Name: 135065-70-2|(R)-2-((benzyloxy)methyl)morpholine|98%
Brand: Ambeed
SKU: A992092
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1
[ 926-39-6 ]
[ 14618-80-5 ]
[ 135065-70-2 ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium hydroxide; In methanol; water; at 50℃;	Example 1; (R)-Quinuclidin-3-yl 5-((S)-2-((4-amino-5-chloro-2-ethoxybenzamido)methyl)morpholino)pentanoate [Show Image] Mono-(2-amino-ethyl) sulfate (35.2 g, 250 mmol) was dissolved in 160 mL of aqueous sodium hydroxide solution (40percent) with stirring, and to the mixture was added with a solution of (R)benzyl glycidyl ether 1a (8.2 g, 50 mmol) in methanol. The reaction mixture was reacted overnight at 50°C and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was diluted with 100 mL of water and 100 mL of concentrated hydrochloric acid, and extracted with dichloromethane (200 mL.x.3). The combined organic phase was washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-2-benzyloxymethyl-morpholine 1b (5.08 g, yield 49percent) as a yellow liquid. MS m/z (ESI): 208.7 [M+1]. 1H NMR (CDCl3, 400 MHz) delta 7.4-7.2 (m, 5H), 4.56 (s, 2H), 3.9 (d, 1H, J=11Hz) 3.8-3.35 (m, 4H), 2.92 (dd, 1H, J1=2.5Hz, J2=12.0Hz), 2.85-2.75 (m, 2H), 2.66 (dd, 1H, J1=10.5Hz, J2=12.0Hz), 2.4 (s, 1H).
49%	With sodium hydroxide; In methanol; water; at 50℃;	Mono-(2-amino-ethyl) sulfate (35.2 g, 250 mmol) was dissolved in 160 mL of aqueous sodium hydroxide solution (40percent) with stirring, and to the mixture was added with a solution of (R)benzyl glycidyl ether 1a (8.2 g, 50 mmol) in methanol. The reaction mixture was reacted overnight at 50° C. and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was diluted with 100 mL of water and 100 mL of concentrated hydrochloric acid, and extracted with dichloromethane (200 mL.x.3). The combined organic phase was washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-2-benzyloxymethyl-morpholine 1b (5.08 g, yield 49percent) as a yellow liquid.MS m/z (ESI): 208.7 [M+1].1H NMR (CDCl3, 400 MHz) delta 7.4-7.2 (m, 5H), 4.56 (s, 2H), 3.9 (d, 1H, J=11 Hz), 3.8-3.35 (m, 4H), 2.92 (dd, 1H, J1=2.5 Hz, J2=12.0 Hz), 2.85-2.75 (m, 2H), 2.66 (dd, 1H, 1H, J1=10.5 Hz, J2=12.0 Hz), 2.4 (s, 1H).
	With sodium hydroxide; In water; at 55℃;	Step 1: (R)-2-(Benzyloxymethyl)morpholine: A stirred mixture of (R)-benzyl glycidyl ether (16.4 g) and 2-aminoethyl hydrogen sulfate (56.4 g) was treated with a solution of sodium hydroxide (16 g) in water (33 mL). The reaction mixture was warmed to 55 0C overnight. Water (250 mL) was added and the mixture extracted into toluene (200 mL x 3). The organic layers were combined, washed with brine and then dried over magnesium sulfate, filtered and concentrated to yield the subtitle compound as a pale oil (16.5 g) which was used directly in the next step.1H NMR delta(CDCl3):1.85-2.00 (IH, br s), 2.14-2.28 (IH, m), 2.38-2.50 (IH, m), 2.60- 2.95 (3H, m), 3.39-3.55 (2H, m), 3.57-3.70 (IH, m), 3.89 (IH, dm), 4.51-4.54 (2H, ABq), 7.18-7.36 (5H, m).

	With water; sodium hydroxide; In methanol; at 40℃; for 2h;	Step 1. (i?)-2-(Benzyloxymethyl)morpholine: To a stirred mixture of (R)-2- (benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 niL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition was complete, the reaction mixture was stirred at 4O0C for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol), followed by toluene (70 mL), and stirred at 650C overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were concentrated to give crude (R)-2- (benzyloxymethyl)morpholine (~14 g), which was used without purification. MS m/z 208 (M+H+).
	With sodium hydroxide; In methanol; water; toluene; at 40 - 65℃;	To a stirred mixture of (2R)-2-[(benzy[oxy)methy[]oxirane (27.7 g, 0.17 mo[) and NaOH (54.0 g, 1.3 mo[) in water (130 mL) and MeOH (50 mL) was added 2-aminoethy[ hydrogen su[fate (100 g, 0.7 mo[) portionwise. After addition was comp[ete, the reaction mixture was stirred at 40 °C for 2 h. On coo[ing, the mixture was treated with a further portion of NaOH (40.5 g, 1 .0 mo[), fo[[owed by to[uene (200 mL) and stirred at 65 °C overnight. The mixture was coo[ed, di[uted with to[uene and water. The to[uene [ayer was separated and the aqueous [ayerextracted with DCM (2 x 100 mL). The combined organic [ayers were concentrated to give the tit[e compound, which was used in the next step without purification.
		Benzyl-(R)-glycidyl ether (2.00 g, 12.2 mmol) and NaOH (4.00 g,100 mmol) in H2O (9.2 mL) and MeOH (3.6 mL) were treated with2-aminoethyl hydrogen sulphate (7.00 g, 49.59 mmol). The reactionmixturewas stirred for 90 min at 40 °C. The mixturewas allowed tocool to room temperature, toluene (14 mL) and NaOH (2.00 g,50.0 mmol) were added and then it was stirred overnight at 65 °C.Toluene (5 mL) and H2O (20 mL) were added and the organic layerwas separated. The water layer was extracted with CH2Cl2(2 10 mL). The combined organic layers were dried over Na2SO4,filtered and concentrated in vacuo to give crude amine which wastaken up in acetone (20 mL) and H2O (6 mL) at 0 °C. Di-tert-butyldicarbonate (2.60 g, 11.9 mmol) was added and the resultingmixture was stirred vigorously for 2 h. The acetone was removedunder reduced pressure and the aqueous solution was extractedwith CH2Cl2. The organic layer was washed with brine, dried overNa2SO4, filtered and concentrated in vacuo. FCC (hexane/EtOAc10:0 ? 7:3) afforded the title compound as a colorless oil in 43percent(over 2 steps). 1H NMR (300 MHz, 80 °C, DMSO-d6) delta ppm 1.41 (s,9 H) 2.69 (dd, J 12.9, 9.4 Hz, 1 H) 2.87 (ddd, J 13.2, 11.4, 3.5 Hz,1 H) 3.28e3.56 (m, 4 H) 3.68 (ddt, J 13.2, 3.0, 1.6 Hz, 1 H)3.75e3.86 (m, 2 H) 4.50 (s, 2 H) 7.22e7.38 (m, 5 H). 13C NMR(75 MHz, 80 °C, DMSO-d6) delta ppm 27.7, 43.0, 45.3, 65.1, 70.2, 72.2,73.6, 78.7, 126.9, 127.0, 127.7, 138.0, 153.6. HRMS (ESI-TOF) m/z:[M+H]+ Calcd for C17H26NO4 308.18563; Found 308.1867.
		Step 1. (R)-2-(Benzyloxymethyl)morpholine. To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL), there was added 2-aininoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition, the reaction mixture was- stirred at 4O0C for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol) then toluene (70 mL) and stirred at 650C overnight. The mixture was cooled,. diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2CI2 (2 x 50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (~14 g), which was used without purification. MS m/z 208 (M+H+).

Reference： [1]Heterocycles,1993,vol. 35,p. 105 - 109
[2]Patent: EP2189451,2010,A1 .Location in patent: Page/Page column 9
[3]Patent: US2010/210640,2010,A1 .Location in patent: Page/Page column 8-9
[4]Chemical and Pharmaceutical Bulletin,1994,vol. 42,p. 877 - 882
[5]Patent: WO2007/11292,2007,A1 .Location in patent: Page/Page column 28-29
[6]Patent: WO2008/124582,2008,A1 .Location in patent: Page/Page column 96
[7]Patent: WO2016/91776,2016,A1 .Location in patent: Page/Page column 289
[8]European Journal of Medicinal Chemistry,2017,vol. 127,p. 757 - 770
[9]Patent: WO2007/117557,2007,A2 .Location in patent: Page/Page column 78

2
[ 24424-99-5 ]
[ 135065-70-2 ]
[ 135097-68-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In dichloromethane at 20 - 25℃; for 2h;
64%	With potassium carbonate In dichloromethane at 20℃;	1 (R)-2-Benzyloxymethyl-morpholine 1b (2.07 g, 10 mmol) was dissolved in 20 mL of dichloromethane with stirring, and to the mixture was added potassium carbonate (1.38 g, 10 mmol) and di-tert-butyl-dicarbonate (3.27 g, 15 mmol). The reaction mixture was stirred overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The resulting mixture was added with saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-2-benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1c (1.967 g, yield 64%) as a colorless transparent liquid. MS m/z (ESI): 308.1 [M+1]. 1H NMR (CDCl3, 400 MHz) δ 7.35-7.25 (m, 5H), 4.56 (s, 2H), 3.91-3.88 (m, 3H), 3.53-3.45 (m, 4H), 3.0-2.9 (m, 1H), 2.8-2.7 (m, 1H), 1.46 (s, 9H).
64%	With potassium carbonate In dichloromethane at 20℃;	1 (R)-2-Benzyloxymethyl-morpholine 1b (2.07 g, 10 mmol) was dissolved in 20 mL of dichloromethane with stirring, and to the mixture was added potassium carbonate (1.38 g, 10 mmol) and di-tert-butyl-dicarbonate (3.27 g, 15 mmol). The reaction mixture was stirred overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The resulting mixture was added with saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (R)-2-benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1c (1.967 g, yield 64%) as a colorless transparent liquid.MS m/z (ESI): 308.1 [M+1].1H NMR (CDCl3, 400 MHz) δ 7.35-7.25 (m, 5H), 4.56 (s, 2H), 3.91-3.88 (m, 3H), 3.53-3.45 (m, 4H), 3.0-2.9 (m, 1H), 2.8-2.7 (m, 1H), 1.46 (s, 9H).

38%	With potassium carbonate In water; acetone at 0 - 20℃; for 18h;	111 tert-butyl (2R)-2-[(benzyloxy)methyl]morpholine-4-carboxylate A so[ution of Intermediate 110 in acetone (400 mL) and water (120 mL) was coo[ed to 0 °C and potassium carbonate (70 g, 0.5 mo[) was added fo[[owed by di-tertbuty[ dicarbonate (44 g, 0.2 mo[). The reaction mixture was a[[owed to warm to ambient temperature and was stirred for 18 h. Acetone was removed under reduced pressure and the aqueous solution extracted twice with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by Biotage IsoleraTM chromatography(eluting with 0 - 25 % EtOAc in heptane on a pre-packed 340 g silica gel column) to give 19.8 g (38% yield) of the title compound as pale yellow oil.1H NMR (250 MHz, chloroform-d): 6 [ppm] 7.39 - 7.27 (m, 5H), 4.56 (5, 2H), 4.03 -3.73 (m, 3H), 3.69- 3.34 (m, 4H), 3.05-2.86 (m, 1H), 2.84- 2.65 (m, 1H), 1.46 (5,9H).LC-MS (Method A) Rt =1.27 mm, MS (ESipos): m/z = 252 (M-tBu).
	With triethylamine In dichloromethane	3.b 3(b) 3(b) (R)-2-(Benzyloxymethyl)-4-t-butoxycarbonylmorpholine 7.3 ml of triethylamine were added to 100 ml of methylene chloride containing 10.9 g of (R)-2-(benzyloxymethyl)morpholine [prepared as described in step (a) above], and then 20 ml of methylene chloride containing 12.1 g of di-t-butyl pyrocarbonate was added dropwise to the mixture on an ice bath. The mixture was then stirred for 2 hours at room temperature, after which the reaction mixture was condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography using a 1: 4 by volume mixture of ethyl acetate and hexane as the eluent, to obtain 14. 2 g of the title compound as a syrup. Optical rotation [α] [25/D ] - 17.2° (c = 1, chloroform). Nuclear Magnetic Resonance Spectrum (CDCl3), δ ppm: 1.48 (9H, singlet); 2.5 - 4.05 (9H, multiplet); 4.52 (2H, singlet); 7.32 (5H, singlet).
	In 1,4-dioxane; water at 20℃; for 5h;	2.a Step a) 2R-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester2g of S-(+)-2-(benzyloxymethyl)-oxirane and 7 g of 2-aminoethyl hydrogen sulfate were weighed into a 100 ml round bottle flask, 2 g of NaOH dissolved in H2O was added and the stirred mixture was heated at 50 0C for 1 hour. 4 g of NaOH dissolved in 10 ml H2O, solution was added to the stirred mixture, which was then heated at 55 0C for 16 h. After cooling the mixture to room temperature, it was diluted with 100 ml H2O and 100 ml dioxane and 2.66 g of di-tert-butyl dicarbonate was added. The mixture was stirred at room temperature for 5 hours, transferred into a separation funnel and extracted with 2 x 75 ml of toluene. Combined organic phases were washed with 2 x 50 ml of 1 M citric acid (aq.), once with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified on silica yielding 2R- Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1.85 g (49%) as a clear oil.
	With triethylamine In dichloromethane for 16h;	1.2 Step 2: (R)-2-(Benzyloxymethyl)morpholine-4-carboxylic acid tert-butyl ester: To a stirred solution of (R)-2-(benzyloxymethyl)morpholine (Stepl) (16.0 g) and triethylamine (12.9 mL) in DCM (230 mL) was added di-tert-butyl dicarbonate (18.5 g). After 16 h, aqueous sodium bicarbonate (200 mL) was added and the mixture was extracted into DCM (100 mL x 3). The organic layers were combined, washed with brine and dried over magnesium sulfate, filtered and concentrated. The resulting oil was chromatographed (SiO2: eluent 1 : 5 ethyl acetate/40-60 petroleum ether) to yield the subtitle compound as a colourless oil (12.1 g).1H NMR δ(CDCl3): 1-46 (9H, s), 2.74 (IH, t), 2.95 (IH, t), 3.42 - 3.65 (4H, m), 3.79 3.97 (3H, m), 4.56 (2H, s), 7.24 - 7.39 (5H, m).
	With potassium carbonate In water; acetone at 0 - 20℃; for 0.5h;	9.2 To a solution of crude (i?)-2-(benzyloxymethyl)morpholine (~14 g) in acetone (100 mL) and H2O (30 mL) at O0C, there was added K2CO3 (25.2 g, 182.7 mmol), followed by (Boc)2O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (~30 min). Acetone was removed under vacuum, and the aqueous solution was extracted with CH2Cl2 (4 x 10 mL). The combined organic layers were washed with H2O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)-tert- butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1H NMR (400MHz, CDCl3): 7.34 (m, 5 H), 4.56 (s, 2 H), 3.88 (d, 2 H), 3.82 (br, 1 H), 3.40 (m, 1 H), 3.48 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.44 (s, 9 H); MS m/z 330 (M+Na+).
	With potassium carbonate In water; acetone at 0 - 20℃;	3.2 Step 2. (R)-tert-Butyl 2-(benzyloxymethyl)morpholine-4-carboxylate To a solution of crude (R)-2-(benzyloxymethyl)morpholine (~14 g) in acetone (100 mL) and H2O (30 mL) at 0° C., was added K2CO3 (25.2 g, 182.7 mmol), followed by (Boc)2O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (~30 min). The acetone was removed under vacuum and the aqueous solution was extracted with CH2Cl2 (4*10 mL). The combined organic layers were washed with H2O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)-tert-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1H NMR (400 MHz, CDCl3): δ=7.34 (m, 5H), 4.56 (s, 2H), 3.88 (d, 2H), 3.82 (br, 1H), 3.40 (m, 1H), 3.48 (m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.44 (s, 9H); MS m/z 330 (M+Na+).
	In 1,4-dioxane; water at 20℃; for 5h;	10.1 2g of S-(+)-2-(benzyloxymethyl)-oxirane and 7 g of 2-aminoethyl hydrogen sulfate were weighed into a 100 ml round bottle flask, 2 g of NaOH dissolved in H2O was added and the stirred mixture was heated at 50 0C for 1 hour. 4 g of NaOH dissolved in 10 ml H2O, solution was added to the stirred mixture, which was then heated at 55 0C for 16 h. After cooling the mixture to room temperature, it was diluted with 100 ml H2O and 100 ml dioxane and 2.66 g of di-tert-butyl dicarbonate was added. The mixture was stirred at room temperature for 5 hours, transferred into a separation funnel and extracted with 2 x 75 ml of toluene. Combined organic phases were washed with 2 x 50 ml of 1 M citric acid (aq.), once with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified on silica yielding 2R-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1.85 g (49%) as a clear oil.
	With potassium carbonate In water; acetone at 0 - 20℃; for 0.5h;	26.2 To a solution of crude (R)-2-(benzyloxymethyl)morpholine (~14 g) in acetone(100 mL) and H2O (30 mL) at O°C, there was added K2CO3 (25.2 g, 182.7 mmol), followed by (Boc)2O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (-30 min), acetone was removed under vacuum, and the aqueous solution was extracted with CH2Cl2 (4 x 10 mL). The combined organic layers were washed with H2O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)-tert-butyl 2- (benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1H NMR (400MHz, CDCl3): 7.34 (m, 5 H), 4.56 (s, 2 H), 3.88 (d, 2 H), 3.82 (br, 1 H), 3.40 (m, 1 H), 3.48 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.44 (s, 9 H); MS m/z 330 (M+Na+).
	With potassium carbonate In water; acetone at 0 - 20℃;	6.2 To a solution of crude (R)-2-(benzyloxymethyl)morpholine (14 g) in acetone (100 mL) and H2O (30 mL) at 0° C., there was added K2CO3 (25.2 g, 182.7 mmol), followed by (Boc)2O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (30 min). Acetone was removed under vacuum, and the aqueous solution was extracted with CH2Cl2 (4×10 mL). The combined organic layers were washed with H2O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)-tert-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1H NMR (400 MHz, CDCl3) δ ppm 7.34 (m, 5H), 4.56 (s, 2H), 3.88 (d, 2H), 3.82 (br, 1H), 3.40 (m, 1H), 3.48 (m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.44 (s, 9H); MS m/z 330 (M+Na+).
	With potassium carbonate In water; acetone at 0 - 20℃; for 0.5h;
	With potassium carbonate In water; acetone at 0 - 20℃;	10.2 Step 2. (R)-tert-Buty 2-(benzyloxymethyl)morpholine-4-carboxylate: To a solution of crude (i?)-2-(benzyloxymethyl)morpholine (~14 g) in acetone (100 rnL) and H2O (30 rnL) at O0C, there was added K2CO3 (25.2 g, 182.7 mmol), followed by (Boc)2O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (~30 min). Acetone was removed under vacuum, and the aqueous solution was extracted with CH2Cl2 (4 x 10 mL). The combined organic layers were washed with H2O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)-tert-buty{ 2- (benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1H NMR (400MHz, CDCl3): 7.34 (m, 5 H), 4.56 (s, 2 H), 3.88 (d, 2 H), 3.82 (br, 1 H), 3.40 (m, 1 H), 3.48 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.44 (s, 9 H); MS m/z 330 (M+Na+).
	With potassium carbonate In water; acetone at 0℃; for 2h; Inert atmosphere;	6.1.32. Tert-butyl (R)-2-((benzyloxy)methyl)morpholine-4-carboxylate (30) Benzyl-(R)-glycidyl ether (2.00 g, 12.2 mmol) and NaOH (4.00 g,100 mmol) in H2O (9.2 mL) and MeOH (3.6 mL) were treated with2-aminoethyl hydrogen sulphate (7.00 g, 49.59 mmol). The reactionmixturewas stirred for 90 min at 40 °C. The mixturewas allowed tocool to room temperature, toluene (14 mL) and NaOH (2.00 g,50.0 mmol) were added and then it was stirred overnight at 65 °C.Toluene (5 mL) and H2O (20 mL) were added and the organic layerwas separated. The water layer was extracted with CH2Cl2(2 10 mL). The combined organic layers were dried over Na2SO4,filtered and concentrated in vacuo to give crude amine which wastaken up in acetone (20 mL) and H2O (6 mL) at 0 °C. Di-tert-butyldicarbonate (2.60 g, 11.9 mmol) was added and the resultingmixture was stirred vigorously for 2 h. The acetone was removedunder reduced pressure and the aqueous solution was extractedwith CH2Cl2. The organic layer was washed with brine, dried overNa2SO4, filtered and concentrated in vacuo. FCC (hexane/EtOAc10:0 → 7:3) afforded the title compound as a colorless oil in 43%(over 2 steps). 1H NMR (300 MHz, 80 °C, DMSO-d6) δ ppm 1.41 (s,9 H) 2.69 (dd, J 12.9, 9.4 Hz, 1 H) 2.87 (ddd, J 13.2, 11.4, 3.5 Hz,1 H) 3.28e3.56 (m, 4 H) 3.68 (ddt, J 13.2, 3.0, 1.6 Hz, 1 H)3.75e3.86 (m, 2 H) 4.50 (s, 2 H) 7.22e7.38 (m, 5 H). 13C NMR(75 MHz, 80 °C, DMSO-d6) δ ppm 27.7, 43.0, 45.3, 65.1, 70.2, 72.2,73.6, 78.7, 126.9, 127.0, 127.7, 138.0, 153.6. HRMS (ESI-TOF) m/z:[M+H]+ Calcd for C17H26NO4 308.18563; Found 308.1867.
	With potassium carbonate In water; acetone at 0 - 20℃; for 0.5h;	34.2; 36.2 To a solution of crude (R)-2-(benzyloxymethyl)morpholine (~14 g) in acetone (100 mL) and H2O (30 mL) at O0C, was added K2CO3 (25.2 g, 182.7 ramol), followed by (Boc)2O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (~30 min). Acetone was removed under vacuum and the aqueous solution was extracted with CH2Cl2 (4 x 10 mL). The combined organic layers were washed with H2O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)- •tert-butyl 2-(benzyloxymelhyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1H NMR (400MHz3 CDCl3): 7.34 (m, 5 H), 4.56 (s, 2 H), 3.88 (d, 2 H), 3.82 (br, 1 H)5 3.40 (m, 1 H), 3.48 (m, 3 H)5 2.94 (m, 1 H), 2.76 (m, 1 H), 1.44 (s, 9 H); MS m/z 330 (M+Na+).
	With potassium carbonate In water; acetone at 0 - 20℃; for 0.5h;	4.2 Step 2. (R)-tert-Butyl 2-(benzyloxymethyl)morpholine-4-carboxylate. To a solution of crude (R)-2-(benzyloxymethyl)morpholine (~14 g) in acetone (100 mL) and H2O (30 mL) at O0C5 was added K2CO3 (25.2 g, 182.7 mmol), • followed by (Boc)2O (14.6 g, 67.0 mmol). The resulting solution was warmed to rt, and stirred until no starting material remained (~30 min). Acetone was removed under vacuum and the aqueous solution was extracted with CH2Cl2 (4 x 10 mL). The combined organic layers were washed with H2O (10 mL) and the solvent was removed. The residue was purified by flash column chromatography to give (R)- rer/-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 44% over 2 steps). 1H NMR (400MHz, CDCl3): 7.34 (m, 5 H)5 4.56 (s, 2 H), 3.88 (d5 2 H), 3.82 (br, 1 H), 3.40 (m, 1 H), 3.48 (m, 3 H), 2.94 (m, 1 H), 2.76 (m, 1 H), 1.44 (s, 9 H); MS m/z 330 (M+Na+). .

Reference： [1]Yanagisawa, Hiroaki; Kanazaki, Takuro [Heterocycles, 1993, vol. 35, # 1, p. 105 - 109]
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - EP2189451, 2010, A1 Location in patent: Page/Page column 9-10
[3]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - US2010/210640, 2010, A1 Location in patent: Page/Page column 9
[4]Current Patent Assignee: EVOTEC AG; BAYER AG - WO2016/91776, 2016, A1 Location in patent: Page/Page column 289; 290
[5]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP411912, 1991, A2
[6]Current Patent Assignee: MEDIVIR AB - WO2007/6715, 2007, A1 Location in patent: Page/Page column 28
[7]Current Patent Assignee: ASTRAZENECA PLC - WO2007/11292, 2007, A1 Location in patent: Page/Page column 29
[8]Current Patent Assignee: ABBVIE INC - WO2008/124575, 2008, A1 Location in patent: Page/Page column 112; 113
[9]Current Patent Assignee: ABBVIE INC - US2010/184805, 2010, A1 Location in patent: Page/Page column 30
[10]Current Patent Assignee: MEDIVIR AB - WO2007/6714, 2007, A1 Location in patent: Page/Page column 120
[11]Current Patent Assignee: ABBVIE INC - WO2007/70201, 2007, A1 Location in patent: Page/Page column 176
[12]Current Patent Assignee: ABBVIE INC - US2010/317697, 2010, A1 Location in patent: Page/Page column 51
[13]Location in patent: scheme or table Yuan, Jing; Simpson, Robert D.; Zhao, Wei; Tice, Colin M.; Xu, Zhenrong; Cacatian, Salvacion; Jia, Lanqi; Flaherty, Patrick T.; Guo, Joan; Ishchenko, Alexey; Wu, Zhongren; McKeever, Brian M.; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Panemangalore, Reshma; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Singh, Suresh B.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843]
[14]Current Patent Assignee: ABBVIE INC - WO2008/124582, 2008, A1 Location in patent: Page/Page column 96-97
[15]Vermote, Arno; Brackman, Gilles; Risseeuw, Martijn D.P.; Coenye, Tom; Van Calenbergh, Serge [European Journal of Medicinal Chemistry, 2017, vol. 127, p. 757 - 770]
[16]Current Patent Assignee: ABBVIE INC - WO2007/117560, 2007, A2 Location in patent: Page/Page column 182
[17]Current Patent Assignee: ABBVIE INC - WO2007/117557, 2007, A2 Location in patent: Page/Page column 79

3
[ 135065-70-2 ]
[ 156925-22-3 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1994,vol. 42,p. 877 - 882

4
[ 135065-70-2 ]
[ 156334-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 3 g / hydrogen / palladium-on-carbon / ethanol / 50 °C 2: NaI, K₂CO₃ / butan-2-one / 18 h / Heating 3: triethylamine, 4-(dimethylamino)pyridine / CH₂Cl₂ / 1.) 5 deg C, 2.) RT, 24 h 4: 2.1 g / sodium azide / dimethylformamide / 2 h / 120 °C 5: 70percent sodium bis(2-methoxyethoxy)aluminium hydride / toluene / 1.5 h / -5 - 20 °C

Reference： [1]Morie; Kato; Harada; Yoshida; Matsumoto [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 4, p. 877 - 882]

5
[ 135065-70-2 ]
[ 156925-21-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 3 g / hydrogen / palladium-on-carbon / ethanol / 50 °C 2: NaI, K₂CO₃ / butan-2-one / 18 h / Heating

Reference： [1]Morie; Kato; Harada; Yoshida; Matsumoto [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 4, p. 877 - 882]

6
[ 135065-70-2 ]
(S)-2-(azidomethyl)-4-(4-fluorobenzyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 3 g / hydrogen / palladium-on-carbon / ethanol / 50 °C 2: NaI, K₂CO₃ / butan-2-one / 18 h / Heating 3: triethylamine, 4-(dimethylamino)pyridine / CH₂Cl₂ / 1.) 5 deg C, 2.) RT, 24 h 4: 2.1 g / sodium azide / dimethylformamide / 2 h / 120 °C

Reference： [1]Morie; Kato; Harada; Yoshida; Matsumoto [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 4, p. 877 - 882]

7
[ 135065-70-2 ]
[ 156925-20-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 3 g / hydrogen / palladium-on-carbon / ethanol / 50 °C 2: NaI, K₂CO₃ / butan-2-one / 18 h / Heating 3: triethylamine, 4-(dimethylamino)pyridine / CH₂Cl₂ / 1.) 5 deg C, 2.) RT, 24 h

Reference： [1]Morie; Kato; Harada; Yoshida; Matsumoto [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 4, p. 877 - 882]

8
[ 135065-70-2 ]
(S)-(-)-4-amino-5-chloro-2-ethoxy-N-<<4-(4-fluorobenzyl)-2-morpholinyl>methyl>benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 3 g / hydrogen / palladium-on-carbon / ethanol / 50 °C 2: NaI, K₂CO₃ / butan-2-one / 18 h / Heating 3: triethylamine, 4-(dimethylamino)pyridine / CH₂Cl₂ / 1.) 5 deg C, 2.) RT, 24 h 4: 2.1 g / sodium azide / dimethylformamide / 2 h / 120 °C 5: 70percent sodium bis(2-methoxyethoxy)aluminium hydride / toluene / 1.5 h / -5 - 20 °C 6: 86 percent / 1-<3-(dimethylamino)propyl>-3-ethyl-carbodiimide hydrochloride / CH₂Cl₂ / 3 h / Ambient temperature

Reference： [1]Morie; Kato; Harada; Yoshida; Matsumoto [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 4, p. 877 - 882]

9
[ 135065-70-2 ]
N-(S)-<<4-(4-fluorobenzyl)-2-morpholinyl>methyl>-(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 3 g / hydrogen / palladium-on-carbon / ethanol / 50 °C 2: NaI, K₂CO₃ / butan-2-one / 18 h / Heating 3: triethylamine, 4-(dimethylamino)pyridine / CH₂Cl₂ / 1.) 5 deg C, 2.) RT, 24 h 4: 2.1 g / sodium azide / dimethylformamide / 2 h / 120 °C 5: 70percent sodium bis(2-methoxyethoxy)aluminium hydride / toluene / 1.5 h / -5 - 20 °C 6: 55 percent / pyridine / CH₂Cl₂ / 2 h / 0 - 20 °C

Reference： [1]Morie; Kato; Harada; Yoshida; Matsumoto [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 4, p. 877 - 882]

10
[ 135065-70-2 ]
[ 135065-71-3 ]

Reference： [1]Heterocycles,1993,vol. 35,p. 105 - 109
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[3]Patent: WO2016/91776,2016,A1
[4]European Journal of Medicinal Chemistry,2017,vol. 127,p. 757 - 770
[5]Patent: WO2007/117560,2007,A2
[6]Patent: WO2007/117557,2007,A2
[7]Patent: WO2008/124582,2008,A1

11
[ 135065-70-2 ]
[ 135065-64-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 88 percent / Et₃N / CH₂Cl₂ / 2 h / 20 - 25 °C 2: 100 percent / H₂ / 5percent Pd/C / ethanol / 9 h / 70 °C 3: Et₃N / CH₂Cl₂ / 16 h / 20 - 25 °C
	Multi-step reaction with 3 steps 1: potassium carbonate / water; acetone / 18 h / 0 - 20 °C 2: palladium 10% on activated carbon; hydrogen / 16 h 3: triethylamine; trimethylamine hydrochloride / dichloromethane / 2 h / 20 °C

Reference： [1]Yanagisawa, Hiroaki; Kanazaki, Takuro [Heterocycles, 1993, vol. 35, # 1, p. 105 - 109]
[2]Current Patent Assignee: EVOTEC AG; BAYER AG - WO2016/91776, 2016, A1

12
[ 135065-70-2 ]
[ 148638-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 88 percent / Et₃N / CH₂Cl₂ / 2 h / 20 - 25 °C 2: 100 percent / H₂ / 5percent Pd/C / ethanol / 9 h / 70 °C 3: Et₃N / CH₂Cl₂ / 16 h / 20 - 25 °C

Reference： [1]Yanagisawa, Hiroaki; Kanazaki, Takuro [Heterocycles, 1993, vol. 35, # 1, p. 105 - 109]

13
[ 135065-70-2 ]
[ 135065-63-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 88 percent / Et₃N / CH₂Cl₂ / 2 h / 20 - 25 °C 2: 100 percent / H₂ / 5percent Pd/C / ethanol / 9 h / 70 °C 3: Et₃N / CH₂Cl₂ / 16 h / 20 - 25 °C

Reference： [1]Yanagisawa, Hiroaki; Kanazaki, Takuro [Heterocycles, 1993, vol. 35, # 1, p. 105 - 109]

14
[ 135065-70-2 ]
[ 135065-62-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 88 percent / Et₃N / CH₂Cl₂ / 2 h / 20 - 25 °C 2: 100 percent / H₂ / 5percent Pd/C / ethanol / 9 h / 70 °C 3: Et₃N / CH₂Cl₂ / 16 h / 20 - 25 °C

Reference： [1]Yanagisawa, Hiroaki; Kanazaki, Takuro [Heterocycles, 1993, vol. 35, # 1, p. 105 - 109]

15
[ 2930-05-4 ]
2-aminomethyl hydrogen sulphate [ No CAS ]
[ 135065-70-2 ]

Yield	Reaction Conditions	Operation in experiment
		12.A Step A Step A (-)-2(R)-(Phenylmethyloxymethyl)morpholine The title compound was obtained (2.85 g, 32%) from 2-aminomethyl hydrogen sulphate and (+)-2(benzyloxymethyl)oxirane as described in Example 2, Step A. MS, CI+, m/z=208 for (M+H)+. [α]27° C.D =-2.0° (c=1.0, methanol).

Reference： [1]Current Patent Assignee: MERCK & CO INC - US5614518, 1997, A

16
C₁₂H₁₉NO₆S [ No CAS ]
[ 135065-70-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In water at 55℃; for 16h;	2.a Step a) 2R-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester2g of S-(+)-2-(benzyloxymethyl)-oxirane and 7 g of 2-aminoethyl hydrogen sulfate were weighed into a 100 ml round bottle flask, 2 g of NaOH dissolved in H2O was added and the stirred mixture was heated at 50 0C for 1 hour. 4 g of NaOH dissolved in 10 ml H2O, solution was added to the stirred mixture, which was then heated at 55 0C for 16 h. After cooling the mixture to room temperature, it was diluted with 100 ml H2O and 100 ml dioxane and 2.66 g of di-tert-butyl dicarbonate was added. The mixture was stirred at room temperature for 5 hours, transferred into a separation funnel and extracted with 2 x 75 ml of toluene. Combined organic phases were washed with 2 x 50 ml of 1 M citric acid (aq.), once with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified on silica yielding 2R- Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1.85 g (49%) as a clear oil.
	With sodium hydroxide In methanol; water; toluene at 65℃; for 2h;	9.1 To a stirred mixture of (7?)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition was complete, the reaction mixture was stirred at 4O0C for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol), followed by toluene (70 mL), and stirred at 650C overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were concentrated to give crude (i?)-2-(benzyloxymethyl)morpholine (~14 g), which was used without purification. MS m/z 208 (M+H+).
	With sodium hydroxide In methanol; water; toluene at 65℃; for 2h;	3.1 Step 1. (R)-2-(Benzyloxymethyl)morpholine 2-Aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) was added in portions to a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL). After addition, the reaction mixture was stirred at 40° C. for 2 h. After cooling to rt, the mixture was treated with NaOH (15.0 g, 375.0 mmol), then toluene (70 mL) and stirred at 65° C. overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2*50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (~14 g), which was used without purification. MS m/z 208 (M+H+).

	With sodium hydroxide In water at 50℃; for 16h;	10.1 2g of S-(+)-2-(benzyloxymethyl)-oxirane and 7 g of 2-aminoethyl hydrogen sulfate were weighed into a 100 ml round bottle flask, 2 g of NaOH dissolved in H2O was added and the stirred mixture was heated at 50 0C for 1 hour. 4 g of NaOH dissolved in 10 ml H2O, solution was added to the stirred mixture, which was then heated at 55 0C for 16 h. After cooling the mixture to room temperature, it was diluted with 100 ml H2O and 100 ml dioxane and 2.66 g of di-tert-butyl dicarbonate was added. The mixture was stirred at room temperature for 5 hours, transferred into a separation funnel and extracted with 2 x 75 ml of toluene. Combined organic phases were washed with 2 x 50 ml of 1 M citric acid (aq.), once with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified on silica yielding 2R-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1.85 g (49%) as a clear oil.
	With water; sodium hydroxide In toluene at 65℃;	6.1 To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition was complete, the reaction mixture was stirred at 40° C. for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol), followed by toluene (70 mL), and stirred at 65° C. overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (14 g), which was used without purification. MS m/z 208 (M+H+).
	With sodium hydroxide In water; toluene at 65℃; for 16h;
	With sodium hydroxide In methanol; water; toluene at 65℃;	34.1; 36.1 To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL), there was added 2-aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition, the reaction mixture was stirred at 400C for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol) then toluene (70 mL) and stirred at 650C overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethy])morpholine (-14 g), which was used without purification. MS m/z 208 (M+H+).

Reference： [1]Current Patent Assignee: MEDIVIR AB - WO2007/6715, 2007, A1 Location in patent: Page/Page column 28
[2]Current Patent Assignee: ABBVIE INC - WO2008/124575, 2008, A1 Location in patent: Page/Page column 112; 113
[3]Current Patent Assignee: ABBVIE INC - US2010/184805, 2010, A1 Location in patent: Page/Page column 30
[4]Current Patent Assignee: MEDIVIR AB - WO2007/6714, 2007, A1 Location in patent: Page/Page column 120
[5]Current Patent Assignee: ABBVIE INC - US2010/317697, 2010, A1 Location in patent: Page/Page column 51
[6]Location in patent: scheme or table Yuan, Jing; Simpson, Robert D.; Zhao, Wei; Tice, Colin M.; Xu, Zhenrong; Cacatian, Salvacion; Jia, Lanqi; Flaherty, Patrick T.; Guo, Joan; Ishchenko, Alexey; Wu, Zhongren; McKeever, Brian M.; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Panemangalore, Reshma; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Singh, Suresh B.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843]
[7]Current Patent Assignee: ABBVIE INC - WO2007/117560, 2007, A2 Location in patent: Page/Page column 181-182; 188-189

17
C₁₁H₁₇NO₅S [ No CAS ]
[ 135065-70-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In methanol; water; toluene at 65℃;	26.1 To a stirred mixture of (R)-2-(benzyloxymethyl)oxirane (10.0 g, 60.9 mmol) and NaOH (19.49 g, 487.2 mmol) in H2O (46 mL) and MeOH (18 mL), there was added 2- aminoethyl hydrogen sulfate (36.8 g, 255.8 mmol) in portions. After addition the reaction mixture was stirred at 4O°C for 2 h. After cooling, the mixture was treated with NaOH (15.0 g, 375.0 mmol) then toluene (70 mL) and stirred at 65°C overnight. The mixture was cooled, diluted with toluene (27 mL) and H2O (92 mL). The toluene layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were concentrated to give crude (R)-2-(benzyloxymethyl)morpholine (~14 g), which was used without purification. MS m/z 208 (M+H+).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2007/70201, 2007, A1 Location in patent: Page/Page column 175-176

18
[ 135065-70-2 ]
[ 952593-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2: palladium on carbon; hydrogen / methanol / 20 °C 3: 2,2,6,6-tetramethyl-piperidine-N-oxyl; methyl-cyclopentane; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / acetone 4: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide
	Multi-step reaction with 4 steps 1.1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2.1: hydrogen / palladium on activated charcoal / methanol / 20 °C 3.1: sodium hydrogencarbonate / water; acetone / 0 °C 3.2: 0.33 h / 0 - 20 °C 4.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C 3.1: 2,2,6,6-tetramethyl-piperidine-N-oxyl; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / water; acetone / 0 - 20 °C 3.2: 0.5 h / 20 °C 4.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C

Multi-step reaction with 4 steps 1: potassium carbonate / water; acetone / 0 - 20 °C 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C 3: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / water; acetone / 0 - 20 °C 4: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 20 °C

Reference： [1]Yuan, Jing; Simpson, Robert D.; Zhao, Wei; Tice, Colin M.; Xu, Zhenrong; Cacatian, Salvacion; Jia, Lanqi; Flaherty, Patrick T.; Guo, Joan; Ishchenko, Alexey; Wu, Zhongren; McKeever, Brian M.; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Panemangalore, Reshma; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Singh, Suresh B.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843]
[2]Current Patent Assignee: ABBVIE INC - WO2007/117560, 2007, A2
[3]Current Patent Assignee: ABBVIE INC - WO2007/117557, 2007, A2
[4]Current Patent Assignee: ABBVIE INC - WO2008/124582, 2008, A1

19
[ 135065-70-2 ]
[ 884512-77-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4836 - 4843
[2]Patent: WO2007/117560,2007,A2
[3]Patent: WO2007/117557,2007,A2
[4]Patent: WO2008/124582,2008,A1

20
[ 135065-70-2 ]
[ 952593-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2: palladium on carbon; hydrogen / methanol / 20 °C 3: 2,2,6,6-tetramethyl-piperidine-N-oxyl; methyl-cyclopentane; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / acetone 4: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 5: tetrahydrofuran / 0.17 h / -20 °C 6: tetrahydrofuran; toluene / 0.17 h / -20 °C
	Multi-step reaction with 6 steps 1.1: potassium carbonate / water; acetone / 0 - 20 °C 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C 3.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / water; acetone / 0 - 20 °C 4.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 20 °C 5.1: tetrahydrofuran / -20 - 20 °C 6.1: tert.-butyl lithium / diethyl ether; pentane / -78 - -70 °C 6.2: -20 - 20 °C

Reference： [1]Yuan, Jing; Simpson, Robert D.; Zhao, Wei; Tice, Colin M.; Xu, Zhenrong; Cacatian, Salvacion; Jia, Lanqi; Flaherty, Patrick T.; Guo, Joan; Ishchenko, Alexey; Wu, Zhongren; McKeever, Brian M.; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Panemangalore, Reshma; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Singh, Suresh B.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843]
[2]Current Patent Assignee: ABBVIE INC - WO2008/124582, 2008, A1

21
[ 135065-70-2 ]
[ 952593-45-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2: palladium on carbon; hydrogen / methanol / 20 °C 3: 2,2,6,6-tetramethyl-piperidine-N-oxyl; methyl-cyclopentane; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / acetone 4: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 5: tetrahydrofuran / 0.17 h / -20 °C
	Multi-step reaction with 5 steps 1.1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2.1: hydrogen / palladium on activated charcoal / methanol / 20 °C 3.1: sodium hydrogencarbonate / water; acetone / 0 °C 3.2: 0.33 h / 0 - 20 °C 4.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 5.1: tetrahydrofuran / -20 - 20 °C
	Multi-step reaction with 5 steps 1.1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C 3.1: 2,2,6,6-tetramethyl-piperidine-N-oxyl; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / water; acetone / 0 - 20 °C 3.2: 0.5 h / 20 °C 4.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 5.1: tetrahydrofuran / -20 °C 5.2: 20 °C

Multi-step reaction with 5 steps 1: potassium carbonate / water; acetone / 0 - 20 °C 2: hydrogen / palladium on activated charcoal / ethanol / 20 °C 3: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / water; acetone / 0 - 20 °C 4: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 20 °C 5: tetrahydrofuran / -20 - 20 °C

Reference： [1]Yuan, Jing; Simpson, Robert D.; Zhao, Wei; Tice, Colin M.; Xu, Zhenrong; Cacatian, Salvacion; Jia, Lanqi; Flaherty, Patrick T.; Guo, Joan; Ishchenko, Alexey; Wu, Zhongren; McKeever, Brian M.; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Panemangalore, Reshma; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Singh, Suresh B.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843]
[2]Current Patent Assignee: ABBVIE INC - WO2007/117560, 2007, A2
[3]Current Patent Assignee: ABBVIE INC - WO2007/117557, 2007, A2
[4]Current Patent Assignee: ABBVIE INC - WO2008/124582, 2008, A1

22
[ 135065-70-2 ]
(R)-1-(6-fluoro-3'-methylbiphenyl-2-yl)-5-methoxy-1-((R)-morpholin-2-yl)-pentan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: potassium carbonate / water; acetone / 0.5 h / 0 - 20 °C 2: palladium on carbon; hydrogen / methanol / 20 °C 3: 2,2,6,6-tetramethyl-piperidine-N-oxyl; methyl-cyclopentane; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / acetone 4: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide 5: tetrahydrofuran / 0.17 h / -20 °C 6: tetrahydrofuran; toluene / 0.17 h / -20 °C 7: hydrogenchloride / water; acetonitrile / 16 h / 20 °C
	Multi-step reaction with 7 steps 1.1: potassium carbonate / water; acetone / 0 - 20 °C 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C 3.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / water; acetone / 0 - 20 °C 4.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 20 °C 5.1: tetrahydrofuran / -20 - 20 °C 6.1: tert.-butyl lithium / diethyl ether; pentane / -78 - -70 °C 6.2: -20 - 20 °C 7.1: hydrogenchloride / water; acetonitrile / 20 °C 7.2: pH 10

Reference： [1]Yuan, Jing; Simpson, Robert D.; Zhao, Wei; Tice, Colin M.; Xu, Zhenrong; Cacatian, Salvacion; Jia, Lanqi; Flaherty, Patrick T.; Guo, Joan; Ishchenko, Alexey; Wu, Zhongren; McKeever, Brian M.; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Panemangalore, Reshma; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Singh, Suresh B.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4836 - 4843]
[2]Current Patent Assignee: ABBVIE INC - WO2008/124582, 2008, A1

23
[ 135065-70-2 ]
[ 952593-27-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / water; acetone / 0 - 20 °C 2.1: hydrogen / palladium on activated charcoal / ethanol / 20 °C 3.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide / water; acetone / 0 - 20 °C 4.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0 - 20 °C 5.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 5.2: -78 - 20 °C