N,N-diethylethanamine;hydrochloride

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

Procedure: To a suspension of 3-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzonitrile (compound T1) (5.0 g, 12.7 mmol) in N-methylpyrrolidinone (80 mL) are added sodium azide (2.90 g, 44.6 mmol) and triethyl amine hydrochloride (6.14 g, 44.6 mmol). The mixture is stirred at 100° C. for 2 days. Upon cooling, water (400 mL) is added to the reaction mixture and the resulting precipitate is filtered. The solid is washed successively with MeOH, AcOEt, a saturated solution of NH4Cl and water. The residue is dried azeotropically with toluene to yield 2.97 g (54%) of the title compound as light brown solid. Upon cooling the resulting precipitate is filtered The solid is washed successively with MeOH, AcOEt The residue is dried azeotropically with toluene

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

Procedure: A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl may be added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt. The resulting layers were separated the organic layer was washed with water/methanol (115 mL/46 mL) concentrated

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 0.08 g (0.16 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethylamino}-benzonitrile in 2 ml o-xylene were added 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mmol) sodium azide. The resulting mixture was heated to 145° C. After 72 h another 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mMol) sodium azide were added and the temperature of the oil bath was elevated to 160° C. After 24 h the oil bath was removed and the reaction mixture was poured on saturated aqueous ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The resulting light brown solid was dissolved in ethyl acetate. Upon evaporation a suspension formed which was filtered and washed with ethyl acetate. The resulting solid was taken up in 2 ml acetonitrile, heated to reflux and then cooled down to 4° C. The suspension was filtered, the solid washed with acetonitrile and dried under high vacuum. Light brown solid (25%). MS (Turbo Spray): m/z=534.2 [M+H]. was elevated to 160° C After 24 h the oil bath was removed the reaction mixture was poured on saturated aqueous ammonium chloride solution The aqueous phase was extracted three times with ethyl acetate the combined organic layers were washed with water and brine dried over magnesium sulfate filtered evaporated The resulting light brown solid was dissolved in ethyl acetate Upon evaporation a suspension formed which was filtered washed with ethyl acetate heated to reflux cooled down to 4° C The suspension was filtered the solid washed with acetonitrile dried under high vacuum

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.17 g (0.34 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-ethoxy}-3,5-dimethyl-benzonitrile in 4 ml o-xylene, were added 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide and the solution was heated at 150° C. (oil bath temperature) for 19.5 h. Another 0.231 g (1.68 mmol) triethylamine hydrochloride and 0.109 g (1.68 mmol) sodium azide were added and the reaction mixture was heated for an additional 4 h, then stirred for 3 days at room temperature. The reaction mixture was poured onto aqueous 1M hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was suspended in acetonitrile, filtered and washed with acetonitrile. The obtained crude material was purified on a preparative HPLC (Zorbax column) eluting with a gradient of acetonitrile and water containing 0.5% formic acid. White solid (18%). MS (Turbo Spray): m/z=549.199 [M+H]. the reaction mixture was heated for an additional 4 h the phases were separated the aqueous phase extracted three times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate filtered evaporated filtered washed with acetonitrile The obtained crude material was purified on a preparative HPLC (Zorbax column) eluting with a gradient of acetonitrile and water containing 0.5% formic acid

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.16 g (0.29 mmol) 4-[2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-ethoxy]-3,5-dimethyl-benzonitrile in 4 ml o-xylene were added 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide and heated for 21 h at 150° C. (oil bath temperature). Another 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide were added and the reaction mixture was heated for another 4 h and after cooling down to room temperature stirred 3 days. The reaction was then poured onto 1M aqueous hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The solid was suspended in acetonitrile, filtered, washed with acetonitrile and dried under high vacuum. White solid (77%). MS (Turbo Spray): m/z=599.194 [M+H]. the reaction mixture was heated for another 4 h after cooling down to room temperature the phases were separated the aqueous phase extracted three times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate filtered evaporated filtered washed with acetonitrile dried under high vacuum

Conditions: temp:145.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.18 g (0.33 mmol) 4-{2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethoxy}-3,5-dimethyl-benzonitrile in 3 ml o-xylene were added 0.227 g (1.65 mmol) triethylamine hydrochloride and 0.107 g (2.65 mMol) sodium azide and the solution was heated for 7 h at 145° C. (oil bath temperature). The reaction was allowed to cool down to room temperature overnight and then was poured onto 1M aqueous hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining oil was dissolved in acetonitrile, the solution was completely evaporated and the residue dissolved in 20 ml tert-butyl methyl ether under warming to 45° C. The solution was partially evaporated, then stored at 4° C. overnight. The resulting suspension was filtered, washed with tert-butyl methyl ether and dried under high vacuum. Light brown solid (75%). MS (Turbo Spray): m/z=590.44 [M+H]. to cool down to room temperature overnight extracted three times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate filtered evaporated The remaining oil was dissolved in acetonitrile the solution was completely evaporated the residue dissolved in 20 ml tert-butyl methyl ether under warming to 45° C The solution was partially evaporated The resulting suspension was filtered washed with tert-butyl methyl ether dried under high vacuum

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

Procedure: In 100 ml of ethyl acetate was suspended 3.2 g of alpha-(2-furyl)-aminoacetonitrile hydrochloride, and with ice cooling, 4.5 g of triethylamine was added. Then, 3.8 g of 1-methyl-3-methoxymethylpyrazole-4-carboxylic acid chloride was gradually added at 0° to 5° C. with stirring. After the addition, the mixture was further stirred at room temperature for 2 hours. Water (50 ml) was added to dissolve the precipitated triethylamine hydrochloride. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was chromatographed on a silica gel column, and the column was eluted with hexane/ethyl acetate to give 4.3 g (yield 78.6%) of the desired alpha-(1-methyl-3-methoxymethylpyrazol-4-ylcarbonylamino)-(2-furyl)acetonitrile. After the addition the mixture was further stirred at room temperature for 2 hours The ethyl acetate layer was separated washed with water dried over anhydrous sodium sulfate distilled under reduced pressure to remove the solvent The residue was chromatographed on a silica gel column the column was eluted with hexane/ethyl acetate

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

Procedure: 2-Chloro-1,3-benzothiazole (503 mg) was added to a suspension of ethyl (2S)-2-piperidinecarboxylate (471 mg) [J.A.C.S. (1993), 115(22), 9925-9938], triethylamine hydrochloride (414 mg) and copper powder (38 mg) in xylene (5 ml). The reaction mixture was refluxed for 28 hours, after which time ethyl acetate (20 ml) was added to the cooled mixture and the solids filtered off. The organic layer was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure to afford ethyl (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylate (705 mg) as a brown solid. The reaction mixture was refluxed for 28 hours the solids filtered off The organic layer was washed with water dried over magnesium sulphate the solvent removed under reduced pressure

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to a protocol of A. Dondoni, et al., (Synth. Commun. 1994, 24, 2537-2550), an ovendried 250 mL round-bottomed flask equipped with a magnetic stir bar, reflux condenser and adapter to an argon line was charged with 2.512 g (20.0 mmol) of N-tert-butylhydroxylamine hydrochloride (1), 2.144 g (20.0 mmol) of pyridine-3-carboxaldehyde (2b), and 2.889 g (22.0 mmol) of MgSO4.100 mL of anhydrous toluene were added followed by 2.024 g (20.0 mmol, 2.79 mL) of anhydrous Et3N. The reaction mixture was heated to 100-110° C. under atmosphere of argon, and the reaction course was followed by t.l.c. and GC/MS. After 3-5 h, the reaction was cooled to room temperature, MgSO4 was filtered off, and the solvent was evaporated under reduced pressure to yield a dark yellow-green mixture of product and Et3N HCl. The solids were dissolved in EtOAc and the solution was subsequently washed with a saturated aq. NaHCO3-solution (50 mL) to remove Et3N HCl, water (50 mL), and brine (50 mL), dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by passing through a short plug of silica gel (EtOAc/hexanes (1: 1) to yield after evaporation 3.000 g (84%) of a pale yellow solid. Rf: 0.61 (EtOAc/hexanes=1:9, UV254-quenching). GC: Rt: 3.92 min. 1H NMR (300 MHz, CDCl3, room temp.): δ9.06 (dt, J=8.4,1.8 Hz, 1H, Ar-H), 8.93 (d, J=1.8 Hz, 1H, Ar-H), 8.53 (dd, J=8.8, 1.8 Hz, 1H, Ar-H), 7.56 (s, 1H, HC(═N)), 7.31 (dd, J=8.1, 4.8 Hz, 1H, Ar- H), 1.54 (s, 9H, C(CH3)3) ppm. 13C NMR (75 MHz, CDCl3, room temp.): δ150.20, 150.09, 134.57, 127.49, 126.91, 123.40, 71.43, 28.24 ppm. MS: m/z=178 (M+), 147, 122 (b.p., M+—H2C═C(CH3)2), 106, 79, 57. Dondoni, et al., (Synth. Commun. 1994, 24, 2537-2550), an ovendried 250 mL round-bottomed flask equipped with a magnetic stir bar reflux condenser and adapter to an argon line the reaction was cooled to room temperature MgSO4 was filtered off the solvent was evaporated under reduced pressure to yield the solution was subsequently washed with a saturated aq. NaHCO3-solution (50 mL) to remove Et3N HCl, water (50 mL), and brine (50 mL) dried over MgSO4 filtered evaporated under reduced pressure The crude product was purified to yield after evaporation 3.000 g (84%) of a pale yellow solid

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (28 kg) and triethylamine hydrochloride (2.7 kg) were added to anisole (244 kg). N,N-Diisopropylethylamine (19.2 kg) was added, followed by a line wash of anisole (20 kg). The mixture was cooled to 15° C. and phosphorus oxychloride (19.8 kg) added over 5 minutes, followed by a line wash of anisole (13.9 kg). After stirring for 15 minutes the mixture was heated to 80° C. over 90 minutes and held at 80° C. for 1 hour. When the reaction was complete the batch was transferred to a new reactor, followed by a line wash of anisole (39.7 kg). The mixture was cooled to 40° C. and 16.19% w/w aqueous sodium hydroxide solution (132 kg) added over 15 minutes, allowing the temperature to rise to 50° C., followed by a line wash of water (5 kg). The mixture was held at 50° C. for 30 minutes, then heated to 80° C. The batch was filtered through a Gaf filter, followed by a line-wash of anisole (10 kg). The lower aqueous layer was separated and the upper organic layer washed at 80° C. with 20.9% w/w aqueous sodium chloride solution (98.2 kg). The mixture was distilled under reduced pressure (80 mbar) to leave a residual volume of 224 l. 1-Methyl-2-pyrrolidinone (28.9) was added and the mixture heated to 80° C. to give a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline. wash of anisole (20 kg) phosphorus oxychloride (19.8 kg) added over 5 minutes wash of anisole (13.9 kg) was heated to 80° C. over 90 minutes held at 80° C. for 1 hour was transferred to a new reactor wash of anisole (39.7 kg) The mixture was cooled to 40° C. 16.19% w/w aqueous sodium hydroxide solution (132 kg) added over 15 minutes to rise to 50° C. wash of water (5 kg) The mixture was held at 50° C. for 30 minutes heated to 80° C The batch was filtered through a Gaf filter a line-wash of anisole (10 kg) The lower aqueous layer was separated the upper organic layer washed at 80° C. with 20.9% w/w aqueous sodium chloride solution (98.2 kg) The mixture was distilled under reduced pressure (80 mbar) to leave a residual volume of 224 l the mixture heated to 80° C.

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

Procedure: To solid tert-butyl (6S)-6′-oxo-5,6′,7,7′-tetrahydrospiro[cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylate (255 mg, 0.536 mmol) containing one equivalent of triethylamine hydrochloride (from previous step) was added hydrochloric acid solution (20 mL, 4 M in dioxane). After 16 h, the mixture was concentrated to give the title compound as a bis hydrochloric acid salt with one equivalent of triethylamine hydrochloride. MS: m/z=283.2 (M+1). 1H NMR (500 MHz, DMSO): δ 11.75 (s, 1H); 9.50 (s, 1H); 8.90 (s, 1H); 8.80 (s, 1H); 8.40 (s, 1H); 8.20 (s, 1H); 3.50-3.40 (m, 4H). the mixture was concentrated

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

Procedure: A mixture of 4-nitrophenoxy acetic acid (2.25 g, 11.4 mmole), acetamideoxime, triethylamine hydrochloride (3.85 g, 27.62 mmole), EDCI.HCl (4.37 g, 22.79 mmole) and diisopropylethylamine (7.42 g, 57.40 mmole) in anhydrous THF (250 ml) was refluxed for 18 h. The unhomogenous brown colored reaction mixture was quenched with water and extracted with EtOAc (3×300 mL). The combined organic layers washed successively with aqueous NaHCO3, brine and dried over anhydrous Na2SO4. Removal of solvent and purified by chromatographic purification provided 5-[(4-nitrophenoxy)methyl]-3-methyl-1,2,4-oxadiazole (1.62 g, 60%). 1H NMR (CDCl3): δ 8.24 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 5.36 (s, 2H), 2.44 (s, 3H). was refluxed for 18 h The unhomogenous brown colored reaction mixture was quenched with water extracted with EtOAc (3×300 mL) The combined organic layers washed successively with aqueous NaHCO3, brine dried over anhydrous Na2SO4 Removal of solvent purified by chromatographic purification