1-bromo-4-(chloromethyl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4-bromobenzyl chloride (4.39 g, 20 mmol) in 40 mL dichloromethane at 0° C., propargylamine (1.10 g, 20 mmol) was added, followed by triethylamine (4.05 g, 40 mmol). The mixture was stirred at room temperature for 40 minutes. 150 mL ethyl acetate was added and filtered. The filtrate was washed with 2×40 mL water and 40 mL brine, dried and concentrated to give 4-Bromo-N-(2-propynyl) benzamide. 4-Bromo-N-(2-propynyl) benzamide was added into ice cooled 47 mL concentrated sulfuric acid. The reaction was stirred at 5°-10° C. for 3 hours and at room temperature overnight. The mixture was poured into 500 mL ice water, neutralized with sodium carbonate to pH 8 and extracted with 3×250 mL ethyl acetate. The combined organic extracts were washed with 200 mL water and 100 mL brine, dried and concentrated to afford compound A (4.5 g, 95%) as a light yellow solid. filtered The filtrate was washed with 2×40 mL water and 40 mL brine dried concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of (+)-2-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (9.2 g) in toluene (180 ml) was added sodium hydride (60% in oil, 2.0 g). After stirring at 50° C. for 30 min, a solution of 4-bromobenzyl chloride (9.7 g) in toluene (45 ml) was added to the reaction mixture, which was heated under reflux for one hr. The reaction mixture was diluted with water and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was dissolved in solvent mixture of ethyl acetate/hexane (1:4) and the precipitate was filtered off. The filtrate was concentrated and the residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:50 to 1:4) and converted into its hydrochloride. The crystals were washed with diisopropyl ether to obtain the titled compound (17.0 g). was heated under reflux for one hr concentrated The residue was diluted with water extracted with ethyl acetate The organic layer was washed with saturated aqueous sodium chloride dried concentrated The residue was dissolved in solvent mixture of ethyl acetate/hexane (1:4) the precipitate was filtered off The filtrate was concentrated the residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:50 to 1:4) The crystals were washed with diisopropyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesis of 4-fluoro-4'-phenylethynylbenzophenone In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser was placed fluorobenzene (117 g, 1.2 mol), and 4-bromobenzyl chloride (39.8 g, 0.181 mol). The mixture was cooled to 0° C. an anhydrous aluminum chloride (27 g, 0.20 mol) was added. The mixture was stirred at 23° C. for 16 hours. The resulting slurry was poured into 2 L of acidic (HCl) water. The organics were extracted with methylene chloride, and dried over magnesium sulfate. The slurry was filtered and the methylene chloride was removed under reduced pressure. Recrystallization from ethanol afforded 43.3 g (86%) of 4-bromo-4'-fluorobenzophenone as white crystals: mp 106°-107° C. (Lit 107°-108° C.). equipped with a nitrogen inlet reflux condenser was added The mixture was stirred at 23° C. for 16 hours The organics were extracted with methylene chloride dried over magnesium sulfate The slurry was filtered the methylene chloride was removed under reduced pressure Recrystallization from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 4-hydroxybenzyl-pyrrolidine (177 mg), 4-bromo-benzylchloride (205 mg), and t-Bu3ONa (192 mg) in ethanol (10 mL) was heated at 80° C. for overnight. Concentration and preparative TLC provided the title compound (200 mg). 1H NMR (400 MHz, CDCI3)δ7.50 (d, J=6.5 Hz, 2 H), 7.32 (d, J=6.5 Hz, 2 H), 7.25 (d, J=6.5 Hz, 2 H), 6.90 (d, J=6.5 Hz, 2 H), 2.84 (s, 2 H), 2.50 (m, 4 H), 1.42 (m, 4 H). Concentration and preparative TLC

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 4-hydroxybenzyl-pyrrolidine (177 mg), 4-bromo-benzylchloride (205 mg), and t-Bu3ONa (192 mg) in ethanol (10 mL) was heated at 80° C. for overnight. Concentration and preparative TLC provided the title compound (200 mg). 1H NMR (400 MHz, CDCI3)δ7.50 (d, J=6.5 Hz, 2 H), 7.32 (d, J=6.5 Hz, 2 H), 7.25 (d, J=6.5 Hz, 2 H), 6.90 (d, J=6.5 Hz, 2 H), 2.84 (s, 2 H), 2.50 (m, 4 H), 1.42 (m, 4 H). Concentration and preparative TLC

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of (+)-2-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (9.2 g) in toluene (180 ml) was added sodium hydride (60% in oil, 2.0 g). After stirring at 50° C. for 30 min, a solution of 4-bromobenzyl chloride (9.7 g) in toluene (45 ml) was added to the reaction mixture, which was heated under reflux for one hr. The reaction mixture was diluted with water and concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was dissolved in solvent mixture of ethyl acetate/hexane (1:4) and the precipitate was filtered off. The filtrate was concentrated and the residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:50 to 1:4) and converted into its hydrochloride. The crystals were washed with diisopropyl ether to obtain the titled compound (17.0 g). was heated under reflux for one hr concentrated The residue was diluted with water extracted with ethyl acetate The organic layer was washed with saturated aqueous sodium chloride dried concentrated The residue was dissolved in solvent mixture of ethyl acetate/hexane (1:4) the precipitate was filtered off The filtrate was concentrated the residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:50 to 1:4) The crystals were washed with diisopropyl ether