2,3-dibromobutane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium hydride (600 mg, 15 mmol) in anhydrous THF (5 mL) at 0° C., was added dropwise 2-(4-(trifluoromethoxy)phenyl)acetonitrile (1006 mg, 5 mmol) and then the reaction mixture was stirred for 5 mins, followed by dibromobutane (1075 mg, 5 mmol) dropwise. The reaction mixture was heated to reflux for 16 h, then cooled to 0° C., quenched with MeOH (1 mL), diluted with EtOAC (50 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give 1-(4-(trifluoromethoxy)phenyl)cyclopentanecarbonitrile as a yellow oil (905 mg, 71%) (1H NMR (400 MHz, CDCl3) 7.50 (dd, J=2.1, 6.7 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 2.53-2.49 (m, 2H), 2.10-1.97 (m, 6H) The reaction mixture was heated to reflux for 16 h quenched with MeOH (1 mL) diluted with EtOAC (50 mL) washed with brine (3×50 mL) The organic layer was dried over sodium sulfate concentrated in vacuo

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

Procedure: 5-Indanol (1 g, 7.45 mmol) in NaOH(aq) (5.22 mL, 20.88 mmol, 4 M soln.) was treated with dibromobutane (3.38 mL, 28.3 mmol) and t-butylammoniumhydrogensulfate (catalytic). The solution was placed in a Robbins™ oven for 14 hours at 99° C. Upon cooling, the pH was adjusted to ˜8 with 4 N NaOH. CH2Cl2 was then added and the solution washed with H2O (×2) and brine. The organic layer was dried over MgSO4 and concentrated to an oil. The oil was then dissolved in 4:1 hexane/EtOAc and passed through a plug of silica gel which was then washed with 4:1 hexane/EtOAc. The filtrate was concentrated to afford 4-bromo-1-indan-5-yloxybutane. Upon cooling the solution washed with H2O (×2) and brine The organic layer was dried over MgSO4 concentrated to an oil The oil was then dissolved in 4:1 hexane/EtOAc was then washed with 4:1 hexane/EtOAc The filtrate was concentrated

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

Procedure: 5-Indanol (1 g, 7.45 mmol) in NaOH(aq) (5.22 mL, 20.88 mmol, 4 M soln.) was treated with dibromobutane (3.38 mL, 28.3 mmol) and t-butylammoniumhydrogensulfate (catalytic). The solution was placed in a Robbins™ oven for 14 hours at 99° C. Upon cooling, the pH was adjusted to ˜8 with 4 N NaOH. CH2Cl2 was then added and the solution washed with H2O (×2) and brine. The organic layer was dried over MgSO4 and concentrated to an oil. The oil was then dissolved in 4:1 hexane/EtOAc and passed through a plug of silica gel which was then washed with 4:1 hexane/EtOAc. The filtrate was concentrated to afford 4-bromo-1-indan-5-yloxybutane. Upon cooling the solution washed with H2O (×2) and brine The organic layer was dried over MgSO4 concentrated to an oil The oil was then dissolved in 4:1 hexane/EtOAc was then washed with 4:1 hexane/EtOAc The filtrate was concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 200 ml of dimethylformamide was dissolved 10.0 g (54.9 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 15.2 g (110 mmol) of potassium carbonate and 10.1 ml (82.3 mmol) of 2,3-dibromobutane were added to the solution, followed by stirring at 80° C. for 3 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 1.57 g (12%) of Compound 41. The compound was recrystallized from ethyl acetate/hexane for purification. were added to the solution After evaporation of the solvent to partition between chloroform and water the chloroform layer was concentrated to dryness under reduced pressure eluted with chloroform

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 200 ml of dimethylformamide was dissolved 10.0 g (54.9 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 15.2 g (110 mmol) of potassium carbonate and 10.1 ml (82.3 mmol) of 2,3-dibromobutane were added to the solution, followed by stirring at 80° C. for 3 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 1.57 g (12%) of Compound 41. The compound was recrystallized from ethyl acetate/hexane for purification. were added to the solution After evaporation of the solvent to partition between chloroform and water the chloroform layer was concentrated to dryness under reduced pressure eluted with chloroform

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.802 g (33 mmol) of magnesium chips were put into 5 ml of tetrahydrofuran. Then 2.37 g (11 mmol) of dibromobutane in 30 ml tetrahydrofuran was added in 1 hour. The reaction mixture was refluxed for 2 hours, then 2.55 g (22 mmol) of tetramethylethylenediamine was added and refluxed for another hour. To the suspension, cooled to 0° C., was then added 3.52 g (10 mmol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-thieno[3,4-d]imidazol-2,4(3H,3aH)-dione in 50 ml of tetrahydrofuran. Then the reaction mixture was stirred for 2 hours at room temperature and then cooled to °0 C. Carbon dioxide gas was introduced in 1 hour at 0° C. and 1 hour at room temperature. The reaction mixture was poured onto a mixture of 85 g of ice and 11.5 ml of conc. hydrochloric acid and then extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried with magnesium sulfate and finally concentrated. 50 mg of p-toluenesulfonic acid was added to the residue, which was then taken up in 170 ml of toluene. The reaction water was refluxed and distilled off by means of a water separator. The remaining toluene solution was concentrated and the resulting oil was chromotographed over silica gel with acetic acid ethyl ester/toluene. 1.22 g (28 percent) of the title product was obtained as a light yellowish oil. The reaction mixture was refluxed for 2 hours refluxed for another hour cooled to °0 C extracted with ethyl acetate The combined organic phases were washed with water and saturated sodium chloride solution dried with magnesium sulfate finally concentrated 50 mg of p-toluenesulfonic acid was added to the residue, which The reaction water was refluxed distilled off by means of a water separator The remaining toluene solution was concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-tert-butyloxycarbonyl-4-[(4-aminophenyloxy)methyl]piperidine (0.75 g) obtained in Example 13 were added dimethylformamide (10 ml), potassium carbonate (1.4 g) and dibromobutane (0.54 g) and the mixture was heated to 70° C. and stirred overnight. To the reaction solution was added water which was extracted with ethyl acetate (50 ml×3). The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[(4-pyrrolidinophenyloxy)methyl]piperidine (0.55 g) as colorless crystals, m.p. 141°-145° C. was extracted with ethyl acetate (50 ml×3) The combined extract was dried over sodium sulfate concentrated under reduced pressure The residue thus obtained was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1 (v/v))

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

Procedure: 1-[1,1-Dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 0.50 g), 1,4-dibromobutane (0.21 ml) and potassium carbonate (0.30 g) are refluxed in 4 ml of acetonitrile for 1 week. After 1 week, additional dibromobutane (0.21 ml) is added and refluxing is continued for 3 days. The reaction mixture is poured into water, extracted with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography eluting with ethyl acetate/hexane (10/90) to ethyl acetate/hexane (25/75). The appropriate fractions are pooled and concentrated to give the title compound, NMR (300 MHz, CDCl3) 7.78, 6.98, 6.78, 3.52, 3.20-3.10, 1.87 and 1.44δ. After 1 week refluxing extracted with methylene chloride dried over anhydrous sodium sulfate concentrated under reduced pressure The concentrate is purified by flash column chromatography eluting with ethyl acetate/hexane (10/90) to ethyl acetate/hexane (25/75) concentrated

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

Procedure: 5-Indanol (1 g, 7.45 mmol) in NaOH(aq) (5.22 mL, 20.88 mmol, 4 M soln.) was treated with dibromobutane (3.38 mL, 28.3 mmol) and t-butylammoniumhydrogensulfate (catalytic). The solution was placed in a Robbins™ oven for 14 hours at 99° C. Upon cooling, the pH was adjusted to ˜8 with 4 N NaOH. CH2Cl2 was then added and the solution washed with H2O (×2) and brine. The organic layer was dried over MgSO4 and concentrated to an oil. The oil was then dissolved in 4:1 hexane/EtOAc and passed through a plug of silica gel which was then washed with 4:1 hexane/EtOAc. The filtrate was concentrated to afford 4-bromo-1-indan-5-yloxybutane. Upon cooling the solution washed with H2O (×2) and brine The organic layer was dried over MgSO4 concentrated to an oil The oil was then dissolved in 4:1 hexane/EtOAc was then washed with 4:1 hexane/EtOAc The filtrate was concentrated

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

Procedure: To demonstrate the utility of the process and the EWOD chips 98 for chemical reactions other than radiochemistry, a simple chemical synthesis (not involving radioisotope) in a volatile organic solvent was performed using an EWOD chip. Due to the “open” structure of an EWOD chip, microliter droplets of organic solvents evaporate very rapidly, especially at elevated temperatures, before chemical reactions can occur. An approach utilized to allow the reactions to progress before the solvent is evaporated was to continually replenish the reaction site with new solvent droplets using the electrowetting mechanism to transport microliter volumes of solvent from a loading site 60 to the reaction site 100. A modified etherification reaction was performed between 1-napthol and dibromobutane in acetonitrile (MeCN; bp. 82° C.) to yield 1-(4-bromobutoxy) naphthalene. The reaction is shown schematically in FIG. 30. In this chemical synthesis, 1-napthol (74 mM; 2 μL) was first allowed to be reacted with K2CO3 (250 mM; 1 μL) in MeCN at 60° C. for 3 minutes. MeCN was continuously added to the reaction droplet to maintain a liquid phase reaction. Subsequently, dibromobutane solution in MeCN (3.7 M; 1 μL) was added to the reaction site and the substitution reaction was performed at 60° C. for 5 minutes. the EWOD chips 98 for chemical reactions other than radiochemistry, a simple chemical synthesis (not Due to the “open” structure of an EWOD chip, microliter droplets of organic solvents evaporate very rapidly, especially at elevated temperatures, before chemical reactions is evaporated A modified etherification reaction

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

Procedure: To demonstrate the utility of the process and the EWOD chips 98 for chemical reactions other than radiochemistry, a simple chemical synthesis (not involving radioisotope) in a volatile organic solvent was performed using an EWOD chip. Due to the “open” structure of an EWOD chip, microliter droplets of organic solvents evaporate very rapidly, especially at elevated temperatures, before chemical reactions can occur. An approach utilized to allow the reactions to progress before the solvent is evaporated was to continually replenish the reaction site with new solvent droplets using the electrowetting mechanism to transport microliter volumes of solvent from a loading site 60 to the reaction site 100. A modified etherification reaction was performed between 1-napthol and dibromobutane in acetonitrile (MeCN; bp. 82° C.) to yield 1-(4-bromobutoxy) naphthalene. The reaction is shown schematically in FIG. 30. In this chemical synthesis, 1-napthol (74 mM; 2 μL) was first allowed to be reacted with K2CO3 (250 mM; 1 μL) in MeCN at 60° C. for 3 minutes. MeCN was continuously added to the reaction droplet to maintain a liquid phase reaction. Subsequently, dibromobutane solution in MeCN (3.7 M; 1 μL) was added to the reaction site and the substitution reaction was performed at 60° C. for 5 minutes. the EWOD chips 98 for chemical reactions other than radiochemistry, a simple chemical synthesis (not Due to the “open” structure of an EWOD chip, microliter droplets of organic solvents evaporate very rapidly, especially at elevated temperatures, before chemical reactions is evaporated A modified etherification reaction

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

Procedure: N-[(5-amino-8-hydroxyquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide (200 mg, 0.5 mmol), dibromobutane (0.1 ml), TEA (0.2 ml) in isopropanol were heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in methylene chloride, washed with brine. The organic layer was dried over sodium sulfate and filtered. To the filtrate was added 1M HCl/ether, the solids filtered, washed with ether to give N-[(8-hydroxy-5-pyrrolidin-1-ylquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide as a purple solid. at reflux for 16 h The reaction mixture was concentrated in vacuo the residue dissolved in methylene chloride washed with brine The organic layer was dried over sodium sulfate filtered To the filtrate was added 1M HCl/ether the solids filtered washed with ether