(2S)-2-(methoxymethyl)pyrrolidine

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

Procedure: Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (2S)-2-methoxymethyl-pyrrolidine (0.087 g, 0.76 mmol) gives the title compound.

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 (S)-2-(methoxymethyl)pyrrolidine and isolated as light-yellow gum (12.0 mg, 61%). MS (m/e): 415.4 (MH+).

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

Procedure: By using the method of Example 89, 1.2 g (3.5 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 2.4 g (21 mmol) of (S)-(+)-2-(methoxymethy) pyrrolidine were converted to 1.5 g the title compound, obtained as a yellow powder: mass spectrum (electrospray, m/e): M+H 524.0, (M+2H)+2 262.4. This reaction can also be done with (R)-(−)-2-(methoxymethy) pyrrolidine or racemic 2-(methoxymethy) pyrrolidine giving the R-entaniomer or the racemate, respectively.

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

Procedure: To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. (S)-(+)-2-(Methoxymethyl)pyrrolidine (380 mg, 3.3 mmol) is added to the filtrate, and the reaction mixtire is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 4.12 (d, J=17 Hz, 1H), 3.90 (s, 3H), 3.85 (m, 2H), 3.51 (m, 2H), 3.44 (m, 2H), 3.15 (s, 1H), 2.38 (s, 3H), 1.94 (m, 3H), 1.72 (m, 3H). filtered the reaction mixtire is stirred at room temperature for 5 h washed with 1 N hydrochloric acid, and saturated sodium bicarbonate dried (magnesium sulfate) filtered concentrated under reduced pressure Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes)

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

Procedure: A suspension comprising (S)-2-(methoxymethyl)pyrrolidine (1 g, 8.68 mmol), tert-butyl 2-bromoethylcarbamate (1.946 g, 8.68 mmol), triethylamine (1.210 ml, 8.68 mmol) and potassium carbonate (1.200 g, 8.68 mmol) in MeCN (10 ml) was heated at 85° C. overnight. The resulting mixture was filtered and washed with MeCN. Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM afforded the title compound as a colourless oil; The resulting mixture was filtered washed with MeCN Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM

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

Procedure: 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (350 mg, 1.103 mmol), (s)-(+)-2-(methoxymethyl)pyrrolidine (230 mg, 2.00 mmol), absolute ethanol (40 ml), activated 3 Å molecular sieves (350 mg), titanium (IV) isopropoxide (1.62 ml, 5.48 mmol) and STAB (2.09, 9.74 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (330 mg, 72%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.84-3.70 (m, 2H), 3.59 (td, 1H), 3.45 (td, 1H), 3.27 (s, 3H), 3.10 (dd, 1H), 3.02 (dd, 1H), 2.94 (d, 1H), 2.63 (t, 2H), 2.59-2.45 (m, 5H), 2.39 (m, 1H), 2.21 (m, 1H), 2.06-1.34 (m, 15H). The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1)

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

Procedure: 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (350 mg, 1.103 mmol), (s)-(+)-2-(methoxymethyl)pyrrolidine (230 mg, 2.00 mmol), absolute ethanol (40 ml), activated 3 Å molecular sieves (350 mg), titanium (IV) isopropoxide (1.62 ml, 5.48 mmol) and STAB (2.09, 9.74 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (330 mg, 72%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.84-3.70 (m, 2H), 3.59 (td, 1H), 3.45 (td, 1H), 3.27 (s, 3H), 3.10 (dd, 1H), 3.02 (dd, 1H), 2.94 (d, 1H), 2.63 (t, 2H), 2.59-2.45 (m, 5H), 2.39 (m, 1H), 2.21 (m, 1H), 2.06-1.34 (m, 15H). The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1)

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

Procedure: Intermediate V step 4 (947 mg, 2.8 mmol) was allowed to react with (2S)-2-(methoxymethyl)pyrrolidine (980 mg, 8.5 mmol) using the procedure to make 5-bromo-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine. The reaction was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layer was washed with brine (10 mL) then dried with sodium sulfate. The reaction was concentrated under vacuum to quantitatively yield crude product. 1H-NMR (DMSO-d6) 7.83 (s, 1H), 6.61 (s, 1H), 3.25 (m, 1H), 3.19 (s, 3H), 3.12 to 2.72 (m, 6H), 2.23 (m, 1H), 2.04 (m, 1H), 1.77 (m, 3H), 1.62 (m, 2H), 1.40 (m, 1H); MS [M+H]+=622.2; LCMS RT=2.68. The reaction was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (20 mL) The aqueous layer was extracted with EtOAc (10 mL) The combined organic layer was washed with brine (10 mL) then dried with sodium sulfate The reaction was concentrated under vacuum to quantitatively yield crude product LCMS RT=2.68

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 193 step 1) (50 mg, 0.088 mmol) and (2S)-2-(methoxymethyl)pyrrolidine (36 uL, 0.263 mmol) were added to a vial. DMF was added (1 mL) followed by triethylamine (15 uL, 0.109 mmol) and KI (spatula tip). The vial was capped and the reaction heated at 55° C. for two hours. Upon cooling the product precipitated out of solution. The solids were collected by filtration and rinsed with ether to yield 35 mg (65%) of clean product. 1H-NMR (DMSO-d6) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.21 (m, 4H), 6.57 (s, 1H), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37 to 1.45 (m, 5H); MS [M+H]+=604.2; LCMS RT=2.59 The vial was capped Upon cooling the product precipitated out of solution The solids were collected by filtration rinsed with ether

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 193 step 1) (50 mg, 0.088 mmol) and (2S)-2-(methoxymethyl)pyrrolidine (36 uL, 0.263 mmol) were added to a vial. DMF was added (1 mL) followed by triethylamine (15 uL, 0.109 mmol) and KI (spatula tip). The vial was capped and the reaction heated at 55° C. for two hours. Upon cooling the product precipitated out of solution. The solids were collected by filtration and rinsed with ether to yield 35 mg (65%) of clean product. 1H-NMR (DMSO-d6) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.21 (m, 4H), 6.57 (s, 1H), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37 to 1.45 (m, 5H); MS [M+H]+=604.2; LCMS RT=2.59 The vial was capped Upon cooling the product precipitated out of solution The solids were collected by filtration rinsed with ether

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 193 step 1) (50 mg, 0.088 mmol) and (2S)-2-(methoxymethyl)pyrrolidine (36 uL, 0.263 mmol) were added to a vial. DMF was added (1 mL) followed by triethylamine (15 uL, 0.109 mmol) and KI (spatula tip). The vial was capped and the reaction heated at 55° C. for two hours. Upon cooling the product precipitated out of solution. The solids were collected by filtration and rinsed with ether to yield 35 mg (65%) of clean product. 1H-NMR (DMSO-d6) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.21 (m, 4H), 6.57 (s, 1H), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37 to 1.45 (m, 5H); MS [M+H]+=604.2; LCMS RT=2.59 The vial was capped Upon cooling the product precipitated out of solution The solids were collected by filtration rinsed with ether

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

Procedure: 5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. (S)-2-(Methoxymethyl)-pyrrolidine (0.207 g, 1.800 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (55%) of the indole-amine was obtained as a white solid. This was converted to the HCl salt. LC/MS (ESI+) 407 (M+1); Anal. Calcd for C25H30N2O3.1HCl.1H2O: C, 65.14; H, 7.22; N, 6.08; Found: C, 65.48; H, 7.14; N, 6.04. heated to reflux for 18 hours Then the reaction was quenched with saturated sodium bicarbonate extracted with ethyl acetate (3×) The combined organic phases were washed with brine dried over Na2SO4 After removing the solvent chromatographed eluting with ethyl acetate/methanol/triethyl amine (100/10/1)