Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH3:20])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.C([O-])(=O)C.[K+].O1CCCCC1[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.Cl>C(#N)C.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>[CH3:20][N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:21]=[CH:22][C:2]([C:40]5[CH:39]=[N:38][N:37]([CH2:36][CH2:35][OH:34])[CH:41]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(CCO)c4)cc2OCC3)n(C)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a microwave vial was added 8-Bromo-2-(2,5-dimethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.150 g, 0.000416 mol) and Potassium acetate (0.123 g, 0.00125 mol) in Acetonitrile (2.0 mL) and Water (2.0 mL). The solution was thoroughly purged with N2. 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.148 g, 0.000458 mol) and Tetrakis(triphenylphosphine)palladium(0) (0.0481 g, 0.0000416 mol) were added and the vial was immediately sealed. The reaction was heated in the microwave to 140° C. for 20 minutes. The mixture was partitioned between saturated NH4Cl and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was dissolved in methylene chloride (5.0 mL) and hydrogen chloride (0.00125 mol, 4N in dioxane, 0.31 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated and partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. Most of the product precipitated in the aqueous phase—the mixture was filtered and submitted to reverse-phase HPLC, then recrystallized in EtOH/MeOH to afford 24 mg 285 as a white solid. MS (ESI+) 392.2. 1H NMR (500 MHz, DMSO) δ 8.40 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.36 (dd, J=8.4, 1.7 Hz, 1H), 7.27 (d, J=1.7 Hz, 1H), 4.90 (t, J=5.3 Hz, 1H), 4.54-4.48 (m, 4H), 4.21 (s, 3H), 4.16 (t, J=5.7 Hz, 2H), 3.77 (q, J=5.6 Hz, 2H), 2.24 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)nc1)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
2-chloropyridine-5-acetic acid (0.2 gm, 1.21 mmole), 3-fluorobenzylamine (0.15 ml, 1.2 mmole), PyBOP (0.67 gm, 1.3 mmole), and DIEA (0.43 ml, 2.6 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.3 gm, 85%); H1-NMR INOVA-500 (CDCl3) δ 3.562 (s, 2H), 4.429 (d, J=6.5 Hz, 2H), 5.868 (s, 1H), 6.929-7.015 (m, 3H), 7.300-7.333 (m, 2H), 7.668 (dd, J=8, 2.5 Hz, 1H), 8.280 (d, J=2.5 Hz, 1H).
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[NH:23][CH:22]=[CH:21]3)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]([CH2:8][CH2:9][N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[NH:23][CH:22]=[CH:21]3)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)ccc12
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2cc(OC3CCN(CCOc4ccccc4)CC3)ccc12
Reaction time: 17 h

Procedure:
2-Phenoxyethyl bromide (1 mol eq) was added to a suspension of 6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol) and potassium carbonate (50 mgs, 3 mol) in N, N-dimethylformamide (1 ml) and shaken for 17 hours. The reactions was quenched with hydrochloric acid (2M) and methanol and passed down an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean product was isolated by evaporation under reduced pressure to afford 6-[1-(2-phenoxyethyl)piperidin-4-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=365.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[O:18])[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[O:18])[C:5]2=[N+:6]([O-:27])[CH:7]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2cc(Br)cnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2cc(Br)c[n+]([O-])c21
Reaction time: 42 h
Yield: 66 %

Procedure:
To a solution of 3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (2 g) (6.2 mmoles) in anhydrous dichloromethane (14 ml) at 0° C. and under an argon atmosphere, was added a solution of 3-chloroperbenzoic acid (1.76 g) (10.4 mmoles) in anhydrous dichloromethane (35 ml) dropwise over a period of 30 minutes. The mixture was allowed to warm to room temperature and after 18 h additional 3-chloroperbenzoic acid (0.88 g) (5.2 mmoles) in anhydrous dichloromethane (25 ml) was added and the mixture was stirred for a total of 42 h. The mixture was diluted with dichloromethane and washed with 1N NaOH (200 ml). The aqueous layer was extracted with additional dichloromethane (2X200 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25%-0.5%-1% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give the title compound (Yield:1.386 g, 66%): ESIMS; m/z 338.1 (MH+); δc (CDCl3) CH2: 30.5, 34.0; CH: 126.9, 127.6, 130.3, 132.5, 140.4; C: 121.0, 135.1, 138.3, 139.7, 141.6, 145.3, 188.0 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:9][CH2:8]2)[CH:6]=1.[K+].[CH:21]1([B-](F)(F)F)[CH2:23][CH2:22]1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>[Cl-].[Na+].O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[CH:21]1([C:2]2[CH:3]=[N:4][N:5]([C:7]3([C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:11])[CH2:9][CH2:8]3)[CH:6]=2)[CH2:23][CH2:22]1
Reactant: O=C(OCc1ccccc1)C1(n2cc(Br)cn2)CC1
Reactant: F[B-](F)(F)C1CC1
Agent: [Fe+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1(n2cc(C3CC3)cn2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
Into a 20 mL microwave vial were added benzyl 1-(4-bromo-1H-pyrazol-1-yl)cyclopropanecarboxylate (421 mg, 1.31 mmol), cyclopropyltrifluoroborate potassium salt (582 mg, 3.93 mmol), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (42.5 mg, 0.052 mmol) and cesium carbonate (1710 mg, 5.24 mmol). The vial was sealed, evacuated and backflushed with nitrogen two times followed by the addition of tetrahydrofuran (7 mL). The reaction mixture was stirred at 80° C. for 18 h. The solvent was removed under reduced pressure and to the residue was added water (100 mL) and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). After the second extraction an emulsion formed that was cleared with the addition of brine, ethyl acetate and aqueous hydrochloric acid (1N). The aqueous layers were extracted again with ethyl acetate (2×), the solvent was removed under reduced pressure and the residue was purified via flash chromatography (0-100% ethyl acetate in heptanes) to afford benzyl 1-(4-cyclopropyl-1H-pyrazol-1-yl)cyclopropanecarboxylate (91 mg, 25%). MS (ES+) (M+H) 283.3; LCMS retention time: 3.38 minutes (Method L).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[CH:19]([CH3:25])[C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:22]1([C:20](=[O:21])[CH:19]([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]2[CH3:1])[CH3:25])[CH2:24][CH2:23]1
Reactant: Cc1[nH]c2ncccc2c1C(=O)OC(C)(C)C
Reactant: CC(Br)C(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(=O)C1CC1
Yield: 54 %

Procedure:
The solution of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300.00 mg, 1.29 mmol), 2-bromo-1-cyclopropylpropan-1-one (342.98 mg, 1.94 mmol), Cs2CO3 (841.63 mg, 2.58 mmol), KI (42.88 mg, 0.26 mmol) in DMF (4 ml) were stirred at 25° C. for 18 h. After the reaction completed, the solution was partitioned between EtOAc and H2O. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column (Eluent: PE:EtOAc=10:1) to get tert-butyl 1-(1-cyclopropyl-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (230 mg, yield 54%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>C(O)C.[Pd]>[NH2:10][C:9]1[C:2]([CH3:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH2:4][OH:5]
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1CO
Yield: 101.4 %

Procedure:
A solution of 2-methyl-3-nitrobenzyl alcohol (2.0 g, 12 mmol) in ethanol (100 ml) was hydrogenated over 10% palladium/charcoal (0.1 g) for 2 hours, at an initial pressure of 3.5 bar. The solution was filtered through celite and evaporated to give 3-amino-2-methylbenzyl alcohol (1.67 g, quantitative), m.p. 104°-106°
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd].[C]>[CH:8]1([C:4]2[C:3]([CH3:14])=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1c(Cl)cccc1C1=CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)cccc1C1CCCCC1
Reaction time: 8 h
Yield: 49.8 %

Procedure:
103 g of 1-(3'-chloro-2'-methylphenyl)-cyclohexene are dissolved in 1,200 ml of ethanol, and 5 g of Pd/carbon are added. Hydrogenation is carried out for 8 hours at room temperature and under a hydrogen pressure of 80 bar. The catalyst is filtered off from the reaction mixture and the solution is evaporated down. Fractional distillation gives 51.8 g of 3-cyclohexyl-2-methylchlorobenzene (Example 3 in Table 1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][S:11][CH2:12][C@H:13]([O:29][C:30](=[O:42])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:14][O:15][C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CCN(C(C)C)C(C)C.[C:52](Cl)(=[O:68])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>C(Cl)Cl>[CH2:32]([NH:31][C:30]([O:29][C@H:13]([CH2:14][O:15][C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][S:11][CH2:10][C@H:2]([NH:1][C:52](=[O:68])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-tert-butyl 2-amino-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoate in dry DCM (0.1 M) at 0° C. was added DIEA (1.2 eq) and palmitoyl chloride (1.1 eq). The reaction was allowed to warm to room temperature then stirred for 16 hours. The crude reaction was then concentrated and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient 0-60% EtOAc/Hex to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10]C)=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:9]([OH:10])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])c(O)c1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
17.2 g of 2-hydroxy-3-methoxy-4-nitrobenzaldehyde (J. Het. Chem. 33, (1996), 1171) in 350 ml of dichloromethane is slowly mixed at 0° C. with 175 ml of boron tribromide solution (1 M in dichloromethane), and it is stirred for another 4 hours. The batch is added to ice water, the organic phase is separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water, and the solvent is removed in a vacuum. 15.2 g of 2,3-dihydroxy-4-nitrobenzaldehyde is obtained as a red solid, flash point 122-126° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([OH:24])[CH:26]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 3-hydroxybenzoic acid as brown solid (49%). MS 438 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(I)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Yield: 62.2 %

Procedure:
Using 5-iodosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:36])[N:13]2[C:16](=[C:30](S(C)(=O)=O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>C1C=CC=CC=1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:36])[N:13]2[C:16](=[C:30]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)S(C)(=O)=O
Solvent: O
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 2.17 h
Yield: 97.1 %

Procedure:
To a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonylethylidene)acetate (298 mg) in benzene (3 ml) is added morpholine (0.095 ml) at 7° to 10° C. After 130 minutes, the reaction mixture is filtered to give filtrate, which is poured into iced water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)-acetate (284 mg). Foam. Yield: 97.1%.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl.CCOCC>[CH:3]12[O:22][CH:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[CH2:2]2
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
A solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (9.93 g, 45.76 mmol) in CH2Cl2 (75 mL) was cooled to 0° C. (ice/water bath), Solid m-chloroperoxybenzoic acid (77%, 15.38 g, 1.5 equiv) was added. After 10 min, the reaction mixture was warmed slowly to rt. A white precipitate formed after 1 h. After stirring for another 1 h, LC-MS showed the reaction was complete. The mixture was diluted with ether (300 mL), washed by with 5% aq NaOH (2×40 mL), 25% aq Na2S2O3 solution (3×20 mL) and brine (30 mL), and dried over Na2SO4. After concentration, the residue was purified by flash chromatography (120 g silica gel column, 12%-70% EtOAc in hexanes gradient, 2nd UV peak) to afford benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (7.87 g, 74% yield). LC-MS (3 min) tR=1.41 min., m/z 234 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](O)=[O:7].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: COc1cc(C(=O)O)ccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of 3-methoxy-4-methyl-benzoic acid (20.0 g, 0.12 mol) in dry THF (200 mL) at 0° C., LiAlH4 (6.9 g) was slowly added. The reaction was warmed to room temperature and stirred overnight. Water (20 mL) was slowly added at 0° C., and then 15% aqueous NaOH solution (50 mL) was added. The mixture was filtered, and the filtrate was extracted with ethyl acetate (3×100 mL). The combined extracts were dried over MgSO4, filtered and evaporated to give the title compound as pale yellow oil (16.0 g). 1H NMR (CDCl3): δ 7.13 (d, 1H), 6.85-6.79 (m, 2H), 4.64 (s, 2H), 3.84 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]=[O:2].Cl.CON=C[C:8]1[CH:13]=[C:12]([N:14]2[C:22](=[O:23])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:15]2=[O:24])[C:11]([Cl:25])=[CH:10][C:9]=1[Cl:26]>C(O)(=O)C>[Cl:26][C:9]1[CH:10]=[C:11]([Cl:25])[C:12]([N:14]2[C:15](=[O:24])[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[C:22]2=[O:23])=[CH:13][C:8]=1[CH:1]=[O:2]
Reactant: C=O
Reactant: CON=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: O=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Temperature: 55 °C

Procedure:
9 ml of a 37% strength by weight aqueous formaldehyde solution and 9 ml of concentrated hydrochloric acid were added to a solution of 10.6 g (30 mmol) of 2,4-dichloro-5-(1,3,4,5,6,7-hexahydro-1,3-dioxo-2H-isoindol-2-yl)benzaldehyde (O-methyl)oxime in 45 ml of acetic acid. The mixture was subsequently heated for 1 hour at 50-60° C., whereupon the reaction mixture was poured into 300 ml of ice-water. The product was extracted from the resulting mixture using 200 ml of dichloromethane. The extract was dried over magnesium sulfate and then concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 5.2 g; 1H NMR (270 MHz; in CDCl3): δ [ppm]=1.85 (s, 4H), 2.45 (s, 4H), 7.67 (s, 1H), 7.81 (s, 1H), 10.40 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:22])[C:12]([O:14]CC2C=CC=CC=2)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.[N+](C)([O-])=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:22])[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.9 %

Procedure:
To a solution of benzyl 2-p-isobutylphenylpropionate (3 g) in methylene chloride (18 ml) are added a solution of aluminum chloride (4 g) in nitromethane (50 ml) and anisole (3 ml) at 0° C., and the mixture is stirred at room temperature for 6 hours. The reaction mixture is diluted with ethyl acetate, washed with hydrochloric acid and water, dried and evaporated. The residue is recrystallized with n-hexane to give 2-p-isobutylphenylpropionic acid (186 mg) melting at 75°-77.5° C. Yield 91%.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](O)=[O:19].P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([Cl:24])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Cl)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Retinoic acid (1.00 g, 0.0033 mol) was dissolved in anhydrous toluene (10 ml) and phosphorus trichloride (PCl3) (0.46 g, 0.0033 mol) was added dropwise thereto. The mixture was stirred for 15 hours at room temperature under nitrogen atmosphere and under the condition for light and moisture to be intercepted. The retinoic acid chloride solution thus obtained was added dropwise together with the retinol prepared in Preparation 1 (0.95 g, 0.0033 mol) and triethylamine (0.61 g, 0.0041 mol) to anhydrous methylene chloride (30 ml) over 20 minutes at 0° C. The reaction solution was then stirred for 5 hours at room temperature. The reaction solution was added to saturated aqueous sodium chloride solution (30 ml). The organic layer was separated, washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel 60 for cc part, Merk Co., mesh size 270–400, hexane/diethylether=9/1, v/v) to give 1.54 g (Yield 82%) of the pale yellow title compound. 1H NMR data of this compound were the same as those in Example 1.