Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:9]([CH3:14])([CH3:13])N(C)C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:15][C:16]([F:29])([F:28])[S:17]([O:20]S(C(F)(F)F)(=O)=O)(=[O:19])=[O:18]>>[F:15][C:16]([F:29])([F:28])[S:17]([O:20][Si:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH3:14])[CH3:13])(=[O:19])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCC[Si](C)(C)N(C)C
Product: CCCCCCCC[Si](C)(C)OS(=O)(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing octyldimethyl(dimethylamino)silane as the silicon compound B and trifluoromethanesulfonic anhydride as the acid B, the trifluoromethanesulfonic anhydride is rapidly reacted to form octyldimethylsilyl trifluoromethanesulfonate as the acid A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].C([O-])(O)=O.[Na+].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH:6][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(N)ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(NC(=O)C(C)(C)C)ccc1C
Reaction time: 12 h

Procedure:
5.1 g (37 mmol) of 3-methoxy-4-methylaniline are dissolved in 70 ml of methylene chloride, and treated with 70 ml of satd. NaHCO3 solution and with 4.6 ml (37 mmol) of pivaloyl chloride. After stirring vigorously for 12 hours, the organic phase is separated off, washed with 1N hydrochloric acid and water, dried over magnesium sulphate and concentrated in vacuo. The product is obtained in crystalline form and is further processed without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].C(N(CC)CC)C.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23]>C(#N)C>[O:4]=[C:3]1[C@H:2]([O:1][C:15]([O:16][N:17]2[C:21](=[O:22])[CH2:20][CH2:19][C:18]2=[O:23])=[O:24])[CH2:7][CH2:6][O:5]1
Reactant: O=C1OCC[C@H]1O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O[C@@H]1CCOC1=O)ON1C(=O)CCC1=O

Procedure:
(R)-alpha-Hydroxybutyrolactone (8 μL, 0.11 mmol) was dissolved in acetonitrile (0.5 mL) and treated with triethylamine (45 μL, 1.5 equivalents), and disuccinimidyl carbonate (42 mg, 1.5 equivalent) at 25° C. for 16 hrs. The solvents were evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:16]([N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCI
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)oc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
3,1-Benzoxazin-2,4-(1H)-dione (1.0 g, 6.13 mmol) was dissolved in N,N-dimethylformamide (10 ml), 60% sodium hydride (0.296 g, 7.39 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. 1-Iodopentane (0.97 ml, 7.32 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 1-pentyl-3,1-benzoxazin-2,4-(1H)-dione (0.634 g, 2.72 mmol, yield 44%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH:14]=[O:15])=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1C=O
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
Phosphorus oxychloride (2.0 mL) was added to N-methylformanilide (2.9 g), and after the mixture was stirred for 15 minutes, 1,2-dichloroethane (50 mL) and 5-chloroindole-2-carboxylic acid ethyl ester (4.0 g) were added thereto, followed by heating under reflux for 1 hour. The reaction mixture was poured into an aqueous solution (28 mL) of sodium acetate (14 g) under ice cooling, and the thus-obtained mixture was stirred for 18 hours. Insoluble matter was collected by filtration, and was sequentially washed with water and diethyl ether, to thereby give the title compound (3.56 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([NH:24][N:25]=[CH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[C:4]2[CH3:9])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: NNc1ccccc1
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=NNc2ccccc2)C(C)=C1C
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (20.0 mmol) in ethanol (60.0 mL) was added dropwise phenylhydrazine (22.0 mmol) and the mixture was stirred at room temperature for 2-hrs. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde phenylhydrazone (4.8 g, yield 76.3%).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:2]1([F:1])[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (0.472 g) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1.4 mL), stirred at ambient temperature for 4 hours, and concentrated. The product was free-based using a MEGA BE-SCX column with 1:1 CH2Cl2/methanol as eluent for the trifluoroacetic acid. The product was released from the column with 5% (7 M ammonia in methanol) in CH2Cl2 as eluent.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]1(=[O:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.C(OC(=O)C)C>OS(O)(=O)=O.CCCCCC>[N+:1]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7][C:6]2=[O:16])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1NCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
KNO3 (348 mg, 3.7414 mmol) was added to a solution of 3,4-dihydro-2H-isoquinolin-1-one (I-23b: 500 mg, 3.4013 mmol) in concentrated H2SO4 (10.2 mL) at 0° C. and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mixture was quenched in chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The concentrate was crystallized from diethyl ether to afford 400 mg of the product (61.2% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:3]([N:2]([CH3:1])[CH3:14])=[O:4])=[CH:13][CH:12]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)N(C)C)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(N,N-Dimethylaminocarbonyl)benzoic acid (100 mg, 0.54 mmol; described in: U.S. Pat. No. 3,607,918, 1971) was dissolved in thionyl chloride (5 mL). When the acid was dissolved, the excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. The crude acid chloride was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazine-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.73 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 160 mg (79%) of the title compound as white foam: [α]21D -30° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 420 (10, M+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:6][N:5]=1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20].O>CN(C)C=O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:6][N:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)c1cc(O)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
Sodium hydride (60%, oily, 1.40 g) was added to a solution of methyl 3-hydroxyisoxazole-5-carboxylate (5.01 g) in N,N-dimethylformamide (70 ml) at 0° C., which was stirred for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (7.26 g) was added to the mixture. After being stirred at 60° C. for 2 hours, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.96 g, yield 72%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 123–124° C.
Reaction SMILES: [Cl-].[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=O)=[CH:4][CH:3]=1.[NH+:13]1C=CC=C[CH:14]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[S:8]1(=[O:10])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[CH:14]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: c1cc[nH+]cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S1(=O)N=Cc2ccccc21

Procedure:
For longer side chains, the rearrangement is performed with n-BuLi (ca 1.6 M in hexane) in THF at −78° C. as above, followed by addition of a cosolvens such as DMPU and reaction with O-protected 1-bromo-alcohols or α-chloro-ω-iodoalkane (e.g. 1-bromo-n-tetrahydro-pyaranyloxyalkane) to yield the O-protected compounds 9b or the chloro compound 9c (step i). O-protected compounds 9b can be deprotected to the corresponding alkynol 9a (in MeOH at 50-60° C., in the presence of catalytic amount of pyridinium toluene-4-sulfonate). Alcohol 9a can be reacted with Huenig's base/trifluoromethane sulfonic acid anhydride at −15° C. in CH2Cl2 (in situ generation of the corresponding triflate) followed by treatment with Huenig's base and the corresponding amine NHA1A2at −15° C. to RT to give amine 5. Alternatively, mesylation of alcohol 9a with methanesulfonylchloride, pyridine and DMAP in CH2Cl2 at 0° C. to RT gives mesylate 10. Conversion of the mesylate 10 or the chloride 9c (or the in situ generated iodide) to the amine 5 can be accomplished with an excess of the corresponding amine NHA1A2 in DMA at RT or as described above (step 1).
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2ccc(OCc3ccccc3)cc2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(OCc4ccccc4)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 0.5 g of 4-(4-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.29 g of p-toluenesulfonyl chloride was stirred for 4 houtd with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with methylene chloride. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.7 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the residue was chromatographed on 100 g of Kieselgel 60 with diethyl ether as the eluent. The product-containing fractions were concentrated and, after recrystallization from ethyl acetate, yielded 0.22 g of N-[4-(4-benzyloxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: C([O:8][CH2:9][C:10](Cl)=[O:11])C1C=CC=CC=1.[C:13]1([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:26]([Si:29](Cl)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27].N1C=CN=C1>CN(C)C=O.CCCCC>[OH:11][CH2:10][C:9]([O:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8].[CH:26]([Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[O:8][CH2:9][C:10]([O:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])([CH3:28])[CH3:27]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC(=O)O[C@@H]1CCCC[C@H]1c1ccccc1)(C(C)C)C(C)C
Product: O=C(CO)O[C@@H]1CCCC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of (−)-(1R,2S)-2-phenyl-1-cyclohexyl hydroxyacetate (851 mg, 3.63 mmol) was prepared through esterification of benzyloxyacetyl chloride with (−)-(1R,2S)-2-phenyl-1-cyclohexanol followed by hydrogenolysis. Then, triisopropylsilyl chloride (840 mg, 4.36 mmol) and imidazole (618 mg, 9.08 mmol) in dimethylformamide (DMF) (1.7 mL) was added and stirred at room temperature for 12-20 hours. The mixture was poured into pentane (25 mL), and washed with water and brine. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was subjected to a purification on a short silica gel column using hexane/chloroform (3/1) as the eluant to give pure (−)-(1R,2S)-2-phenyl-1-cyclohexyl triisopropylsilyloxyacetate (1.35 g, 95% yield) as a colorless oil: [α]D20−17.1° C. 3.15, CHCl3); IR (neat) 1759, 1730 (nCO) cm−1; 1H NMR (CDCl3) δ0.93-0.99 (m, 21H), 1.30-1.62 (m, 4H), 1.72-2.0 (m, 3H), 2.10-2.19 (m, 1H), 2.66 (dt, J=11.5, 4.0 Hz, 1H), 3.90 (d, J=16.6 Hz, 1H), 4.07 (d, J=16.6 Hz, 1H), 5.07 (dt, J=10.6, 4.0 Hz, 1H), 7.16-7.30 (m, 5H). Anal. Calcd for C23H38O3Si: C, 70.72; H, 9.81. Found: C, 70.79; H, 9.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][C:13](=O)[C@@:12]2(O)[C:11]2[C:24]([O:31][CH2:32][CH3:33])=[CH:25]C(OCC)=C[C:10]=2[O:9]3)=[CH:4][CH:3]=1.CO[C:36](=[O:38])[O-:37].CO[Mg+].[C:42]([O:45][CH2:46][CH3:47])(=[O:44])[CH3:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]23[C@H:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@H:14]([C:36]([OH:37])=[O:38])[CH2:13][C@@H:12]2[C:43]2[C:42]([O:45][CH2:46][CH3:47])([OH:44])[CH2:25][C:24]([O:31][CH2:32][CH3:33])=[CH:11][C:10]=2[O:9]3)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(Cl)cc3)[C@H](c3ccccc3)CC(=O)[C@@]21O
Reactant: COC(=O)[O-]
Agent: CO[Mg+]
Solvent: CN(C)C=O
Product: CCOC1=CC2=C([C@H]3C[C@@H](C(=O)O)[C@@H](c4ccccc4)[C@]3(c3ccc(Cl)cc3)O2)C(O)(OCC)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 500 mg (1.08 mmol) of (3S*,3aR*,8bR*)-3a-(4-chlorophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1-one (Example 15A) and 1.08 ml (2.15 mmol) of a 2 M solution of methoxymagnesium methyl carbonate in DMF is heated with stirring at 100° C. in a closed vessel for 16 h. The resulting suspension is then poured into a mixture of ice-cold 5 N hydrochloric acid and ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered with suction and concentrated. 531 mg of crude product are employed directly in the next stage without further characterization.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]Br>C(O)(=O)C>[BrH:18].[Br:18][CH:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=1)[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:17]
Reactant: BrBr
Reactant: Cc1cccc(C(=O)Cc2ccnc(C)c2)c1
Solvent: CC(=O)O
Product: Br
Product: Cc1cccc(C(=O)C(Br)c2ccnc(C)c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)ethanone (150 g) was dissolved in acetic acid (450 mL), bromine (34.3 mL) was added to this, and the mixture was stirred for 3 hours at 70° C. The reaction solution was cooled by ice water, and the deposited crystal was filtrated off. The crystal was washed with ethyl acetate to obtain a title compound (168 g, yield 66%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[B]([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[O:38]1CCCC1>>[C:11]1([CH2:10][O:9][CH2:8][C@H:2]2[CH:1]=[CH:5][CH2:4][C@@H:3]2[OH:38])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: C1=CCC=C1
Reactant: ClCOCc1ccccc1
Agent: C[C@H]1[C@H]([B][C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Agent: [Na]
Product: O[C@H]1CC=C[C@@H]1COCc1ccccc1
Reaction time: 1.5 h

Procedure:
Cyclopentadiene (39 g., 0.59 mol.) at -20° was added over 35 minutes to a stirred mixture of 31.0 g. of 40% sodium sand in mineral oil (0.54 g. atm.) in 264 ml. of dry tetrahydrofuran at -15°. The mixture was stirred at -10° for 1.5 hours, warmed to 0°, and cannulated to an addition funnel at 0°. The mixture was then added over 30 minutes to a stirred solution of benzyl chloromethyl ether (100 g., 0.64 mol.) in 200 ml. of tetrahydrofuran at -50° to -55°. The mixture was stirred at -55° to -40° for 1 hour and then cooled to -65°. To this was added, by cannula over 5 minutes, the crystalline slurry of (-)-diisopinocampheylborane from step A, which had been cooled to -60°. The reaction was stirred at -60° for 1 hour, warmed to -10° and stored at -20° overnight. The reaction mixture was stirred for 1 hour at 5° and concentrated in vacuo to one half its original volume. Ether (600 ml.) was added, the stirred mixture was cooled to 0°, and 188 ml. of 3N sodium hydroxide was added dropwise keeping the temperature below 5°. Cold 30% hydrogen peroxide (188 ml.) was added dropwise over 1 hour keeping the temperature below 12°, and then the mixture was stirred for 1 hour longer while maintaining the temperature below 12°. The layers were separated, and the aqueous layer was washed with ether. The ether extracts were combined, dried(sodium sulfate), and concentrated in vacuo to a residue (337 g.). Chromatography of this residue on a column of Merck silica gel [2300 g., packed in petroleum ether-ether (2:1)] using petroleum ether-ether (2:1) and then (1:1)]gave fraction A (17.56 g. of impure desired product), fraction B (11.03 g. of pure desired product), and fraction C (3.52 g. of impure desired product). Similar chromatography of fraction A on 800 g. of silica gel, and fraction C on 140 g. of silica gel, gave 8.08 g. and 2.33 g., respectively, of additional pure desired product for a total yield of 21.44 g. of title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(C)[CH:19]=CC=C(S(O)(=O)=O)[CH:15]=1.C(O)C=C>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH2:19][CH:14]=[CH2:15])=[O:6]
Reactant: Cc1cccc(S(=O)(=O)O)c1
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C=CCO
Product: C=CCOC(=O)c1cc(F)cc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
3-Fluoro-5-nitrobenzoic acid (3 g, 16.2 mM), m-toluenesulfonic acid (1.54 g, 8.1 mM), and allyl alcohol (50 ml) were heated to reflux, passing the distillate through 3å molecular sieves, for 16 hours. After cooling, the mixture was neutralised with triethylamine, and solvent removed. The residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, aqueous NaHCO3, and brine, and dried over MgSO4. Crude product was purified by chromatography on silica, using a gradient elution from dichloromethane to ethyl acetate/dichloromethane (3:1), to give allyl 3-fluoro-5-nitrobenzoate. Nmr (CDCl3): δ4.89 (dt, 2H); 5.33-5.49 (m, 2H); 5.95-6.15 (m, 1H); 8.11 (m, 2H); 8.70 (t, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[CH3:14][O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH2:4][S:5][CH3:6])[NH2:1]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CSCC[C@H](N)C(=O)O
Product: COC(=O)[C@@H](N)CCSC
Product: Cl
Yield: 98 %

Procedure:
L-Methionine (0.5 g, 1 equivalent) was suspended in methanol (30 ml C=0.1M) in a 100 ml flask equipped with a magnetic stirrer and placed under nitrogen. Thionyl chloride (0.5 ml, 2 equivalents) was added to the solution dropwise at 0° C. then heated under reflux for 16 hours. The reaction mixture was then evaporated to yield a pale yellow solid. The solid was triturated with hot diethyl ether and the solution discarded to leave the title compound 2′ a white solid which was further dried under vacuum. (0.65561 g, 98% yield).