Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[N:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[N:14]=[CH:13][C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24][CH3:23])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cn1
Reactant: CSc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CSc1ccccc1-c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Yield: 96.3 %

Procedure:
2-[Bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). 2-methylthiophenylboronic acid (2.24 g, 13.3 mmol), aq. sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutyl ammonium bromide (86 mg, 0.26 mmol), and bis(triphenylphosphine)palladium(II)chloride (190 mg, 0.27 mmol) were added, and the resulting mixture was first purged with vacuum and argon, then refluxed 17 hours. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organic was dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (50% EtOAc/hexanes), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc/hexanes) to yield the desired product (2.13 g, 96%). 1H NMR (CDCl3): δ8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[N:3]1.[BH4-].[Na+]>CCO>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([OH:11])[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1ncc2c1CCCC2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 1-methyl-6,7-dihydro-1H-indazol-4(5H)-one (1 g, 6.7 mmol) in EtOH (20 mL) was added NaBH4 (1.2 g, 33.3 mmol) in portions. The resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure to afford the crude 1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (700 mg, 68.8%), which was used in the next step directly. MS-ESI (m/z): 153 (M+1)+ (Acq Method: 10-80AB_2 min_220 &254.1 cm; Rt: 0.17 min)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:29]=[CH:28][CH:27]=[CH:26][C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:11])[CH:2]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:29]=[CH:28][CH:27]=[CH:26][C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=2)=[O:11])[CH:2]=1
Reactant: O=C(NCc1ccc(C(O)C(F)(F)F)cc1)c1cccnc1Oc1cccnc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C(NCc1ccc(C(=O)C(F)(F)F)cc1)c1cccnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
To a stirred solution of 2-(Pyridin-3-yloxy)-N-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzyl]-nicotinamide (0.350 grams, 0.87 mmole), NMO (0.153 grams, 1.3 mmole) and 4 Å molecular sieves (0.5 g) in methylene chloride was added TPAP (0.015 grams, 0.04 mmole) and stirred at room temperature for 4 hours. The mixture was filtered through celite, washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give an oil which was purified by chromatography on silica eluting with 5% methanol/methylene chloride to give a solid (0.151 g). M.P. 134-136°C.; Anal. calcd. for C20H14N3O3F3: C, 59.85; H, 3.52; N, 10.47. Found: C, 59.56; H, 3.63; N, 10.20.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[C:4](=[O:17])[C:3]=1[C:18]([O:20]CC1C=CC=CC=1)=[O:19]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[C:4](=[O:17])[C:3]=1[C:18]([OH:20])=[O:19]
Reactant: COC(=O)c1ccc2c(O)c(C(=O)OCc3ccccc3)c(=O)n(C)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(O)c(C(=O)O)c(=O)n(C)c2c1
Yield: 88.7 %

Procedure:
Palladium, 10 wt. % on activated carbon, (5.1 mg, 48 μmol) was added to a solution of 3-benzyl 7-methyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3,7-dicarboxylate (88 mg, 240 μmol) in ethyl acetate (19 ml) and brought under an atmosphere of H2 while stirring vigorously. After the reaction was complete, the mixture was filtered through a Celite pad, rinsing with EtOAc/DCM to give an off-white powder (59 mg, 89%) which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C(Cl)(=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([S:11]([N:8]3[CH2:7][CH2:6][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:10][CH2:9]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)phenyl]methanamine 7b (3.00 g, 10.1 mmol) was dissolved in DCM (20 ml), pyridine (976 μl, 12.1 mmol), 4-chlorobenzoyl chloride (1.41 ml, 11.1 mmol) and dimethylaminopyridine (catalytic amount) were added and the mixture was stirred at room temp overnight. Excess benzoylchloride was scavenged with aminomethyl-PS (2.0 g, 2.2 mmol) by shaking for 2 h. The resin was filtered off and washed with DCM (20 ml). The combined filtrates were washed with saturated aqueous citric acid (20 ml), dried over magnesium sulphate and evaporated to dryness to yield 2.7 g (59%) sulfonamide 4-chloro-N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzyl]benzamide 7c in >90% purity (LC-MS).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH:8]=[C:7]([O:31]C)[N:6]=1)(=[O:4])=[O:3].Br>C(O)(=O)C>[CH3:1][S:2]([C:5]1[NH:6][C:7](=[O:31])[CH:8]=[C:9]([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cc(S(C)(=O)=O)n1
Agent: Br
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cc(=O)[nH]1
Reaction time: 16 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2-methanesulfonyl-6-methoxy-pyridin-4-ylmethyl)-amide (58 mg, 0.13 mmol) in acetic acid (5 mL) was added 48% aqueous HBr (3 mL). After 16 hours, HPLC-MS indicated partial conversion to the desired product. The mixture was then warmed at 60° C. After 5 hours, the mixture was cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (4×20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0-20% MeOH in EtOAc to afford the title compound as a pale yellow crystalline solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.OC1C=CC=CC=1C(OC1C=CC=CC=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:4]3[CH:3]=[C:2]([NH:26][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Br)cc21
Reactant: NCc1ccccc1
Agent: I[Cu]I
Agent: O=C(Oc1ccccc1)c1ccccc1O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2cnc(NCc3ccccc3)cc21
Temperature: 170 °C
Yield: 12.7 %

Procedure:
Under Ar, a suspension of the product from Example 9, Step 2 (18.9 mg, 61.1 μmol) in DMF (1 mL) was treated with benzylamine (12 μl, 110 μmol), copper iodide (2.3 mg, 12.2 μmol), phenyl 2-hydroxybenzoate (6.6 mg, 30.6 μmol), and potassium carbonate (16.9 mg, 122.2 μmol). This mixture was then heated to 170° C. by microwave for 40 min. After cooling rt, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (2.6 mg, 10%). MS (ES+) m/e 336 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](OC=C)(=O)[CH3:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH:24]=[CH2:25])=[CH:10][CH:9]=2)[CH:16]=1
Reactant: C=COC(C)=O
Reactant: OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=COCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a solution of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol (intermediate AK) (1.5 g, 4.81 mmol), [IrCl(cod)]2 (31 mg, 0.046 mmol) and sodium carbonate (0.29 g, 2.73 mmol) in toluene (6 mL) was added vinyl acetate (0.84 mL, 9.10 mmol) under argon. The reaction mixture was heated to 100° C. and stirred for 4 h. The solution was allowed to cool to room temperature, and then diluted with 50 mL of ethyl acetate. The mixture was washed with water (20 mL) and then with brine (20 mL), and dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE:Et3N=1:30:0.01) to provide 1.09 g of white solid. 1H NMR (CDCl3, 400 MHz): δ 7.36˜7.28 (m, 5H), 7.22 (d, 2H), 6.61 (dd, J=14.4 and 6.8 Hz, 1H), 4.78 (s, 2H), 4.37˜4.33 (dd, J=14.4 and 2.4 Hz, 1H), 4.14˜4.12 (dd, J=6.8 and 2.4 Hz, 1H), 4.09 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]1([C:33]2[NH:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:33]2[N:34]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[N:3]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: c1ccc2[nH]c(C3CCC3)nc2c1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CCC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-cyclobutylbenzimidazole were reacted to give 237. LCMS m/z: 545.3 (MH+)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (75 mg, 94%), MS (ISP) m/z=320.4 [(M+H)+], mp 230° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:30]=[N:31][C:32](Cl)=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl.[CH3:38][OH:39]>>[CH3:38][O:39][C:32]1[N:31]=[N:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:21][CH2:22]3)=[CH:24][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(Cl)nn5)cc4)CC3)n2CCS1
Reactant: CO
Agent: Cl
Product: COc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nn1
Yield: 47 %

Procedure:
A solution of the compound (1.35 mg, 2.5 mmol) obtained in Example 37-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2.5 mL) in methanol (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (498 mg, 47%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11](O)=[O:12])=O)=[CH:5][C:4]=1[OH:16])#[N:2].O.[NH2:18][NH2:19]>>[C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]2[CH2:9][CH2:10][C:11](=[O:12])[NH:18][N:19]=2)=[CH:5][C:4]=1[OH:16])#[N:2]
Reactant: NN
Reactant: N#Cc1ccc(C(=O)CCC(=O)O)cc1O
Solvent: O
Product: N#Cc1ccc(C2=NNC(=O)CC2)cc1O

Procedure:
3-(4-Cyano-3-hydroxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(4-cyano-3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:32][CH2:31]5)[CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:33]=[CH:34][N:35]=[C:10]12.C(N(C(C)C)CC)(C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>CN(C)C=O.C(OCC)(=O)C>[C:45]([N:27]1[CH2:26][C:25]2([CH2:31][CH2:32]2)[C:24]2[C:29](=[CH:30][C:21]([NH:20][C:18]3[N:17]=[CH:16][C:13]4[C:14](=[O:15])[N:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])[C:10]5[N:11]([CH:33]=[CH:34][N:35]=5)[C:12]=4[N:19]=3)=[CH:22][CH:23]=2)[CH2:28]1)(=[O:47])[CH3:46]
Reactant: O=c1c2cnc(Nc3ccc4c(c3)CNCC43CC3)nc2n2ccnc2n1-c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1Cc2cc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)c5nccn5c4n3)ccc2C2(CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 109B (200 mg, 0.397 mmol) in 5 mL N,N-dimethylformamide was added diisopropylethylamine (0.346 ml, 1.983 mmol) followed by acetic anhydride (0.041 ml, 0.436 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate. The organics were washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by chromatography was performed with an Analogix 280 with an SF 25-40 column, 0% to 4% methanol/dichloromethane gradient over 30 minutes to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.02 (d, J=8.14 Hz, 4H) 2.10 (d, J=21.70 Hz, 3H) 3.46-3.64 (m, 2H) 4.75 (s, 2H) 6.75-7.04 (m, 1H) 7.12 (s, 1H) 7.44-7.90 (m, 6H) 9.16 (s, 1H) 10.80 (s, 1H). MS (ESI+) m/z 546.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:11]=[N:12]2)=[CH:7][N:6]=1)=[O:4].[I:24]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:11]=[N:12]2)=[C:7]([I:24])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ncc2cc(Cc3ccc(F)cc3)cnc2c1O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a dimethylformamide solution (200 ml) of the above Compound 6 (3.56 g, 11.4 mmol) was added N-iodo succinimide (3.06 g, 13.6 mmol), and the solution was stirred overnight at room temperature. The reaction solution was distilled off under reduced pressure, and the residue was added with chloroform, washed with 10% sodium hydrogen sulfite aqueous solution and water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. Precipitated crystals were collected by filtering, and washed with methanol to give 3-(4-fluorobenzyl)-8-hydroxy-5-iodo[1,6]naphthyridine-7-carboxylic acid methyl ester 7 (4.97 g) in 99% yield.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a solution of benzyl magnesium chloride (40 ml of 2.0 M soln. in THF, 80 mmol)in THF (80 ml) was added 1-benzyl-4-piperidinone (7.4 ml, 40 mmol) over 7 min. and stirred overnight. The o reaction mixture was poured over ice and extracted with ether (2×). The combined ether extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to a pale green syrup. This material was chromatographed on silica with 50-60% EtOAc/hexane as eluent. The appropriate fractions were combined and concentrated in vacuo to afford the product as an off white solid.
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:42]C(=O)C)([CH3:41])[CH2:7][CH2:8][C:9]1[N:10]([CH3:40])[C:11]([C:14]([O:26]C(=O)CCCC2C=CC(C#N)=CC=2)=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)(=O)C.O.[OH-].[Li+].C(Cl)Cl>O1CCCC1.CO.O>[NH2:42][C@:6]([CH3:41])([CH2:7][CH2:8][C:9]1[N:10]([CH3:40])[C:11]([C:14](=[O:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C(=CCCc2ccc(C#N)cc2)OC(=O)CCCc2ccc(C#N)cc2)n1C)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cn1c(CC[C@@](C)(N)CO)ccc1C(=O)CCCc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
(2R)-1-Acetoxy-2-acetylamino-2-methyl-4-{1-methyl-5-[4-(4-cyanolphenyl)-1-(4-(4-cyanophenyl)butanoyloxy)but-1-enyl]pyrrol2-yl}butane (4.10 g, 6.90 mmol) obtained in Example 10 (10a) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (10 mL), and water (10 mL) and lithium hydroxide monohydrate (2.90 g, 69 mmol) were added thereto, followed by stirring of the mixture at 80° C. for 1 hour. After cooling, water and methylene chloride were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by basic silica gel (NH type) chromatography (methylene chloride:methanol, 100:1) to obtain (2R)-2-amino-2-methyl-4-{1-methyl-5-[4-(4-cyanophenyl)butanoyl]pyrrol-2-yl}butan-1-ol (1.90 g, yield: 79%). A solution of fumaric acid (0.630 g, 5.40 mmol) in methanol (10 mL) was added to a solution of the thus obtained (2R)-2-amino-2-methyl-4-{1-methyl-5-[4-(4-cyanophenyl)butanoyl]pyrrol-2-yl}butan-1-ol (1.90 g, 5.40 mmol) in methanol (10 mL) under ice-cooling. After methanol was evaporated under reduced pressure, the residue was dissolved in a small amount of methanol, ethyl acetate was added thereto and recrystallization was carried out to obtain a crude crystal (1.29 g) of the title compound. Recrystallization of the thus obtained crude crystal (1.29 g) was carried out again using methanol to obtain the title compound (1.01 g, yield: 45%) as a white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=1.C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[N:15]=[C:16]([NH:12][C@H:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:11])[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2cc3ccccc3c(-c3cccc4ccccc34)c2P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cccc(Br)n1)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 32.6 %

Procedure:
A mixture of (1S)-1-(3-nitrophenyl)ethanamine (365 mg, 2.2 mmol), 2,6-dibromopyridine (474 mg, 2 mmol), tris(dibenzylidene)dipalladium(0) (92 mg, 0.1 mmol), (+/−)-bis(diphenyphosphino)-1,1′-binaphthalene (125 mg, 0.2 mmol) and sodium tert-butoxide (270 mg, 2.8 mmol) in anhydrous toluene (4 mL) was heated at 80° C. for 17 hours. The mixture was cooled, diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate (3×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give a black oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give 6-bromo-N-[(1S)-1-(3-nitrophenyl)ethyl]pyridin-2-amine (210 mg, 33%) and the di-addition product (205 mg, 50%) both as yellow oils.