Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:28]1[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:38][C:2]([F:1])([F:37])[CH:3]([C:28]1[CH:29]=[C:30]([Cl:36])[C:31]([Cl:35])=[C:32]([Cl:34])[CH:33]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 80 °C

Procedure:
To a stirred solution of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH:26]([CH3:28])[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CC1CCO
Temperature: 25 °C
Reaction time: 9 h
Yield: 87.9 %

Procedure:
To a solution of the crude TBDPS-protected alcohol 11a (464 mg, 0.742 mmol) in dry THF (6 mL) at 0° C. was added TBAF (1.0M/THF, 0.93 mL, 0.927 mmol), and the reaction mixture was allowed to warm to rt while stirring under N2. Since TLC showed uncomplete reaction after 5 h, 0.75 eq. TBAF (0.56 mL) was added. After 9 h, the reaction mixture was quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 177 mg (88%) of the title compound as a colorless oil which solidified upon high vacuum to give a white powder. mp 49.8-50.2° C.; [α]D22 −30.8 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 4.50 (appbd, 1H, J=4.5 Hz), 3.66 (bs, 2H), 2.94 (m, 1H), 2.36 (bs, 1H), 1.82 (bs, 1H), 1.71 (m, 1H), 1.45 (s, 9H), 1.39 (t, 2H, J=7.2 Hz), 1.01 (bs, 2H), 0.90 (dd, 6H, J=102, 6.6 Hz), 0.50 (m, 1H), 0.43-027 (m, 2H); HRMS (ESI) m/z calcd for C15H29NO3Na 294.2045, found 294.2064.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][C:4](=[O:7])[CH2:5][CH3:6].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>CN(C)C=O>[CH3:11][N:12]([CH:14]=[C:3]([C:4](=[O:7])[CH2:5][CH3:6])[C:2](=[O:8])[CH3:1])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)C(=CN(C)C)C(C)=O
Reaction time: 8 h

Procedure:
A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said 3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p. 265°-268° C. with decomposition the acidic mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile. Preliminary attempts to separate the two compounds by fractional crystallizaton were unsuccessful; however, the two compounds should be separable.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:17][CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][C:9]=2[CH:15]=1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3nc(-c4ccccc4)[nH]c3c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 50 °C

Procedure:
Tosylate 191 (0.2 g) was dissolved in DMF (10 mL) and NaN3 (99 mg) was added as a solid. A condenser was affixed under nitrogen, and the mixture was heated to 50° C. for 16 h. The reaction was cooled to rt before being extracted with EtOAc. The organic layer was rinsed several times with water to ensure complete removal of DMF. The organic layer was then separated and dried over Na2SO4 before the solvent was removed under reduced pressure to give 192.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[C:4]([C:7](OCC)=[O:8])[NH:5][CH:6]=1>CC(O)=O.[Fe]>[CH3:1][C:2]1[C:3]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:7]([OH:8])[C:4]=2[NH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1c[nH]c2c(O)nc3ccccc3c12
Temperature: 100 °C
Yield: 86.5 %

Procedure:
A solution of ethyl 4-methyl-3-(2-nitrophenyl)-1H-pyrrole-2-carboxylate (3.2 g, 11.67 mmol) in AcOH (117 mL) was treated at 20° C. with iron dust (6.52 g, 117 mmol). The reaction mixture was heated at 100° C. for 3 h. The white precipitate was removed by filtration and the filtrates were concentrated to give a residue that was purified on silica gel (gradient elution, 50-100% MeOH/Acetone) to afford the title compound (2.0 g, 86%) as a solid. LCMS (ES+) m/z 199 (M+H)+.
Reaction SMILES: [N+:1](=[C:3]([C:10]([CH3:12])=[O:11])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2].[I-].[Na+].C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C(#N)C>[N+:1](=[C:3]([C:10]([O:11][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH2:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)C(=[N+]=[N-])C(=C)O[Si](C)(C)C
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Into 5 ml of dry acetonitrile were added 167 mg (1 millimole) of allyl 2-diazoacetoacetate and 210 mg (1.4 millimoles) of sodium iodide. To the mixture were added 220 μl (1.6 millimoles) of triethylamine and then 190 μl (1.5 millimoles) of trimethylsilyl chloride while agitating under an argon atmosphere at a room temperature. After the resultant was agitated at a room temperature for an hour, it was concentrated under a reduced pressure. To the residue was added 10 ml of dry hexane, and the resultant was agitated for 30 min. at a room temperature. Isoluble materials were removed by filtration and the hexane solution was concentrated to dryness under a reduced pressure to give 176 mg (yield 78.8%) of the desired compound in an oily state.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([N:13]1[C:17]2[C:18]([Br:22])=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:23])(=[O:12])[CH3:11]>>[C:10]([N:13]1[C:17]2[C:18]([Br:22])=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]1=[O:23])(=[O:12])[CH3:11]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)n1c(=O)[nH]c2cccc(Br)c21
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1c(=O)n(C(C)=O)c2c(Br)cccc21
Reaction time: 4 h

Procedure:
Sodium hydride (353 mg of a 60% dispersion in mineral oil, 8.84 mmol) and ethyl bromoacetate (1.15 mL, 8.84 mmol) were added to a solution of 1-acetyl-7-bromo-1,3-dihydro-2H-benzimidazol-2-one from Step B (1.5 g, 5.89 mmol) in DMP (20 mL) at 0° C. After 4 h, the reaction mixture was quenched with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2::EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=343 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:24]([F:39])=[CH:25][C:26]([CH:36]2[CH2:38][CH2:37]2)=[C:27]([N:29]2[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]2)[CH:28]=1>C(O)(C(F)(F)F)=O.C(O)(C)C>[F:21][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)=[N:7][C:2]([NH:22][C:23]2[C:24]([F:39])=[CH:25][C:26]([CH:36]3[CH2:38][CH2:37]3)=[C:27]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:28]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC2CCC(=O)N21
Reactant: Cn1nnn(-c2cc(N)c(F)cc2C2CC2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(NC4CC5CCC(=O)N5C(C)(C)C4)n3)c(F)cc2C2CC2)c1=O
Temperature: 100 °C

Procedure:
A mixture of 7-(2-chloro-5-fluoropyrimidin-4-ylamino)-hexahydro-5,5-dimethylindolizin-3(5H)-one isomer A (cis) (50 mg), 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (50 mg) and TFA (5 drops) in isopropanol (1 ml) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed in vacuo and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give product as racemic mixture.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[S:25]1[CH2:29][CH2:28][NH:27]C1.[H-].[Na+]>C1COCC1>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:27][CH2:28][CH2:29][SH:25])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: C1CSCN1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCNCCS

Procedure:
Using 1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 0.89 g of thiazolidine, 0.5 g of sodium hydride, and 30 ml THF, a reaction similar to that conducted in Example 180 was carried out. As a result, 0.45 g of N-(trans-4-methylcyclohexyl) -4-{2-[(2-mercaptoethyl)amino]ethoxy}-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH2:33]([N:35]=C=O)[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH:35][CH2:33][CH3:34])=[O:30])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: CCN=C=O
Product: CCNC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
By a method similar to Example 17, and using tert-butyl [(1S)-2-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate and ethyl isocyanate, the title compound was obtained.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C[N+](C)(C)[CH2:16][C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1.[I-].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:16][C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2scc(C[N+](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=C(C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
1-isopropenylbenzimidazolone (0.5 g, 2.9 mmol) in DMA (8 mL) was added and trimethyl-(4-methyl-benzo[b]thiophen-3-ylmethyl)-ammonium; iodide (1.0 g, 2.9 mmol) and K2CO3 (0.80 g, 5.74 mmol). The reaction mixture was heated to 120° C. for 15 min in a microwave and then 150° C. for another 5 min. The mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 0.7 g of the desired product as a white solid
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:17][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH2:16])[C:14]=3[S:15][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:4].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CC(O)=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:17][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:16][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:14]=3[S:15][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:4]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N)cccc12
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NC3CCCCC3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Step A Reductive Amination: To a solution of 7-Amino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (250 mg, 0.68 mmol) in DCE (6.5 mL) was added cyclohexanone (0.071 mL, 0.68 mmol), and NaBH3(OAc)3 (250 mg, 1.2 mmol). HOAc (0.05 mL, 0.82 mmol) was then added drop-wise and the solution was allowed to stir at ambient temperature for two hours after which the reaction was judged complete by TLC. The solution was filtered through silica gel, concentrated in vacuo and purified via normal phase SiO2 chromatography using a 0% to 15% ethyl acetate/hexane gradient, affording 180 mg of 7-Cyclohexylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as a viscous yellow oil.
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16](OCC)=[O:17])[CH:11]2[CH3:21])=[CH:7][CH:6]=1>C1COCC1>[OH:17][CH2:16][CH:12]1[CH:11]([CH3:21])[N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:23][CH:22]=2)[C:14](=[O:15])[CH2:13]1
Reactant: CCOC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC(CO)C2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium borohydride (3.5 g, 0.16 mol) in THF (50 mL) was slowly added dropwise to a solution of ethyl rac-(2R,3S)-1-(4-methoxybenzyl)-2-methyl-5-oxopyrrolidine-3-carboxylate (18.5 g, 0.064 mol) in THF (350 mL) at 0° C. The reaction mixture was allowed to stir at room temperature for 16 hours and then quenched by the slow addition of saturated aqueous ammonium chloride solution (30 mL). After removal of THF under reduced pressure, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (300 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give rac-(4R,5S)-4-(hydroxymethyl)-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one. MS ESI calc'd. for C14H20NO3 [M+H]+ 250. found 250. 1H NMR (CDCl3, 400 MHz): δ 7.10 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 4.83 (d, J=14.8 Hz, 1H), 3.85 (d, J=14.8 Hz, 1H), 3.74 (s, 3H), 3.47 (d, J=6.4 Hz, 2H), 3.30-3.27 (m, 1H), 2.76 (s, br, 1H), 2.58-2.52 (m, 1H), 2.24-2.18 (m, 1H), 2.06-2.02 (m, 1H), 1.15 (d, J=6.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH:23](/[C:20]1[CH:21]=[CH:22][C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(/C=C/c3ccccc3)cc2)OC1(C)C
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: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(/C=C/c2ccccc2)cc1

Procedure:
Pd(dppf)Cl2 (0.141 g) was added to a mixture of (E)-1-bromo-4-styrylbenzene (1.00 g), potassium acetate (1.14 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.03 g) in DMF (dry) (10 ml). The mixture was stirred at 90° C. under nitrogen for 12 hr. The insoluble solid was removed by filtration through Celite pad (eluted with EtOAc). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate. Activated-carbon powder and silica-gel were added and the mixture was shaken, sonicated and filtered through silica-gel/Celite pad (eluted with EtOAc). The filtrate was concentrated in vacuo to give the crude (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (0.186 g) was added to a suspension of 3-bromopyridin-2-amine (0.557 g), the prepared (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane and sodium carbonate (1.02 g) in DME (20 mL) and water (4 mL) and the mixture was stirred at 80° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (532 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC1(C)COC1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (115 mg, 0.843 mmol) and 3-(bromomethyl)-3-methyloxetane (139 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 38.5%).
Reaction SMILES: [O:1]=[C:2]1[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][N:4]3[C:3]1=[O:18].C1C(=O)N([Cl:26])C(=O)C1>CN(C)C=O>[Cl:26][C:10]1[CH:9]=[C:8]2[C:13]3=[C:12]([C:2](=[O:1])[C:3](=[O:18])[N:4]3[CH2:5][CH2:6][CH:7]2[C:14]([O:16][CH3:17])=[O:15])[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C1CCN2C(=O)C(=O)c3cccc1c32
Solvent: CN(C)C=O
Product: COC(=O)C1CCN2C(=O)C(=O)c3cc(Cl)cc1c32
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A mixture of methyl 5,6-dihydro-1,2-dioxo-4H-pyrrolo[3,2,1-ij]quinoline-6-carboxylate (Example 1; 3 g)and N-cholorsuccinimide (NCS, 1.96 g) in dimethylformamide (DMF, 30 ml) was heated at 80° C. with stirring for an hour. After cooling, the mixture was concentrated. The residue was extracted with chloroform (200 ml). Chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give the title compound (3.28 g, 96.2%) which was recrystallized form acetonitrile to dark red needles, mp 132° C.-133° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:14][CH2:15][CH2:16][O:17]1)[CH2:13][Br:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC)C1(C)OCCO1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C1(CBr)OCCO1

Procedure:
A solution of bromine (14.72 g) in chloroform (30 ml) was added to a stirred solution of ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 20 g) in chloroform (200 ml) at ambient temperature and stirred at the same temperature for an hour. To the resultant solution was added 5% sodium thiosulfate aqueous solution (100 ml) and stirred at ambient temperature for 10 minutes. The organic layer was separated, washed with 5% sodium thiosulfate aqueous solution (100 ml), water (100 ml), a sodium bicarbonate saturated aqueous solution and sodium chloride saturated solution in turn and then dried over magnesium sulfate. The solution was evaporated in vacuo and the remaining oil (33.4 g) was distilled under reduced pressure to give an oil of ethyl 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyrate (syn isomer), bp 0.95 mm/Hg 115°-118° C. (Yield:quantitative).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[ClH:24].[NH2:25]O.O>C(O)C>[ClH:24].[NH2:25][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:9][CH:10]=1)[CH2:15][CH3:16]
Reactant: CCC(=O)c1ccc(CC(=O)OC(C)(C)C)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(N)c1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To tert-butyl(4-propionylphenyl)acetate (1 g) in ethanol (20 ml) solution, sodium acetate (0.7 g) and hydroxylamine hydrochloride (0.44 g) were added and the mixture was stirred at 90° C. for 3 hours. Distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. Ethanol (22 ml) and 10% palladium carbon (0.6 g) were added to the residue, and the mixture was stirred under hydrogen atmosphere at 5 atm for 40 hours. The insoluble compound was filtered out, then a 4N hydrochloric acid/ethyl acetate solution was added to the filtrate and the mixture concentrated. Hexane/ethyl acetate was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (0.74 g).