Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC1C(OCCCCCC)=CSC=1)[CH2:2]CCCC.S1C=C[CH:22]=[CH:21]1.S(=O)(=O)(O)O.[C:30]([OH:38])(=[S:37])[CH2:31][O:32][CH2:33][C:34]([OH:36])=[O:35]>C(O)C>[CH2:1]([O:38][C:30](=[S:37])[CH2:31][O:32][CH2:33][C:34]([O:36][CH2:21][CH3:22])=[O:35])[CH3:2]
Reactant: CCCCCCOc1cscc1OCCCCCC
Reactant: c1ccsc1
Reactant: O=C(O)COCC(O)=S
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)COCC(=S)OCC
Reaction time: 24 h
Yield: 90 %

Procedure:
An example of synthesizing 3,4-dihexoxythiophene as a thiophene monomer is shown below. 2 mL of sulfuric acid was added in an ethanol solution (800 mL) of thiodiglycolic acid (250 g, 1.67 mol) to prepare a reaction solution, then the reaction solution was refluxing under heating for 12 hr after stirring for 24 hr. Subsequently, substantially 500 mL of water and ethanol was removed from the reaction solution according to azeotropy. Furthermore, 400 mL of ethanol was added and after refluxing under heating for 20 hr, the reaction solution was added water to extract with ether. A layer of ether was dried with magnesium sulfate, followed by filtering and concentrating. The residue was distilled under reduced pressure of 200 Pa and a temperature of 100 to 110 degree centigrade, and thereby thiodiglycolic acid diethylester was obtained at a yield of 90 percent.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[S:29]1[CH:34]=[C:33]([C:35](=[N:39][O:40][CH3:41])[C:36](O)=[O:37])[S:32][CH2:31][CH2:30]1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[S:29]1[CH:34]=[C:33]([C:35](=[N:39][O:40][CH3:41])[C:36]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[NH:15][N:14]=[N:13][CH:12]=4)[CH2:7][S:8][C@H:3]23)=[O:37])[S:32][CH2:31][CH2:30]1
Reactant: CON=C(C(=O)O)C1=CSCCS1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12)C1=CSCCS1
Yield: 71.7 %

Procedure:
A solution of 7-amino-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.57 g.) and trimethylsilylacetamide (4.6 g.) in ethyl acetate (20 ml.) and a mixture of 2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 1.1 g.), N,N-dimethylformamide (0.44 g.) and phosphoryl chloride (0.92 g.) were treated in a similar manner to that of Example 21 to give 7-[2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.85 g.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH3:15]I>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:15]
Reactant: CI
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C)c1Cl
Yield: 81.2 %

Procedure:
2-Chloro-3-methyl-4-nitrophenol (9.39 g, 50.0 mmol) was reacted with sodium hydride (50%, 2.64 g, 55.0 mmol) and methyl iodide (7.81 g, 55.0 mmol) in dry DMF (200 ml) by the method described in 1 (a). After treatment with water, the product was extracted with chloroform, and the dried extract evaporated to dryness, leaving an oil which crystallised on cooling, leaving solid 2-chloro-3-methyl-4-nitroanisole (8.19 g).
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@H:39]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]>ClCCl>[F:69][C:68]([F:71])([F:70])[C:66]([OH:72])=[O:67].[CH3:6][NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@H:39]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26 mg (29 μmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 1.8 ml of dichloromethane, and 370 μl of TFA were added. The reaction mixture was stirred at RT for 30 min and then concentrated. The residue was taken up in water and lyophilized. 26.4 mg (quant.) of the title compound were obtained.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1[C:18]2[C:17]3=[N:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:16]3[CH:15]=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:23]1[CH:24]=[CH:25][C:20]2[N:19]=[C:17]3[C:18]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[CH:14]=[CH:15][N:16]3[C:21]=2[CH:22]=1
Reactant: c1ccc2c(c1)ccn1c3ccccc3nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Brc1ccc2nc3c4ccccc4ccn3c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
32.6 g (183 mmol) of NBS are added to a solution of 40 g (183 mmol) of benzimidazo[2,1-a]isoquinoline in 500 ml of THF, and the mixture is stirred at 60° C. for 4 h. The solution is subsequently stirred at room temperature overnight, the solid is filtered off with suction, washed with ethanol and dried. Yield: 51.3 g (181 mmol), 98%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2NCCC)=[C:4](C)[N:3]=1.[F:16][C@@H:17]1[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19](N2C=CC(=O)NC2=O)[CH2:18]1.[N-]=[N+]=[N-].[K+].[C@@H:36]1([N:44]2C=C(C)C(=O)N[C:45]2=O)O[C@H](CO)[C@@H:38](O)[CH2:37]1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:19]2[O:20][C@H:21]([CH2:22][OH:23])[C@@H:17]([F:16])[CH2:18]2)=[C:4]([N:44]([CH3:45])[CH2:36][CH2:37][CH3:38])[N:3]=1
Reactant: CCCNn1cnc2c(C)nc(N)nc21
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: CCCN(C)c1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 192 h
Yield: 56 %

Procedure:
2-Amino-6-methylpropylamino-9H-purine (0.54 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in potassium phosphate buffer, (50 ml, 10 mM), pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 8 days, MeOH (170 ml) was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (92:8). Solvent was removed and lyophilization yielded 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-(methylpropylamino)-9H-purine (0.40 g, 56%): mp 80°-84° C.;
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH3:28][CH2:29]O>O>[CH2:28]([O:15][C:14](=[O:16])[CH:13]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:29]
Reactant: CCO
Reactant: O=C(O)C(c1ccccc1)c1c(O)c2ccccc2oc1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid in EtOH with a catalytic amount of conc. sulfuric acid was heated to reflux for 5 hours, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4 and conc. in vacuo to give (4-Hydroxy-2-oxo-2H-chromen-3-yl) -phenyl-acetic acid ethyl ester as colorless oil, which crystallize upon standing (910 mg). MS: 323[M−H].
Reaction SMILES: C[O-].[Na+].[CH2:4]([NH:11][C:12]([NH2:14])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][C:16]([CH3:27])([C:22](OCC)=[O:23])[C:17](OCC)=[O:18]>CO>[CH2:4]([N:11]1[C:17](=[O:18])[C:16]([CH3:27])([CH3:15])[C:22](=[O:23])[NH:14][C:12]1=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N(Cc2ccccc2)C1=O
Temperature: 5 °C

Procedure:
A mixture of-sodium methoxide (0.343 g, 14.9 mmol), benzylurea (1.6 g, 10.6 mmol), diethyl dimethylmalonate (1.9 g, 10 mmol) and methanol (15 mL) was heated 6 hours at reflux. The reaction mixture was concentrated and the residue was stirred with water (30 mL) at 5° C. and then hydrochloric acid was added. The solids were collected, washed with water and dried to give 1-benzyl-5,5-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione, m.p 136°-137° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:10]#[CH:11]>C(NCC)C.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccccc1I
Reactant: C#CCN1CCCCC1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: Cc1ccccc1C#CCN1CCCCC1
Yield: 62.3 %

Procedure:
A mixture of 2-iodotoluene (6.54 g), N-(2-propynyl)piperidine (3.69 g), dichlorobis(triphenylphosphino)palladium(II) (0.05 g) and copper(I) iodide (0.1 g) in dry diethylamine (50 ml) was heated under reflux for 5 hours. The solvent was removed under reduced pressure and the residue was taken up in diethyl ether and washed with water. The organic phase was dried over magnesium sulfate and concentrated completely under reduced pressure. Distillation of the residue under reduced pressure gave 3.98 g of an oil of boiling point 96–98° C./0.08 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]3[CH2:13][CH:12]([CH2:14][OH:15])[O:11][CH:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[OH2:40]>C(Cl)Cl>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]3[CH2:13][CH:12]([CH2:14][OH:15])[O:11][CH:10]3[C:4]=2[CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O-:38])(=[O:37])=[O:40])=[CH:32][CH:31]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCC1CC2c3ccccc3Cc3ccc(F)cc3C2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[2R-(2α, 3aα, 12bβ)]-11-fluoro-2-hydroxymethyl-3,3a,8,12b-tetrahydro-2H-dibenzo [3,4:6,7]cyclohepta[1,2-b]furan (4.1 g, 0.0144 mol) was dissolved in DCM (20 ml). Triethylamine (0.0173 mol) was added and the mixture was cooled on an ice-bath. A solution of 4-methyl-benzenesulfonyl chloride (0.0159 mol) in DCM (10 ml) was added over ±5 min. The mixture was stirred for 2 hours at 0° C. then allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. Water (20 ml) was added. The layers were separated. The organic phase was stirred in a 10% aqueous potassium carbonate solution for one hour. The layers were separated. The organic layer was dried (MgSO4), filtered and the solvent evaporated. The residue was stirred in toluene (30 ml). A 10% aqueous potassium carbonate solution (30 ml) was added. The layers were separated. The organic layer was dried (MgSO4), filtered and the solvent evaporated, yielding 5.8 g (92%) of [2R-(2α, 3aα, 12bβ)]11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-methanol-4-methylbenzenesulfonate, intermediate 1. An alternative method of preparing this intermediate is described in W003/048146 [CAS number=543741-40-8].
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.NCCN1CCNCC1.[F:27][C:28]([F:32])=[C:29](F)F.C(=O)([O-])[O-:34].[Na+].[Na+]>CN(C)C=O>[F:27][CH:28]([F:32])[C:29]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:34]
Reactant: FC(F)=C(F)F
Reactant: O=C([O-])[O-]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Agent: NCCN1CCNCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 33 h
Yield: 70 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and 1-(2-aminoethyl)piperazine (0.78 g, 6.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at 50° C. for 33 hours. After cooling to an ambient temperature, the reaction mixture was poured into saturated aqueous sodium carbonate solution, and extracted with diethyl ether. The diethyl ether layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.18 g, 3.5 mmol, yield 70%). Unreacted part of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.12 g) was recovered.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.60 g) with 2-methoxybenzoyl chloride (1.0 g) and N,N-diisopropylethylamine (1.7 ml) in tetrahydrofuran (60 ml) was performed according to the method described in example 6.
Reaction SMILES: O=[O+][O-].[O:4]=O.[CH3:6][C:7]1([CH2:28][CH:29]=C)[CH2:12][CH2:11][C:10]2[C:13]([CH3:27])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:9]=2[O:8]1>CO>[CH3:6][C:7]1([CH2:28][CH:29]=[O:4])[CH2:12][CH2:11][C:10]2[C:13]([CH3:27])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:9]=2[O:8]1
Reactant: C=CCC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Reactant: O=O
Agent: O=[O+][O-]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC=O)O2
Temperature: -78 °C

Procedure:
An ozone-oxygen gas mixture is passed into a solution of 0.67 g (2 mmoles) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-(2-propenyl)-6-(phenylmethoxy)-2H-1-benzopyran in 100 ml of methanol, with stirring, at -78° C. After the starting olefin has been consumed, the ozone flow is stopped and the solution is treated with excess dimethyl sulfide and allowed to warm to room temperature. The solution is concentrated in vacuo. The residue is chromatographed on silica gel giving rac-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran-2-acetaldehyde, which can be converted to Vitamin E by the procedures in Helv. Chim. Acta set forth in Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]=[C:8]2NN)=[CH:4][CH:3]=1.BrC1C=C2C(CN3C(C4C(C5C=CC=CC=5)=N[O:29]C=4C)=NN=C32)=CC=1.CC1ON=C(C2C=CC=CC=2)C=1C=O>FC(F)(F)C(O)=O.ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:29])=[CH:4][CH:3]=1
Reactant: NNC1=NCc2ccc(Br)cc21
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Agent: Cc1onc(-c2ccccc2)c1C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 152.3 %

Procedure:
Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved in THF/methanol (200 ml) (1:1) and the solution obtained was saturated with dry ammonia gas. The solvent was removed and the residue was triturated with water, diethyl ether and hexane and then recrystallised from ethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one (12.5 g). 1H NMR (400 MHz, d6 DMSO) δ 8.70 (1H, bs), 7.78 (1H,s), 7.77 (1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s). m/z (ES+) 212 (M+). b) 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate Prepared in a similar manner to that of Example 1a using 6-bromo-2,3-dihydro-isoindol-1-one. 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 8.05 (1H,d, J=1 Hz), 7.94 (1H, dd, J=7 and 1 Hz), 7.66 (1H, dd, J=7 and 1 Hz), 5.07 (2H, s), 4.60 (3H, s). m/z (ES+) 226 (M+). c) (6-Bromo-3H-isoindol-1-yl)hydrazine 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate (3.7 g) was dissolved in THF (35 ml) and triethylamine (2.8 ml) was added followed by hydrazine (1 M in THF, 35 ml). After an hour the solid which had precipitated was filter off and dried to give title compound (2.8 g) 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 7.85 (1H,d, J=1 Hz), 7.51 (1H, dd, J=7 and 1 Hz), 7.25 (1H, dd, J=7 and 1 Hz), 4.49 (2H, s). m/z (ES+) 226 (M+). d) 8-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (6-Bromo-3H-isoindol-1-yl)hydrazine (2.8 g) was stirred in 10% trifluoroacetic acid in dichloromethane (40 ml) and 5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (2.33 g) and the reaction was stirred for 0.5 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated sodium hydrogen carbonate, dried, filtered and evaporated. The residue was taken up into methanol and dichloromethane, sodium acetate was added and the stirred suspension was treated dropwise with bromine (0.5 ml). The reaction was diluted with water and extracted into dichloromethane and dried, filtered and evaporated. The product was purified by silica chromatography using ethyl acetate as eluant to yield the title compound (1.46 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)([O-:3])=[O:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1

Procedure:
A solution of EXAMPLE 415A (0.8 g) in methylene chloride (10 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours. The solvents were evaporated and the residue was triturated with diethyl ether. The resulting solid was dissolved in 5% aqueous sodium carbonate solution (20 mL). The solution was evaporated to dryness and the resulting solid was triturated with a solution of 10% methanol in dichloromethane several times. Evaporation of the organic solution gave the title compound.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]([CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:30][CH2:31][CH3:32])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[CH3:10])=[O:8])=[CH:3][CH:2]=1.O.[OH-].[Li+].O.CO>C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]([CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[CH3:10])=[O:8])=[CH:5][CH:6]=1
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccc(-c4ccccc4)cc3)c2)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccc(-c4ccccc4)cc3)c2)cc1)C(=O)O
Reaction time: 4 h

Procedure:
360 mg (0.7 mmol) of methyl (S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionate in 10 ml of THF are introduced into a round-bottomed flask. 60 mg (1.4 mmol) of lithium hydroxide monohydrate, 1 ml of water and 1 ml of methanol are added and the mixture is stirred for 4 hours. The reaction medium is poured into water, acidified to pH 1, extracted with ethyl acetate, the organic phase decanted off, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture and 280 mg (80%) of (S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionic acid are obtained in the form of an amorphous white solid.
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:20]([O-:22])=[O:21])=[C:10]([NH:12]C(=O)OC(C)(C)C)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:20]([O-:22])=[O:21])=[C:10]([CH:11]=2)[NH2:12])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of tert-butyl (5-(cyclopent-1-en-1-yl)-2-nitrophenyl)carbamate (4.3 g, 14.13 mmol, 1.0 equiv.) in dichloromethane (50 mL) was added TFA (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction was then evaporated under reduced pressure. The crude residue was quenched with a saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate, washed with water and brine, dried, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 60% EtOAc/hexanes) to give 5-(cyclopent-1-en-1-yl)-2-nitroaniline (2.5 g, 87% yield).