(2S,6R)-2,6-dimethylmorpholine

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

Procedure: N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylmorpholine (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(2,6-dimethylmorpholin))nicotinamide. MS (Q1) 465.0 (M)+ The product was purified by RP-HPLC

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

Procedure: A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (50 mg, 0.11 mmol), cis-2,6-dimethylmorpholine (50 mg, 0.40 mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated to provide 4-chloro-N-[5-chloro-2-(cis-2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was directly used in the next step without any purification. The mixture was concentrated

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,6R)-2,6-dimethylmorpholine and isolated as white solid (13.1 mg, 67%). MS (m/e): 415.5 (MH+).

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

Procedure: A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), cis-2,6-dimethylmorpholine (2.5 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature, poured into water (300 mL). The resulting crude yellow solid was collected by vacuum filtration, air dried, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 95/5 CHCl3/ether) to yield the product as a yellow solid (1.2 g, 68%). The reaction mixture was cooled to room temperature The resulting crude yellow solid was collected by vacuum filtration, air dried purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 95/5 CHCl3/ether)

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

Procedure: A solution of 7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 1.50 g, 5.20 mmol) and cis-2,6-dimethylmorpholine (6.4 mL, 52.0 mmol, 10 equiv.) in DMF (36 mL) was heated in two portions in a microwave reactor for 45 min. at 140° C. The resulting combined mixtures were concentrated under reduced pressure and purified using MPLC to give N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine (2.02 g, 96%): Preparative HPLC ret. time 4.29 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.10 (d, J=7.3 Hz, 3H), 1.14 (d, J=7.3 Hz, 3H), 2.69 (t, J=11.6 Hz, 1H), 2.76 (t, J=11.6 Hz, 1H), 3.23-3.32 (m, 2H), 3.43-3.54 (m, 2H), 3.80 (s, 3H), 3.81-3.87 (m, 1H), 3.88-3.97 (m, 1H), 4.31 (app dd, J=8.6, 12.1 Hz, 2H), 4.35-4.43 (m, 1H), 7.22 (J=9.4 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H); mass spectrum m/z 404 ((M+1)+, 100%). were concentrated under reduced pressure purified

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice cooled solution of 3-chloro-6,7-difluoro-1,2-benzoxazole-5-carbaldehyde (prepared according to the procedure described in International Application Publication No. WO 2010/043893, 5.0 g, 23.0 mmol) in anhydrous acetonitrile (50 ml) was added diisopropylethylamine (5.9 g, 45.9 mmol) followed by cis-2,6-dimethylmorpholine (2.6 g, 23.0 mmol) and the mixture was heated at 85° C. for 12 hours in a sealed tube. The solution was cooled to room temperature and the volatiles were removed under vacuum. The residue was dissolved in Ethyl acetate, washed with water followed by brine and then dried over anhydrous Na2SO4. Removal of solvent under vacuum afforded the crude product, which was purified over silica gel column using a gradient of ethyl acetate in pet. ether to give title compound as solid. Yield: 6.0 g (84%). 1H NMR (400 MHz, DMSO-d6) δ: 1.0 (d, 6H), 2.9 (t, 2H), 3.1 (d, 2H), 3.8 (m, 2H), 7.7 (s, 1H), 10.2 (s, 1H). MS (ES) MH+: 313 for C14H14ClFN2O3. The solution was cooled to room temperature the volatiles were removed under vacuum The residue was dissolved in Ethyl acetate washed with water dried over anhydrous Na2SO4 Removal of solvent under vacuum afforded the crude product, which was purified over silica gel column

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

Procedure: A microwave vial was charged with (S)-2-amino-5′-fluoro-2′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (150 mg, 0.302 mmol), Pd2(dba)3 (13.84 mg, 0.015 mmol), biphenyl-2-yldi-tert-butylphosphine (10.82 mg, 0.036 mmol) and (2R,6S)-2,6-dimethylmorpholine (104 mg, 0.907 mmol) and capped under argon. LiHMDS (1 M in THF) (1.511 mL, 1.511 mmol) was added and the mixture was heated in the microwave at 110° C. for 1 hr. To the reaction was added 1 ml of water and the mixture was concentrated in vacuo. The product was purified via Gilson HPLC (gradient elution 20-70% MeCN/H2O, 0.1% TFA) and freebased with sodium bicarbonte to afford (S)-2′-((2R,6S)-2,6-dimethylmorpholino)-4′-fluoro-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. MS m/z=462.0 [M+H]. capped under argon the mixture was concentrated in vacuo The product was purified via Gilson HPLC (gradient elution 20-70% MeCN/H2O, 0.1% TFA) and freebased with sodium bicarbonte

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene (100 mg, 0.366 mmol), (2R,6S)-2,6-dimethyl-morpholine (84 mg, 0.732 mmol) and triethylamine (77 μL, 0.55 mmol) in IMS (2 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in cyclohexane) affording 3-Chloro-1-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene as a white solid (128 mg, 99%). LCMS (method A): RT=3.62 min, [M+H]+=352. concentrated in vacuo The resulting residue was purified by column chromatography (SiO2, 10% ethyl acetate in cyclohexane)

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

Procedure: Using a procedure similar to that described in Example 82, except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone and employing cis 2,6-dimethylmorpholine, the title compound was formed in 59% yield as a white solid, mp >300° C. (dec). free base: NMR (CDCl3, 250 MHz) 7.22 (m, 2H), 7.14 (m, 2H), 6.92 (m, 4H), 4.24 (s, 1H), 3.63 (m, 2H), 3.36 (s, 2H), 3.05 (br d, J=11.7 Hz, 2H), 2.71 (d, J=10.5 Hz, 2H), 2.56 (d, J=1.2 Hz, 2H), 2.18 (m, 3H), 1.87 (t, J=10.8 Hz, 2H), 1.73 (m, 2H), 1.52 (dt, J=3.6, 11.9 Hz, 2H), 1.14 (d, J=6.3 Hz, 6H) MS (CI, CH4) m/z 403 (M+1,100), 431 (M+29,21), 287 (45) hydrochloride salt:

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

Procedure: Using a procedure similar to that described in Example 82, except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone and employing cis 2,6-dimethylmorpholine, the title compound was formed in 59% yield as a white solid, mp >300° C. (dec). free base: NMR (CDCl3, 250 MHz) 7.22 (m, 2H), 7.14 (m, 2H), 6.92 (m, 4H), 4.24 (s, 1H), 3.63 (m, 2H), 3.36 (s, 2H), 3.05 (br d, J=11.7 Hz, 2H), 2.71 (d, J=10.5 Hz, 2H), 2.56 (d, J=1.2 Hz, 2H), 2.18 (m, 3H), 1.87 (t, J=10.8 Hz, 2H), 1.73 (m, 2H), 1.52 (dt, J=3.6, 11.9 Hz, 2H), 1.14 (d, J=6.3 Hz, 6H) MS (CI, CH4) m/z 403 (M+1,100), 431 (M+29,21), 287 (45) hydrochloride salt:

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

Procedure: A suspension of 2.0 g of 4,6-dihydro-4-oxo-3-phenyl-pyrido[2,1-a]isoindole-1-carboxylic acid in 25 ml of N,N-dimethylformamide was treated under argon with 0.91 ml of cis2,6-dimethylmorpholine and then with 0.81 ml of N-methylmorpholine and 2.8 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and stirred at room temperature for a further 4.5 hours. The reaction mixture was then poured into a mixture of 50 ml of saturated sodium hydrogen carbonate solution and 250 ml of water. The crystallized-out crude product was filtered under suction and dried. After chromatography on silica gel with toluene and toluene/acetone (9:1) recrystallization was carried out twice from ethyl acetate. There was obtained 1.19 g of cis-4-[(4,6-dihydro-4-oxo-3-phenylpyrido-[2,1-a]isoindole -1-yl)carbonyl]-2,6-dimethylmorpholine as yellow crystals with a m.p. of 226°-228°. The crystallized-out crude product was filtered under suction dried After chromatography on silica gel with toluene and toluene/acetone (9:1) recrystallization

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

Procedure: A suspension of 2.0 g of 4,6-dihydro-4-oxo-3-phenyl-pyrido[2,1-a]isoindole-1-carboxylic acid in 25 ml of N,N-dimethylformamide was treated under argon with 0.91 ml of cis2,6-dimethylmorpholine and then with 0.81 ml of N-methylmorpholine and 2.8 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and stirred at room temperature for a further 4.5 hours. The reaction mixture was then poured into a mixture of 50 ml of saturated sodium hydrogen carbonate solution and 250 ml of water. The crystallized-out crude product was filtered under suction and dried. After chromatography on silica gel with toluene and toluene/acetone (9:1) recrystallization was carried out twice from ethyl acetate. There was obtained 1.19 g of cis-4-[(4,6-dihydro-4-oxo-3-phenylpyrido-[2,1-a]isoindole -1-yl)carbonyl]-2,6-dimethylmorpholine as yellow crystals with a m.p. of 226°-228°. The crystallized-out crude product was filtered under suction dried After chromatography on silica gel with toluene and toluene/acetone (9:1) recrystallization