spiro[2H-isoindole-3,4'-piperidine]-1-one

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

Procedure: Sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added to a stirred solution of spiro[isoindoline-1,4′-piperidin]-3-one 3a (20 mg, 0.10 mmol) and bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (18 mg, 0.15 mmol) in 1,2-dichloroethane (1 mL) and the mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no. 267. LC/MS m/z [M+H]+ 309.0 retention time 1.7 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min). The solvent was removed under reduced pressure the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no

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

Procedure: Sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added to a stirred solution of spiro[isoindoline-1,4′-piperidin]-3-one 3a (20 mg, 0.10 mmol) and bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (18 mg, 0.15 mmol) in 1,2-dichloroethane (1 mL) and the mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no. 267. LC/MS m/z [M+H]+ 309.0 retention time 1.7 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min). The solvent was removed under reduced pressure the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no

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

Procedure: Sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added to a stirred solution of spiro[isoindoline-1,4′-piperidin]-3-one 3a (20 mg, 0.10 mmol) and bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (18 mg, 0.15 mmol) in 1,2-dichloroethane (1 mL) and the mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no. 267. LC/MS m/z [M+H]+ 309.0 retention time 1.7 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min). The solvent was removed under reduced pressure the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no

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

Procedure: To a solution of 0.060 g (0.31 mmol) 6-chloro-1H-indole-3-carboxylic acid in 3 ml dichloromethane were added 0.045 ml (0.38 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. After stirring for 1 h the reaction mixture was concentrated in vacuo. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A solution of 0.062 g (0.31 mmol) spiro[isoindole-1,4′-piperidin]-3(2H)-one and 0.064 ml (0.46 mmol) triethylamine in 1 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml), 0.5 M aqueous hydrochloric acid solution (1×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was triturated in warm diethyl ether, filtrated and dried in vacuo to give the title compound (0.031 g, 22%) as light brown solid with a purity of approx. 80% by LC-.MS. was concentrated in vacuo The residue was redissolved in 2 ml dry N,N-dimethylformamide After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) extracted with ethyl acetate (3×50 ml) The combined organic layers were washed with water (2×30 ml), 0.5 M aqueous hydrochloric acid solution (1×30 ml) and brine (1×30 ml) dried over sodium sulfate concentrated in vacuo The crude product was triturated in warm diethyl ether filtrated dried in vacuo

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

Procedure: To a solution of 0.060 g (0.31 mmol) 6-chloro-1H-indole-3-carboxylic acid in 3 ml dichloromethane were added 0.045 ml (0.38 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. After stirring for 1 h the reaction mixture was concentrated in vacuo. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A solution of 0.062 g (0.31 mmol) spiro[isoindole-1,4′-piperidin]-3(2H)-one and 0.064 ml (0.46 mmol) triethylamine in 1 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml), 0.5 M aqueous hydrochloric acid solution (1×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was triturated in warm diethyl ether, filtrated and dried in vacuo to give the title compound (0.031 g, 22%) as light brown solid with a purity of approx. 80% by LC-.MS. was concentrated in vacuo The residue was redissolved in 2 ml dry N,N-dimethylformamide After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) extracted with ethyl acetate (3×50 ml) The combined organic layers were washed with water (2×30 ml), 0.5 M aqueous hydrochloric acid solution (1×30 ml) and brine (1×30 ml) dried over sodium sulfate concentrated in vacuo The crude product was triturated in warm diethyl ether filtrated dried in vacuo

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

Procedure: Tert-butyl 2-(4-methoxybenzyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate (50 mg, 0.12 mmol, 1.0 equiv) and TFA (7 mL) were heated to 75° C. for 19 h. After this time LC-MS showed removal of the Boc- and p-methoxybenzyl groups. The mixture was concentrated to leave crude spiro[isoindoline-1,4′-piperidin]-3-one which was used directly. removal of the Boc- and p-methoxybenzyl groups The mixture was concentrated

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

Procedure: Sodium triacetoxyborohydride (31 mg, 0.15 mmol) was added to a stirred solution of spiro[isoindoline-1,4′-piperidin]-3-one 3a (20 mg, 0.10 mmol) and bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (18 mg, 0.15 mmol) in 1,2-dichloroethane (1 mL) and the mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no. 267. LC/MS m/z [M+H]+ 309.0 retention time 1.7 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min). The solvent was removed under reduced pressure the crude product was purified by preparative HPLC (5-70% CH3CN—H2O gradient with 0.05% TFA, 15 min) to give compound no