Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH:15]([OH:21])[CH2:16][C:17](OC)=[O:18]>C(O)C>[CH2:16]1[C:17](=[O:18])[N:2]([CH2:3][C:4]([NH2:6])=[O:5])[CH2:14][CH:15]1[OH:21]
Reactant: COC(=O)CC(O)CCl
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CN1CC(O)CC1=O
Yield: 75 %

Procedure:
In 10 ml of ethanol, 1.11 g (10 m.moles) of glycinamide hydrochloride, 1.06 g (10 m.moles) of sodium carbonate, and 1.53 g (10 m.moles) of methyl 4-chloro-3-hydroxybutyrate were stirred and refluxed simultaneously for 20 hours. After completion of the reaction, the warm reaction mixture was filtered to expel inorganic salts. The filtrate was analyzed by gas chromatography (Fluoxylate-K 1% Uniport HP 100/120, column length 0.5 m and column temperature 220° C., RT 2.8 min) (hereinafter referred to as "GC" for short). Consequently, the reaction was found to have produced oxiracetam in a yield of 75%. The filtrate was concentrated, dissolved in a small amount of water, and poured on a bed of 40 ml of Amberlite IR-120 (--SO3H form) (tradename: Rohm & Haas Co.). The adsorbate was eluted with water. The eluate was fractionated, with the first and second fractions discarded and the third and following fractions were collected. The collected fractions were concentrated. The concentrate was dissolved in methanol and the solution was ice cooled ad crystallized with crystals of oxiracetam used as mother crystals. The produced crystals were collected and vaccum dried, to afford 0.55 g (yield of isolation 35%) of oxiracetam, having a melting point of 155° to 160° C. (as compared with 161° to 163° C. reported in the specification of Japanese Patent Publication Sho 58-22,034/1983).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:25])=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([Cl:25])=[O:16])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 14.5 °C
Reaction time: 5.5 h

Procedure:
A reactor was charged with 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175 kg THF. The reaction mixture was adjusted to 12 to 17° C. and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12 to 17° C. for 3 to 8 hours. This solution was used in the next step without further processing.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:16][C:17]1[NH:31][C:20]2=[C:21]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CO>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([C:18]1[C:19]2[C:20](=[C:21]([NH:25][C:26]([CH:28]3[CH2:29][CH2:30]3)=[O:27])[N:22]=[CH:23][CH:24]=2)[NH:31][C:17]=1[CH3:16])=[O:6]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1[nH]c2c(NC(=O)C3CC3)nccc2c1C(=O)c1c(F)cccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of 2,6-difluorobenzoic acid (176 mg, 1.15 mmol) in dry dichloromethane, was added thionyl chloride (5 mL) and heated at 100° C. for about 3 hours. The reaction mass was concentrated under vacuum. The residual mass was dissolved in dry dichloromethane (3 mL) and added to a well stirred solution of N-(2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (120 mg, 0.55 mmol) in aluminium chloride (743 mg, 5.57 mmol) drop wise. The resulting reaction mixture was stirred overnight at room temperature. After completion, methanol (10 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was neutralized using aq. sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-[3-(2,6-difluorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (80 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25](O)[C:26]([OH:28])=[O:27].C(N(S(F)(F)[F:36])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25]([F:36])[C:26]([OH:28])=[O:27]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Solvent: ClCCl
Product: O=C(O)C(F)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 0.75 h
Yield: 47 %

Procedure:
To a stirred solution of Example 1 Part B compound (461 mg, 1.00 mmol) in CH2Cl2 (10 mL) under argon at 0° C. was added a solution of diethylaminosulfur trifluoride [DAST] (265 μL, 2.0 mmol) in CH2Cl2 (5 mL) over 20 min. The reaction mixture was stirred for an additional 45 min, then quenched with saturated sodium bicarbonate solution and extracted twice with CH2Cl2. The extracts were combined, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a light yellow oil, 218 mg (47% yield). LC/MS gave the correct molecular ion [(M+H)+=463] for the desired compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:13][CH2:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc(-c2ccccc2)on1
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution of ethyl 5-phenylisoxazole-3-carboxylate (5.90 g, 27 mmol) in ether (30 ml) was added dropwise to a suspension of lithium aluminium hydride in ether (20 ml). When addition was complete, the mixture was heated at reflux for 1 h then a further quantity of lithium aluminium hydride (0.25 g) was added and reflux continued for 0.5 h. The reaction was cautiously quenched with 2% sulphuric acid and the ether layer separated, dried (MgSO4) and the solvent removed under reduced pressure to yield 3-hydroxymethyl-5-phenylisoxazole (2.10 g, 12 mmol, 44%); δH (CDCl3) 3.60 (1H, br, OH), 4.75 (2H, s, CH2), 6.35 (1H, s, CH), 7.2-7.8 (5H, m, C6H5).
Reaction SMILES: C([O:4][C@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=O)[CH3:26])[O:19]C(=O)C)[O:14]C(=O)C)[O:9]C(=O)C)[CH:6]=[O:7])(=O)C.[C:28]1([O:38][CH3:39])[C:29](=[CH:31][CH:32]=[C:33]([CH:37]=1)[CH2:34]C=C)O>C1(C)C=CC=CC=1>[CH3:39][O:38][C:28]1[CH:37]=[C:33]([CH2:32][CH:31]=[CH2:29])[CH:34]=[CH:26][C:25]=1[O:24][C@@H:23]1[O:4][C@H:5]([CH2:6][OH:7])[C@@H:8]([OH:9])[C@H:13]([OH:14])[C@H:18]1[OH:19]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(OC)c1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
8.0 g of glucose pentaacetate were dissolved in 40 ml of absolute toluene, to which 3.28 g of eugenol and 2.0 g of molecular sieves 4A were then added. The mixture was stirred for about one hour. Next, 1 ml of a boron trifluoridediethyl ether complex was added to the mixture. Stirring was further continued for a day and night. After the end of the reaction, molecular sieves 4A was filtered off. The filtrate was washed twice with each 50 ml of a 0.5N aqueous solution of potassium hydroxide to remove unreacted eugenol. After washed further with water and dried with sodium sulfate, it was dried under reduced pressure to obtain 2.4 g of the intended product. According to 13C-NMR of the crystals obtained, a signal of C-1 position was detected at 102.9 ppm. It was, therefore, confirmed that the product had a β-bonding.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:15]([S:23]([CH3:26])(=[O:25])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1C=CC=C[CH:3]=1.C1CCCCC=1.C([OH:35])C>[Pd]>[CH3:26][S:23]([N:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C@@H:2]2[CH2:3][O:35]2)[CH:10]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N(c1cccc(OCc2ccccc2)c1)S(C)(=O)=O
Reactant: CCO
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)N(c1cccc(OC[C@@H]2CO2)c1)S(C)(=O)=O

Procedure:
tert-Butyl 3-(benzyloxy)phenyl(methylsulfonyl)carbamate (2.6 g, 6.88 mmol) was dissolved in ethanol (25 mL), 10% palladium on carbon (0.75 g) and cyclohexene (1.5 mL) were added. The solution was heated to reflux for 3 hours. The solution was cooled and filtered through Celite. The solvent was removed in vacuo to yield crude title compound (1.93 g, 6.7 mmol).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[NH:5][CH:6]=1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[NH:5][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(Br)c[nH]2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1Br
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-2-(2,6-dichloro-4-trifluoromethyl-phenyl)-imidazole (0.9 g, 0.025 mol), nitric acid (70% w/w, 1 ml) and sulphuric acid (98%w/w, 1 ml) was stirred and heated at 70° C. for 7.5 hours. After cooling it was added to a mixture of ice and water (50 ml). The precipitated solid was filtered off and purified by mplc on silica eluted with a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:5) to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro-imidazole (0.2 g), m.p. 292°-293° C., as an off-white solid.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:19][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH:15]([OH:16])[CH3:19])[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: C[Al](C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(C=O)co1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-4-carbaldehyde (223 mg, 0.92 mmol) in CH2Cl2 (8.0 mL) was treated at 0° C. with trimethylaluminum (2.50 mL of a 2M solution in toluene, 5.00 mmol). The reaction mixture was then stirred at 0° C. for 45 min. Sat. aq. NH4Cl was then added and the aq. layer was extracted twice with CH2Cl2 and twice with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a colorless oil. TLC:rf (1:1 hept-EA)=0.32. LC-MS-conditions 02: tR=0.97 min, [M+H]+=258.30.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][CH:11]1Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Hg](C#N)[C:36]#[N:37]>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[C:36]#[N:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1OC(Br)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: N#C[Hg]C#N
Solvent: ClCCl
Product: N#C[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 524.3 %

Procedure:
A suspension of 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide (I) (1.98 mol) and dry Hg(CN)2 (750 g; 2.97 mol) (mercury (II) cyanide was dried in vacuo at 140° for 12 hours) in dry CH2Cl2 (10.0 L), was stirred for 16 h at room temperature protected from moisture. The insolubles were collected and discarded. The filtrate was washed in succession with 5% aqueous KI (2×6.0 L) and water (2×6.0 L), dried over Na2SO4 (1.0 kg) and charcoal (35 g), then concentrated in vacuo to an oil. This material was diluted with EtOH (2.0 L) then concentrated in vacuo to an oil. The oil was slowly added to petroleum ether (bp, 63°-75°)-EtOH (21.0 L; 7.0 L) with vigorous stirring. The oil slowly solidified, and after 3 h of stirring, the resulting solid was collected and washed with petroleum ether (bp, 63°-75°) (1.0 L). This material was washed by resuspension (17 h) in EtOH (1.50 L). The off-white colored solid was collected, washed with petroleum ether (bp, 63°-75°) (2×500 ml) then dried to constant weight in vacuo to give 598 g (64°) of product; mp, 77.5°-79°. Additional reactions were carried out to give a total of 4894 g of product suitable for further transformation.
Reaction SMILES: [C:1]([NH:4][C:5]#[N:6])(=[O:3])[CH3:2].[Na].[CH:8](Br)([CH3:10])[CH3:9].CC(C)=O>CN(C)C=O>[CH:8]([N:4]([C:5]#[N:6])[C:1](=[O:3])[CH3:2])([CH3:10])[CH3:9]
Reactant: CC(=O)NC#N
Reactant: CC(C)Br
Agent: [Na]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(C#N)C(C)C
Reaction time: 3 h

Procedure:
31.8 g (0.30 mol) of sodium acetylcyanamide are dissolved in 75 ml of dimethylformamide at 100° C., and 36.9 g (0.30 mol) of isopropyl bromide are added dropwise in the course of 11/2 hours. The mixture is allowed to afterreact at 100° C. for 3 hours, and then 200 ml of acetone are added and the NaBr which has precipitated is filtered off with suction (28.2 g=0.27 mol). The acetone is then removed on a rotary evaporator and the residue is distilled under a waterpump vacuum in order to isolate all the distillable constituents. Fractional distillation of this distillate over a spinning bank column give 14.3 g (37.8% of theory) of a product of boiling point 107° C./90 mbar which, according to gas chromatography, is a single product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]1[O:16][CH2:15][CH2:14][O:13]1>C(OCC)(=O)C.[Pt]=O>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH:12]2[O:13][CH2:14][CH2:15][O:16]2)[C:4]([CH3:11])=[CH:5][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C1OCCO1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)c(C)c1C1OCCO1
Yield: 100.5 %

Procedure:
A solution of 2.7 g of 2-(2,6-dimethyl-3-nitrophenyl)-1,3-dioxolane in 30 ml of ethyl acetate was hydrogenated in the presence of 0.2 g of platinum oxide for 45 minutes. The catalyst was filtered off and the solution was concentrated to a crystalline residue. Recrystallization from hexane yielded 2.35 g of 2-(3-amino-2,6-dimethylphenyl)-1,3-dioxolane, m.p. 100-103° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[CH3:32][CH:33]([CH3:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36]>>[CH2:34]([S:35]([N:29]1[CH2:28][CH:27]=[C:26]([C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([O:16][CH:13]4[CH2:14][CH2:15][N:10]([C:7]5[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=5)[CH2:11][CH2:12]4)[S:18][C:19]=3[CH:25]=2)[CH2:31][CH2:30]1)(=[O:37])=[O:36])[CH:33]([CH3:39])[CH3:32]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Reactant: CC(C)CS(=O)(=O)Cl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CC(C)C)CC5)cc4s3)CC2)nc1

Procedure:
Example 11 was prepared from Compound 1E and 2-methylpropane-1-sulfonyl chloride in a similar manner to the procedure described in Example 1. LCMS (M+H)+=556.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[S:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CO.C(OCC)(=O)C.CCCCCC>[CH3:1][N:2]([CH3:3])[C:5]1[S:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1nc(CCl)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of dimethylamine in ethanol (0.5 ml×33%) was added to a stirred suspension of 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (540 mg)(J. Goerdeler, Chem. Ber. 1957, 90, p 182 or ICI EP 0006679) and potassium carbonate (1.0 g) in methanol. The solution was stirred at room temperature for three hours, and then the solvent removed under reduced pressure. The residue was taken up in ethyl acetate (40 ml), washed with water (20 ml) and brine (20 ml). The organic layers were dried (MgSO4), filtered and the solvent removed to afford a yellow gum. Flash chromatography using 10% ethyl acetate in hexane as eluent, afforded the product as a yellow oil (330 mg). 1H NMR (360 MHz, CDCl3) d 3.15 (6H, s, N(CH3)2), 4.51 (2H, s, Cl--CH2); MS (CI+) m/z 178 ((M+1)+, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH:19]([NH:22][CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:22]([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])=[O:7]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)c1cc(F)cc(C(F)(F)F)c1)C(C)C
Temperature: 85 °C
Yield: 85 %

Procedure:
To a suspension of 15.9 mmol 3-Fluoro-5-(Trifluoromethyl)benzoic acid in 20 ml toluene containing 2 drops of DMF was added 79.7 mmol thionylchloride at 0° C. The mixture was heated at 85° C. for 5 hours. The solvent was carefully removed in vacuo. The colorless liquid was dissolved in 25 ml dichloromethane and cooled to 0° C. 63.8 mmol diisopropylamine was added dropwise. The mixture was allowed to warm to RT. After 1 hour the solvent was removed in vacuo. The residue was taken in ethyl acetate and washed twice with water. The washings were extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light yellow solid (85% yield). MS (m/e): 291.9 (M+, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
Reflux 2-amino-5-iodo-benzoic acid (Aldrich; 10 g, 38 mmol) in formamide (30 mL) at 120° C. for 18 h. Upon cooling to room temperature, the product is crystallized from the solvent. The product is collected via filtration and the resulting crystals are washed with ether providing the desired 9.2 g (89%) of the titled compound as a pale solid. MS ES+ m/e 273.0 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:9]#[N:10].O.[OH-].[Na+]>C(OCC)C>[CH3:11][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH2:9][NH2:10]
Reactant: CC(C)(C#N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of lithium aluminium hydride (4.85 g, 0.128 mol) in anhydrous diethyl ether (245 ml) at ambient temperature under argon was added a solution of α,α-dimethylphenylacetonitrile (12.4 g, 0.085 mol) in anhydrous diethyl ether (105 ml) dropwise over 0.5 hour. The resultant was heated at reflux for 3 hours, cooled to ambient temperature and treated with water (4.6 ml), 15% aqueous sodium hydroxide (4.6 ml) and water (13.8 ml) dropwise sequentially. The mixture was stirred for 1.5 hours, filtered and the filtrate dried (Na2SO4) and treated with 1N hydrogen chloride in ether (100 ml). The precipitated solid was filtered and dried to afford the title compound as the hydrochloride salt (9.4 g, 52%).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1.[CH3:19]O>>[CH3:19][O:2][CH:3]1[O:18][C:6]2=[C:7]([O:16][CH3:17])[C:8]3[O:13][C:12](=[O:14])[CH:11]=[CH:10][C:9]=3[CH:15]=[C:5]2[CH2:4]1
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(O)O2
Reactant: CO
Agent: Cl
Product: COc1c2c(cc3ccc(=O)oc13)CC(OC)O2
Reaction time: 1 h

Procedure:
Dry methanol was saturated at 0° with gaseous hydrogen chloride. A sample of 0.576 g. (2.46 mmoles) of 2-hydroxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one was dissolved in the resultant solution, and the dark reaction was allowed to proceed at room temperature for one hour. The solvent was evaporated and the residue was taken up in ethyl acetate/benzene. 1:4 and filtered through 50 g. silica, eluting with the same solvent system. Fractions containing the product, which is first eluted, were combined and evaporated to give pure 2,9-dimethoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one as a white solid. Recrystallization from methanol afforded an analytical sample of this product, mp 131°-132°.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].[CH3:25][CH:26]([N-]C(C)C)[CH3:27].C(=O)=O.CC(C)=O.C(Br)C=C.Cl>C1COCC1.CCOC(C)=O>[CH2:27]([CH:16]1[C:15](=[O:18])[C:14]([CH3:19])=[C:13]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][C:7]3[C:12]2=[CH:11][CH:10]=[C:9]([O:20][CH2:21][O:22][CH3:23])[CH:8]=3)[CH2:17]1)[CH:26]=[CH2:25]
Reactant: CC(C)[N-]C(C)C
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Agent: Cl
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1CC2(CCCC)Cc3cc(OCOC)ccc3C2=C(C)C1=O
Temperature: 25 °C

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (230 mg, 0.73 mmol) in anhydrous THF (3.8 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated with freshly prepared 0.4M LDA in THF (2.2 mL, 0.88 mmol). The resulting solution was stirred at 0° C. for 30 minutes, then cooled to −78° C. (dry ice-acetone bath) and treated with allyl bromide (0.316 mL, 3.65 mmol). The reaction mixture was allowed to gradually warm to room temperature then stirred at room temperature overnight. The mixture was diluted with EtOAc (60 mL) and shaken with 1N HCl (35 mL). The aqueous phase was extracted with EtOAc (20 mL) and the combined organics were washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to a yellow oil. The crude product was purified by preparative layer chromatography on three 0.1×20×20 silica gel GF plates using 4:1 hexanes-EtOAc as developing solvent. The UV visible band at Rf 0.44-0.56 was eluted with EtOAc and the eluant evaporated under vacuum to afford (2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (193 mg) as an oil.