N-BOC-(S)-2-AMINO-1-BUTANOL, 96%

Step A2: (S)-tert-butyl 1-oxobutan-2-ylcarbamate Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2Cl2 (100 ml) to give a colorless solution. The reaction was cooled to -60 C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2Cl2 (20 ml) was added dropwise at -60 C. The reaction was stirred for 10 min at -60 C. Then (S)-tert-butyl-1-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml CH2Cl2 was added dropwise at -70 C. The reaction was allowed to warm to -40 C. for 10 min and then cooled to -70 C. again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2Cl2 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2*150 mL). The organic layer was back-extracted with brine (1*50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e)=188.2 [M+H+]).Step B; 2 (1.02 g, 5.39 mmol, 1 eq) is dissolved in 60 mL of dry DCM and cooled to 0C. Trichloroisocyanuric acid (1.32 g, 5.65 mmol, 1.05 eq) is added and mixed for 10 minutes resulting in a white slurry. TEMPO is added (8.8 mg, 0.056 mmol, 0.01 eq) to the chilled reaction mixture which immediately turns orange and additional precipitate is formed. The reaction vessel is removed from the cold bath and the mixture is stirred for additional 45 minutes. The reaction mixture is then filtered through a pad of celite, washed with 5% citric acid followed by saturated bicarbonate, dried over MgS04, filtered, and stripped to yield pure 3 (0.979 g, 97 % yield) which was used immediately in step C.Reference Example 102 tert-butyl[(1S)-1-formylpropyl]carbamate A solution of tert-butyl[(1S)-1-(hydroxymethyl)propyl]carbamate (30.0 g) in dimethyl sulfoxide (300 mL) was ice-cooled under a nitrogen atmosphere, and triethylamine (64.4 mL) and a solution of sulfur trioxide·pyridine complex (80.7 g) in dimethyl sulfoxide (300 mL) were successively added. The mixture was stirred at the same temperature for 30 min and then at room temperature for 3 hr, 1 mol/L aqueous citric acid solution (500 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0'30%) to give the title compound as a white powder (yield: 24.3 g, 85%). 1H-NMR(CDCl3)delta:0.97(3H, dd, J=7.6, 7.4 Hz), 1.45(9H, s), 1.54-1.77(1H, m), 1.85-2.02(1H, m), 4.14-4.29(1H, m), 5.11(1H, brs), 9.59(1H, s). mp: 39-43 C.To a solution of 2 (S)-Boc-aminobutanol in dichloromethane (10 vol) and water (7 vol) were added at 20 C TEMPO (0. 01 equiv. ), sodium bromide (1 equiv.) and sodium hydrogen carbonate (3 equiv. ). The reaction mixture was stirred at 0 C and diluted bleach (1. 3 equiv. , 9 vol) was added over 40 min. The reaction mixture was stirred for 30 min., and then quenched with aq. thiosulfate. After decantation, and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, giving 77% of 2 (S)- ( tert-butoxycarbonyl) amino-butyraldehyde as a low- melting solid.To a solution of 2(5)-5oc-aminobutanol (50 g; 264 mmol) in dichloromethane (500mL) and water (350 mL) were added at 20 C TEMPO (0.01 eq), sodium bromide (1 eq) andsodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0 C and diluted bleach(1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0 Cand then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacua to dryness, giving2(S)-( fert-butoxycarbonyl)aminobutyraldehyde as a low-melting solid (38.1 g; yield: 77%).Step 2 To a solution of 2 (59-BOC-AMINOBUTANOL (50 g; 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added at 20 C TEMPO (0. 01 EQ), sodium bromide (1 EQ) and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0 C and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0 C and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, giving 2 (- (TERT-BUTOXYCARBONYL)-AMINO-BUTYRALDEHYDE as a low-melting solid (38.1 g ; yield: 77%).To a solution of 2 (S)-Boc-aminobutanol (50 g; 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added at 20 C TEMPO (0.01 eq), sodium bromide (1 eq) and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0 C and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0 C and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuum to dryness, giving 2 ($)-test- butoxycarbonylaminobutyraldehyde as a low-melting solid (38. 1 g; yield: 77%).Reference U Synthesis of [()-2-AMINO-1-BENZOXAZOL-2-YLBUTAN-1-OL] hydrochloride Step 1 To a solution of benzoxazole (28. 6 g, 240 mmol) in toluene (150 mL) was added during ca 20 min. , at about a 2 M solution of isopropyl-magnesium chloride in THF (120 mL, 240 mmol). The red-brown mixture was stored at [CA-4C] and used as needed. Step 2 To a solution of (S)-2-Boc-aminobutanol (50 g; 264 mmol) in dichloromethane (500 [ML)] and water (350 mL) were added at [20 C] TEMPO (0.01 [EQ), ] sodium bromide (1 [EQ)] and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at [0 C] and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at [0] C and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated [IN VACUO] to dryness, giving [(2-2-(TERT-BUTOXYVARBONYL)-AMINOBUTYRALDEHYDE] as a low-melting solid (38. 1 g ; yield: 77%). Step 3 A solution of [()-2- (TERT-BUTOXYCARBONYL)] amino-butyraldehyde (30 g, 160 mmol) in toluene (150 mL) was added over 30 min. [AT-5 C] to a solution of Grignard reagent of benzoxazole (prepared as described in Step 1 above). The reaction mixture was stirred for 0.5 h at [0 C, ] then 2.5 h at RT. Quenching with 5% aq. acetic acid, washings with 5% aq. sodium carbonate, then brine and concentration to dryness gave crude (S)-2- (tert- butoxycarbonyl)-amino-l-benzoxazol-2-yl-butan-l-ol. The residue was diluted with toluene, and silica gel was added. The slurry was filtered. Elution by toluene removed the non-polar impurities. Then an 8/2 mixture of toluene and ethyl acetate desorbed the [(S)-2- (TERT-] butoxycarbonyl) [AMINO-1-BENZOXAZOL-2-YLBUTAN-1-OL.] Step 4 To a solution of [(S)-2- (TERT-BUTOXYCARBONYL) AMINO-L-BENZOXAZOL-2-YL-PROPAN-L-OL] (26.3 g, 86 mmol) in isopropanol (118 mL) at [20-25 C] was added trimethylchlorosilane (1.4 eq). The solution was stirred for 5 h at [50C.] Concentration of the reaction mixture to 52 mL followed by addition of isopropyl ether [(210 ML), ] filtration and drying under vacuum afforded [(S)-2-AMINO-1-BENZOXAZOL-2-YLBUTAN-1-OL] hydrochloride salt as a grey solid (16.4 g; yield = 79 %; mixture of diastereomers).A solution of oxalyl chloride (40.39 g, 265 ramol) in MeCk (700 mL) was stirred andcooled to -60 C. Dimethylsulfoxide (51.7 g, 663 mmol) in MeCl2 (100 mL) was addeddropwise. After 10 min., a solution of 2(Step 2 A solution of oxalyl chloride (40.39 g, 265 mmol) in CH2C12 (700 mL) was stirred and COOLED TO-60 C. Dimethylsulfoxide (51.7 g, 663 mmol) in CH2C12 (100 mL) was added dropwise. After 10 min, a solution of (6 )-2-8OC-AMINO-L-BUTANOL (50 g, 265 mmol) in CH2C12 (100 mL) was added dropwise AT-70 C. The reaction mixture was allowed to warm to-40 C for 10 min and then cooled to-70 C again. A solution of triethylamine (74.9 g, 742 mmol) in CH2CI2 (100 mL) was added. The reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 mL) was added, and then the organic layer was washed with brine and dried over MGS04. The solvent was removed to yield 45g of 2 (S)-BOC-AMINO-BUTYRALDEHYDE.A solution of oxalyl chloride (40. 39 g, 265 mmol) in CH2Cl2 (700 mL) was stirred and cooled to-60 C. Dimethylsulfoxide (51.7 g, 663 mmol) in CH2C12 (100 mL) was added dropwise. After 10 min, a solution of 2 (S)-Boc-amino-l-butanol (50 g, 265 mmol) in CH2CI2 (100 mL) was added dropwise at-70 C. The reaction mixture was allowed to warm to-40 C for 10 min and then cooled to-70 C again. A solution of triethylamine (74.9 g, 742 mmol) in CH2C12 (100 mL) was added and the reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 mL) was added and then the organic layer was washed with brine and dried over MgS04. The solvent was removed to yield 45 g of 2 (@-Boc-aminobutyraldehyde (1-formylpropyl) carbamic acid tert-butyl ester.Reference P Synthesis of [()-2-AMINO-1- (5-METHOXYMETHYL- [1, ] 3, 4] [OXADIAZOL-2-YL)-BUTAN-1-OL] Step 1 [(S)- (+)-2-AMINO-L-BUTANOL] (50 g, 561 mmol) in a mixture of water and dioxane (200 mL of water and: 200 mL) dioxane was cooled to [0 C] and mixed with [NAOH] (26.9 g, 673 mmol) and di-tert-butyl-dicarbonate (146.96 g, 673 mmol). After the addition, the reaction was allowed to warm to room temperature. The reaction mixture was stirred for 2 h. After removing the dioxane, the residue was extracted with EtOAc, then washed with brine and dried with anhydrous [MGS04, ] filtered and concentrated. Without further purification, the crude [(S)-2-BOC-AMINO-L-BUTANOL] (120 g) was used for next step reaction. Step 2 A solution of oxalyl chloride (40.39 g, 265 mmol) in [MECLZ] (700 mL) was stirred and cooled to-60 [C.] Dimethylsulfoxide (51.7 g, 663 mmol) in [MECL2] (100 [ML)] was added dropwise. After 10 min. , a solution of [(S)-2-BOC-AMINO-L-BUTANOL] (50 g, 265 mmol) in [MECL2] (100 mL) was added dropwise [AT-70 C.] The reaction mixture was allowed to warm to-40 C for 10 min. and then cooled to-70 C again. A solution of triethylamine (74.9 g, 742 mmol) in MeCl2 (100 mL) was added. The reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 [ML)] was added, and then the organic layer was washed with brine and dried over [MGS04. THE] solvent was removed to yield 45g of [(S)-2-BOC-AMINO-BUTYRALDEHYDE (L-FORMYL-PROPYL)-CARBAMIC] acid [TERT-BUTYL] ester. Step 3 A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate (30 mL) was heated to reflux for 8 h. Excess hydrazine and water were removed under vacuum. The residue was extracted with n-butanol, dried with [NA2SO4.] Excess n-butanol was removed to yield 45g of hydrazide. Step 4 A mixture of above hydrazide (45 g), [TRIETHYLORTHOFORMATE] (146 mL) and p- toluenesulfonic acid (61mg) was heated at [140 C] for 8 h. Excess [TRIETHYLORTHOFORMATE] was removed under vacuum. The product was purified by silica gel column chromatography to yield 4.6g of 2-methoxymethyl-1, 3, 4-oxadiazole. Step 5 To a stirred solution of 2-methoxymethyl-1, 3, 4-oxadiazole (4.6 g, 40 mmol) in THF (100 mL) was added n-BuLi (1.6 M solution in 25.2 mL of hexane) dropwise under N2 at-78 [C.] After 1 h, MgBr. Et2O (10.4 g, 40.3 mmol) was added and the reaction mixture was allowed to warm to-45 [C] for 1 h before being treated with (S)-2-Boc-amino- propanylaldehyde butyraldehyde (5.28 g, 28.25 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated [NH4C1, ] and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgS04 and concentrated. The residue was purified by silica gel column chromatography to yield [(S)-2-BOC-AMINO-1- (5-] methoxymethyl-[1, 3, [4]-OXADIAZOLE-2-YL)-1-PROPANOL] butanol (500 mg). Step 6 [2-BOC-AMINO-1- (5-METHOXYMETHYL- [1, ] 3, [4]-OXADIAZOLE-2-YL)-1-PROPANOL] butanol (500 mg, 1.66 mmol), and MeCl2 (5 mL) were mixed and TFA (0.5 mL) was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed under vacuum to produce [(S)-2-AMINO-L- (5-METHOXYMETHYL- [1, ] 3, 4] oxadiazol-2-yl)-butan-1-ol. TFA salt (340 mg).Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2CI2 (100 ml) to give a colorless solution. The reaction was cooled to - 60C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2C12 (20ml) was added dropwise at - 60C. The reaction was stirred for 10 min at -60C. Then (S)-tert-butyl -l-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20ml CH2C12 was added dropwise at -70C. The reaction was allowed to warm to -40C for 10 min and then cooled to -70C again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2C12 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2 x 150 mL).The organic layer was back-extracted with brine (1 x 50 mL). The organic layers were dried over Na2S04 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e) = 188.2 [M+H+]).A solution of oxalyl chloride (40.39 g, 265 mmol) in CH2Cl2 (700 ml) was stirred and cooled to-60 C. Dimethylsulfoxide (51.7 g, 663 mmol) in CH2Cl2 (100 ml) was added dropwise. After 10 min, a solution of (S)-2-Boc-amino-1-butanol (50 g, 265 mmol) in CH2C12 (100 ml) was added dropwise at-70 C. The reaction mixture was allowed to warm to-40 C for 10 min and then cooled to-70 C again. A solution of triethylamine (74.9 g, 742 mmol) in CH2C12 (100 ml) was added and the reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 ml) was added, and then the organic layer was washed with brine and dried over MgS04. The solvent was removed to yield (S)-2-Boc-amino-butyraldehyde (1-formylpropyl) carbamic acid ter-butyl ester (45 g).General procedure: To a solution of intermediates 10a-g (1 equiv) in dichloromethane, TsCl (1.2 equiv), DMAP (0.2 equiv) and trimethylamine(3 equiv) were added. The solutionwas stirred at 20 C.The reaction was followed by TLC and quenched with water. Theorganic phase was washed with citric acid (1 N) and saturatedNaHCO3 then dried over Na2SO4 and filtered. The filtrate wasconcentrated and purified by a silica column to afford compounds11a-g as a white solid.A mixture of 1-2 (100 mg, 0.53 mmol), R-2 (Hi mg, 0.59 mmol), and triphenylphosphine (210 mg, 0.80 mmol) is treated with DEAD (0.13 mE, 0.80 mmol) and stirred at ambient temperature for 2 h. The mixture is concentrated the purified by flash chromatography (5i02, 0-20% EtOAc in Rep) to afford 1-3 (181 mg, 95%). A solution of 1-3 (181 mg, 0.5 mmol) in dioxane (4 mE) is treated with a 4.OM RC1 solution in dioxane (1.0 mE). The mixture is concentrated in vacuo to afford the free amine (114 mg, 0.44 mmol) which is dissolved in dioxane (10 mE) then treated with Pd2(dba)3 (40 mg, 0.044 mmol), 9, 9- dimethyl-4, 5-bis(diphenylphosphino)xanthene (51 mg, 0.088 mmol) and Cs2CO3 (431 mg, 1.3 mmol). The mixture is heated at 80 C. overnight then cooled and pured into water, extracted with EtOAc, and concentrated in vacuoafford a mixture of 1-4 and I-S. The mixture is treated with MeOR (1 mE), water (0.25 mE) and EiOH-H20 (10 mg) and heated at 60 C. for 4 h. Mixture is cooled to ambient temperature then poured into water, acidified with 1 M aqueous HC1 and extracted with EtOAc to give afier concentration in vacuo 1-5 (105 mg, 84%), mlz=209.02 [M+H], RT=0.41 mm (HPEC-Method A)

Molecular Weight:189.25
XLogP3:1.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:189.13649347
Monoisotopic Mass:189.13649347
Topological Polar Surface Area:58.6
Heavy Atom Count:13
Complexity:163
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes