820971-67-3|tert-Butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate| Ambeed

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Quality Control of [ 820971-67-3 ] Purity: 98% SDS Specification

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Product Details of [ 820971-67-3 ]

CAS No. :	820971-67-3
Formula :	C₁₁H₂₀N₂O₄
M.W :	244.29
SMILES Code :	CON(C)C(=O)C1CN(C1)C(=O)OC(C)(C)C
MDL No. :	MFCD11975576
InChI Key :	RPCWHOFDACENQM-UHFFFAOYSA-N
Pubchem ID :	21306970

Safety of [ 820971-67-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338

Application In Synthesis of [ 820971-67-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 820971-67-3 ]
Downstream synthetic route of [ 820971-67-3 ]

[ 820971-67-3 ] Synthesis Path-Upstream 1~3

1
[ 820971-67-3 ]
[ 75-16-1 ]
[ 870089-49-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: at 0 - 20℃; for 3.66667 h; Stage #2: at 0℃;	B. Preparation of tert-butyl 3-acetylazetidine-1-carboxylate (C56). A solution of C55 (27.1 g, 0.111 mol) in THF (200 mL) was added drop-wise to a 1.4M solution of methylmagnesium bromide in a mixture of THF and toluene (25:75) (99.0 mL, 0.139 mol) over 40 mins, while the reaction temp was kept at about 0° C. After completion of the addition, the mixture was stirred at 10-15° C. for 2 hours, followed by 1 h at room temp. The reaction mixture was cooled to 0° C. and quenched with a 10percent aqueous citric acid solution (150 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2250 mL), and dried over sodium sulfate. Filtration and removal of solvent gave a residue, which was purified by silica gel chromatography (Eluant: chloroform) to afford C56. Yield: 20.6 g, 0.10 mol, 93percent. ¹H NMR (400 MHz, CDCl₃): δ 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1H), 2.16 (s, 3H), 1.42 (s, 9H).
93.4%	Stage #1: at 0 - 20℃; for 3.66667 h; Stage #2: With water; citric acid In tetrahydrofuran; toluene at 0℃;	Preparation 85 tert-Butyl 3-acetylazetidine-1 -carboxylate; A solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (Preparation 84, 27.1 g, 0.111 mol) in tetrahydrofuran (20OmL) was added dropwise to a 1.4 M solution of methylmagnesium bromide in a 25:75 mixture of tetrahydrofuran and toluene (99.0 mL, 0.139 mol, 1.25 eq) over 40 minutes. The reaction temperature was kept at ~0°C. After the addition, the mixture was stirred at 10-15⁰C for 2 hours and then at room temperature for 1 hour. The mixture was cooled to 0⁰C and 10percent aqueous citric acid (15OmL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (60OmL). The organic layers were combined, washed with brine (50OmL) and dried using anhydrous sodium sulfate to give a residue which was purified by chromatography on silica gel, eluting with chloroform, to afford the title compound (20.6 g, 93.4percent).¹H NMR (400 MHz, CDCI₃): δ = 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1 H), 2.16 (s, 3H), 1.42 (s, 9H) ppm.
77%	at 0 - 20℃; for 17 h;	Methylmagnesium bromide (3M solution in THF, 10.4 mL, 31.3 mmol) was added dropwise to a cooled (0° C.) solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (87a, 5.1 g, 20.88 mmol) in anhydrous THF (100 mL). Stirring was continued at 0° C. for one hour, then at room temperature for 16 hours. The mixture was cooled to 0° C. and quenched with sat. aq. NaHCO3 (35 mL), then extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine (3×40 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate from 10:1 to 3:1) to give tert-butyl 3-acetylazetidine-1-carboxylate (87b, (3.20 g, 77percent yield) as light yellow oil. ¹H NMR (400 MHz, CDCl3) δ 4.05 (d, J=7.6 Hz, 4H), 3.41 (quint, J=7.6 Hz, 1H), 2.18 (s, 3H), 1.43 (s, 9H).

References: [1] Patent: US2010/190771, 2010, A1, . Location in patent: Page/Page column 31-32.
[2] Patent: WO2010/131145, 2010, A1, . Location in patent: Page/Page column 87.
[3] Patent: US2015/361067, 2015, A1, . Location in patent: Paragraph 0621.
[4] Patent: WO2018/137573, 2018, A1, . Location in patent: Page/Page column 65; 66.
[5] Patent: WO2014/173289, 2014, A1, . Location in patent: Paragraph 0296; 0300; 0301.
[6] Patent: TWI602818, 2017, B, . Location in patent: Paragraph 0300; 0301.

2
[ 820971-67-3 ]
[ 917-54-4 ]
[ 870089-49-9 ]

References: [1] Patent: US2008/58348, 2008, A1, . Location in patent: Page/Page column 13.

3
[ 820971-67-3 ]
[ 676-58-4 ]
[ 870089-49-9 ]

References: [1] Patent: WO2009/45382, 2009, A1, . Location in patent: Page/Page column 53.

[ 820971-67-3 ] Synthesis Path-Downstream 1~35

Yield	Reaction Conditions	Operation in experiment
98.6%		General procedure: Corresponding N-Boc protected cyclic aminocarboxylic acid (0.02mol), dissolved in DCM (50ml),Stir at room temperature, slowly add 1,1-carbonyldiimidazole (0.024mol), stir for 15-30min after completion, and when no more gas is generated, add N, O-dimethylhydroxylamine hydrochloride (0.024mol) and react overnight. TLC showed that (petroleum ether: ethyl acetate = 4: 1) the reaction was complete.Water (20 ml) was added to quench the reaction, and the mixture was extracted with DCM (30 ml x 3). The organic phases were combined and washed with saturated brine (50 ml).After drying over anhydrous sodium sulfate, it was filtered and concentrated. The crude product was purified by silica gel column chromatography with a yield of 70-90%.

2
[ 820971-67-3 ]
[ 917-54-4 ]
[ 870089-49-9 ]

Yield	Reaction Conditions	Operation in experiment
		2) Synthesis of N-t.butoxycarbonyl-3-acetyl-azetidine 110 mg (0.45 mmol) of N-t.butoxycarbonyl-3-(methoxy-methyl-carbamoyl)-azetidine is solubilized in 2 ml of ether under argon. This solution is cooled down to 0 C. using an ice bath and 1 ml of a 1.6 M solution of methyllythium in ether is added dropwise. The reaction medium is stirred for 2 hours at this temperature then treated with a 1 M aqueous solution of hydrochloric acid. The aqueous and ether phases are decanted and separated. This operation is repeated 3 times then the ethereal phases are collected and dried over MgSO4, then after filtration the ether is evaporated under reduced pressure. 40 mg of a colourless oil is recovered. TLC: Rf=0.35 (silica gel, eluent: heptane/ethyl acetate 50:50 1H-NMR (CDCl3): δ 1.44 (s, 9H,); 2.2 (s, 3H, -CO-C); 3.45 (m, 1H,); 3.67 (s, 3H, -O-C); 4.07 (m, 4H, and)

References: [1]Patent: US2008/58348,2008,A1 .Location in patent: Page/Page column 13.

3
[ 6638-79-5 ]
[ 142253-55-2 ]
[ 820971-67-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (22.3 g, 0.111 mol) in THF (250 mL), 1,3-dicyclohexylcarbodiimide (24.4 g, 0.150 mol) was added portion-wise. The reaction mixture was stirred at room temperature for 1.5 h before addition of a suspension of N,O-dimethylhydroxylamine hydrochloride (15.0 g, 0.154 mol) in a mixture of acetonitrile (300 mL) and triethylamine (22.6 mL, 0.162 mol). The resulting mixture was stirred at room temperature for 24 h, and then the reaction was concentrated in vacuo. The residue was taken up in water (300 mL) and EtOAc (800 mL), the organic layer was separated, washed with a 5% aqueous citric acid solution (2200 mL), water (2150 mL), and saturated aqueous sodium chloride solution (2*150 mL), and then dried over magnesium sulfate. Filtration and removal of solvent gave C55 as a light yellow oil. Yield: 28.15 g, 0.12 mol, 100%. 1H NMR (400 MHz, CDCl3) δ 4.12-4.09 (m, 2H), 4.03-3.99 (m, 2H), 3.64-3.56 (m, 1H), 3.63 (s, 3H), 3.17 (s, 3H), 1.40 (s, 9H).
100%		Preparation 84 tert-Butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate; Carbonyldiimidazole (24.4 g, 0.150 mol) was added in portions to a solution of 1-(tert- butoxycarbonyl)azetidine-3-carboxylic acid (Preparation 83, 22.3 g, 0.11 1 mol) in tetrahydrofuran (25OmL). The mixture was stirred at room temperature for 1.5 hours. A suspension of Λ/,O-dimethylhydroxylamine hydrochloride (15.O g, 0.154 mol) in a mixture of acetonitrile (30OmL) and triethylamine (22. mL, 0.162 mol) was added. The resulting mixture was stirred at room temperature for 24 hours. The solvents were evaporated and water (30OmL) and ethyl acetate (80OmL) were added to the residue. The organic layer was separated, washed with a 5% aqueous citric acid (40OmL), water (30OmL) and brine (30OmL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a pale yellow oil (28.15 g, 100%).1H NMR (400 MHz, CDCI3): δ = 4.12-4.09 (m, 2H), 4.03-3.99 (m, 2H), 3.64-3.56 (m, 1 H), 3.63 (s, 3H), 3.17 (s, 3H), 1.40 (s, 9H) ppm.
100%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a solution of l-tert-butoxycarbonylazetidine-3-carboxylic acid (1.0 g) in DMF (25 mL) were added Ν,O dimethylhydroxylamine hydrochloride (0.51 g), HATU (2.3 g), and DIPEA (2.6 mL). After stirring for 1 hour at room temperature, the reaction mixture was diluted with brine and extracted with EtOAc twice. The combined organic layer was washed with brine twice, dried over MgS04, and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (25-55% EtOAc in /hexane) to give the title compound (1.3 g, quant.) as colorless oil. MS (ESI) m/z 267 [M+l]. RT = 0.771 min. LCMS condition B.

99%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;	DMF (40 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.89 g, 29.8 mmol), EDC (5.55 g, 29.8 mmol), HOBt (3.36 g, 24.9 mmol) and DIPEA (9.82 mL, 54.7 mmol). The reaction was stirred at room temperature for 20 h. The reaction was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (150 mL) and brine (150 mL), dried over MgSO4 and concentrated under vacuum to afford 4 as a clear colorless oil (6.06 g, 99%); Η-nmr (400 MHz, CDCI3) δ 4.21-4.11 (m, 2H), 4.05 (t, J= 8.0 Hz, 2H), 3.66 (s, 3H), 3.68-3.59 (m, IH), 3.21 (s, 3H), 1.44 (s, 9H); m/z 189.1 [M-1Bu].
99%		To a solution of 1-(te/-bυtoxycarbonyl)azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) in THF (50 mL) was added EDCI (2.10 g, 10.93 mmol), HOBt (1.48 g, 10.93 mmol), and /V,/V-diisopropylethylamine (5.19 mL, 29.82 mmol). The mixture was stirred at rt for 15 min. Λ/,Odimethylhydroxylamine hydrochloride (1.16 g, 11.93 mmol) was added and stirring continued for 64 h. The crude reaction was purified via ISCO chromatography using 3:1 ethyl/hexanes to afford 2.4 g (99%) of the desired product, which was used without further characterization.
99%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	1-Boc-azetidine-3-carboxylic acid (5 g; 24.9 mmol) and N,O-dimethylhydroxylaminehydrochloride (3.64 g; 37.3 mmol) were placed in a round bottom flask under N2. DCM(75 mL) was added, followed by EDCI.HC1 (7.15 g; 37.3 mmol), DMAP (155 mg; 1.27mmol) and DIPEA (6.5 mL, 37.4 mmol). The reaction mixture was stirred at RT for 16h and diluted with DCM (100 mL). The organic layer was washed with aqueous 1M HC1 (2 x 50 mL), sat. NaHCO3 solution (50 mL), and brine (50 mL). The organic phasewas decanted, dried over MgSO4, filtered, and evaporated to dryness yielding 6.04 g(99%) of intermediate 73.
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	A mixture of 298 (1.8 g, 9 mmol), N,O-dimethylhydroxylamine hydrochloride (2.6 g, 27 mmol), EDCI (5 g, 27 mmol), HOBt (0.1 g, 1 mmol), and DIPEA (12.5 mL, 72 mmol) in DMF (30 mL) was stirred at 20C overnight. The reaction was then concentrated to half volume in vacuo, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water and brine, dried (Na2SO4), and concentrated to give 299 as a clear oil (2.1 g, 98%).
84%	With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 17h;	A solution of 1-boc-azetidine-3-carboxylic acid (5.00 g, 24.8 mmol, and CDI (4.23 g, 26.1 mmol) in dichloromethane (100 mL) was stirred at room temperature for 1 hour, then N,O-dimethylhydroxylamine hydrochloride (4.0 g, 29.8 mmol) was added and stirring continued at room temperature for 16 hours. The resulting suspension was washed with water (3×30 mL), sat. aq. NaHCO3 (3×30 mL), and brine (3×30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (87a, 5.1 g, 84% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.14 (br s, 2H), 4.05 (t, J=8.6 Hz, 2H), 3.66 (s, 3H), 3.65 (m, 1H), 3.20 (s, 3H), 1.43 (s, 9H).
83%	With triethylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h;	Example 232: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzvϖ- azetidine.; Step A: Preparation of 3-(Methoxy-methyl-carbamoyl)-azetidine-1 - carboxylic acid tert-butyl ester.; To a solution of azetidine-1 ,3-dicarboxylic acid mono-tert-butyl ester (3.5 g, 17 mmol) in DMF (50 ml_) was added O1N- dimethyl-hydroxylamine hydrochloride (3.4 g, 34 mmol), thethylamine (9.6 mL, 69 mmol), HATU (13.4 g, 34.6 mmol) and DCM (125 mL). After stirring for 16 h, saturated NaHCO3 solution and ethyl acetate were added. The aqueous portion was extracted three times with ethyl acetate. The combined organic fractions were dried (Na2SO4) and concentrated and the crude product was purified using RP HPLC (basic conditions) to provide the title compound (3.5 g, 83%) MS (ESI): mass calcd. for CnH2ON2O4, 244.1 ; m/z found, 189.1 [M-t- Bu]+. 1H NMR (CDCI3): 4.14-4.03 (m, 2H), 4.05 (t, J = 8.7 Hz, 2H), 3.66 (s, 3H), 3.63-3.59 (m, 1 H), 3.21 (s, 1 H), 1.43 (s, 9H).
80%	With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a stirred solution of l-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.0 g, 14.9 mmol, CAS 142253-55-2) in DMF (45 mL) at room temperature was added N,0-dimethyl hydroxylamine hydrochloride (1.75 g, 17.9 mmol), HBTU (8.48 g, 22.4 mmol) and iV-methyl morpholine (6.56 mL, 59.6 mmol). After 16 hours, the reaction mixture was poured into a 1: 1 mixture of water and saturated NH4C1 and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHC03 and brine, dried (Na2S04) and concentrated in vacuo to afford the title compound (2.9 g, 80%) as a colorless oil. MS (ISP): 189.1 ([M- C4H8+H]+).
77%	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;	Intermediate 24: tert-Butvl 3- {r methoxy( methyl) amino 1 carbonyl } azetidine-l-carboxylate; To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (H. Itani et al, Biorg. Med. Chem. Lett. 12 (5), 757-762,2002) (0.5 g, 2.48 mmol) and bis (2-oxo-3- oxazolidinyl) phosphinic chloride (0.633 g, 2.48 mmol) in DMF (4 mL) was added N,O- dimethylhydroxylamine hydrochloride (339 mg, 3.48 mmol), followed by diisopropylethyl amine (1.3 mL, 7.45 mmol). The exothermic reaction was allowed to cool to room temperature and was stirred for 2 hours. Excess base was removed under reduced pressure, the residue was diluted with ethyl acetate (100 mL), washed with potassium phosphate buffer (1M, pH 7,2x 100 mL) and with water (2x 100 mL) and dried over sodium sulfate. Chromatography on silica gel with hexanes/ acetone (3:1) gave 470 mg (77%) of the product as a colourless solid. MS (ESP): 267.23 (MNa+) for C11H20N2O4 'H-NMR (DMSO-d(at) 5: 1.36 (s, 9H); 3.10 (s, 3H); 3.61 (s, 3H); 3.68 (m, 1H); 3.83-4.00 (m, 4H).
76%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; for 16h;	A solution of R-1 (50 g, 250 mmol) and HATU (104 g, 270 mmol) in CH2C12 (8000 mL) is treated with TEA (135 mL, 1000 mmol). The mixture is stirred for 16 h then washed with saturated aqueous ammonium chloride and filtered through a phase separator. The organics are collected and volatiles are removed in vacuo to afford a crude residue that is purified by flans chromatography (Si02, 12% EtOAc in heptane to 100%EtOAc) to afford 1-1 (46 g, 76%) m/z 245.1 [M+H].
72%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 25℃; for 16h;Inert atmosphere;	A mixture of l-Boc-azetidine-3-carboxylic acid (50 g, 248 mmol), triethylamine (69.3 mL, 497 mmol), 1 -hydroxybenzotriazole (33.5 g, 248 mmol) and EDC1 (47.6 g, 248 mmol) and (9, /V-dimcthyl hydroxy laminc HC1 (24.24 g, 248.5 mmol) in DMF (1000 mL) was stirred at 25 C for 16 h. The mixture was concentrated in vacuo to give a residue, which was neutralized by HC1 (1M) to pH = 7 and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with NaHCO, (2 x sat.aq. 200 mL), dried over Na2S04 and concentrated in vacuo to give tert- butyl 3- (1025) [methoxy(methyl)carbamoyl]azetidine-l-carboxylate (55 g, 72%) as colorless oil; LC-MS: 189.1 [M-56+H]+.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 6h;	To a solution of 980 mg (4.87 mmol) of boc-azetidine-3-carboxylic acid, 951 mg (9.75 mmol) OF N, O- dimethylhydroxylamine hydrochloride, 329 mg (2.435 mmol) of HOBT and 1.87g (9.75 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride in 30 mL of CH2CL2 was added 2.54 mL (44.61 mmol) of N, N-diisopropylethylamine at 0 oC and it was stirred for 6h at rt. Then the reaction mixture was poured into 100 mL of ether and washed with 20 mL of aq NAHC03. The organic layer was dried over Na2S04 and concentrated. to afford the title compound. 1NMR (CDC13) 8 1.46 (s, 9H), 3.23 (s, 3H), 3.62 (m, 1H), 3.68 (s, 3H), 4.07 (M, 2H), 4.09 (m, 2H).
		EXAMPLE 6; 1 - [5 -fluoro-2-(methylsulfonyl)benzoyl] -3 -( 1 -methyl- 1 - { [3 - (trifluoromethyl)phenyl] sulfonyl } ethyl)azetidineStep 1 : tert-butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-l-carboxylateTo a 100 ml round bottom flask was added l-(fert-butoxycarbonyl)azetidine-3- carboxylic acid (3.75 g, 18.6 mmol) and 20 ml tetrahydrofuran, followed by CDI (3.63 g, 22.4 mmol). Vigorous gas evolution was observed. After gas evolution stopped, the reaction mixture was stirred at room temperature for additional 30 minutes. Methoxy(methyl)ammonium chloride (2.55 g, 26.1 mmol) was added, followed by diisopropylethyl amine (6.5 ml, 37.3 mmol). The resulting reaction mixture was stirred at room temperature overnight. It was diluted with 120 ml ether and washed with 60 ml saturated NH4Cl. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column, eluted with 1 :2 to 3:2 ethyl acetate/hexane to give 3.6 g desired product was colorless oil. <n="54"/>1H-NMR (CDCl3): 54.17 (m, 2H), 4.08 (t, J = 8.7 Hz, 2H), 3.69 (s, 3H), 3.5 (b, IH), 3.24 (s, 3H), 1.47 (s, 9H).
	With triethylamine; HATU; at 20℃; for 19h;	EXAMPLE 8; F5-(2- 13 - [2-(Trifluoromethyl)benzovnazetidin- 1 -vU - 1 ,3 -thiazol-5 -yl)-2//-tetrazol-2-yllacetic acid; Step 1 : ferf -Butyl 3 - { [methoxy (methyl)amino] carbonyl ) azetidine- 1 -carboxylate; To a solution of l-(/er/-butoxycarbonyl)azetidine-3-carboxylic acid (3.78 g, 18.8 mmol), N, 0-dimethylhydroxylamine hydrochloride (2.75 g, 28.2 mmol), and Et3N (7.85 mL, 56.4 mmol) was added HATU (7.86 g, 20.7 mmol). The resulting mixture was stirred at room temperature for 19 h. A second portion of HATU (4.5 g, 11.8 mmol) was added and the reaction was stirred at room temperature for 19 h. The mixture was poured into a 250 mL separatory funnel containing water (150 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 20% EtOAc in hexanes to 70% EtOAc in hexanes as a gradient, to afford the title compound as a colorless oil.
	With triethylamine; HATU; at 20℃; for 38h;	Step 1: tert-Butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.78 g, 18.8 mmol), N,O-dimethylhydroxylamine hydrochloride (2.75 g, 28.2 mmol), and Et3N (7.85 mL, 56.4 mmol) was added HATU (7.86 g, 20.7 mmol). The resulting mixture was stirred at room temperature for 19 h. A second portion of HATU (4.5 g, 11.8 mmol) was added and the reaction was stirred at room temperature for 19 h. The mixture was poured into a 250 mL separatory funnel containing water (150 mL) and extracted with EtOAc (2*50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 20% EtOAc in hexanes to 70% EtOAc in hexanes as a gradient, to afford the title compound as a colorless oil.
	With triethylamine; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 16h;	[0299] To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.15 g, 25.6 mmol)in THF (100 mL) was added DCC (7.11 g, 34.5 mmol), Et3N (5.18 g, 51.2 mmol) andN,Odimethylhydroxylaminehydrochloride (3.44 g, 35.3 mmol), the reaction was stirred at RT forabout 16 hr. Concentrated under reduced pressure to remove solvent, the residue was portionedbetween EA (100 mL) and water (50 mL), the aqueous was further extracted with EA (50 mL x3). The combined organic phases were washed with brine (20 mL), concentrated under reducedpressure to remove solvent, then purified by column chromatography on silica gel (200-300mesh, CH2Cb/MeOH = 2011) to give the crude product ( -8.0 g) as a colorless oil. MS (ESI) m/e[M+23t 266.9, [M-55t 189.0.
7.30 g		(1) Synthesis oftert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.00 g) in tetrahydrofuran (62.1 mL), 1,1'-carbonyldiimidazole (6.05 g) was added and the mixture was stirred at room temperature for an hour. To the reaction mixture, a solution of N,O-dimethylhydroxylamine hydrochloride (3.64 g) and triethylamine (4.02 g) in acetonitrile (62.1 mL) was added and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. Extraction was conducted with ethyl acetate and the combined organic layers were washed with an aqueous solution of 5% citric acid and saturated brine. The washed organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a pale yellow oil (7.30 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 3.21 (s, 3 H) 3.56 - 3.68 (m, 4 H) 4.00 - 4.09 (m, 2 H) 4.09 - 4.19 (m, 2 H).
	With triethylamine; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 16h;	To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.15 g, 25.6 mmol) in THF (100 mL),Add DCC (7.11g, 34.5 mmol),Et3N (5.18 g, 51.2 mmol)And N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.3 mmol),The reaction was stirred at room temperature for about 16 hours.Concentration under reduced pressure to remove the solvent, the residue was partitioned between EA (100 mL) and water (50 mL) and the aqueous phase was further extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), concentrated under reduced pressure to remove the solvent, and then purified on a tannin gel column (200-300 mesh CH 2 Cl 2 /MeOH=20/1).The crude product was obtained as a colorless oil (-8.0 g).
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	Example 5 1) Synthesis of N-t.butoxycarbonyl-3-(methoxy-methyl-carbamoyl)-azetidine 2 g (10 mmol) of N-t.butoxycarbonyl-azetidine-3-carboxylic acid is dissolved in 20 ml of dimethylformamide under argon. This solution is cooled down to 0 C. using an ice bath and 5.46 g (12.3 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 1.4 g (14.3 mmol) of N,O-dimethylhydroxylamine chloride and 6 ml of diisopropylethylamine are added. The reaction mixture is left to return to ambient temperature and is stirred for 18 hours at ambient temperature. The dimethylformamide and diisopropylethylamine are evaporated off under reduced pressure (2 kPa). Purification is carried out by chromatography on silica gel eluding with a heptane/ethyl acetate 50:50 mixture 2.1 g of colourless oil is recovered. TLC: Rf=0.25 (silica gel, eluent: heptane/ethyl acetate 50:50 1H-NMR (CDCl3): δ 1.44 (s, 9H, tBu); 3.22 (s, 3H, -N-C); 3.64 (m, 1H, H3); 3.67 (s, 3H, -O-C); 4.05 and 4.15 (m, 4H, H2 and H2')
		Carbonyldiimidazole (24.4 g, 150 mmol) was added in portions to a solution of 1-tert-butoxycarbonylazetidine-3-carboxylic acid (23.2 g, 115 mmol) in THF (250 ml) and the mixture was stirred at room temperature for 1.5 h. A suspension of N,O-dimethylhydroxylamine hydrochloride (15.0 g, 154 mmol) in a mixture of acetonitrile (300 ml) and triethylamine (22.0 ml, 162 mmol) was added and the reaction was stirred at room temperature for 24 h. The solvents were evaporated and the residue was partitioned between water (300 ml) and ethyl acetate (800 ml). The organic layer was separated, washed with a 5% aqueous citric acid solution (400 ml), water (300 ml) and brine (300 ml), dried over anhydrous magnesium sulfate, and concentrated in vac- uo to afford the title compound (28.2 g, quant).
	With triethylamine; 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 1h;	To a stirred solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) and CDI (1.80 g, 10.9 mmol) in DCM (10 mL) were added Et3N (1.20 g, 11.93 mmol) and N,O-methoxy(methyl)amine hydrochloride (0.90 g, 14.91 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 h. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford tert-butyl 3- [methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a light yellow oil (2.10 g, 78%): LCMS (ESI) calc’d for C11H20N2O4 [M + H - 56]+: 189, found 189; 1H NMR (300 MHz, CD3OD) δ 4.14-3.99 (m, 4H), 3.89-3.76 (m, 1H), 3.72 (s, 3H), 3.22 (s, 3H), 1.46 (s, 9H).

References: [1]Patent: US2010/190771,2010,A1 .Location in patent: Page/Page column 31-32.
[2]Patent: WO2010/131145,2010,A1 .Location in patent: Page/Page column 86.
[3]Patent: WO2018/216822,2018,A1 .Location in patent: Page/Page column 180.
[4]Patent: WO2010/114907,2010,A1 .Location in patent: Page/Page column 59; 89.
[5]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 119-120.
[6]Patent: WO2018/50686,2018,A1 .Location in patent: Page/Page column 94; 95.
[7]Patent: WO2008/108957,2008,A2 .Location in patent: Page/Page column 99.
[8]Patent: US2015/361067,2015,A1 .Location in patent: Paragraph 0620.
[9]Patent: WO2010/59393,2010,A1 .Location in patent: Page/Page column 161-162.
[10]Patent: WO2016/30310,2016,A1 .Location in patent: Page/Page column 70.
[11]Journal of Medicinal Chemistry,2007,vol. 50,p. 4868 - 4881.
[12]Patent: WO2005/116022,2005,A1 .Location in patent: Page/Page column 61-62.
[13]Patent: WO2017/123695,2017,A1 .Location in patent: Page/Page column 36.
[14]Patent: WO2019/105915,2019,A1 .Location in patent: Page/Page column 67; 142.
[15]Patent: WO2005/809,2005,A1 .Location in patent: Page 95.
[16]Patent: WO2009/45382,2009,A1 .Location in patent: Page/Page column 52-53.
[17]Patent: WO2010/94126,2010,A1 .Location in patent: Page/Page column 115.
[18]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5559 - 5566.
[19]Patent: US2011/301143,2011,A1 .Location in patent: Page/Page column 67.
[20]Patent: WO2014/173289,2014,A1 .Location in patent: Paragraph 0296; 0298; 0299.
[21]Patent: EP2881384,2015,A1 .Location in patent: Paragraph 0531; 0532.
[22]Patent: TWI602818,2017,B .Location in patent: Paragraph 0298; 0299.
[23]Patent: WO2018/137573,2018,A1 .Location in patent: Page/Page column 65.
[24]Patent: US2008/58348,2008,A1 .Location in patent: Page/Page column 13.
[25]Patent: WO2019/219517,2019,A1 .Location in patent: Page/Page column 192.
[26]Patent: WO2021/684,2021,A1 .Location in patent: Page/Page column 50.
[27]Patent: WO2021/71806,2021,A1 .Location in patent: Paragraph 0431; 0432.

4
[ 820971-67-3 ]
[ 223463-13-6 ]
tert-butyl 3-[(5-bromopyridin-2-yl)carbonyl]azetidine-1-carboxylate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 4868 - 4881.

5
[ 820971-67-3 ]
[ 62351-47-7 ]
[ 820971-68-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 0℃; for 2h;	A solution of 1.19 g (4.87 mmol) of tert-butyl 3-[methoxy (methyl) amino] carbonyl} azetidine-1- carboxylate in 15 mL of THF was added to a solution of 14.6 mL (7.31 mmol) of 3,5- difluorophenylmagnesium bromide (0.5M in THF). The reaction mixture was stirred for 2h at 0 oC, then poured into 100 mL of ether and washed with 10 mL of water. The organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound. LNMR (CDCL3) 8 1.48 (s, 9H), 4.08 (m, 1H), 4.24 (m, 4H), 7.36 (m, 1H), 7.38 (m, 2H).

References: [1]Patent: WO2005/809,2005,A1 .Location in patent: Page 96.

6
[ 109-04-6 ]
[ 820971-67-3 ]
[ 416852-81-8 ]

Yield	Reaction Conditions	Operation in experiment
11%		To a solution of 2-bromopyridine (1.2 mL, 12 mmol) in THF (60 mL) at -78C was added n-BuLi (8 mL of a 1.6 M solution in hexanes, 12 mmol) dropwise over 15 min. After stirring for an additional 30 min at -78 C, a solution of 299 (1 g, 4 mmol) in THF (20 mL) was slowly added. The reaction was then heated to 60 C for 1 h. After cooling to 20 C, the reaction was diluted with ether, quenched with saturated aqueous Na2SO4, and dried with solid Na2SO4. The mixture was filtered through a plug of solid Na2SO4 and concentrated in vacuo. Flash column chromatography (0-20% ethyl acetate-hexanes) yielded 300 as a yellow oil (0.12 g, l l%).
		To a solution of 2-bromopyridine (1.43 g, 9.42 mmol) in THF (70 mL) at -780C was added /?-BuLi (1.5 M solution, 6.63 mL, 9.42 mmol) and stirred at -78 0C for 1.5 h. A solution of 4 (2.0 g, 8.19 mmol) in THF (30 mL) was added dropwise over 30 mins. The reaction was stirred for 5 h whilst warming to room temperature. The reaction was diluted with water (250 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over MgSO4, concentrated under vacuum and purified by column chromatography (silica gel) using 0 to 50% EtOAc in hexanes to afford 5 as a clear yellow oil (752 mg, 35%); Η-nmr (400 MHz, CDCl3) δ 8.65 (d, J= 4.0 Hz, IH), 8.09 (d, J= 8.0 Hz, IH), 7.86 (td, J= 8.0, 1.5 Hz, IH), 7.48 (ddd, J= 8.0, 4.0, 1.0 Hz, IH), 4.57-4.48 (m, IH), 4.28-4.13 (m, 4H), 1.44 (s, 9H); m/z 263.2 [M+H].

References: [1]Patent: WO2008/108957,2008,A2 .Location in patent: Page/Page column 99.
[2]Patent: WO2010/114907,2010,A1 .Location in patent: Page/Page column 59; 89.

7
[ 820971-67-3 ]
[ 676-58-4 ]
[ 870089-49-9 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 0℃; for 1h;	Step 2: tert-butyl 3-acetylazetidine-l-carboxylateTo a 100 ml round bottom flask was added tert-butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-l-carboxylate (2.6 g, 10.6 mmol) and 20 ml tetrahydrofuran. The resulting solution was cooled to 0C and methylmagnesium chloride tetrahydrofuran solution (4.3 ml, 3M, 12.8 mmol) was added by a syringe. The reaction mixture was stirred at 0 C for 1 hour. It was diluted with 100 ml ether, and the resulting mixture was washed twice with 100 ml saturated ammonium chloride solution. The organics were dried over sodium sulfate, filtered and concentrated. The crude product was used for the next step without further purification.1H-NMR (CDCl3): 64.05 (m, 4H), 3.43 (m, IH), 2.20 (s, 3H), 1.45 (s, 9H).

References: [1]Patent: WO2009/45382,2009,A1 .Location in patent: Page/Page column 53.

8
[ 142253-55-2 ]
[ 1117-97-1 ]
[ 820971-67-3 ]

Yield	Reaction Conditions	Operation in experiment
98%		Commercially available l-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.50g, 1.0 eq) was dissolved in tetrahyrdofuran (5 ml) then treated with carbonyl diimidazole (0.48g, 1.2 eq) and diisopropylethylamine (0.95ml, 2.2 eq). The reaction stirred for 30 minutes at room temperature then the weinrib amine (0.27 g, 1.1 eq) was added. The reaction continued for 15 hours at room temperature. The reaction was worked up by diluting with saturated NH4C1 aq. (5 ml) then extracted with ethylacetate (2x-10 ml). The organics were pooled and washed with water (2x-10 mL) then brine (lx-10 mL). The organics were dried over Na2S04 and concentrated to give 0.60 g of compound VI (98% yield). 1H-NMR (DMSO-de): δ 4.0-3.8 (m, 4H), 3.8-3.7 (m, 1H), 3.6 (s, 3H), 3.1 (s, 3H); LC/MS m/z calc M+Na 267, obs M+Na 267.
78%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; for 2h;	7-1-1 3-(Methoxymethylcarbamoyl)azetidine-1-tert-butoxycarbonyl; 2 g (9.94 mmol) of i -tert-butoxycarbonyl-S-azetidinecarboxylic acid are dissolved in 8 imL of dichloromethane, and 3.19 g (9.94 mmol) of TBTU and then 4 mL of dimethylformamide are added. 0.97 g (9.94 mmol) of N,O-dimethylhydroxylamine in 1 O mL of dichloromethane and 5.17 mL (29.8 mmol) of diisopropylethylamine are added. After stirring for 2 hours, dichloromethane is added and the medium is washed with saturated NaHCCb solution and then with 5% citric acid solution. The organic phase is dried over MgSO4, filtered and concentrated on a rotary evaporator. The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/ethyl acetate). 1 .9 g in the form of a colourless oil are obtained in a yield of 78%.

References: [1]Patent: WO2012/9649,2012,A1 .Location in patent: Page/Page column 92-93.
[2]Patent: WO2010/52255,2010,A1 .Location in patent: Page/Page column 49-50.
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1062 - 1066.

9
[ 820971-67-3 ]
[ 931-50-0 ]
[ 1225652-50-5 ]

Yield	Reaction Conditions	Operation in experiment
62%		7-1 -2 S-Cyclohexanecarbonylazetidine-I -tert-butoxycarbonyl; To 301 mg (1 .23 mmol) of 3-(methoxymethylcarbamoyl)azetidine-1 -tert- butoxycarbonyl in 5 mL of THF at 00C are added 1 .48 ml. (1 .48 mmol) of a 1 M solution of cyclohexylmagnesium bromide in THF. A further 3.35 mL (3.35 mmol) of magnesium reagent are necessary for the disappearance of the starting material.Dichloromethane is added, the organic phases are washed with saturated NH4CI solution and then with saturated NaCI solution, and then dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel(eluent: 7/3 heptane/ethyl acetate). 205 mg in the form of a colourless oil are obtained in a yield of 62%.

References: [1]Patent: WO2010/52255,2010,A1 .Location in patent: Page/Page column 50.

10
[ 820971-67-3 ]
[ 16750-63-3 ]
[ 1227622-84-5 ]

Yield	Reaction Conditions	Operation in experiment
		Step B: Preparation of 3-(2-Methoxy-benzoyl)-azetidine-1 -carboxylic acid tert-butyl ester.; To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1 - carboxylic acid tert-butyl ester (3.48 g, 14.2 mmol) in dry ether (150 mL) at 0 0C was added 2-methoxylphenylmagnesium bromide (1.0 M in THF, 17 mL, 17 mmol). The reaction was allowed to slowly warm to rt and stirred for 36 h. Then a solution of 1 M KHSO4 and EtOAc were added and the aqueous portion was extracted once with EtOAc. The combined organic fractions were dried (Na2SO4) and concentrated to provide the title compound. This material was used in subsequent reactions without additional purifications. MS (ESI): mass calcd. for Ci6H21NO4, 291.1 ; m/z found, 236.1 [M-t-Bu]+. 1H NMR (CDCI3): 7.83 (dd, J = 7.8, 1.8 Hz, 1 H), 7.51 (ddd, J = 8.5, 7.3, 1.8 Hz, 1 H), 7.06-6.95 (m, 2H), 4.13-4.03 (m, 5H), 3.90 (s, 3H), 1.44 (s, 9H).

References: [1]Patent: WO2010/59393,2010,A1 .Location in patent: Page/Page column 162.

11
[ 820971-67-3 ]
[ 75-16-1 ]
[ 870089-49-9 ]

Yield	Reaction Conditions	Operation in experiment
93%		B. Preparation of tert-butyl 3-acetylazetidine-1-carboxylate (C56). A solution of C55 (27.1 g, 0.111 mol) in THF (200 mL) was added drop-wise to a 1.4M solution of methylmagnesium bromide in a mixture of THF and toluene (25:75) (99.0 mL, 0.139 mol) over 40 mins, while the reaction temp was kept at about 0 C. After completion of the addition, the mixture was stirred at 10-15 C. for 2 hours, followed by 1 h at room temp. The reaction mixture was cooled to 0 C. and quenched with a 10% aqueous citric acid solution (150 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2250 mL), and dried over sodium sulfate. Filtration and removal of solvent gave a residue, which was purified by silica gel chromatography (Eluant: chloroform) to afford C56. Yield: 20.6 g, 0.10 mol, 93%. 1H NMR (400 MHz, CDCl3): δ 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1H), 2.16 (s, 3H), 1.42 (s, 9H).
93.4%		Preparation 85 tert-Butyl 3-acetylazetidine-1 -carboxylate; A solution of <strong>[820971-67-3]tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate</strong> (Preparation 84, 27.1 g, 0.111 mol) in tetrahydrofuran (20OmL) was added dropwise to a 1.4 M solution of methylmagnesium bromide in a 25:75 mixture of tetrahydrofuran and toluene (99.0 mL, 0.139 mol, 1.25 eq) over 40 minutes. The reaction temperature was kept at ~0C. After the addition, the mixture was stirred at 10-150C for 2 hours and then at room temperature for 1 hour. The mixture was cooled to 00C and 10% aqueous citric acid (15OmL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (60OmL). The organic layers were combined, washed with brine (50OmL) and dried using anhydrous sodium sulfate to give a residue which was purified by chromatography on silica gel, eluting with chloroform, to afford the title compound (20.6 g, 93.4%).1H NMR (400 MHz, CDCI3): δ = 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1 H), 2.16 (s, 3H), 1.42 (s, 9H) ppm.
77%	In tetrahydrofuran; at 0 - 20℃; for 17h;	Methylmagnesium bromide (3M solution in THF, 10.4 mL, 31.3 mmol) was added dropwise to a cooled (0 C.) solution of <strong>[820971-67-3]tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate</strong> (87a, 5.1 g, 20.88 mmol) in anhydrous THF (100 mL). Stirring was continued at 0 C. for one hour, then at room temperature for 16 hours. The mixture was cooled to 0 C. and quenched with sat. aq. NaHCO3 (35 mL), then extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine (3×40 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate from 10:1 to 3:1) to give tert-butyl 3-acetylazetidine-1-carboxylate (87b, (3.20 g, 77% yield) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.05 (d, J=7.6 Hz, 4H), 3.41 (quint, J=7.6 Hz, 1H), 2.18 (s, 3H), 1.43 (s, 9H).

	In tetrahydrofuran; at 0 - 20℃; for 2h;	[0301] To a solution of <strong>[820971-67-3]tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate</strong> (7.0 g,28.7 mmol) in THF (150 mL) was added CH3MgBr (43 mL, 43 mmol) at 0 C, then slowlywarmed to R T for about 2 hr. 10% aqueous of citric acid (30 mL) was added to the mixture, andextracted with EA (50 mL x 3), the combined organic phases were washed with brine (20 mL),dried over N a2S04, filtered, concentrated and purified by column chromatography on silica gel(200-300 mesh, PE/EA = 211), to give the crude product (4.0 g, 70%) as a colorless oil. MS(ESI) m/e [M-55t 144.0.
	In tetrahydrofuran; at 0 - 20℃; for 2h;	At 0C,To a solution of tert-butyl 3-(methoxy(methyl)carbamomidonyl)azetidine-1-carboxylate (7.0 g, 28.7 mmol) in THF (150 mL),Add CH3MgBr (43 mL, 43 mmol),It is then slowly warmed to room temperature over about 2 hours.To the mixture was added 10% aqueous citric acid solution (30 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated, and applied on a silica gel column (200-300). Head, PE/EA = 2/1) purification,The crude product was obtained as a colorless oil (4.0 g, 70%).
	In tetrahydrofuran; diethyl ether; at -20℃; for 2.25h;	(1) To a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (120 mg) obtained from methoxy(methyl)amine by the method described in Example 005-(1) or a method equivalent thereto in THF (2.5 mL) was added a 3 mol/L solution of methyl magnesium bromide in diethyl ether (250 μL) at -20 C., and the mixture was stirred at the same temperature for 135 minutes. To the reaction solution was added an aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane) to obtain crude tert-butyl 3-acetylazetidine-1-carboxylate.

12
[ 820971-67-3 ]
[ 392-83-6 ]
[ 1241898-68-9 ]

Yield	Reaction Conditions	Operation in experiment
		ter /-Butyl 3 - r2-(trifluoromethyl)benzoyll azetidine- 1 -carboxylate; To a solution of 1 -bromo-2-(trifluoromethyl)benzene (1.01 g, 4.5 mmol) and TMEDA (1.36 mL, 9.0 mmol) in THF (20 niL) at -78 0C was added slowly a solution of tenbutyl lithium (1.7 M in hexanes, 5.3 mL, 9.0 mmol). After stirring at -78 0C for 0.5 h, a solution of the product of tert-butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-l -carboxylate (1.0 g, 4.1 mmol) in THF (5 mL) was added via syringe and the reaction mixture was allowed to warm to room temperature. After 6 h, the reaction was quenched by the addition of saturated aqueous NH4Cl solution (5 mL). The mixture was poured into a 250 mL separatory funnel containing saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 5% EtOAc in hexanes to 25% EtOAc in hexanes as a gradient, afforded the title compound.
		Step 2: tert-Butyl 3-[2-(trifluoromethyl)benzoyl]azetidine-1-carboxylate To a solution of 1-bromo-2-(trifluoromethyl)benzene (1.01 g, 4.5 mmol) and TMEDA (1.36 mL, 9.0 mmol) in THF (20 mL) at -78 C. was added slowly a solution of tert-butyl lithium (1.7 M in hexanes, 5.3 mL, 9.0 mmol). After stirring at -78 C. for 0.5 h, a solution of the product of <strong>[820971-67-3]tert-butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate</strong> (1.0 g, 4.1 mmol) in THF (5 mL) was added via syringe and the reaction mixture was allowed to warm to room temperature. After 6 h, the reaction was quenched by the addition of saturated aqueous NH4Cl solution (5 mL). The mixture was poured into a 250 mL separatory funnel containing saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 5% EtOAc in hexanes to 25% EtOAc in hexanes as a gradient, afforded the title compound.

References: [1]Patent: WO2010/94126,2010,A1 .Location in patent: Page/Page column 116.
[2]Patent: US2011/301143,2011,A1 .Location in patent: Page/Page column 67.

13
[ 820971-67-3 ]
[ 937046-98-5 ]
[ 937047-70-6 ]

Yield	Reaction Conditions	Operation in experiment
83%		To a stirred suspension of Intermediate B (1.30 g, 6.08 mmol) in THF (31 mL) was added chlorotrimethylsilane (1.54 mL, 12.15 mmol), dropwise. The mixture was stirred at rt for 3 h and 2-propylmagnesium chloride (2M in THF; 12.76 mL, 25.52 mmol) was added dropwise. The suspension immediately went into solution. The mixture was stirred at rt for 2 h and te/-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (1.93 g, 7.90 mmol) was added in one portion. The reaction was stirred at rt for 16 h. The reaction was poured over a mixture of ice and saturated, aqueous ammonium chloride (200 mL). The mixture was allowed to warm to rt and was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 1.6 g (83%) of the desired product. ES-MS m/z 318.14 [M+H]+, HPLC RT (min) 2.58.

References: [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 120.

14
[ 820971-67-3 ]
[ 128564-66-9 ]
[ 1252867-24-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5559 - 5566.

15
[ 820971-67-3 ]
[ 5713-61-1 ]
C₁₃H₁₇NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Compound VI (0.60 g, 1.0 eq) was taken up in tetrahydrofuran (6 ml) then cooled to OdC. A solution of commercially available thiophen-2-yl-magnesium bromide (1.0 M, 2.95 ml, 1.2 eq) was dripped in over 5 minutes. The reaction was allowed to warm to room temperature while stirring over 2 hours. Reaction was diluted with saturated NH4C1 aq. then extracted with ethyl acetate (2x-10 ml). The organics were pooled and washed with water (2x-10 mL) then brine (lx-10 mL). The organics were dried over Na2S04 and concentrated for crude oil that was purified via silica gel eluting with 0-75% ethylacetate :hexanes to afford the intermediate as a clear oil. Half of the oil was taken up in dioxane (3 ml) and treated with 4 N HC1 in dioxane (3 ml). After stirring for 15 hours at room temperature, the reaction was concentrated to oily residue (0.16 g, 89%> over 2 steps, calc M+H 168, obs M+H 168).

References: [1]Patent: WO2012/9649,2012,A1 .Location in patent: Page/Page column 93.

16
[ 820971-67-3 ]
[ 17318-03-5 ]
[ 1380752-50-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;	Description 27: tert-butyl 3-(3-fluorobenzoyl)azetidine-1-carboxylate (D27)To an ice cooled solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1 - carboxylate (D26) (61 .8 mg, 0.25 mmol) in dry tetrahydrofuran (2 ml), 3- Fluorophenylmagnesiumbromide (1 M in tetrahyfrofuran) (0.506ml, 0.506 mmol) was added dropwise the under stirring under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h then NH4CI sat. sol. (10ml) was added and the mixture was extracted with ethtylacetate (3x20ml). The organic layers were collected, dried with Na2S04 and filtrated. The solvent was evaporated in vacuo to afford the title compound (D27) (69 mg).MS: (ES/+) m/z: 280 [MKT] C15H18FN03 requires 279.131 H NMR (400MHz ,CHLOROFORM-d) δ = 7.63 - 7.54 (m, 2 H), 7.49 (dt, J = 5.6, 7.9 Hz, 1 H), 7.35 - 7.29 (m, 1 H), 4.31 - 4.18 (m, 4 H), 4.13 (q, J = 7.7 Hz, 1 H), 1 .49 - 1 .44 (m, 9 H).
69 mg	In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;	To an ice cooled solution of <strong>[820971-67-3]tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate</strong> (D26) (61.8 mg, 0.25 mmol) in dry tetrahydrofuran (2 ml), 3-Fluorophenylmagnesiumbromide (1M in tetrahyfrofuran) (0.506 ml, 0.506 mmol) was added dropwise the under stirring under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h then NH4Cl sat. sol. (10 ml) was added and the mixture was extracted with ethylacetate (3×20 ml). The organic layers were collected, dried with Na2SO4 and filtrated. The solvent was evaporated in vacuo to afford the title compound (D27) (69 mg).

References: [1]Patent: WO2012/76063,2012,A1 .Location in patent: Page/Page column 49.
[2]Patent: US2013/261100,2013,A1 .Location in patent: Paragraph 0344-0345.

17
[ 820971-67-3 ]
[ 460-00-4 ]
[ 1414777-95-9 ]

Yield	Reaction Conditions	Operation in experiment
96%		n-butyl lithium (76.8 ml, 123 mmol, 1.6M solution of in hexane) was added dropwise to a solution of 1-bromo-4-fluorobenzene (20.0 g, 114 mmol) in dry THF (200 ml) at -78C under nitrogen and the reaction was stirred at the same temperature for 1H. Then, a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (Intermediate 233A, 20.0 g. 81.9 mmol) in THF (75 ml) was added. The reaction mixture was stirred for 1H at -78C and then quenched with ice. The product was extracted with ethyl acetate (2 c 100 ml). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was puri fied by silica gel column chromatography (petroleum ether/ethyl acetate 80:20) to afford the title compound (21.9 g, 96% of theory).
95%		Steo 1: ferf-Butyl 3-(4-fluorobenzovnazetidine-1-carboxylateTo a solution of 1-Bromo-4-fluorobenzene (20 g, 0.0984 mol) in dry tetrahydrofuran (200 mL) was added n-Butyl lithium (76.8 mL, 0.1229 mol. 1.6 M solution in hexane) in drops at -78 C under nitrogen and stirred at same temperature for 1hr. To this reaction mixture, tert-Butyl 3-[methoxy (methyl) amino] carbonyl} azetldine-1-carboxylate (20 g. 0.0819 mol) in tetrahydrofuran (75 mL) was added at -78 C, The reaction mixture was stirred for 1 hr at -78 C. The reaction mixture was quenched with ice and extracted with ethyl acetate (2 x 100 mL) and dried over sodium sulphate. The solvent was evaporated and the residue was purified by column chromatography by using silica gel (60-120 mesh) using pet ether and ethyl acetate (80:20) as an eluent to afford (23 g, 96 %) of the title compound as a pale brown liquid. TLC: Pet ether / Ethyl acetate :( 5/5), R/ = 0.6; NMR (400MHz. D SO-d6): δ 7.98-7.94 (m, 2H), 7.39-7.34 (m, 2H). 4.41- 4.34 (m. 1H), 4.12 (s. 2H), 3.95 (s, 2H), 1.36 (ε, 9Η).

References: [1]Patent: WO2019/219517,2019,A1 .Location in patent: Page/Page column 192.
[2]Patent: WO2012/155199,2012,A1 .Location in patent: Page/Page column 77-78.

18
[ 820971-67-3 ]
[ 6793-92-6 ]
[ 1414777-97-1 ]

Yield	Reaction Conditions	Operation in experiment
75%		Step 1 ; 3-(4-Benzyloxy-benzoyl)-azetidine-1-carboxylic aoid tert-butyl esterTo a stirred solution of 1-(Benzyloxy)-4-bromobenzene (32.3 g, 0.12 mol) in dry THF (250 mL) was added n-Butyl lithium (83 mL. 0.13 mol. 1.6 M solution in hexane) in drops at -78 C under nitrogen and the reaction mixture was stirred at same temperature for 1 nr. To this reaction mixture, a solution of fert-butyl 3- [methoxy(methyl)amlno]carbonyl}azetidine-1-carboxylate (25 g, 0.10 mol) in dry THF (150 mL) was added in drops. The reaction mixture was stirred at -78 C for 1 nr. After completion of reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate (2 x 200 mL). The combined organic layer washed with water (200 mL), brine (100 mL) and dried over sodium sulphate. The solvent was concentrated under reduced pressure; the crude product was slurred with pet ether (100 mL) and ethyl acetate (50 mL). The solids were filtered to afford (30g, 75 %) of the titled compound as white solid. TLC-Pet ether/ Ethyl acetate (8:2), R, = 0.7; 'H NMR (400MHz, DMSO-de) δ 7.84-7.82 (t. J = 8.0 Hz, 2H). 7.46-7.31 (m, 5H), 7.14-7.10 (m, 2H), 5.20 (s, 2H), 4.35-4.28 (m, 1H), 4.10 (s, 2H), 3.93 (s, 2H). 1.36 (s, 9H).

References: [1]Patent: WO2012/155199,2012,A1 .Location in patent: Page/Page column 79.

19
[ 820971-67-3 ]
[ 1414777-94-8 ]

References: [1]Patent: WO2012/155199,2012,A1 .
[2]Patent: WO2019/219517,2019,A1 .

20
[ 820971-67-3 ]
[ 1414777-96-0 ]

References: [1]Patent: WO2012/155199,2012,A1 .

21
[ 820971-67-3 ]
[ 1414777-98-2 ]

References: [1]Patent: WO2012/155199,2012,A1 .

22
[ 820971-67-3 ]
[ 1414777-99-3 ]

References: [1]Patent: WO2012/155199,2012,A1 .

23
[ 820971-67-3 ]
[ 1414778-00-9 ]

References: [1]Patent: WO2012/155199,2012,A1 .

24
[ 820971-67-3 ]
tert-butyl 3-[(Z)-[4-(difluoromethoxy)phenyl](hydroxyimino)methyl]azetidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2012/155199,2012,A1 .

25
[ 820971-67-3 ]
C₁₅H₂₀N₂O₃ [ No CAS ]