Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][NH2:21]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH3:20])[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Reactant: CN
Product: CNc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 100 °C

Procedure:
A suspension of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 (0.3 g, 0.0011 mol) in 10 mL of methylamine (40% water solution) was heated in a sealed tube at 100° C. overnight. The mixture was then cooled to room temperature and the precipitate was filtered, air-dried to give 0.2 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine, as a white solid (68% yield), mp: 217-218° C.; Anal Calc'd for C14H12FN5: C, 62.45; H, 4.49; N, 26.01. Found: C, 62.58; H, 4.36; N, 25.90.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27][C:28](=[O:31])[CH2:29][NH2:30])[CH2:23]2)=[C:19]([CH3:32])[O:18][N:17]=1.CO>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:30][CH2:29][C:28]([NH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([CH2:21][C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:32])[CH2:23]1)=[O:31])=[O:6]
Reactant: Cc1noc(C)c1CN1CC[C@@H](NC(=O)CN)C1
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1noc(C)c1CN1CC[C@@H](NC(=O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-5-(trifluoromethyl)benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added to a mixture of (R)-1-(3,5-dimethylisoxazol-4-ylmethyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and piperidinomethylpolystyrene (58 mg) in chloroform (0.2 mL) and dichloromethane (0.75 mL). After the reaction mixture was stirred at room temperature for 2 h, methanol (1.0 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was loaded onto Varian™ SCX column, and washed with CH3OH (16 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford (R)-3-[N-(3-fluoro-5-(trifluoromethyl)benzoyl)glycyl]amino-1-(3,5-dimethylisoxazol-4-ylmethyl)pyrrolidine (Compound No. 1191) (19.5 mg, 88%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 443.2 (M++H, C20H22F4N4O3).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.[C-:21]#[N:22].[Na+].C(OCC)(=O)C.O>CS(C)=O>[C:21]([C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1)#[N:22]
Reactant: [C-]#N
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CN1C(=O)C(C#N)(c2ccc(O)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a stirred solution of 2-chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (10.0 g, compound No. 2) in dimethylsulfoxide (100 ml), sodium cyanide (8.0 g) is added. The mixture is stirred for 2 hours at room temperature, and poured into a mixture of ethyl acetate and water. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 6.9 g (71.0%) of the titled compound.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][C:8]([Cl:17])=[N:7][C:6]=2[N:18]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>CN(C=O)C>[Cl:17][C:8]1[N:9]=[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:4][C:3]([CH2:2][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])=[N:18][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)nc2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(2-(bromomethyl)-5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 57 in DMF was added K2CO3, and phthalimide. The resulting solution stirred 20 h at room temperature. The reaction was concentrated in vacuo and diluted with water (10 mL). The heterogeneous mixture was filtered to afford 2-((5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methyl)isoindoline-1,3-dione 58.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH:17]=1)[CH:15]=[O:16]>C1COCC1.O1CCOCC1.O=[Mn]=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([C:15](=[O:16])[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Reactant: C#Cc1ccccc1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Br)cc1C(=O)C#Cc1ccccc1
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a stirred solution of phenyl-acetylene (0.27 ml, 2.46 mmol) in anhydrous THF (3 ml) 2M iPrMgCl in THF (1.25 ml) was added drop wise at 0° C. under N2. After stirring for 15 min, the solution of product of Step A (0.5 g, 2.06 mmol) in anhydrous THF (2 ml) was added drop wise and the mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4. and filtered. The filtrate was evaporated to dryness to give a creamy paste (0.59 g; 83%). [1H-NMR (CDCl3) 7.68 (d, 1H, J=2.49 Hz); 7.46-7.43 (m, 2H); 7.36 (dd, 1H, J=8.75, 2.54 Hz); 7.32-7.28 (m, 3H); 6.79 (d, 1H, J=6.77 Hz); 5.79 (d, 1H, J=5.23 Hz); 4.64-4.58 (m, 1H); 3.13 (d, 1H, J=5.91 Hz); 1.37 (d, 6H)]. This was dissolved in dioxane (10 ml) and MnO2 (1 g) was added to it. The resulting suspension was stirred for 6 h at reflux, then filtered through Celite and the solvent was evaporated to dryness to give the title compound (0.54 g, 76.5%), as light yellow paste. 1H-NMR (CDCl3) 8.00 (d, 1H, J=2.61 Hz); 7.61-7.52 (m, 3H); 7.44-7.35 (m, 3H); 6.88 (d, 1H, J=8.91 Hz); 4.68-4.60 (m, 1H); 1.36 (d, 6H).
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[S:19][CH2:20][CH2:21][S:22][CH:23]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.C(=O)(O)[O-].[Na+].[CH3:34][C:35]1[S:36][C:37](=[S:40])[NH:38][N:39]=1>O.C(OC(C)C)(C)C>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][S:40][C:37]1[S:36][C:35]([CH3:34])=[N:39][N:38]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[S:19][CH2:20][CH2:21][S:22][CH:23]=1)[C:10]2=[O:25])([OH:28])=[O:27]
Reactant: Cc1n[nH]c(=S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=CSCCS3)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC4=CSCCS4)C3SC2)s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
The sodium salt of 3 -acetoxymethyl-2-carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-8-oxo-5-thia-1-aza-bicyclo [4,2,0]oct-2-ene (10 g.) is dissolved in distilled water (200 cc.). Sodium bicarbonate (2.25 g.) followed by 2-methyl-5-thioxo-1,3,4-thiadiazoline (3.54 g.) are added to the solution and the mixture is heated with stirring at 60° C. for 16 hours. After cooling, the reaction mixture is washed with ethyl acetate (200 cc.). The pH of the mixture is brought to 6.5 by addition of 4N hydrochloric acid and then the mixture is washed again with ethyl acetate (200 cc.). The mixture is acidified to pH 2 by addition of 4N hydrochloric acid in the presence of ethyl acetate (200 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (total 200 cc.). The organic extracts are combined, washed three times with water (total 500 cc.), dried over sodium sulphate, treated with decolourizing charcoal, filtered and then concentrated to dryness under reduced pressure (20 mm.Hg). The solid residue obtained is taken up in diisopropyl ether (200 cc.), filtered off and then dried under reduced pressure (2 mm.Hg). 2-Carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl )thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (6 g.), melting at 170° C., is thus obtained.
Reaction SMILES: C(O)(=O)C.I[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH2:17]2)[N:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]([CH3:52])[C:30]2[O:34][C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39](B4OC(C)(C)C(C)(C)O4)=[CH:38][CH:37]=3)=[N:32][C:31]=2[CH:51]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[NH2:15][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:8]([C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH2:17]3)[N:7]=[C:6]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33]4[O:34][C:30]5[C:29]([CH3:52])=[CH:28][C:27]([CH3:26])=[CH:51][C:31]=5[N:32]=4)=[CH:41][CH:40]=3)[C:14]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: COCCN1CCC[C@H](n2nc(I)c3c(N)ncnc32)C1
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: CN(C)C=O
Solvent: CC(=O)O
Product: COCCN1CCC[C@H](n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
A mixture of (S)-3-iodo-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.64 g, 0.0014 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.64 g, 0.00175 mol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (0.081 g, 0.00007 mol) and sodium carbonate (0.37 g, 0.0035 mol) in N,N-dimethylformamide (15 mL) and water (7 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water (25 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish oil, which was purified by flash column chromatography on silica using 2%-10% methanol/dichloromethane as a mobile phase to give (S)-N2-(4-{4-amino-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (0.60 g, 0.0012 mol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cn1

Procedure:
To a 100 mL round bottle flask with 5-bromopicolinic acid (7.0 g, 35 mmol) in methanol (60 mL) was added dropwise thionyl chloride (3.0 mL) at ambient temperature. After addition the reaction mixture was heated to reflux for 3 h. Methanol was removed and ethyl acetate (80 mL) was added to the residue and was adjusted pH to 7.0 by addition of sodium bicarbonate solution. The organic phase was separated and dried over sodium sulfate. The organic solvent was removed and methyl 5-bromopicolinate 2 was obtained as a white solid which was used for the next step of the reaction without further purification. Yield: 6.57 g, 86.9%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)c(F)c1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (280 mg, 0.72 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (250 mg, 0.72 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (75 mg, 0.072 mM) and tri-2-furylphosphine (34 mg, 0.145 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (170 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][C:16]([Si:19]([CH3:21])([CH3:20])[O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([CH3:18])[CH3:17]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
To a solution of 3-cyanophenol (5 g, 42 mmol) and imidazole (6.3 g, 92 mmol) in N,N-dimethylformamide (85 mL) at 0° C. was added (1,1-dimethylethyl)dimethylsilylchloride (7.6 g, 50 mmol). After stirring 10 min, the reaction was warmed to room temperature and stirred for 24 h. The solvent was removed in vacuo and the residual oil was partitioned between water (100 mL) and diethyl ether (300 mL). The separated diethyl ether layer was washed with water (3×100 mL) and brine (100 mL), then was dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure and the residue was flash chromatographed (silica gel, 50% ethyl acetate in petroleum ether) to yield 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzonitrile (9 g, 92% yield) as an oil.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(NCc1ccccc1)c1cccc(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Yield: 84.7 %

Procedure:
Reaction N-Benzyl-3-hydroxymethyl-benzenesulfonamide (crude from previous step, 1.36 mmol), MnO2 (1.40 g, 13.60 mmol) in CH2Cl2 (10 mL) at 40° C. under N2 overnight gave the title compound (317 mg, 85%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:26]([O:28]C)=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)=[O:12].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:26]([OH:28])=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C[C@H](NC(=O)C=Cc2cc(F)ccc2F)C(=O)O)c2ccccc21
Yield: 75.1 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 26 (2.9 g), 1 mol/L of an aqueous sodium hydroxide solution (15.0 mL), and methanol (150 mL), to give the captioned compound (2.1 g, 74%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:5]#[N:6].Br[C:20]1[CH:21]=[C:22]([CH:26]([CH:33]2[CH2:35][CH2:34]2)[NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([C:20]2[CH:21]=[C:22]([CH:26]([CH:33]3[CH2:35][CH2:34]3)[NH:27][S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:23]=[N:24][CH:25]=2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)cc2F)c1)C1CC1
Temperature: 100 °C
Yield: 55.6 %

Procedure:
(General Suzuki reaction procedure 2) A mixture of 3-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (333 mg, 1.35 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (430 mg, 1.35 mmol), PdCl2(PPh3)2 (77 mg, 0.10 mmol) and Na2CO3 (2M in water, 1.35 mL, 2.70 mmol) in DMF (6 mL) heated at 100° C. under N2 for 2 h. The solvent was removed in vacuo, and the residue was purified by flash column (EtOAc/Heptane, v/v, 0-50%) to give the title compound (270 mg, 56% yield); ESI-MS m/z: 360 [M+1]+. 1HNMR (MeOD, 400 MHz) δ 8.72 (1H, d, J=2.0 Hz), 8.71 (1H, d, J=2.0 Hz), 8.17 (1H, bs), 7.83-7.75 (3H, m), 3.95 (1H, d, J=8.8 Hz), 3.52 (3H, s), 3.05-2.92 (2H, m), 1.32-1.28 (1H, m), 1.30 (1H, t, J=7.2 Hz), 0.80-0.76 (1H, m), 0.67-0.61 (2H, m), 0.52-0.48 (1H, m). Enantiomers were separated by chiral HPLC (Chiralpak AS-H, EtOH/Heptane, v/v, 30/70) to the first peak (enantiomer 1, t=9.68 min), and the second peak (enantiomer 2, t=13.68 min).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)=[O:27])#[N:2]
Reactant: Nc1ccncc1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccncc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl]prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-aminopyridine (152 mg, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective product as a solid material. Yield (amount) 181 mg, yield (rate) 50.1%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)c2ccc3ccccc3c2N1
Yield: 12.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 3-(trifluoromethyl)benzoyl chloride (17 μL, 0.114 mmol), the title compound (6 mg, yield 13%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:8])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1ccc(F)cc1Oc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2ccc(F)cc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-fluoro-2-(4-fluorophenoxy)benzoic acid (step 1) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 7.99–7.89 (2H, m), 7.38–7.28 (4H, m), 7.12–7.00 (4H, m), 6.41 (1H, dd, J=2.7, 8.1 Hz), 4.63 (2H, br.s), 3.86 (3H, s); MS (ESI) m/z 398 (M+H)+, 396 (M+H)+.