1H-indole-2-carbonitrile

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

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Cyanophenylhydrazine hydrochloride (26.24 kg) and the Amine Ketal hydrochloride (1 mol equiv. 38.57 kg) were charged to the reaction vessel (RV3; nominal capacity 250 L; working capacity ca300 L) followed by water (92 L) and conc. hydrochloric acid (65.6 L). The reaction mixture was stirred and heated to 80-90° for up to ca 5 h and monitored by proton NMR (see note below). When the reaction was deemed to be complete, the reaction mixture was cooled to 0-5° C. and aged for 1 hour at this temperature. The racemic Indole Nitrile Hydrochloride was filtered using a 27″ nutsche filter and washed thoroughly with water (3×26 L or until the washing is >pH5). The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3, followed by water (164.5 L) and THF (66 L). The pH was adjusted to pH 13 with 6M NaOH (ca 30 L) and the reaction mixture stirred for 30 min. A sample was removed, the solid filtered off and checked by proton NMR (see note be low) to ensure the free base had been generated. The THF was then distilled off in vacuo at <40° C., the aqueous reaction mixture cooled to 0-5° C. and aged for a further 1 h. The solid was isolated by filtration using a 27″ nutsche filter, washed by displacement with water (2×33 L or until the washings are <pH9) and dried in vacuo at 55-60° C. to constant weight to give the racemic Indole Nitrile as an off-white solid (25.13 kg corrected for water content, 72.2% th, 65%w/w vs the Hydrazine hydrochloride input). heated to 80-90° for up to ca 5 h The racemic Indole Nitrile Hydrochloride was filtered filter washed thoroughly with water (3×26 L The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3 the reaction mixture stirred for 30 min A sample was removed the solid filtered off The THF was then distilled off in vacuo at <40° C. the aqueous reaction mixture cooled to 0-5° C. The solid was isolated by filtration filter washed by displacement with water (2×33 L dried in vacuo at 55-60° C. to constant weight

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Cyanophenylhydrazine hydrochloride (26.24 kg) and the Amine Ketal hydrochloride (1 mol equiv. 38.57 kg) were charged to the reaction vessel (RV3; nominal capacity 250 L; working capacity ca300 L) followed by water (92 L) and conc. hydrochloric acid (65.6 L). The reaction mixture was stirred and heated to 80-90° for up to ca 5 h and monitored by proton NMR (see note below). When the reaction was deemed to be complete, the reaction mixture was cooled to 0-5° C. and aged for 1 hour at this temperature. The racemic Indole Nitrile Hydrochloride was filtered using a 27″ nutsche filter and washed thoroughly with water (3×26 L or until the washing is >pH5). The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3, followed by water (164.5 L) and THF (66 L). The pH was adjusted to pH 13 with 6M NaOH (ca 30 L) and the reaction mixture stirred for 30 min. A sample was removed, the solid filtered off and checked by proton NMR (see note be low) to ensure the free base had been generated. The THF was then distilled off in vacuo at <40° C., the aqueous reaction mixture cooled to 0-5° C. and aged for a further 1 h. The solid was isolated by filtration using a 27″ nutsche filter, washed by displacement with water (2×33 L or until the washings are <pH9) and dried in vacuo at 55-60° C. to constant weight to give the racemic Indole Nitrile as an off-white solid (25.13 kg corrected for water content, 72.2% th, 65%w/w vs the Hydrazine hydrochloride input). heated to 80-90° for up to ca 5 h The racemic Indole Nitrile Hydrochloride was filtered filter washed thoroughly with water (3×26 L The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3 the reaction mixture stirred for 30 min A sample was removed the solid filtered off The THF was then distilled off in vacuo at <40° C. the aqueous reaction mixture cooled to 0-5° C. The solid was isolated by filtration filter washed by displacement with water (2×33 L dried in vacuo at 55-60° C. to constant weight

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

Procedure: The A ring indole of compounds 31 and 32 was synthesized using the same approach as 8f described in Scheme 3 above from 1H-indole-5-carbonitrile or 1H-indole-2-carbonitrile as starting material. Crude product was purified by column chromatography. Description of synthesis of compounds 31 and 32 is provided below in Example 11. Crude product was purified by column chromatography Description of synthesis of compounds 31 32 is provided below in Example 11

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Cyanophenylhydrazine hydrochloride (26.24 kg) and the Amine Ketal hydrochloride (1 mol equiv. 38.57 kg) were charged to the reaction vessel (RV3; nominal capacity 250 L; working capacity ca300 L) followed by water (92 L) and conc. hydrochloric acid (65.6 L). The reaction mixture was stirred and heated to 80-90° for up to ca 5 h and monitored by proton NMR (see note below). When the reaction was deemed to be complete, the reaction mixture was cooled to 0-5° C. and aged for 1 hour at this temperature. The racemic Indole Nitrile Hydrochloride was filtered using a 27″ nutsche filter and washed thoroughly with water (3×26 L or until the washing is >pH5). The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3, followed by water (164.5 L) and THF (66 L). The pH was adjusted to pH 13 with 6M NaOH (ca 30 L) and the reaction mixture stirred for 30 min. A sample was removed, the solid filtered off and checked by proton NMR (see note be low) to ensure the free base had been generated. The THF was then distilled off in vacuo at <40° C., the aqueous reaction mixture cooled to 0-5° C. and aged for a further 1 h. The solid was isolated by filtration using a 27″ nutsche filter, washed by displacement with water (2×33 L or until the washings are <pH9) and dried in vacuo at 55-60° C. to constant weight to give the racemic Indole Nitrile as an off-white solid (25.13 kg corrected for water content, 72.2% th, 65%w/w vs the Hydrazine hydrochloride input). heated to 80-90° for up to ca 5 h The racemic Indole Nitrile Hydrochloride was filtered filter washed thoroughly with water (3×26 L The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3 the reaction mixture stirred for 30 min A sample was removed the solid filtered off The THF was then distilled off in vacuo at <40° C. the aqueous reaction mixture cooled to 0-5° C. The solid was isolated by filtration filter washed by displacement with water (2×33 L dried in vacuo at 55-60° C. to constant weight

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

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

Procedure: The A ring indole of compounds 31 and 32 was synthesized using the same approach as 8f described in Scheme 3 above from 1H-indole-5-carbonitrile or 1H-indole-2-carbonitrile as starting material. Crude product was purified by column chromatography. Crude product was purified by column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.0 g (0.02 mol) of 2-cyanoindole, 4.2 g (0.02 mol) of tert-butyl-4-fluorobenzoate, and 5.5 g (0.04 mol) of potassium carbonate in 30 ml dimethyl sulfoxide was heated at 110° C. for 48 hours. The reaction was poured onto ice-water and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and dried over magnesium sulfate. Evaporation yielded a dark oil which was flash chromatographed on silica gel, eluting with ethyl acetate-hexane 1:9 to give 3.6 g (0.011 mol) of 1-[4-(tertbutoxycarbonyl)phenyl]-2-cyanoindole as an oil. The reaction was poured onto ice-water extracted twice with ethyl acetate washed with water dried over magnesium sulfate Evaporation yielded a dark oil which chromatographed on silica gel eluting with ethyl acetate-hexane 1:9

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

Procedure: LAH (42 mL, 1M solution in THF) was added dropwise through a syringe to a solution of 2-cyanoindole (2.0 g, 14.1 mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was stirred at RT under argon for 5 h. H2O was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3) and concentrated to afford the title compound (2.11 g, quantitative) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, 1H), 7.29 (d, 1H), 6.97 (t, 1H), 6.91 (t, 1H), 6.20 (s, 1H), 3.82 (s, 2H), 2. 18 (br, 1H). with cooling with cooling to destroy excess LAH the colorless precipitate was removed by filtration washed with THF The filtrate was dried (K2CO3) concentrated

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

Procedure: A solution of indole-2-carboxamide (3.02 g, 18.8 mmol) in dichlorophenylphosphine oxide (20 mL) was heated at 80° C. overnight. The cooled reaction mixture was then poured over 100 mL ice and the pH was adjusted to 11 with 50% aqueous sodium hydroxide. Extraction with ethyl acetate followed by concentration in vacuo gave an off-white solid which was purified by silica gel chromatography (1% MeOH/CH2Cl2) to yield the title compound (2.41 g, 90%): 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, 1H), 7.46 (d, 1H), 7.36 (s, 1H), 7.34 (t, 1H), 7.14 (t, 1H). The cooled reaction mixture Extraction with ethyl acetate followed by concentration in vacuo gave an off-white solid which was purified by silica gel chromatography (1% MeOH/CH2Cl2)

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

Procedure: The A ring indole of compounds 31 and 32 was synthesized using the same approach as 8f described in Scheme 3 above from 1H-indole-5-carbonitrile or 1H-indole-2-carbonitrile as starting material. Crude product was purified by column chromatography. Description of synthesis of compounds 31 and 32 is provided below in Example 11. Crude product was purified by column chromatography Description of synthesis of compounds 31 32 is provided below in Example 11

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Cyanophenylhydrazine hydrochloride (26.24 kg) and the Amine Ketal hydrochloride (1 mol equiv. 38.57 kg) were charged to the reaction vessel (RV3; nominal capacity 250 L; working capacity ca300 L) followed by water (92 L) and conc. hydrochloric acid (65.6 L). The reaction mixture was stirred and heated to 80-90° for up to ca 5 h and monitored by proton NMR (see note below). When the reaction was deemed to be complete, the reaction mixture was cooled to 0-5° C. and aged for 1 hour at this temperature. The racemic Indole Nitrile Hydrochloride was filtered using a 27″ nutsche filter and washed thoroughly with water (3×26 L or until the washing is >pH5). The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3, followed by water (164.5 L) and THF (66 L). The pH was adjusted to pH 13 with 6M NaOH (ca 30 L) and the reaction mixture stirred for 30 min. A sample was removed, the solid filtered off and checked by proton NMR (see note be low) to ensure the free base had been generated. The THF was then distilled off in vacuo at <40° C., the aqueous reaction mixture cooled to 0-5° C. and aged for a further 1 h. The solid was isolated by filtration using a 27″ nutsche filter, washed by displacement with water (2×33 L or until the washings are <pH9) and dried in vacuo at 55-60° C. to constant weight to give the racemic Indole Nitrile as an off-white solid (25.13 kg corrected for water content, 72.2% th, 65%w/w vs the Hydrazine hydrochloride input). heated to 80-90° for up to ca 5 h The racemic Indole Nitrile Hydrochloride was filtered filter washed thoroughly with water (3×26 L The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3 the reaction mixture stirred for 30 min A sample was removed the solid filtered off The THF was then distilled off in vacuo at <40° C. the aqueous reaction mixture cooled to 0-5° C. The solid was isolated by filtration filter washed by displacement with water (2×33 L dried in vacuo at 55-60° C. to constant weight