Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][C:29]([O:31]CC)=[O:30])[C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:24]2)=[CH:18][CH:17]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[C:25]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:24]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(Cn2cc(CC(=O)O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
After a mixture of ethyl [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (575 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid (466 mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 148–149° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH:20]1[O:24][CH:23]([CH3:25])[CH:22]([CH3:26])[O:21]1>>[CH3:26][CH:22]1[CH:23]([CH3:25])[O:24][CH:20]([CH2:19][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[O:21]1
Reactant: CC1OC(CBr)OC1C
Reactant: CCCOc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCOc1ccccc1NCC1OC(C)C(C)O1

Procedure:
2-Propoxyaniline (0.5 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-propoxyaniline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15][CH2:14]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][CH3:9])=[CH:20][CH:19]=3)[CH2:14][CH2:15][CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2c(c1)CCCN2
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCCN2c1ccnc(Cl)n1
Temperature: 40 °C
Yield: 79.9 %

Procedure:
The reaction flask containing 2,4-dichloropyrimidine (372 mg, 2.5 mmol), 6-methoxy-1,2,3,4-tetrahydroquinoline (489 mg, 3 mmol) and diisopropylethylamine (0.52 mL, 3 mmol) in n-butanol (10 mL) was heated at 40° C. overnight. The solvent was evaporated, and the residue was purified by flash column chromatography to give 2-Chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (551 mg, 80%). This intermediate (250 mg, 0.91 mmol) was then dissolved in dichloromethane and treated with BBr3 (1 M in dichloromethane) (1 mL, 1 mmol) at −78° C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hr, poured into water, extracted with dichloromethane. The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 2-Chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (154 mg, 65%). To a stirred solution of 2-chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (29 mg, 0.11 mmol) and 4-amino-N-(cyclopropylmethyl)benzenesulfonamide (27 mg, 0.12 mmol) in DMF (0.5 mL) was added p-toluenesulfonic acid (2 M in dioxane) (55 μL, 0.11 mmol). The reaction mixture was stirred at 90° C. overnight, then purified by HPLC to give the title compound (27 mg, 56%).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[S:4][C:3]=1[CH3:9].C([Li])CCC.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C(OCC)C.O1CCCC1>[Br:7][C:6]1[C:2]([CH:21]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=2)[OH:22])=[C:3]([CH3:9])[S:4][C:5]=1[CH3:8]
Reactant: Cc1sc(C)c(Br)c1Br
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1sc(C)c(C(O)c2ccc(C(F)(F)F)cc2)c1Br
Reaction time: 0.5 h

Procedure:
To a vigorously stirred solution of 3,4-dibromo-2,5-dimethylthiophene (53.2 g, 197 mmol) from Example 11, Step 1, in a mixture of diethyl ether (1 L) and tetrahydrofuran (80 mL) at −74° C. under nitrogen is added n-butyllithium (1.6 M/hexanes, 123 mL, 197 mmol) with a syringe slowly such as to maintain an internal temperature between −70° C. and −74° C. The reaction is stirred for an additional 30 minutes. A solution of p-trifluoromethylbenzaldehyde (27.0 mL, 200 mmol) in 30 mL of diethyl ether is added over 3 minutes. The reaction is stirred for 5 minutes. The cold bath was removed and the solution was stirred for 15 minutes while warming up. It was quenched with 5 mL of methanol then with 300 mL of 1N hydrochloric acid and stirred for 30 minutes. The phases are separated. The organic layer is washed with brine (200 mL), dried over magnesium sulphate and concentrated under reduced pressure to afford the desired compound as a faint yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:14])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH2:14])=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: Nc1cc(N2CCOCC2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(N2CCOCC2)cc1N
Yield: 97.9 %

Procedure:
35 g of 4-fluoro-5-morpholin-4-yl-2-nitrophenylamine in solution in 618 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 3.4 g of palladium-on-charcoal at 22° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 30 g of 4-fluoro-5-morpholin-4-ylbenzene-1,2-diamine in the form of a brown solid are isolated. 1H NMR (400 MHz, (CD3)2SO, δ in ppm): 2.78 (m: 4H); 3.68 (m: 4H); 4.25 (broad s: 2H); 4.35 (broad s: 2H); 6.27 (d, J=8 Hz: 1H); 6.31 (d, J=14 Hz: 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([CH2:13][OH:14])[O:11][C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[OH:17].[Na+].CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+]>O.C(#N)C>[CH2:1]([C@H:8]1[C@H:12]([C:13]([OH:17])=[O:14])[O:11][C:10](=[O:15])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@H](CO)O1
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1N[C@@H](Cc2ccccc2)[C@H](C(=O)O)O1
Yield: 93 %

Procedure:
To (4S,5R)-4-benzyl-5-hydroxymethyloxazolidin-2-one obtained in the same manner as in Example 3 (4.68 g) were added acetonitrile (46.8 ml) and water (46.8 ml), and then sodium hydrogencarbonate (4.68 g), TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy (0.0468 g) and potassium bromide (2.69 g) were added. The mixture was stirred and 12% aqueous sodium hypochlorite solution (35.0 g) was added dropwise at room temperature over 30 min. The mixture was stirred at room temperature for 7 hr, and 12% aqueous sodium hypochlorite solution (14.0 g) was further added. The mixture was stirred for 12 hr and 12% aqueous sodium hypochlorite solution (7.0 g) was further added, which was followed by stirring for 3 hr. The reaction was quenched by adding sodium hydrogensulfite (2.84 g). The reaction mixture was analyzed by HPLC to confirm that (4S,5R)-4-benzyl-2-oxo-5-oxazolidinecarboxylic acid (4.67 g, yield 93%) was obtained. The mixture was extracted twice with dichloromethane (50 ml, 50 ml) and the solvent of the organic layer was removed under reduced pressure. The obtained oil was analyzed by HPLC to confirm that (4S,5R)-4-benzyl-2-oxo-5-oxazolidinecarboxylic acid (4.00 g, yield 80%) was obtained.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[S:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2sc(-c3ccccc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)sc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methanol (286 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (183 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.4 mL) and 1,1′-(azodicarbonyl)dipiperidine (505 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methoxy]benzoate as an amorphous compound. The obtained methyl 4-[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methoxy]benzoate was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (251 mg, 62%) as a white crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH2:26][CH2:27][CH3:28].CN(C=O)C>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]1[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(C(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 48.7 %

Procedure:
A solution of benzyl 3-[(tert-butoxycarbonyl)amino]azetidine-1-carboxylate obtained in Example (227a) (500 mg, 1.63 mmol) in THF (6 mL) was added to a suspension of sodium hydride (55%) (142 mg, 3.26 mmol) in THF (10 mL) at 0° C. Subsequently, butyl iodide (0.93 mL, 8.15 mmol) was added at 0° C., and the mixture was stirred at room temperature for 19 hours. DMF (2 mL) was added, followed by stirring for four hours. Then, sodium hydride (55%) (36 mg, 0.82 mmol) and butyl iodide (0.37 mL, 3.26 mmol) were added, followed by stirring for 2.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Thereafter, the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 288 mg of the title compound as a colorless oily substance (49%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].N1CCOCC1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH:30]3[CH2:32][CH2:31]3)[C:21]=2[C:33](OC)=[O:34])=[CH:16][CH:15]=1.S(=O)(=O)(O)O>O1CCCC1.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH:30]3[CH2:31][CH2:32]3)[C:21]=2[CH:33]=[O:34])=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
Lithium aluminum hydride (0.569 g, 15 mmol) was placed in a 50 ml volume three-necked flask equipped with a thermometer, a magnetic stirrer and a dropping funnel, and tetrahydrofuran (10 ml) was added as a solvent, followed by replacement of the system with nitrogen. To this solution was added dropwise morpholine (4.18 g, 48 mmol) gradually at room temperature, and after completion of the addition, the mixture was stirred at room temperature for 1 hr. This solution was cooled to 0° C. and a solution obtained by dissolving methyl 4-(4′-fluorophenyl)-2-cyclopropylquinoline-3-carboxylate (3.21 g, 10 mmol) in tetrahydrofuran (9.63 g) was added dropwise to this solution while maintaining the inner temperature to not higher than 0° C. After the completion of the addition, the mixture was stirred for 2 more hours at 10 to 20° C. This reaction mixture was added dropwise to a 15% aqueous sulfuric acid solution (50 ml) while maintaining the inner temperature to not higher than 10° C., and then, toluene (50 ml) was added to the mixture. The organic layer was separated from the mixture and the aqueous layer was extracted with toluene (10 ml). The extract was combined with the organic layer obtained earlier and the mixture was washed with water (30 ml), dried over anhydrous sodium sulfate, then low boiling point components, such as the solvent and the like, were removed under reduced pressure. The obtained residue was purified by column chromatography (eluent: hexane-ethyl acetate mixture) to give 4-(4′-fluorophenyl)-2-cyclopropylquinoline-3-carbaldehyde (2.27 g, yield 77%) as a pale-yellow solid having the following properties.
Reaction SMILES: CC[N:3](C(C)C)[CH:4]([CH3:6])[CH3:5].[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]1.C(N)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:4]([NH:3][C:15]([C:12]1[CH:13]=[CH:14][NH:10][CH:11]=1)=[O:17])([CH3:6])[CH3:5]
Reactant: O=C(O)c1cc[nH]c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1cc[nH]c1
Reaction time: 0.33 h

Procedure:
DIPEA (284 mg, 381 uL, 2.2 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (111 g, 1.0 mmol) and isopropylamine (118 mg, 170 uL, 2.0 mmol) in DMF (10 mL) at 0° C. Stirring for 20 min, HATU (570 g, 1.5 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (100 mL), washed with H2O (3×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel. Yield: 80 mg (52%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.19 (d, J=6.64 Hz, 6 H), 3.95-4.31 (m, 1 H), 6.52 (dd, J=2.93, 1.56 Hz, 1 H), 6.70 (dd, J=2.93, 2.15 Hz, 1 H), 7.31 (t, J=1.76 Hz, 1 H), 7.58 (s, 1 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]1[O:32][N:31]=[C:30]([CH:33]=O)[CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:30]3[CH:29]=[C:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[O:32][N:31]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc(-c2cccs2)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc(-c5cccs5)on4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 267 mg of 5-(2-thienyl)-3-isoxazolecarbaldehyde, 100 mg of acetic acid was added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 18 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.63 g of 7-methoxy-1-(2-(4-((5-(thiophen-2-yl)isoxazol-3-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH3:15]>>[Cl:1][C:2]1[C:3]([C:4]([NH:13][C@H:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])=[O:6])=[CH:7][C:8]([Cl:11])=[CH:9][N:10]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 2,5-dichloronicotinic acid and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.42 (1H, d, J=2.6 Hz), 8.10 (1H, d, J=2.6 Hz), 8.04 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz), 6.82 (1H, d, J=7.3 Hz), 5.40–5.30 (1H, m), 3.92 (3H, s), 1.64 (3H, d, J=7.0 Hz); MS (ESI) m/z 353 (M+H)+, 351 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.N1CCCC1>CO>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15](/[C:16](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH3:10])/[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: Cc1ccc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: Cc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 92.5 %

Procedure:
5-Chloro-2-methyl-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.5 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as yellow solid (Yield: 4.5 g).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH2:29][NH:30][CH2:31][CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH2:29][NH:30][CH2:31][CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:35][CH:34]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)CNCCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CNCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 43 and 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-ethoxycarbonylmethylamino-ethyl)-aniline in DMF.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[F:49]C1C=C(C=CC=1)N>C(O)(=O)C>[F:49][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(F)c1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1cccc(F)c1
Yield: 12 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.47 ml), 3-fluoroaniline (44.3 mg, 0.4 mmol), and acetic acid (0.06 ml) were used to give 8.1 mg (0.025 mmol, 12% yield) of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH:9]=[CH:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2].[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1.[Cu]>[C:1]([N:4]1[CH:9]2[CH:8]([CH:21]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(=O)N1C=CN(Cc2ccc(F)cc2)C(=O)C1
Agent: [Cu]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C2C1N(Cc1ccc(F)cc1)C(=O)CN2C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one (5.0 g, 20.0 mmol; Example 2, Step 3) and copper bronze (320 mg, 5.0 mmol) in anhydrous toluene (50 mL) under nitrogen at 120° C. (oil bath) was added ethyl diazoacetate (6.4 mL, 60.0 mmol) via a syringe pump at a speed of 2.5 mL/h. After 3 h, TLC (eluted with ethyl acetate) showed no starting material left. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate and methanol as eluents to give both exo and endo diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:21][CH3:22])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)O.S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]([O:21][CH3:22])=[CH:5][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OC

Procedure:
A mixture of 3-(3-Benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester (1 eq), mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature overnight. The Reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield the title compound.