2 h
Yield: 1 %

Procedure:
To a solution of (S)-6-(benzyloxy)-N-(4-(8-cyclopropyl-9-ethyl-6-(3-methylmorpholino)-9H-purin-2-yl)phenyl)pyridin-2-amine (100 mg, 1.78 mmol) in anhydrous MeOH (4 mL) and EtOAc (4 mL) was added 20 wt % Pd(OH)2 on carbon (10.0 mg). The reaction mixture was evacuated with vacuum and purged with H2 (3×), then stirred under an atmosphere of H2 for 2 hours. The reaction mixture was then filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the crude was purified by column chromotagraphy (Si-PPC, gradient 0 to 30% methanol in dichloromethane). Crystallization from ether-heptane afforded the title compound (x-1) (8.6 mg, 10.2%) as a solid. 1H NMR (DMSO-d6, 500 MHz) δ ppm 10.16 (broad s, 1H), 9.05 (broad s, 1H), 8.27 (d, J=8.7 Hz, 2H), 7.76 (broad s, 2H), 7.41 (t, J=7.9 Hz, 1H), 6.29 (broad s, 1H), 5.98 (d, J=6.3 Hz, 1H), 5.36 (broad s, 1H), 5.06 (broad s, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.98 (d, J=8.5 Hz, 1H), 3.78 (d, J=11.2 Hz, 1H), 3.69 (d, J=8.7 Hz, 1H), 3.54 (t, J=10.6 Hz, 1H), 3.44 to 3.33 (m, 1H), 2.30 to 2.19 (m, 1H), 1.40 (t, J=7.1 Hz, 3H), 1.29 (d, J=6.7 Hz, 3H), 1.12 to 0.93 (m, 4H); LC-MS m/z (method C)=472.2 [M+H]+, RT=4.93 min.
Reaction SMILES: CN(C1C=CC=CC=1)C(Cl)=O.[CH3:12][N:13]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)[NH2:29].C1(C)C=CC=CC=1>C(O)C>[CH3:12][N:13]([C:20]([N:22]=[C:23]=[S:24])=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:23]([NH:22][C:20]([N:13]([CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:21])=[S:24])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CN(C(=O)Cl)c1ccccc1
Agent: CN(C(=O)N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(C)c4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
(Methylanilino)methanoyl isothiocyanate was prepared using commercially available N-methyl-N-phenylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Methylanilino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 71%).
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].Cl>CN(C=O)C.CN(C=O)C.C1CN2C(=NCCC2)C1>[C:16]([CH2:15][N:14]1[CH2:21][C:19](=[O:20])[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:2](=[O:3])[CH2:1][N:8]([CH2:7][C:5]([OH:6])=[O:4])[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)([OH:18])=[O:17]
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Reactant: NCCCCN
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NCCCCNC(=O)CN(CC(=O)O)CC1
Reaction time: 8 h

Procedure:
A 1 L three-neck flask was charged with 340 mL of dry DMF. Two syringes were charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (3.00 g, 8.40 mmol) in 100 mL of DMF and 1,4-diaminobutane (0.740 g, 8.40 mmol) in DMF/DBN, (96 mL/4 mL). The solutions were added simultaneously at ambient temperature to the flask at a rate of 30 mL/hour. After the addition was complete, the reaction mixture was allowed to stir overnight, stripped to dryness, and 1N HCl added to adjust the pH to 10.4. The solution was applied to AG1-X8 (100-200 mesh, OAc-) resin and eluted with 0.5N acetic acid to yield 0.52 g (13.6%) as a white solid, after removal of acetic acid and lyophilization.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCCC(O)c2ccccc2N1
Product: CC(=O)OC1CCCCC(=O)Nc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 7-hydroxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (9.2 g) in acetic anhydride (200 ml) is maintainwed at 80° for 3 hours. The reaction mixture is cooled to room temperature and the solvents removed under reduced pressure. Ether (300 ml) is added, and the resulting solution washed with water (150 ml) and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 7-acetoxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.