1-[2-(4-chlorophenyl)phenyl]ethanone

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

Procedure: A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0° C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH3 (0.828 g) in methanol (5 ml), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes. stirred at room temperature overnight concentrated The concentrate was treated with ethyl acetate filtered The organic filtrate was washed with water concentrated The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes

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

Procedure: A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0° C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH3 (0.828 g) in methanol (5 ml), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes. stirred at room temperature overnight concentrated The concentrate was treated with ethyl acetate filtered The organic filtrate was washed with water concentrated The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes

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

Procedure: A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0° C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH3 (0.828 g) in methanol (5 ml), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes. stirred at room temperature overnight concentrated The concentrate was treated with ethyl acetate filtered The organic filtrate was washed with water concentrated The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes

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

Procedure: A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0° C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH3 (0.828 g) in methanol (5 ml), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes. stirred at room temperature overnight concentrated The concentrate was treated with ethyl acetate filtered The organic filtrate was washed with water concentrated The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1-(4′-Chloro-biphenyl-2-yl)-ethanone (2.42 g, 10.5 mmol) and 4-piperidone ethylene ketal (1.50 g, 10.5 mmol) and titanium (IV) isopropoxide (5.96 g, 21.0 mmol) is heated up to 75° C. for 3 hours. The reaction is then cooled to room temperature and is added 50 mL of ethanol followed by sodium borohydride (1.19 g, 31.5 mmol) the reaction is then stirred for 18 hours at room temperature and then quench with 50 mL of methanol. The crude reaction is then dissolved in ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer is then extracted 2 times with ethyl acetate. The combined organic layer are then dried on MgSO4 and the solvent is removed under vacuum. The residue is chromatographed on silica gel gel (gradient: heptane/EtOAc; 0 to 60% EtOAc over 15 minutes) to afford 8-[1-(4′-Chloro-biphenyl-2-yl)-ethyl]-1,4-dioxa-8-aza-spiro[4.5]decane (3.6 g, 96%). Found m/z ES+=358.5 (M+H); 1H NMR (400 MHz, CD2Cl2) δ 7.64 (1H, d, J=8.1 Hz), 7.41 (2H, d, J=8.6 Hz), 7.40 (1H, t), 7.30 (2H, J=8.6 Hz), 7.29 (1H, t), 7.18 (1H, d, J=7.6 Hz), 3.90 (4H, s), 3.51 (1H, m), 2.48 (2H, m), 2.36 (2H, m), 1.62 (4H, m), 1.27 (3H, d, J=6.6 Hz). The reaction is then cooled to room temperature quench with 50 mL of methanol The crude reaction washed with a saturated solution of sodium bicarbonate The aqueous layer is then extracted 2 times with ethyl acetate The combined organic layer are then dried on MgSO4 the solvent is removed under vacuum The residue is chromatographed on silica gel gel (gradient: heptane/EtOAc; 0 to 60% EtOAc over 15 minutes)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57 mmol)-4-chlorophenylboronic acid (2.92 g), (Ph3P)2PdCl2 (bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na2CO3 (3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at 100° C. for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and the insoluble material was removed by filtration. The filtrate was loaded onto a silica gel column, eluted with 0%-50% dichloromethane in hexane to provide the title compound. concentrated the insoluble material was removed by filtration eluted with 0%-50% dichloromethane in hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57 mmol)-4-chlorophenylboronic acid (2.92 g), (Ph3P)2PdCl2 (bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na2CO3 (3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at 100° C. for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and the insoluble material was removed by filtration. The filtrate was loaded onto a silica gel column, eluted with 0%-50% dichloromethane in hexane to provide the title compound. concentrated the insoluble material was removed by filtration eluted with 0%-50% dichloromethane in hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57 mmol)-4-chlorophenylboronic acid (2.92 g), (Ph3P)2PdCl2 (bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na2CO3 (3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at 100° C. for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and the insoluble material was removed by filtration. The filtrate was loaded onto a silica gel column, eluted with 0%-50% dichloromethane in hexane to provide the title compound. concentrated the insoluble material was removed by filtration eluted with 0%-50% dichloromethane in hexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57 mmol)-4-chlorophenylboronic acid (2.92 g), (Ph3P)2PdCl2 (bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na2CO3 (3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at 100° C. for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and the insoluble material was removed by filtration. The filtrate was loaded onto a silica gel column, eluted with 0%-50% dichloromethane in hexane to provide the title compound. concentrated the insoluble material was removed by filtration eluted with 0%-50% dichloromethane in hexane

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

Procedure: A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0° C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH3 (0.828 g) in methanol (5 ml), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes. stirred at room temperature overnight concentrated The concentrate was treated with ethyl acetate filtered The organic filtrate was washed with water concentrated The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57 mmol)-4-chlorophenylboronic acid (2.92 g), (Ph3P)2PdCl2 (bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na2CO3 (3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at 100° C. for 3 hours and concentrated. The concentrate was suspended in dichloromethane (30 mL) and the insoluble material was removed by filtration. The filtrate was loaded onto a silica gel column, eluted with 0%-50% dichloromethane in hexane to provide the title compound. concentrated the insoluble material was removed by filtration eluted with 0%-50% dichloromethane in hexane

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

Procedure: A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0° C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH3 (0.828 g) in methanol (5 ml), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes. stirred at room temperature overnight concentrated The concentrate was treated with ethyl acetate filtered The organic filtrate was washed with water concentrated The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes