Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:6]([CH3:19])([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])[CH3:7])[C:3]([OH:5])=[O:4].[Cl:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][Cl:33])[C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:1][CH:2]([C:6]([CH3:19])([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])[CH3:7])[C:3]([O:5][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH2:22][CH2:21][Cl:20])[CH2:31][CH2:32][Cl:33])=[CH:29][CH:28]=1)=[O:4]
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Reactant: CC1=C(C)C(=O)C(C(C)(C)C(C)C(=O)O)=C(C)C1=O
Product: CC1=C(C)C(=O)C(C(C)(C)C(C)C(=O)Oc2ccc(N(CCCl)CCCl)cc2)=C(C)C1=O
Yield: 20 %

Procedure:
Using an analogous procedure to that described in Example 1, 2,3-dimethyl-3-(2,3,5-trimethyl-1,4-benzoquinonyl)butyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol and the product was purified by column chromatography on silica using a 8.5:1.5 mixture of petroleum ether (b.p. 40 to 60° C.) and ethyl acetate as eluent. There was thus obtained to give 4-[bis(2-chloroethyl)amino]phenyl 2,3-dimethyl-3-(2,3,5-trimethyl-1,4-benzoquinonyl)butyrate as an oil in 20% yield; NMR Spectrum: (CDCl3) 1.25 (d, 3H), 1.45 (s, 3H), 1.50 (s, 3H), 1.95 (s, 3H), 1.97 (s, 3H), 2.21 (s, 3H), 3.60 (t, 4H), 3.67 (t, 4H), 3.85 (q, 1H), 6.61 (d, 2H), 6.82 (d, 2H); Mass Spectrum: (M+Na+) 502, 504 & 506.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([C:35]([O:37]C)=[O:36])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[OH-].[Na+].Cl.O>CO>[C:35]([C:12]1[CH:11]=[C:10]([N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:6][C:7]([OH:9])=[O:8])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)([OH:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 80 %

Procedure:
A solution of 1.0 g (1.87 mmol) of N-(carboxymethyl)-N-[3(methoxycarbonyl)-5-(octadecyloxy)phenyl]glycine and 3.1 ml (9.35 mmol) of 3N NaOH in 100 ml of methanol was stirred at reflux under argon for 48 hours. The warm solution was acidified with 3N HCl to pH 2 and the methanol was removed at reduced pressure. Water was added and the product was filtered and recrystallized from methanol-water to give 0.78 g (80% yield, mp 149°-155°) of N-[3-carboxy-5-(octadecyloxy)phenyl]-N-(carboxymethyl)glycine as a hydrate with 0.75 mole of water.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>COCCOC.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>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:10]1[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1c1ccccc1
Reactant: OB(O)c1cc(F)ccc1F
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 90 °C

Procedure:
To a flame dried flask equipped with stir bar was added (2S)-tert-butyl 2-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydro-1H-pyrrole-1-carboxylate (6-4, 0.250 g, 0.636 mmol), 2,5-difluorophenyl boronic acid (0.251 g, 1.59 mmol), Na2CO3 (0.202 g, 1.91 mmol), and LiCl (0.081 g, 1.91 mmol). The solids were dissolved in 20 mL 4:1 DME/H2O and degassed with nitrogen. Pd(PPh3)4 (0.037 g, 0.032 mmol) was added and the reaction was sealed under nitrogen and heated to 90° C. for 2 hours. Upon completion, the reaction was partitioned between 5% aq. NaHCO3 and EtOAc (3×50 mL), and the combined organic layers were dried over MgSO4. Following filtration, the organic layer was concentrated and purified via flash column chromatography (SiO2, 0-20% EtOAc/hexanes gradient) to provide (2S)-tert-butyl 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (6-5).
Reaction SMILES: [Cl-].[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1.[C:18]([Cl:21])(=[O:20])[CH3:19]>FC(F)(F)C(O)=O>[Cl-:21].[C:18]([O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(6-hydroxy-indan-1-ylmethyl)-1H-imidazol-1-ium chloride (100 mg, 0.399 mmol) was dissolved in 1 ml of trifluoroacetic acid (TFA) and acetic acid chloride (0.510 mmol) was added. The mixture was stirred at room temperature for 24 h. TFA was evaporated and the residue was dissolved in water and made basic with 2 M NH3 (aq.). The aqueous phase was extracted with dichloromethane (DCM). The combined extracts were dried (Na2SO4) and evaporated. The residue was dissolved in diethyl ether and the solution was saturated with dry HCl gas. The precipitate was filtered and dried under vacuum. Yield 105 mg (82%) of a white hygroscopic solid. 1H NMR (CDCl3, TMS): δ 1.72 (m, 1H), 2.18-2.26 (m, 4H), 2.72-2.87 (m, 3H), 3.17 (dd, 1H), 3.56 (qui, 1H), 6.85 (m, 2H), 6.92 (s, 1H), 7.16 (d, 1H), 8.61 (s, 1H), 14.44 (s, 2H). 13C NMR (CDCl3, TMS): δ 21.11, 29.60, 30.46, 31.68, 43.93, 115.72, 117.00, 120.29, 125.33, 132.32, 132.40, 141.37, 146.32, 149.39, 170.11. HPLC-MS (EI): m/z=257.2 ((M+H)+—Cl−. Anal.—Calc. for C15H16N2O2.HCl.0.2CH2Cl2: C, 58.94; H, 5.66; N, 9.04. Found C, 58.66; H, 5.78; N, 8.83.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:10][C:11]1[CH:38]=[CH:37][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29]CC3C=CC=CC=3)=[O:28])=[CH:20][CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:43]([O:42][C:40]([NH:39][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:20][CH:19]=2)=[O:16])=[CH:37][CH:38]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 4-[4-(benzyloxy)-4-oxobutyl]phenyl 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoate (3.98 g) in tetrahydrofuran (40.0 mL) was added 10% palladium-carbon (398 mg), followed by stirring at room temperature for 3 hours under a hydrogen pressure of 3 atm. The reaction suspension was filtered through Celite, and then the filtrate was concentrated under reduced pressure to obtain 4-[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)phenyl]butanoic acid (3.30 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].II.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].Cl>C1C=CC=CC=1.[Zn]>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:2])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a refluxing mixture of 4-acetylbiphenyl (20 g), I2 (5 mg) and Zn (6.8 g) in benzene (200 ml) was added ethylbromoacetate (12 ml) dropwise during 30 minutes. The mixture was refluxed for 1 h and then cooled to room temperature. It was acidified with 10% HCl (100 ml) and benzene layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give 20.6 g (72.1% yield) of ethyl 3-hydroxy-3-([1,1′-biphenyl]-4yl)butanoate (2e, formula 2, R=Ph) m.p. 58-60° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[OH-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>CCOC(C)=O.O>[Cl:30][C:29]([Cl:32])([Cl:31])[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[N:6]([C:7]2[CH:17]=[CH:16][CH:15]=[C:9]([O:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[CH:8]=2)[N:5]=[C:4]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:3]=1
Reactant: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 108.5 %

Procedure:
A solution of Intermediate 152b (69 mg, 0.24 mmol) in EtOAc (1.2 mL) was treated with aqueous 1N NaOH (0.4 mL, 0.43 mmol) then 2,2,2-trichloroethyl chloroformate (0.034 mL, 0.25 mmol) and the mixture was stirred at RT for 2.5 h. The mixture was treated with another portion of 2,2,2-trichloroethyl chloroformate (0.010 mL, 0.07 mmol) and stirred at RT for a further 0.75 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red gum (121 mg). The gum was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound as a pale golden gum (62 mg, 56%). LCMS (Method 3): Rt 4.15 min, m/z 464.2, 466.2 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C([BH3-])#N.[Na+].C=O>C(O)C.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Reactant: O=C(O)C1CNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.7 %

Procedure:
A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D92) (120 mg), 3-azetidinecarboxylic acid (64.8 mg) and acetic acid (0.1 mL) in ethanol (10 mL) was stirred at room temperature for 15 min, then sodium cyanoborohydride (60.4 mg) was added. The mixture was stirred at room temperature for 6 h, then formaldehyde (0.11 mL) was added. The mixture was stirred at room temperature overnight. After concentration, the residue was acidified with 2M HCl to pH 5-6, ethyl acetate was added, the organic phase was washed with saturated brine, then dried and evaporated. The residue was purified by Mass Directed AutoPrep to afford 1-[(3-{2-[3-cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylic acid (E43) (32 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.92 (6H, d), 1.05 (3H, t), 1.98 (1H, m), 2.76 (4H, m), 3.65 (1H, m), 4.27 (4H, m), 4.54 (2H, br. s.), 7.40 (1H, m), 7.48 (2H, m), 7.62 (1H, d), 7.94 (1H, s), 8.22 (1H, dd), 8.35 (1H, d), 10.21 (1H, br s), 13.19 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C27H29N3O2S requires 459. found 460.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl>>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:3][C:4]([O:6][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1)=[O:5]
Reactant: COc1cc(C(=O)CC(=O)O)cc(OC)c1OC
Reactant: COc1cccc(O)c1
Solvent: ClCCl
Product: COc1cccc(OC(=O)CC(=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a mixture of 0.27 g (1.06 mmol) of the product of Step 1 and 0.13 g (1.06 mmol) of 3-methoxyphenol in 2 ml of anhydrous methylenechloride 0.16 ml (1.06 mmol) of diisopropylcarbondiimide was added at room temperature. The resulting mixture was stirred for 24 hours at room temperature and filtered off. The filtrate was evaporated to dryness and purified by flash column chromaytography (silica gel; methylene chloride) to give the title compound as a colorless crystals (0.185 g, 49%); 1H NMR (CDCl3) δ 3.77 (s, 3H, OMe); 3.91 (s, 6H, OMe); 4.17 (s, 3H, OMe); 4.173 (s, 2H, CH2); 6.6-6.8 (m, 3H, CH aromatic); 7.2-7.3 (m, 3H, CH aromatic).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=2)[CH:34]=1
Reactant: CC1(C)OB(c2cnc(N)c(Cl)c2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)c(Cl)c4)nc(N4CCOCC4)c3s2)CC1
Yield: 18.1 %

Procedure:
4-(2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (100 mg) was reacted with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (83 mg) according to General Procedure Suzuki to afford 377 (22 mg) following reverse phase HPLC purification. MS (Q1) 524 (M)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]CC2C=CC=CC=2)[N:3]=1>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C#N)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
A mixture of tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (2.160 g, 4.457 mmol) and 10% Pd—C (0.720 g) in ethyl acetate (30 mL) was stirred at room temperature for 2 days under a hydrogen atmosphere (3 atm). The mixture was filtrated with Celite® and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give tert-butyl 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate as a white solid. (0.180 g, yield; 10%)
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].[Cl-].[NH4+]>C(OCC)C.CCCCCC.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]([C:8]2[C:7]([F:6])=[CH:12][CH:11]=[CH:10][N:9]=2)[OH:18])[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccnc1
Reactant: O=Cc1cccc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1cccc(F)c1)c1ncccc1F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, a solution of 9.75 g of diazabicyclo[2.2.0]octane in 150 mL of dehydrated diethyl ether was cooled to −40° C., added with 56 mL of 1.56 M n-butyllithium in hexane, and stirred at −20° C. for 1 hour. The solution was cooled to-60° C., added dropwise with 6.9 mL of 3-fluoropyridine, stirred at −60° C. for 1 hour, and added with 9.2 mL of 3-fluorobenzaldehyde. After stirring for 1 hour, aqueous ammonium chloride and ethyl acetate were successively added, and the mixture was recovered to room temperature. The organic layer was extracted, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:4), to give 12.6 g of the title compound as colorless needle crystals.
Reaction SMILES: NC1C=C(CNC(C2NC(=O)C3C(=CC=C(C#N)C=3)N=2)=O)C=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH2:32][NH:33][C:34]([C:36]2[NH:37][C:38](=[O:46])[C:39]3[C:44]([CH3:45])=[CH:43][S:42][C:40]=3[N:41]=2)=[O:35])[CH:29]=[CH:30][CH:31]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCC(O)=O)=N2)C=CC=CC=1.[C:76]1([C:82]([C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)([C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)[N:83]2[CH:87]=[N:86][C:85]([C:88](O)=[O:89])=[N:84]2)[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1>>[CH3:45][C:44]1[C:39]2[C:38](=[O:46])[NH:37][C:36]([C:34]([NH:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:88]([C:85]4[N:86]=[CH:87][N:83]([C:82]([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)([C:91]5[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=5)[C:97]5[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=5)[N:84]=4)=[O:89])[CH:27]=3)=[O:35])=[N:41][C:40]=2[S:42][CH:43]=1
Reactant: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1csc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c12
Agent: N#Cc1ccc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c2c1
Agent: O=C(O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: Cc1csc2nc(C(=O)NCc3cccc(NC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Step 1 of Example 32, and using, instead of N-[(3-aminophenyl)methyl]-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide, N-[(3-aminophenyl)methyl]-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide obtained in Reference Example 48 and using, instead of 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoic acid, 1-(triphenylmethyl)-1H-1,2,4-triazole-3-carboxylic acid obtained in Reference Example 35, 5-methyl-4-oxo-N-{[3-({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)phenyl]methyl}-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide was obtained as a white powder (575 mg, 88%).
Reaction SMILES: OC1C=CC2C(=O)C3C4C(=CC(C#N)=CC=4)NC=3C(C)(C)C=2C=1.ClCCN(CC)CC.C(=O)([O-])[O-].[Cs+].[Cs+].C(N(CC)[CH2:41][CH2:42][O:43][C:44]1[CH:45]=[CH:46][C:47]2[C:59](=[O:60])[C:58]3[C:57]4[C:52](=[CH:53][C:54]([C:61]#[N:62])=[CH:55][CH:56]=4)[NH:51][C:50]=3[C:49]([CH3:64])([CH3:63])[C:48]=2[CH:65]=1)C.[C:68]([NH2:72])([CH3:71])([CH3:70])[CH3:69]>CN(C)C(=O)C.O>[C:68]([NH:72][CH2:41][CH2:42][O:43][C:44]1[CH:45]=[CH:46][C:47]2[C:59](=[O:60])[C:58]3[C:57]4[C:52](=[CH:53][C:54]([C:61]#[N:62])=[CH:55][CH:56]=4)[NH:51][C:50]=3[C:49]([CH3:64])([CH3:63])[C:48]=2[CH:65]=1)([CH3:71])([CH3:70])[CH3:69]
Reactant: CC(C)(C)N
Reactant: CCN(CC)CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)NCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
With the same synthesis condition as the Compound A7-17 (8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 25 mg, 0.083 mmol) was dissolved in N,N-dimethylacetamide (1 mL), added with 2-chloroethyldiethylamine (16 mg, 1.1 eq.) and cesium carbonate (54 mg, 2 eq.) in order and stirred at 100° C. for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (ethyl acetate/hexane) to obtain the Compound A7-17 (8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile) (11 mg, 32%)), the title compound was synthesized from the Compound A7-24 and tert-butyl amine.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>C(OCC)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:12]=1)[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=1[N:9]=2)([O-:18])=[O:17]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C1CCCCC1Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc3c(n2c1)CCCC3

Procedure:
Operations similar to Production Example 1-(2) were conducted using 2-chlorocyclohexanone and 2-amino-5-nitropyridine. The resulting solid was suspended in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to provide the title compound as yellow crystals.
Reaction SMILES: [O:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[O:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1csc(Oc2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=Cc1csc(Oc2ccccc2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
19.1 g of manganese dioxide were added to a solution of 4.6 g of (2-phenoxy-4-thiazolyl)-methanol in 100 ml of benzene and the mixture was stirred at 60° C. for 3 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 methylene chloride-ethyl acetate mixture yielded 2.6 g of (2-phenoxy-4-thiazolyl)-methanal melting at 63° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[N+:8]([O-])[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][N:8]=1
Reactant: COC(=O)c1cc(OCC(C)C)c[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)c(OCC(C)C)c1

Procedure:
To 3-isobutoxy-5-(methoxycarbonyl)pyridine 1-oxide (7.04 g) was added phosphoryl chloride (25 mL), and the mixture was heated under reflux for 30 min. The solvent in the reaction mixture was evaporated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added at 0° C. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound (3.18 g) as a white amorphous solid. This compound was used for the next step without further purification.