Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C([Mg]Cl)(C)C.C1COCC1.[Cl:21][C:22]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Cu+2].CCOC(C)=O.O>[Cl:21][C:22]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:23]=1[C:24]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6])=[O:25]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Cc1ccc(C#N)cc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C#N)cc1C(=O)c1ccc([N+](=O)[O-])cc1Cl
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
A dry flask was charged with 3-iodo-4-methyl-benzonitrile (5.15 g, 21.2 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (15 mL) was added, and the solution cooled to −35° C.; then isopropylmagnesium chloride (10.6 mL, 2.0 M in diethyl ether, 21 mmol) was added slowly over 20 min keeping the temperature below −35° C. On completion of the addition the reaction mixture was stirred at −35° C. for 30 min. A THF solution of ZnCl2 (3.61 g, 26.5 mmol, 1.0 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 20 min; then 2-chloro-4-nitro-benzoyl chloride (4.9 g, 22.3 mmol) and Cu(OAc)2 (85 mg, 0.42 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:6 followed by 1:4 as the eluent to give the title compound as yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[N:20]=2)[CH:7]=1)=[O:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][C:30]=1[CH3:37]>C1COCC1>[Br:25][C:21]1[N:20]=[C:19]([CH2:18][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[C:30]([CH3:37])[CH:31]=3)=[CH:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Reactant: COc1ccc([Mg]Br)cc1C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3nc(C)ccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 were used with 85 mg (0.204 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide and 0.896 mL 0.448 mL, 0.5 M in THF) of 4-methoxy-3-methylphenylmagnesium bromide in 1 mL of THF. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to afford 27.9 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(4-methoxy-3-methyl-benzoyl)-7-methyl-1H-[1,8]naphthyridin-4-one as a white solid. LC-MSD, m/z for C24H20BrN3O3 [M+H]: 478.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.6 min.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([C@@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:7]([OH:9])=[O:8])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.C(OCC)(=O)C>[C:4]1(=[O:15])[N:5]([C@@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:7]([O:9][CH3:21])=[O:8])[C:1](=[O:20])[C:2]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:3]12
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 196 %

Procedure:
A slurry of (S)-2-phthalimido-6-hydroxyhexanoic acid (3.752 g., 13.5 mmol.) and cesium carbonate (2.178 g., 6.7 mmol.) in dimethylformamide (44 ml.) was treated with methyl iodide (3.0 ml., 6.84 g., 48.2 mmol.). After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate and washed successively with water containing a small amount of sodium bisulfite, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give the title product as a colorless oil (3.825 g.). The oil was homogeneous by TLC (1:1-acetone:hexanes) Rf =0.37.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([N:12]([CH2:14][C:15](O)=[O:16])[CH3:13])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)(O)[O-].[Na+].O>C(O)C>[C:8]([O:7][C:5](=[O:6])[N:12]([CH2:14][C:15](=[O:16])[NH:4][CH2:1][CH:2]=[CH2:3])[CH3:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
Allylamine (0.377 ml, 5.03 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) (1.89 g, 6.04 mmol) were added to a solution of Boc-sarcosine (1.0 g, 5.29 mmol) in ethanol, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction solution, followed by extraction with ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give allylcarbamoylmethyl-methyl-carbamic acid tert-butyl ester (712 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([N:6]1[CH:10]=[C:9]([CH3:11])[CH:8]=[N:7]1)(=[O:5])=[O:4].[O:13]1[CH2:15][CH2:14]1>C1COCC1>[OH:13][CH2:14][CH2:15][C:8]1[C:9]([CH3:11])=[CH:10][N:6]([S:3]([N:2]([CH3:12])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: Cc1cnn(S(=O)(=O)N(C)C)c1
Reactant: C1CO1
Solvent: C1CCOC1
Product: Cc1cn(S(=O)(=O)N(C)C)nc1CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
Into a 50-mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.1, 1.19 g, 6.26 mmol) in THF (24 mL) n-BuLi (3 mL, 7.5 mmol, 2.5 M in hexanes) was added to the reaction dropwise at −78° C. The resulting mixture was stirred for 30 min at −78° C. This was followed by the addition of a solution of oxirane (5.6 mL, 113.51 mmol) in THF (4 mL) at −78° C. The reaction mixture was then brought to room temperature and stirred for 3 h. The reaction was quenched with 10 mL of NH4Cl (sat.) and the aqueous phase was extracted with 3×50 mL of EtOAc. The combined organic layers were dried over Na2SO4. The solvent was removed to give the crude product which was purified by silica gel chromatography with hexanes/EtOAc (3:1) as the eluent to furnish 636 mg (44%) of the title compound as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:33])[N:21]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O.C(OCC)(=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:23]=[C:22]([NH2:33])[N:21]=[C:20]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([O:9][C:10]4[CH:15]=[CH:14][N:13]=[C:12]5[NH:16][CH:17]=[CH:18][C:11]=45)=[C:2]([F:1])[CH:3]=3)[CH:25]=2)=[CH:31][CH:30]=1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccc(F)cc2)n1

Procedure:
36 mg (0.15 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) and 38.5 mg (0.15 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine (from example LIX) are suspended in 1.5 ml of water, and 0.1 ml of 2 molar hydrochloric acid is added. The mixture is heated under reflux overnight. Ethyl acetate and a few drops of dimethylformamide are then added. The mixture is made alkaline using saturated sodium carbonate solution, the organic phase is separated off and the solvent is removed under reduced pressure. The product is purified by preparative HPLC.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[C:12]([CH2:22][Br:23])=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14](OC)=[O:15]>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([CH2:22][Br:23])=[C:13]([CH2:14][OH:15])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: COC(=O)c1cc(F)cc(Br)c1CBr
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1cc(F)cc(Br)c1CBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of DIBAL-H (2 eq., 1M in toluene) in dry toluene (0.72 M) was cooled to 0° C. Then, a solution of (E5) in dry toluene (0.45 M) was added dropwise, and the resulting solution was stirred at 0° C. for 2 h. The reaction solution was quenched with a solution of 1 N HCl and the crude was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4). The solvent was evaporated to dryness to afford [3-bromo-2-(bromomethyl)-5-fluorophenyl]methanol as a white powder, which was dissolved in DCM (1 M) at 0° C. The resulting solution was treated with 2,6-lutidine (2 eq.) and TBDMSTf (1.5 eq.). The reaction mixture was stirred at RT for 45 min. Then, the resulting solution was partitioned between water and Et2O and the organic phase was separated and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column chromatography on silica, using hexane and Petroleum ether, to yield (83%) the title compound as colourless oil. 1H NMR (400 MHz, CDCl3, 300K) δ 7.15-7.12 (2H, m), 4.74 (2H, s), 4.53 (2H, s), 0.86 (9H, s), 0.04 (6H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:10][C:11]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:13])=[CH:5][C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Reactant: NC1CCCCC1
Product: N#Cc1ccc(N(CC(=O)NC2CCCCC2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and cyclohexylamine: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.92 (dd, J=8.8, 2.7 Hz, 1H), 5.81 (d, J=8.0 Hz, 1H), 4.12 (s, 2H), 4.10 (q, J=8.6 Hz, 2H), 3.80 (m, 1H), 1.83 (m, 2H), 1.63 (m, 3H), 1.32 (m, 2H), 1.08 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=3[F:22])=[CH:12][C:4]=2[O:3]1.[CH3:24][CH:25]([CH3:29])[CH2:26][CH2:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[K+]>ClCCCl>[F:22][C:15]1[CH:16]=[C:17]([CH2:18][NH:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH3:24])[CH:20]=[CH:21][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:23])([CH3:1])[O:3][C:4]=2[CH:12]=1
Reactant: CC1(C)OC(=O)c2ccc(Oc3ccc(C=O)cc3F)cc2O1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCNCc1ccc(Oc2ccc3c(c2)OC(C)(C)OC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2,2-Dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3-fluoro-benzaldehyde (I-1b-1: 30.0 g) and 3-methyl-butylamine (9.15 g) were combined in 1,2-dichloroethane (1.0 L). After stirring at ambient temperature for 1 hour, sodium triacetoxyborohydride (100 g) was added to the solution. After stirring overnight, the reaction mixture was treated with an aqueous 2 N potassium hydroxide solution, the organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to provide the title compound (I-1c-1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]2[N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1)[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]2[N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCc1ccc2c(n1)N(C(C)=O)CC2)c1cnc(C)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCc1ccc2c(n1)N(C(C)=O)CC2)c1cnc(C)nc1
Yield: 33.5 %

Procedure:
To a solution of 23-10 (0.150 g, 0.34 mmol), ammonium formate (0.192 g, 3.09 mmol), and 10% Pd/C (0.150 g) in EtOH (25 mL) was refluxed for 15 minutes. Filtration through celite and evaporative removal of the solvent followed by purification by PCTLC (0-10% MeOH-CHCl3) afforded 0.050 g of 23-11.
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[CH3:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9]/[CH:8]=[C:2](\[F:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C(\F)C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)/C(F)=C/CBr
Yield: 59.1 %

Procedure:
After 9.0 g of (Z)-ethyl 2-fluorocrotonate was dissolved in 60 ml of carbon tetrachloride, 13.5 g of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto. The mixture was heated to reflux for 6 hours. This reaction solution was filtered and the filtrate was concentrated to give a residue. The residue was subjected to silica gel column chromatography (eluent; n-hexane:ethyl acetate=20:1), thereby obtaining 8.5 g of the desired compound.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[C:13](=O)[C:12]2[CH:11]=[C:10]3[NH:15][C:16]([C:18]4[C:19](=[O:38])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][CH:25]([CH3:37])[CH2:26][C:27]4[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([F:35])[C:28]=4[F:36])=[N:17][C:9]3=[C:8]([CH3:39])[C:7]=2[C:6]1=[O:40]>[Zn].C(O)(=O)C>[CH3:41][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:13][C:12]2[CH:11]=[C:10]3[NH:15][C:16]([C:18]4[C:19](=[O:38])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][CH:25]([CH3:37])[CH2:26][C:27]4[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([F:35])[C:28]=4[F:36])=[N:17][C:9]3=[C:8]([CH3:39])[C:7]=2[C:6]1=[O:40]
Reactant: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)CN(CCN(C)C)C2=O
Yield: 81.7 %

Procedure:
A mixture of 6-(2-(dimethylamino)ethyl)-4-methyl-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.25 g, 0.44 mmol), zinc dust (0.29 g, 4.38 mmol), and 7.5 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 0.20 g of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 12.96 (s, 1H, NH), 11.32 (d, J=8.5 Hz, 1H, NH), 11.27 (s, 1H, NH), 7.80 (s, 1H, ArH), 7.77-7.72 (m, 1H, ArH), 7.37 (d, J=8.0 Hz, 1H, ArH), 6.19 (d, J=7.5 Hz, 1H, ArH), 4.46 (d, J=4.0 Hz, 2H, CH2), 4.30-4.24 (m, 1H, CH), 3.67-3.62 (m, 2H, CH2), 3.08 (m, 2H, CH2), 2.52 (m, 2H, CH2), 2.41 (s, 3H, CH3), 2.19 (s, 6H, 2×CH3), 1.36 (d, J=6.0 Hz, 3H, CH3); Mass (ESI, positive) m/z 557.2 [M+H]+.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.Br[C:20]1[CH:21]=[CH:22][C:23]2[N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][C:26]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:37][CH:36]=3)=[O:33])=[CH:25][C:24]=2[CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][C:26]([C:32]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([CH2:41][N:42]([CH3:49])[CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[CH:39][CH:40]=4)=[O:33])=[CH:25][C:24]=3[CH:50]=2)=[CH:4][CH:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-butoxyethoxy)phenyl borate (301 mg) and 7-bromo-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (420 mg). To the solution was added potassium carbonate (279 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (39 mg), and the mixture was refluxed under argon atmosphere for 14 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate→ethyl acetate:ethanol=10:1→ethyl acetate:ethanol:triethylamine=100:10 0.5) and recrystallized from ethyl acetate/IPE to give 7-[4-(2-butoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-H-1-benzazepine-4-carboxamide (Compound 19) (218 mg, 42%) as yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>[C].[Pd].CO>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:12]
Reactant: CN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a methanol (8.0 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate, 10% palladium-carbon (0.75 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 5 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 1.2 g of tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].S(OC)(O[CH3:16])(=O)=O.O.[OH-].[Li+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:11][CH3:16])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COS(=O)(=O)OC
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Cl)c(C#N)cc1Br
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 5-bromo-2-chloro-4-hyroxybenzonitrile (compound 87, 38.1 g, 164 mmol), dimethyl sulfate (20.1 mL, 213 mmol), and lithium hydroxide monohydrate (8.93 g, 213 mmol) in THF (500 mL) was refluxed overnight. The mixture was cooled to ambient temperature and then diluted with EtOAc. The EtOAc solution was washed with water and brine prior to drying over anhydrous MgSO4. Filtration and removal of the voletiles under reduced pressure left the crude product which was purified by column chromatography (5-40% EtOAC/hexanes) to yield 5-bromo-2-chloro-4-methoxybenzonitrile (30.7 g, 76%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl>[CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1cccc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cccc(NC(=O)C(C)(C)C)n1
Reaction time: 2 h
Yield: 54.1 %

Procedure:
A solution of 6-ethyl-pyridin-2-ylamine (20 g, 0.164 mol) and triethylamine (29.6 mL, 0.213 mol) in dichloromethane (200 mL, 0.8 M) is cooled to 0° C. and carefully treated with pivaloyl chloride (26.2 mL, 0.213 mol). After stirring for 2 h, the solution is quenched with aq NaHCO3, extracted with dichloromethane and concentrated. The resulting oil is filtered through a plug of silica gel using ethyl acetate. The filtrate is concentrated and triterated with heptane to give N-(6-ethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (18.3 g, 54%) as a white crystalline solid. mp 59-62° C.; Rf 0.31 (25% ethyl acetate in hexanes); 1H NMR (DMSO-d6, 300 MHz) δ 9.56 (s, 1 H), 7.85 (d, J=8.4 Hz, 1 H), 7.63 (t, J=7.8 Hz, 1 H), 6.93 (d, J=7.5 Hz, 1 H), 2.65 (q, J=7.8 Hz, 2 H), 1.20 (s, 9 H), 1.18 (t, 7.8 Hz, 3 H); LRMS calcd for C12H18N2O: 206.2; found 206.0 (M)+. Anal. Calcd for C12H18N2O: C, 69.87; H, 8.80; N, 13.58. Found C, 69.60; H, 8.67; N, 13.42.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a mixture of 3-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 2 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 3-(4-nitrophenyl)pyridine as a solid (487 mg). A mixture of 3-(4-nitrophenyl)pyridine (487 mg, 2.43 mmol) and Pd—C(10%, 80 mg) in MeOH (25 mL) and EtOAc (5 mL) was hydrogenated under balloon H2 for 5 h. The mixture was then filtered through celite. The filtrate was concentrated in vacuo to give 4-(pyridin-3-yl)aniline as a solid (403 mg).