Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>O.COCCOC.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>[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28]
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC(F)(F)F)cc2)n1
Reactant: COC(=O)C(C)(C)c1cc(B2OC(C)(C)C(C)(C)O2)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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C)(C)c1cc(-c2cc(NCCc3ccc(OC(F)(F)F)cc3)nc(OC)n2)ccc1F
Yield: 30.2 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-trifluoromethoxyphenyl)-ethyl]amine (1.6 g), 2-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methyl-propionic acid methyl ester (0.63 g), Cs2CO3 (11.6 g) and tetrakis(triphenylphosphine)palladium (0) (33 mg) in water (8 mL) and DME (32 mL) is heated at 90° C. for 16 hours. The solution is poured into water and extracted with EtOAc (2×200 mL). The combined extract is dried over sodium sulfate, filtered, evaporated in vacuo and chromatographed on silica gel eluting with EtOAc to afford 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (300 mg). MS: 508 (M+H); 1H NMR (300 MHz, CD3OD), □7.8, (d, 1H, J=0.3 Hz); 7.7 (m, 1H); 7.4 (d, 2H, J=0.4 Hz); 7.2-7.3 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 4 (s, 3H); 3.9 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=1)[CH:16]=[O:17]
Reactant: Oc1cnc(C(F)(F)F)nc1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 130 °C
Yield: 98.2 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidin-5-ol (1.5 g, 9.14 mmol) and 3,4,5-trifluorobenzaldehyde (1.464 g, 9.14 mmol) in DMF (18 mL), was added K2CO3 (1.642 g, 11.88 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.73 g, 8.98 mmol, 98% yield) as brown oil. LCMS: rt=3.16 min, [M+H+]=305
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]2[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].[NH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>C1(C)C=CC=CC=1.C(O)C.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>[NH2:30][C:31]1[CH:36]=[C:35]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 80 °C

Procedure:
To a mixture of tetrakis(triphenylphosphine)palladium (0) (0.12, 0.1 mmol), 2N sodium carbonate (5 mL, 10 mmol), [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (from Example 1, 0.67 g, 2.0 mmol) in 20 mL of toluene and 5 mL of ethanol was added 3-aminobenzeneboronic acid (0.62 g, 4.0 mmol). The reaction mixture was heated to 80° C. for 1 hour, diluted with ethyl acetate, washed with water and dried over MgSO4. Removal of solvent under reduced pressure gave a crude product that was purified by silica gel chromatography eluting with ethyl acetate/hexanes (5% to 50%) to give the title compound as a pale yellow solid; MS (EI) m/z 393.3 (M+H)+; 1H NMR (DMSO-d6): δ 5.21 (s, 2H), 6.39 (d, J=8.8 Hz, 1H), 6.47 (s, 1H), 6.48 (d, J=9.4 Hz, 1H), 6.95 (t, J=9.4 Hz, 1H), 7.39 (t, J=7.5 Hz, 2H), 7.56 (t, J=8.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.80 (t, J=7.8 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.31 (d, J=6.7 Hz, 1H), 9.08 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])[CH3:5].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])[CH3:5]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of methyl 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate (77.4 mmol) in a mixture of THF (232 mL) and methanol (232 mL) was treated with a solution of 2M sodium hydroxide (232 mmol), and the reaction mixture stirred for 4 hours at ambient temperature. The resulting solution was diluted with water (250 mL) and most of the organic solvent removed in vacuo. The resulting suspension was washed with diethyl ether (3×200 mL) and the organic washings discarded. The resulting aqueous solution was acidified to pH4 with 2M hydrochloric acid solution and extracted with ethyl acetate (2×200 mL). The extracts were combined, washed with brine, dried (MgSO4), and evaporated to give the desired compound (99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[N:15]([CH2:16][CH2:17]O)[C:14]2[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=2[N:12]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[C:11]2=[N:12][C:13]3[C:14](=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:21][CH:22]=3)[N:15]2[CH2:16][CH2:17]1
Reactant: COC(=O)c1cccc2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCO)c12
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 14 h
Yield: 88.8 %

Procedure:
To a solution of methyl 3-{[(2,4-dichloro-6-methylphenyl)carbamothioyl]amino}-2-[(2-hydroxyethyl)amino]benzoate (300 mg, 0.70 mmol) in tetrahydrofuran (7.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.77 mmol) and triethylamine (0.108 mL, 0.77 mmol) at room temperature. The mixture was stirred at 50° C. for 14 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (210 mg, 0.53 mmol, 76%) as a pale yellow solid. To a solution of methyl 2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (200 mg, 0.507 mmol) and triethylamine (0.28 mL, 3.8 mmol) was added methanesulfonyl chloride (0.079 mL, 1.02 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hr and at room temperature for 14 hr. Then the mixture was warmed to 45° C. and stirred at 45° C. for 8 hr. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture to give the title compound (170 mg, 0.45 mmol, 89%) as colorless crystals.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13]([OH:15])=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.[CH3:17]O.S(=O)(=O)(O)O>C(Cl)Cl>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13]([O:15][CH3:17])=[O:14])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CC(C(=O)O)CC2=O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)C1CC(=O)N(c2ccc(C)cc2)C1

Procedure:
1-(4-Tolyl)-5-oxo-3-pyrrolidinecarboxylic acid (45.50 g) is suspended in methylene chloride (460 ml) and thereto are added methanol (50.5 ml) and conc. sulfuric acid (0.77 ml) and the mixture is refluxed for 19 hours. After cooling, the reaction mixture is concentrated under reduced pressure and the resulting residue is neutralized by adding water and aqueous sodium hydrogen carbonate solution thereto. The precipitated crystal is collected by filtration and washed with water to give the desired product (46.07 g), m.p. 71°-74° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:23][CH:24]=[CH2:25])[C:13]([NH:15][C@H:16]([C:20]([OH:22])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](OC(NC(CC=C)C(O)=O)=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:26]([O:21][C:20](=[O:22])[C@H:16]([CH:17]([CH3:18])[CH3:19])[NH:15][C:13](=[O:14])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:23][CH:24]=[CH2:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCC(NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: C=CCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCC(NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 19 h

Procedure:
N-(N-Benzyloxycarbonyl-2-Amino-4-Pentenoyl)-L-Valine Benzxyl Ester (4) To a cooled (0-5° C.) solution of 24 mg (0.096 mmol) N-(N-benzyloxycarbonyl-2-amino-4-pentenoic acid (3), 36 mg (0.096 mmol) valine benzyl ester p-toluenesulfonyl salt, and 11 μL (0.096 mmol) N-methylmorpholine in 2 mL CH2Cl2 was added 14 mg (0.101 mmol) HOBt and 21 mg (0.101 mmol) DCC and the mixture was stirred for 19 h. The solution was filtered and the filtrate diluted with 10 mL CH2Cl2 and washed with two 10-mL portions of 0.5 N HCl, with two 10-mL portions of saturated aqueous NaHCO3, and with 10 mL brine. The organic phase was dried (MgSO4) and concentrated. The crude product was applied to a silica gel column (1×15 cm) and elution with 5% MeOH in CH2Cl2 gave pure N-(N-benzyloxycarbonyl-2-amino-4-Pentenoyl)-L-valine benzyl ester (4) as a colorless oil: yield 35 mg (83%); 1H NMR (CDCl3) δ0.80-0.90 (m, 6H); 2.14-2.20 (m, 1H); 2.49-2.56 (m, 2H); 4.20-4.32 (M, 1H); 4.55-4.60 (m, 1H0; 5.07-5.30 (M, 6H); 5.65-5.83 (m, 1H); 6.42-6.49 (m, 1H); 7.30-7.34 (m, 10H); mass spectrum (CI, methane) m/z 439 (M+H)+, 225.
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:44])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)C(C)O3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)C(C)O3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
To a solution of N-[4-[hydroxy(2-pyridyl)methyl]-phenyl]-6—(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 24 hours. To the mixture was add ed sodium thiosulfate, and the mixture was stirred for a few minutes. was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with agnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give crystals, which were recrystallized from ethanol-ethyl acetate to give N-[4-[hydroxy(1-oxidopyridin-2-yl)-methyl]phenyl]-6—(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (Compound 203) (129 mg) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16]([O-])(=O)[CH3:17].[NH4+:20]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:15][C:12](/[CH:13]=[C:16](/[NH2:20])\[CH3:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: [NH4+]
Solvent: CC(=O)O
Product: C/C(N)=C\c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a stirred solution of 5-(3,4-dichlorophenyl)furfural (1.21 g, 5.0 mmol) in acetic acid (15 ml) was added nitroatehane (0.720 ml, 10.0 mmol) and ammonium acetate (1.16 g, 15.0 mmol). The mixture was stirred at 80° C. overnight. The reaction mixture was poured to ice water. The resulting precipitate was filtered, washed with water and dried under vacuum to obtain 1.38 g (93%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.62 (s, 3H), 7.37 (d, 1H), 7.46 (d, 1H), 7.79 (m, 2H), 7.98 (s, 1H), 8.09 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([C:27]4[C:28]([CH3:33])=[N:29][N:30]([CH3:32])[CH:31]=4)=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl>C1COCC1.O>[C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([C:27]4[C:28]([CH3:33])=[N:29][N:30]([CH3:32])[CH:31]=4)=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cn(C)nc4C)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cn(C)nc4C)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 314, 25.6 mg, 0.049 mmol) in THF (250 μL) and water (250 μL) was added 37% aqueous HCl (81 μL, 0.984 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature, quenched by the addition of saturated aqueous NaHCO3 and diluted with DCM. Phases were separated and the water phase was extracted with DCM (2×). The combined organic layers were dried using Na2SO4, filtered and solvents were concentrated. The crude product was suspended and sonicated in EtOAc/heptane (1:1). The solid was filtered and dried to yield the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]=O)=[C:9]([Cl:13])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].[CH2:19](N)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([CH:11]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])=[C:9]([Cl:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=Cc1c(Cl)ccc(C(=O)[O-])c1Cl
Reactant: CC[N+](=O)[O-]
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(C=C(C)[N+](=O)[O-])c1Cl
Temperature: 0 °C

Procedure:
To 100 ml toluene, was added 2,4-dichloro-3-formylbenzoate in an amount of 25.72 g, and the resulting mixture was then added with nitroethane in an amount of 39.0 g and n-butylamine in an amount of 1.5 g and was allowed to a reaction for 21 hours under reflux. The reacted-mixture was poured into ice water, and the mixture was then extracted with ethyl acetate, then the ethyl acetate layer was washed with 1N-hydrochloric acid solution and saturated saline solution in turn and dried with anhydrous magnesium sulfate. The solvent in the layer was distillated out under reduced pressure to obtain methyl 2,4-dichloro-3-(2-nitro-1-propenyl)benzoate in an amount of 34.9 g. The obtained-product in an amount of 30.1 g was then added into a mixed-solvent composed of 120 ml toluene and 360 ml water without taking a purification process for it, and the resulting mixture was fed dropwise with concentrated sulfuric acid in an amount of 104 g at 80° C. following to the addition of both iron powder in an amount of 20.8 g and ferric chloride in an amount of 0.4 g. After the dropping, the mixture was allowed to a reaction for 1 hour under reflux. The reacted-mixture was then allowed to cooling and added with ethyl acetate, and insoluble materials therein were separated by filtration. The organic layer obtained was washed with water and saturated saline solution in turn and dried with anhydrous magnesium sulfate. The solvent in layer was concentrated under reduced pressure, and the residue obtained was purified by using a silica gel column chromatography to obtain 2,4-dichloro-3-(2-oxopropyl)benzoate in an amount of 19.53 g. nD22 1.5537.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH3:13])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:15]([O:14][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:13])[C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(OCC)c1ccc(CNC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1ccc(CN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a stirred solution of 1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g, 4.9 mmol) and triethylamine (0.75 g, 7.35 mmol) in anhydrous dichloromethane (10 mL) was added benzyl carbonochloridate (1.0 g, 5.88 mmol) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with water (50 mL×3), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 20:1) to give benzyl 4-(diethoxymethyl)benzyl(methyl)carbamate (1.0 g, yield 57% for two steps) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 3.82 (s, br 1H), 5.19 (s, 3H), 6.91-6.95 (m, 1H), 7.32-7.36 (m, 2H); LC-MS (ESI) m/z: 358(M+1)+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[O:8][C:7]([C:9]2[CH:14]=[C:13]([N:15]([CH3:21])[CH2:16][CH:17]3[CH2:19][CH:18]3[CH3:20])[N:12]=[C:11]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:10]=2)=[N:6][N:5]=1)[CH3:3].[C:28](=N)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.O.CCOC(C)=O>[C:29]1([C:28](=[N:1][CH:2]([C:4]2[O:8][C:7]([C:9]3[CH:14]=[C:13]([N:15]([CH3:21])[CH2:16][CH:17]4[CH2:19][CH:18]4[CH3:20])[N:12]=[C:11]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[CH:10]=3)=[N:6][N:5]=2)[CH3:3])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(N)c1nnc(-c2cc(N(C)CC3CC3C)nc(N(C)S(C)(=O)=O)c2)o1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(N=C(c1ccccc1)c1ccccc1)c1nnc(-c2cc(N(C)CC3CC3C)nc(N(C)S(C)(=O)=O)c2)o1
Reaction time: 15 h

Procedure:
To a solution of N-(4-[5-(1-aminoethyl)-1,3,4-oxadiazol-2-yl]-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide (0.544 g, 1.26 mmol, example 22) in 10 mL CH2Cl2 was added benzophenone imine (0.25 mL, 1.51 mmol). A white precipitate appeared gradually through the course of the reaction. The reaction was allowed to proceed for 15 h, when a further aliquot of benzophenone imine was added (0.160 mL, 0.894 mmol). After a further 24 h, the reaction was diluted with H2O and EtOAc, and the layers were separated. The aqueous layer was washed with EtOAc(2×), the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography (2->35% EtOAc/hexanes) to afford N-(4-(5-{1-[(diphenyl methylene)amino]ethyl}-1,3,4-oxadiazol-2-yl)-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N -methylmethanesulfonamide as a yellow foam. 1H NMR (CDCl3, 400 MHz) δ 7.63 (m, 4H), 7.54-7.50 (m, 4H), 7.48 (m, 2H), 7.05 (s, 1H), 6.99 (s, 1H), 4.95 (q, J=6.5 Hz, 1H), 3.52 (dd, J=14.3, 6.2 Hz, 1H), 3.38 (s, 3H), 3.34 (dd, J=14.3, 6.3 Hz, 1H), 3.14 (s, 3H), 3.12 (s, 3H), 1.67 (d, J=6.6 Hz, 3H), 1.01 (d, J=6.0 Hz, 3H), 0.74 (m, 1H), 0.65 (m, 1H), 0.40 (m, 1H), 0.25 (m, 1H); LCMS [M+H]+=559.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH:12]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:13][CH2:14][CH3:15]
Reactant: CCCC=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC=CN1CCCC1
Temperature: 0 °C

Procedure:
To a dry 500 milliliter (mL) three neck round bottom flask equipped with magnetic stirrer, nitrogen inlet, addition funnel, and thermometer, was charged with pyrrolidine (83.45 mL, 1.0 mmol) and potassium carbonate (34.55 g, 0.25 mol). The mixture was cooled to 0° C. and butanal (30.05 grams (g), 0.42 mol) was added dropwise with stirring under nitrogen at ad rate that maintained the temperature below 15° C. After the addition was complete (˜10 minutes), the cooling bath was taken away and the reaction mixture allowed to warm to room temperature over three hours. The reaction mixture was filtered through a scintered glass filter to remove the solids. The solid was washed thoroughly with ether, and combined with the filtrate, which was concentrated on the rotary evaporator to give the crude 1-but-1-enylpyrrolidine which was purified by vacuum distillation @15 mmHg 65-78° C.; 1H NMR (CDCl3): δ 6.20 (d, 1H), 4.18 (q, 1H), 2.95 (m, 4H), 1.80, (m, 4H), 0.97 (d, 3H).