[ CAS No. 100202-39-9 ] {[proInfo.proName]}

Name: 100202-39-9|Methyl azetidine-3-carboxylate hydrochloride|97%
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Quality Control of [ 100202-39-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 100202-39-9 ]

SDS Specification

Alternatived Products of [ 100202-39-9 ]

Product Details of [ 100202-39-9 ]

CAS No. :	100202-39-9	MDL No. :	MFCD01861758
Formula :	C₅H₁₀ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UOCWTLBPYROHEF-UHFFFAOYSA-N
M.W :	151.59	Pubchem ID :	21100040
Synonyms :	Methyl azetidine-3-carboxylate hydrochloride	Chemical Name :	Methyl azetidine-3-carboxylate hydrochloride

Calculated chemistry of [ 100202-39-9 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.0
TPSA :	38.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.23
Log Po/w (WLOGP) :	-0.2
Log Po/w (MLOGP) :	0.0
Log Po/w (SILICOS-IT) :	0.36
Consensus Log Po/w :	0.08

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.79
Solubility :	24.4 mg/ml ; 0.161 mol/l
Class :	Very soluble
Log S (Ali) :	-0.59
Solubility :	38.5 mg/ml ; 0.254 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.55
Solubility :	42.5 mg/ml ; 0.281 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.0

Safety of [ 100202-39-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 100202-39-9 ]

* 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 [ 100202-39-9 ]
Downstream synthetic route of [ 100202-39-9 ]

[ 100202-39-9 ] Synthesis Path-Upstream 1~5

1
[ 100202-39-9 ]
[ 501-53-1 ]
[ 757239-60-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 18 h;	A round bottomed flask containing methyl azetidine-3-carboxylate hydrochloride(3 g, 20 mmol), THF (30 mL) and H20 (30 mL) was added with an aqueous solution ofNaOH (4 M, 5 mL, 20 mmol) at 0 °C, followed by benzyl chloroformate (2.84 mL, 20 mmol). The reaction was vigorously stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between Et20 (100 mL) and H20 (30 mL). The aqueous phase was back-extracted withEt20 (3 x 50 mL), the combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound (5 g, 99percent) as a colourless oil, which was used in subsequent steps without further purification.‘H NMR (400 MHz, CDC13): ö 7.43-7.25 (m, 5 H), 5.10 (s, 2 H), 4.23-4.13 (m, 4 H), 3.74 (s, 3 H), 3.38 (q, J = 7.2 Hz, 1 H).

Reference： [1] Patent: WO2016/177849, 2016, A1, . Location in patent: Page/Page column 74; 75
[2] Patent: US2011/183960, 2011, A1, . Location in patent: Page/Page column 27

2
[ 100202-39-9 ]
[ 24424-99-5 ]
[ 610791-05-4 ]

Yield	Reaction Conditions	Operation in experiment
13.5%	With sodium hydrogencarbonate In tetrahydrofuran; water; ethyl acetate at 0 - 20℃; for 23 h;	A crude product of methyl azetidine-3-carboxylate hydrochloride (calculated as 1.93 g of pure product) was dissolved in water (26 ml), sodium hydrogencarbonate (3.2 g), then a solution of di-t-butyl dicarbonate (2.91 g) in tetrahydrofuran (13 ml) were added with stirring and cooling in an ice bath, followed by stirring at the same temperature for 0.5 hours. The reaction mixture was stirred at room temperature for 19.5 hours. Tetrahydrofuran in the reaction mixture was distilled off, extraction was performed with ethyl acetate. The organic layer was washed with brine (70 ml) and dried over anhydrous sodium sulfate. The concentrated organic layer and the aqueous layer were combined, and tetrahydrofuran (50 ml) was added thereto. This was stirred with cooling in an ice bath, and sodium hydrogencarbonate (3.2 g), then di-t-butyl dicarbonate (2.91 g) were again added thereto. The reaction mixture was stirred at the same temperature for 0.5 hours, then at room temperature for 2.5 days. The reaction mixture was partitioned, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1, 1:1, ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated to give the title compound (370 mg, 13.5percent) as a colorless oil.¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44 (9H, s), 3.35 (1H, m), 3.75 (3H, s), 4.10 (4H, d, J=7.6 Hz).
13.5%	Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; for 20 h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water; ethyl acetate at 0 - 20℃; for 60.5 h;	(Production Example 86) Methyl 1-tert-butoxycarbonylazetidine-3-carboxylate A crude product of methyl azetidine-3-carboxylate hydrochloride (assessed as 1.93 g of a pure product) was dissolved in water (26 ml), and sodium hydrogencarbonate (3.2 g) and a solution of di-t-butyl dicarbonate (2.91 g) in tetrahydrofuran (13 ml) were added while stirring and cooling in an ice bath, followed by stirring at the same temperature for 0.5 hr. The reaction mixture was stirred at room temperature for 19.5 hr. Tetrahydrofuran in the reaction mixture was removed, and extracted with ethyl acetate. The organic layer was washed with brine (70 ml), and dried over anhydrous sodium sulfate. The concentrated organic layer and the aqueous layer were combined, and tetrahydrofuran (50 ml) was added. This was stirred while cooling in an ice bath, and sodium hydrogencarbonate (3.2 g), and di-t-butyl dicarbonate (2.91 g) were again added thereto. After stirring at the same temperature for 0.5 hr, stirring was carried out at room temperature for 2.5 days. The reaction mixture was partitioned, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 2:1, 1:1, ethyl acetate, then ethyl acetate:methanol = 10:1). Fractions containing the target compound were concentrated to provide the titled compound as a colorless oil (370 mg, 13.5 percent). ¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44(9H, s), 3.35 (1H, m), 3.75 (3H, s), 4.10 (4H, d, J = 7.6 Hz).
582 kg	Stage #1: at 5 - 10℃; for 7 h; Large scale Stage #2: at 5 - 20℃; Large scale	Triethylamine (TEA, 560 kg, 5544 mol, 2.18 eq) was added dropwise to the crudesolution of 2 at 5-10 °C giving a vigorous exothermic reaction over about 7 hrs. The mixture was cooled to 5-15 °C. More triethylamine was added (210 kg, 2082 mol, 0.82 eq). Di-tertbutyl dicarbonate (boc anhydride, Boc2O, CAS Reg. No. 24424-99-5 (587 kg, 2690 mol, 1.06eq.) dropwise at 5-15 °C, giving a slightly exothermic reaction with gas generated for about 7 hrs. The mixture was stirred at 1 520 °C for 16 hrs. Methanol was removed by evaporation at 50°C over about 5 hrs. Toluene (1360 kg, 5.3 wt) and water (1750 kg, 6.8 wt) were added and stirred for 20 mm. The organic phases were separated. The water phase was extracted with toluene. The combined organic phases were washed with brine and dried over MgSO4 (150 kg, 0.58 wt) for 30 mm, and filtered. The filter cake was washed with toluene. The combined organic phases were evaporated at 50-60 °C under vacuum. (vacuum: about 0.08 Mpa, about 40 hrs) to give 3 (CAS Reg. No. 610791-05-4, 582 kg 90.4 wpercent by qNMR assay)in 96.4percent corrected yield.

Reference： [1] Patent: US2008/214815, 2008, A1, . Location in patent: Page/Page column 15
[2] Patent: EP1889836, 2008, A1, . Location in patent: Page/Page column 80
[3] Patent: WO2018/108954, 2018, A1, . Location in patent: Page/Page column 19; 20

3
[ 53871-06-0 ]
[ 100202-39-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; hydrogen In methanol; ethyl acetate at 20℃; for 11 h;	(Production Example 85) Methyl azetidine-3-carboxylate hydrochloride A solution of methyl 1-benzhydrylazetidine-3-carboxylate (3.57 g) in methanol (360 ml) were added a 4N solution of hydrochloric acid in ethyl acetate (12.7 ml) and 20 percent palladium hydroxide (3.57 g), followed by stirring at room temperature under a pressurized hydrogen atmosphere (0.4 MPa) for 11 hr. The catalyst was removed by filtration and washed with methanol and water. The filtrate was concentrated to provide a crude product of the target compound as a pale yellow oil. The reaction was assessed as quantitative and the product obtained was assessed as 1.93 g, which were used for the subsequent reaction. ESI-MS (m/z): 116 [M+H]⁺.

Reference： [1] Patent: EP1889836, 2008, A1, . Location in patent: Page/Page column 80
[2] Patent: US2008/214815, 2008, A1, . Location in patent: Page/Page column 14-15

4
[ 67-56-1 ]
[ 36476-78-5 ]
[ 100202-39-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride In acetonitrile at 0 - 20℃; for 2.33333 h;	To a stirring suspension of 3-azetidine carboxylic acid in MeOH at O⁰C₃ was added SOCl₂ dropwise. After 20 minutes, the ice bath was removed, the solution was warmed to rt and was stirred for 2 hours. The solvent was removed in vaccuo to afford the title compound as its HCl salt (1.5g, 100percent). ¹H NMR (400 MHz, CD₃OD) δ 3.71 - 3.77 (m, 1 H) 3.77 (s, 3 H) 4.18 - 4.31 (m, 4 H).
100%	at 0 - 25℃; for 2.25 h;	Step 1 : Preparation of C34. A suspension of C33 (1.0 g, 9.89 mmol) in methanol (50 mL) was cooled to 0 °C. Thionyl chloride (1.49 mL, 20.3 mmol) was slowly added dropwise over one minute. The reaction was stirred at 0 °C for 15 minutes. The cooling bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated to dryness. The residue was diluted with toluene, and then re-concentrated to dryness. The residue was dried under vacuum to afford the hydrochloride salt of C34 as a sticky yellow solid. Yield: 1.52 g, 10.0 mmol, quantitative. ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (br s, 1 H), 9.24 (br s, 1 H), 3.98-4.13 (m, 4H), 3.68 (s, 3H), 3.66-3.76 (m, 1 H).
100%	at 5 - 65℃;	A stirred suspension of azetidine-3-carboxylic acid (2 g, 19.8 mmol) in MeOH (8 ml) was cooled to 5 ⁰C in an ice-water bath. Thionyl chloride (4.3 ml, 59 mmol) was added dropwise at such a rate as to maintain reaction temperature below 30 ⁰C. A further portion of MeOH (8 ml) was added carefully and the mixture heated at 65⁰C overnight. Evaporation of the solvent and co-evaporation with MeOH (2 x 20 ml) at reduced pressure provided the title compound as viscous brown oil that crystallized on standing (3.17 g, 100percent). The material was used without purification.LCMS data: Calculated MH⁺ (116); Found 100percent (MH⁺) m/z 116, Rt = 0.18 min.NMR data: ¹H NMR (250 MHz, DMSO) δ ppm 9.60-8.90 (2H, br m), 4.05 (4H, br s), 3.65(3H, s)

90%

at 20℃; Cooling with ice

Synthesis of 192-A. To a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in MeOH (100 mL) was added SOCl2 (11.8 g, 99.0 mmol) dropwise at ice bath. The solution was stirred at room temperature overnight. The reaction mixture concentrated to dryness to give 192-A (6.8 g, 90percent) as a white solid.

Reference： [1] Patent: WO2006/33633, 2006, A1, . Location in patent: Page/Page column 68
[2] Patent: WO2012/73138, 2012, A1, . Location in patent: Page/Page column 55-56
[3] Patent: WO2009/135842, 2009, A1, . Location in patent: Page/Page column 150
[4] European Journal of Medicinal Chemistry, 2010, vol. 45, # 6, p. 2453 - 2466
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9508 - 9530
[6] Patent: WO2017/7756, 2017, A1, . Location in patent: Paragraph 466
[7] Patent: WO2006/64757, 2006, A1, . Location in patent: Page/Page column 126
[8] Patent: WO2009/16084, 2009, A1, . Location in patent: Page/Page column 50
[9] Patent: WO2005/103001, 2005, A1, . Location in patent: Page/Page column 35-36
[10] Patent: WO2010/85584, 2010, A1, . Location in patent: Page/Page column 43-44
[11] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 144 - 148
[12] Patent: WO2018/108954, 2018, A1, . Location in patent: Page/Page column 19

5
[ 36476-78-5 ]
[ 100202-39-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With chloro-trimethyl-silane In methanol	Preparation 41 Azetidine-3-carboxylic acid methyl ester hydrochloride . A mixture of azetidine-3-carboxylic acid (1.26 g) and chlorotrimethylsilane (7.1 mL) in methanol (10 mL) was heated at reflux for 5 h and concentrated leaving a solid (1.88 g, 100percent). ¹H NMR (300 mHz, D₂O) d 4.31 (m, 4H), 3.81 (m, 1H), 3.78 (s, 3H).

Reference： [1] Patent: EP978279, 2000, A1,
[2] Patent: US4534787, 1985, A,

[ 100202-39-9 ] Synthesis Path-Downstream 1~89

1
[ 960391-21-3 ]
[ 100202-39-9 ]
[ 960391-22-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Step F: Methyl l-({2-terf-butyl-l-[(4,4-difluorocyclohexyl)methyl]-lJ-benzimidazol-5- yl}carbonyl)azetidine-3-carboxylate; To a mixture of 2-tert-butyl-l-[(4,4-difluorocyclohexyl)methyl]-lH-benzimidazole-5- carboxylic acid (0.130 g, 0.371 mmol), DIPEA (162 muL, 0.927 mmol) and DMF (5 mL) were added HATU (0.155 g, 0.408 mmol) and methyl azetidine-3-carboxylate HCl salt (0.062 g, 0.41 mmol). The mixture was stirred at room temperature overnight. Partial consumption of the starting material was observed by LC-MS. Additional methyl azetidine- 3-carboxylate HCl salt (0.030, 0.20 mmol), DIPEA (180 muL, 1.03 mmol) and HATU (0.150 g, 0.395 mmol) were added. The mixture was stirred at room temperature for Ih. The solvent was removed under reduced pressure. CH2Cl2 was added to the resulting residue <n="29"/>and the organic layer was washed once with saturated aqueous NaHCtheta3 solution, brine and dried over anhydrous Na2SO4. CH2CI2 was removed under reduced pressure. The resulting residue was purified by column chromatography on silica gel using 100% ethyl acetate. Yield: 166 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.34 - 1.76 (m, 6 H), 1.57 (s, 9 H), 2.07 - 2.21 (m, 3 H), 3.44 - 3.54 (m, 1 H), 3.77 (s, 3 H), 4.24 (d, 7=7.42 Hz, 2 H), 4.31 - 4.65 (m, 4 H), 7.35 (d, 7=8.59 Hz, 1 H), 7.68 (dd, 7=8.40, 1.56 Hz, 1 H), 7.94 (d, 7=1.37 Hz, I H).

Reference： [1]Patent: WO2007/145563,2007,A1 .Location in patent: Page/Page column 27-28

2
[ 1028947-19-4 ]
[ 100202-39-9 ]
methyl 1-({5-[5-(3-fluoro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methyl)azetidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 13h;	{5-[5-(3-Fluoro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2 -yl}methanol (0.16 g, 0.47mmol) that was obtained in Example 23 (23f), carbon tetrabromide (0.23g, 0.71mmol), and triphenylphosphine (0.19 g, 0.71 mmol) were dissolved in dichloromethane (6 ml) at 0C and stirred at the same temperature for 10 minutes. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:6) to afford the reaction intermediate. Subsequently, to a solution of the reaction intermediate obtained in dichloromethane (7 ml) were added successively <strong>[100202-39-9]methyl 3-azetidinecarboxylate hydrochloride</strong> (0.11 g, 0.71 mmol) and N,N-diisopropylethylamine (0.25 ml, 1.4 mmol) with stirring, and the resulting mixture was stirred at room temperature for 13 hours. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (2 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:12) as the eluent to afford the title compound (0.12 g) in a yield of 59 % as a white crystalline solid. 1HNMR Spectrum (400 MHz, CDCl3) delta ppm: 0.96 (d, 6H, J=6.6 Hz), 1.90-2.04 (m, 1H), 2.62 (d, 2H, J=7.0 Hz), 3.35-3.46 (m, 1H), 3.48 (t, 2H, J=7.2 Hz), 3.66 (t, 2H, J=7.4 Hz), 3.73 (s, 3H), 3.87 (s, 2H), 7.35 (t, 1H, J=8.2 Hz), 7.48 (d, 1H, J=7.4 Hz), 7.86 (dd, 1H, J=10.0 Hz, 1.6 Hz), 7.93 (dd, 1H, J=7.8 Hz, 1.6 Hz), 8.39 (dd, 1H, J=8.2 Hz, 2.1 Hz), 9.30 (d, 1H, J=1.2 Hz). IR Spectrum (KBr): 1218, 1340, 1373, 1398, 1500, 1559, 1729 cm-1. Mass Spectrum (FAB+) m/z: 425 ((M+H)+).

Reference： [1]Patent: EP1873153,2008,A1 .Location in patent: Page/Page column 90

3
[ 53871-06-0 ]
[ 100202-39-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; hydrogen;palladium(II) hydroxide/carbon; In methanol; ethyl acetate; at 20℃; under 3000.3 Torr; for 11h;	(Production Example 85) Methyl azetidine-3-carboxylate hydrochloride A solution of methyl 1-benzhydrylazetidine-3-carboxylate (3.57 g) in methanol (360 ml) were added a 4N solution of hydrochloric acid in ethyl acetate (12.7 ml) and 20 percent palladium hydroxide (3.57 g), followed by stirring at room temperature under a pressurized hydrogen atmosphere (0.4 MPa) for 11 hr. The catalyst was removed by filtration and washed with methanol and water. The filtrate was concentrated to provide a crude product of the target compound as a pale yellow oil. The reaction was assessed as quantitative and the product obtained was assessed as 1.93 g, which were used for the subsequent reaction. ESI-MS (m/z): 116 [M+H]+.
	With hydrogenchloride; hydrogen;palladium dihydroxide; In methanol; ethyl acetate; at 20℃; under 3000.3 Torr; for 11h;	4N hydrochloric acid in ethyl acetate (12.7 ml) and 20percent palladium hydroxide (3.57 g) were added to a solution of methyl 1-benzhydrylazetidine-3-carboxylate (3.57 g) in methanol (360 ml), followed by stirring under a pressurized hydrogen atmosphere (0.4 MPa) at room temperature for 11 hours. The catalyst was removed by filtration, and washed with methanol and water. The filtrate was concentrated to give a crude product of the target compound as a pale yellow oil, which was used in the next reaction supposing that the reaction proceeded quantitatively and 1.93 g of the product was obtained.ESI-MS (m/z): 116[M+H]+.

Reference： [1]Patent: EP1889836,2008,A1 .Location in patent: Page/Page column 80
[2]Patent: US2008/214815,2008,A1 .Location in patent: Page/Page column 14-15

4
[ 301162-83-4 ]
[ 100202-39-9 ]
[ 362703-02-4 ]

Yield	Reaction Conditions	Operation in experiment
60%	With 4-methyl-morpholine; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; In DMF (N,N-dimethyl-formamide); at 60℃;	A solution of the acid (154 mg, 0.5 mmol) from reaction (1b), 3-azetidinecarboxylic acid methyl ester hydrochloride (76 mg, 0.5 mmol), N-methylmorpholine (253 mg, 2.5 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (330 mg, 0.75 mmol) in DMF (4 mL) was heated at 60 C. overnight. After cooling to rt, the mixture was diluted with ethyl acetate (50 mL) and washed with H2O (2×30 mL), sat. potassium dihydrogen phosphate (1×20 mL) and brine (1×20 mL). The organic layer was dried and concentrated and the resulting residue purified by silica gel column chromatography (3:1 ethyl acetate:hexanes) to give the desired amide (121 mg, 60%).

Reference： [1]Patent: US2004/72802,2004,A1 .Location in patent: Page/Page column 42

5
[ 67-56-1 ]
[ 36476-78-5 ]
[ 100202-39-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; In acetonitrile; at 0 - 20℃; for 2.33333h;	To a stirring suspension of 3-azetidine carboxylic acid in MeOH at O0C3 was added SOCl2 dropwise. After 20 minutes, the ice bath was removed, the solution was warmed to rt and was stirred for 2 hours. The solvent was removed in vaccuo to afford the title compound as its HCl salt (1.5g, 100%). 1H NMR (400 MHz, CD3OD) delta 3.71 - 3.77 (m, 1 H) 3.77 (s, 3 H) 4.18 - 4.31 (m, 4 H).
100%	With thionyl chloride; at 0 - 25℃; for 2.25h;	Step 1 : Preparation of C34. A suspension of C33 (1.0 g, 9.89 mmol) in methanol (50 mL) was cooled to 0 C. Thionyl chloride (1.49 mL, 20.3 mmol) was slowly added dropwise over one minute. The reaction was stirred at 0 C for 15 minutes. The cooling bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated to dryness. The residue was diluted with toluene, and then re-concentrated to dryness. The residue was dried under vacuum to afford the hydrochloride salt of C34 as a sticky yellow solid. Yield: 1.52 g, 10.0 mmol, quantitative. 1H NMR (400 MHz, DMSO-d6) delta 9.56 (br s, 1 H), 9.24 (br s, 1 H), 3.98-4.13 (m, 4H), 3.68 (s, 3H), 3.66-3.76 (m, 1 H).
100%	With thionyl chloride; at 5 - 65℃;	A stirred suspension of azetidine-3-carboxylic acid (2 g, 19.8 mmol) in MeOH (8 ml) was cooled to 5 0C in an ice-water bath. Thionyl chloride (4.3 ml, 59 mmol) was added dropwise at such a rate as to maintain reaction temperature below 30 0C. A further portion of MeOH (8 ml) was added carefully and the mixture heated at 650C overnight. Evaporation of the solvent and co-evaporation with MeOH (2 x 20 ml) at reduced pressure provided the title compound as viscous brown oil that crystallized on standing (3.17 g, 100%). The material was used without purification.LCMS data: Calculated MH+ (116); Found 100% (MH+) m/z 116, Rt = 0.18 min.NMR data: 1H NMR (250 MHz, DMSO) delta ppm 9.60-8.90 (2H, br m), 4.05 (4H, br s), 3.65(3H, s)

90%	With thionyl chloride; at 20℃;Cooling with ice;	Synthesis of 192-A. To a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in MeOH (100 mL) was added SOCl2 (11.8 g, 99.0 mmol) dropwise at ice bath. The solution was stirred at room temperature overnight. The reaction mixture concentrated to dryness to give 192-A (6.8 g, 90%) as a white solid.
	With chloro-trimethyl-silane; at 20℃;	Intermediate 22: Methyl 3-azetidinecarboxylate hydrochloride. 3-Azetidinecarboxylic acid (200 mg, 1.98 mmol) was suspended in anhydrous MeOH (5 mL) under argon atmosphere. Trimethylchlorosilane (500 mul, 3.91 mmol) was then added at room temperature and the mixture was stirred for 30 minutes and then left still overnight. The solvent was removed and the resulting solid was triturated in diethyl ether and decanted. The sample was dried under vacuum, to give the title compound as pale yellow solid (275 mg);MS m/z (ES): 115.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) delta ppm 8.70 - 9.62 (m, 2 H), 3.96 - 4.20 (m, 4 H), 3.63 - 3.77 (m, 4 H).
	With acetyl chloride; at 20℃;Reflux;	Preparation of Intermediate 3 (Int.3); (Z)-Methyl 1 -(4-(N'-hydroxycarbamimidoyl)benzyl)azetidine-3 -carboxylate; Int.3 -A. Methyl azetidine-3 -carboxylate, HCl ;OCH,HN-J" HCI (Int.3-A); [00111] To methanol (5 mL), pre-cooled to 00C, was added acetyl chloride (0.852 mL, 11.99 mmol). After stirring 5 minutes at 00C, the reaction mixture was allowed to warm to RT. At this time, azetidine-3-carboxylic acid (404 mg, 4.00 mmol) was added and the reaction mixture was refluxed for 2.5 hr. After cooling to rt, the volatiles were removed in vacuo and the residue was dried to afford methyl azetidine- 3-carboxylate, HCl (600 mg, 3.96 mmol) as a white solid. 1H NMR (400 MHz, methanol-cU) delta ppm 3.77 (m, IH) 3.81 (s, 3H) 4.22-4.33 (m, 4H).
	With thionyl chloride; at 5 - 25℃;Inert atmosphere; Large scale;	A 5000 liter reactor was charged with azetidine-3-carboxylic acid 1 (CAS Reg. No.36476-78-5, 256.5 kg, 2540 mol, 1.0 eq.) and MeOH (1026 kg, 4 wt) and purged withnitrogen gas, and cooled to 5-15 C. Thionyl chloride (362 kg, 3043 mol, 1.20 eq.) was added dropwise at 5-25 C giving a violent exothermic reaction over about 3.5 hrs. The mixture was stirred at about 15-20 C for 16 hrs to give crude 2 (CAS Reg. No.. 100202-39-9 HC1 salt, 343238-58-4 free base), used directly in Example 2. A sample showed by ?H NMR that all starting material was consumed.
	With thionyl chloride; at 0 - 25℃; for 2h;	Compound 2-a (1.00 g, 9.89 mmol, 1.00 eq) was dissolved in methanol (50.00 mL), and thionyl chloride (2.44 g, 20.54 mmol, 1.49 mL, 2.08 eq) was added dropwise thereto at 0C, maintained at 0C and stirred for 15 min, followed by stirring at 25C for 2 hours. After the reaction was completed, the reaction solution was spin-dried, added with toluene, and further spin-dried, to give the pale yellow product of compound 2-b (1.40 g, crude), which was used directly in the next step without purification. 1H NMR (400 MHz, DMSO-d6) delta=9.71 (br. s., 1H), 9.39 (br. s., 1H), 4.05 (d, J=10.54 Hz, 4H), 3.69-3.76 (m, 1H), 3.67 (s, 3H).

Reference： [1]Patent: WO2006/33633,2006,A1 .Location in patent: Page/Page column 68
[2]Patent: WO2012/73138,2012,A1 .Location in patent: Page/Page column 55-56
[3]Patent: WO2009/135842,2009,A1 .Location in patent: Page/Page column 150
[4]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2453 - 2466
[5]Journal of Medicinal Chemistry,2017,vol. 60,p. 9508 - 9530
[6]Patent: WO2017/7756,2017,A1 .Location in patent: Paragraph 466
[7]Patent: WO2006/64757,2006,A1 .Location in patent: Page/Page column 126
[8]Patent: WO2009/16084,2009,A1 .Location in patent: Page/Page column 50
[9]Patent: WO2005/103001,2005,A1 .Location in patent: Page/Page column 35-36
[10]Patent: WO2010/85584,2010,A1 .Location in patent: Page/Page column 43-44
[11]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 144 - 148
[12]Patent: WO2018/108954,2018,A1 .Location in patent: Page/Page column 19
[13]Patent: EP3456711,2019,A1 .Location in patent: Paragraph 0085; 0086

6
[ 847585-93-7 ]
[ 100202-39-9 ]
methyl 1-({6-[3-(4-fluorophenyl)propoxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylate [ No CAS ]

Reference： [1]Patent: WO2006/64757,2006,A1 .Location in patent: Page/Page column 82

7
[ 100202-39-9 ]
[ 50921-39-6 ]
[ 7087-68-5 ]
[ 405087-52-7 ]

Yield	Reaction Conditions	Operation in experiment
65%	In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	Example 68 Synthesis of 1-[1-(4-chloro-phenyl)-cyclobutanecarbonyl]-azetidine-3-carboxylic acid methyl ester To a stirred solution of <strong>[100202-39-9]azetidine-3-carboxylic acid methyl ester hydrochloride</strong> (762 mg, 4.60 mmoles) and 1-(4-chloro-phenyl)-cyclobutane carboxylic acid (2.09 g, 9.90 mmoles) in anhydrous DCM (20 mL) was added di-isopropyl ethyl amine (4.6 mL, 26.4 mmoles) dropwise. After completion of addition solid PyBroP (4.63 g, 9.94 mmoles) was added to the stirring reaction mixture. The reaction mixture continued stirring at RT for 10 h and was quenched with water. The aqueous layer was extracted with EtOAc (3*20 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield an oil. This crude material was purified using silica gel chromatography (9:1 hexanes:EtOAc-1:1 hexane:EtOAc) to yield the desired amide (1.0 g, 65%). 1H NMR (300 MHz, CDCl3): delta7.38-7.29 (m, 4H), 4.16 (m, 2H), 3.88 (m, 1H), 3.72 (s, 3H), 3.31-1.63 (m, 8H). LRMS: M+309.
65%	In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	EXAMPLE 68 Synthesis of 1-[1-(4-chloro-phenyl)-cyclobutanecarbonyl]-azetidine-3-carboxylic acid methyl ester To a stirred solution of <strong>[100202-39-9]azetidine-3-carboxylic acid methyl ester hydrochloride</strong> (762 mg, 4.60 mmoles) and 1-(4-chloro-phenyl)-cyclobutane carboxylic acid (2.09 g, 9.90 mmoles) in anhydrous DCM (20 mL) was added di-isopropyl ethyl amine (4.6 mL, 26.4 mmoles) dropwise. After completion of addition solid PyBroP (4.63 g, 9.94 mmoles) was added to the stirring reaction mixture. The reaction mixture continued stirring at RT for 10h and was quenched with water. The aqueous layer was extracted with EtOAc (3*20 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield an oil. This crude material was purified using silica gel chromatography (9:1 hexanes:EtOAc-1:1 hexane:EtOAc) to yield the desired amide (1.0 g, 65%). 1H NMR (300 MHz, CDCl3): delta 7.38-7.29 (m, 4H), 4.16 (m, 2H), 3.88 (m, 1H), 3.72 (s, 3H), 3.31-1.63 (m, 8H). LRMS: M+309.

Reference： [1]Patent: US2003/50309,2003,A1
[2]Patent: US2005/80078,2005,A1

8
1-[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-ium triflate [ No CAS ]
[ 100202-39-9 ]
methyl 1-[[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl](methyl)amino]sulfonyl}azetidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;	To a solution of 1 - { [[2-tert-hutyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- IH- benzimidazol-5-yl](methyl)amino]sulfonyl}-3-methyl-1H-imidazol-3-iuni (100 nig, 0.17 mmol, see Example 10, Steps B-I for its preparation) and diisopropylethylamine (0.12 mL, 0.68 mmol) at rt in MeCN (0.8 mL), was added methyl azetidine-3- carboxylate hydrochloride (51.5 mg, 0.34 mmol). The solution was stirred at rt overnight. After evaporation of the solvent, the residue was purified by flash chromatography (0-100% EtOAc in hexanes, 50 min; 100% EtOAc 10 min; 0-2% MeOH in EtOAc, 10 min) to provide the title compound (7.8 mg, 8%). 1H NMR (400 MHz, CD3OD) delta 1.50 - 1.55 (m, 5 H) 1.56 (s, 9 H) 2.23 - 2.36 (m, 1 H) 3.29 (s, 3 H) EPO <DP n="69"/>3.30 - 3.42 (m, 2 H) 3.75 (s, 3 H) 3.95 - 4.08 (m, 4 H) 4.10 - 4.23 (m, 4 H) 7.28 - 7.31 (m, 2 H) 7.71 - 7.74 (m, 1 H); MS (ESI) (M+H)+ 478.8.

Reference： [1]Patent: WO2006/33633,2006,A1 .Location in patent: Page/Page column 67; 68

9
[ 1722-12-9 ]
[ 100202-39-9 ]
[ 914807-82-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In methanol; at 20 - 50℃; for 5h;	6.13. Preparation of Biphenyl-4-yl-( l-pyrimidin-2-yl-azetidin-3-vD- methanone; To a stirred solution of <strong>[100202-39-9]3-azetidine carboxylic acid methyl ester hydrochloride</strong> (150 mg, 0.99 mmol) and 2-chloropyrimidine (113.4 mg, 0.99 mmol) in methanol, was added TEA (200 mg, 1.98 mmol) at room temperature. The mixture was stirred at 5O0C for 5 hours and concentrated under reduced pressure. The residue was suspended inEtOAc (50 ml) and washed with water (15 ml), brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give l-pyrimidin-2-yl- azetidine-3 -carboxylic acid methyl ester as a light yellow solid (137.3 mg, 72%): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.58 (t, J= 6.4 Hz, 1 H), 4.30 (m, 4 H), 3.77 (s, 3 H), 3.56 (m, 1 H).
72%	With triethylamine; In methanol; at 50℃; for 5h;	To a stirred solution of <strong>[100202-39-9]3-azetidine carboxylic acid methyl ester hydrochloride</strong> (150 mg, 0.99 mmol) and 2-chloropyrimidine (113.4 mg, 0.99 mmol) in methanol, was added TEA (200 mg, 1.98 mmol) at room temperature. The mixture was stirred at 50 C. for 5 hours and concentrated under reduced pressure. The residue was suspended in EtOAc (50 ml) and washed with water (15 ml), brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-azetidine-3-carboxylic acid methyl ester as a light yellow solid (137.3 mg, 72%): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J=6.4 Hz, 2 H), 6.58 (t, J=6.4 Hz, 1 H), 4.30 (m, 4 H), 3.77 (s, 3 H), 3.56 (m, 1 H).

Reference： [1]Patent: WO2008/67121,2008,A2 .Location in patent: Page/Page column 57
[2]Patent: US2006/258672,2006,A1 .Location in patent: Page/Page column 19

10
[ 36476-78-5 ]
[ 100202-39-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With chloro-trimethyl-silane; In methanol;	Preparation 41 Azetidine-3-carboxylic acid methyl ester hydrochloride . A mixture of azetidine-3-carboxylic acid (1.26 g) and chlorotrimethylsilane (7.1 mL) in methanol (10 mL) was heated at reflux for 5 h and concentrated leaving a solid (1.88 g, 100%). 1H NMR (300 mHz, D2O) d 4.31 (m, 4H), 3.81 (m, 1H), 3.78 (s, 3H).
	With thionyl chloride; In methanol;	15.0 g of thionyl chloride was added to a stirred solution of 5.06 g of 3-azetidinecarboxylic acid in 200 ml of dry methanol at 0-5 C. under nitrogen, the addition occurring over a 30-minute period. The resulting solution was stirred at about 0 C. overnight, methanol and thionyl chloride were evaporated under reduced pressure, and the residue was held under very low pressure (<1 Torr.) for several hours to give the methyl ester hydrochloride of 3-azetidinecarboxylic acid (1B), as a colorless solid, m.p.: 86-90 C.

Reference： [1]Patent: EP978279,2000,A1
[2]Patent: US4534787,1985,A

Yield	Reaction Conditions	Operation in experiment
		Example 38 methyl azetidine-3-carboxylate hydrochloride Methanol (70 mL) was added dropwise under stirring at 0C to thionyl chloride (23.4 mL), and azetidine-3-carboxylic acid (CAS No. 36476-78-5, 25 g) was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated, to thereby obtain the title compound (36 g) having the following physical properties. TLC: Rf 0.68 (chloroform:methanol:aqueous ammonia = 20:5:1); 1H-NMR (CD3OD): delta 4.18-4.33 (m, 4H), 3.72-3.81 (m, 4H).

12
[ 100202-39-9 ]
[ 937054-53-0 ]
[ 937055-18-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: Compound 8 (81 mg, 0.19 mmol) and ethyl 2-(4-piperidinyl)acetate (36 mg, 0.21 mmol) were dissolved in dichloromethane (3 ml). To the solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 1-hydroxybenzotriazole (9 mg, 0.06 mmol) were added, followed by stirring at room temperature for 3 h. The reaction mixture was diluted with chloroform and washed with satd NaHCO3 aq and brine. The organic layer was dried over Na2SO4, and then concentrated in vacuo. The residue was purified by preparative TLC (methanol-chloroform = 1:100) to give the title compound 9 (83 mg, 0.15 mmol, 77%).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 15h;	Example 99; Methyl 1-(3-((4R,6S)-8-chloro-6-(2,3-dimethoxyphenyl)-4H,6H-pyrrolo(1,2-a)(4,1)benzoxazepin-4-yl)propanoyl)-3-azetidine carboxylate; [Show Image] To a solution of 3-[(4R,6S)-8-chloro-6-(2,3-dimethoxyphenyl)-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl]propanoic acid (58 mg) in methylene chloride (3.0 mL) were added 3-methylazetidine hydrochloride (27 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg), 1-hydroxybenzotriazole (21 mg), and triethylamine (23 mul). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was purified by preparative thin layer chromatography (10% methanol-chloroform) to give the title compound (51 mg). MS(ESI)m/z:525(M++H). 1H-NMR(CDCl3)delta:2.28-2.48(4H,m),3.24-3.47(4H,m),3.75(3H,s),3.85(3H,s),4.06-4:34(4H,m),4.36-4.40(1H,m),5.70(1H,s),6.32-6.34(1H,m),6.37(1H,t,J=3.2Hz),6.71(1H,d,J=2.0Hz),6.95(1H,d, J=8.1Hz),7.08(1H,dd,J=2.7,1.5Hz),7.19(1H,t,J=8.1Hz),7.26-7.41(3H,m).

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3072 - 3093
[2]Patent: EP1939205,2008,A1 .Location in patent: Page/Page column 148-149

13
[ 100202-39-9 ]
[ 32315-10-9 ]
[ 957203-93-9 ]
[ 957204-51-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]indoline hydrochloride (100 mg) in a dichloromethane/pyridine (10:1) mixture (2.2 mL), triphosgene (23.7 mg) was added at 0C in a nitrogen atmosphere, and the mixture was stirred for 14 hours. To the reaction mixture, <strong>[100202-39-9]azetidine-3-carboxylic acid methyl ester hydrochloride</strong> (36.4 mg) was added, followed by stirring for 7 hours. An equiamount of <strong>[100202-39-9]azetidine-3-carboxylic acid methyl ester hydrochloride</strong> (36.4 mg) was added thereto, followed by further stirring for 17 hours. The reaction mixture was diluted with ethyl acetate, and 1N hydrochloric acid was added thereto, followed by stirring for 30 minutes. The resultant mixture was extracted with ethyl acetate. The extracts were combined and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated brine, followed by drying over sodium sulfate anhydrate. Sodium sulfate anhydrate was removed by filtration, and solvent was removed under reduced pressure. The residue was subjected to silica gel flash column chromatography (Biotage 25S), to thereby yield the title compound (103 mg). NMR (CDCl3) delta : 3.11(2H,t,J=8.8Hz),3.40-3.49(1H,m),3.77(3H,s),3.92(2H,t,J=8.6Hz),4.30(2H,s),4.32(2H,s ),5.18(2H,s),6.77-6.83(2H,m),7.04-7.06(1H,m),7.35-7.44(5H,m),7.61(1H,d,J=8.8Hz). MS (ESI)m/z: 517 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 87

14
[ 100202-39-9 ]
[ 957203-93-9 ]
[ 79-04-9 ]
[ 957204-52-3 ]

Yield	Reaction Conditions	Operation in experiment
		[5-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]indoline] hydrochloride (100 mg) was dissolved in acetonitrile (5 mL), and to the solution, DIEA (85 muL) and chloroacetyl chloride (21 muL) were sequentially added at 0C with stirring, and the mixture was stirred for 1 hour. To the reaction mixture, azetidinecarboxylic acid methyl ester hydrochloride (73 mg) and DIEA (169 muL) were added, followed by stirring at 50C for 2 hours. The resultant mixture was concentrated, and the residue was purified by silica gel flash column chromatography (Yamazen Hi-Flash L), to thereby yield the title compound (109 mg). NMR (CDCl3) delta: 3.16(2H,t,J=8.5Hz),3.36(2H,s),3.39-3.48(2H,m),3.67-3.81(6H,m),4.01(2H,t,J=8.4Hz),5.18(2H,s),6.77-6.84(2H,m),7.05(1H,s),7.35-7.43(5H,m),8.14(1H,d,J=8.8Hz). MS (ESI) m/z 531 (M+H)+.

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 88-89

15
[ 100202-39-9 ]
[ 1111640-58-4 ]
methyl 1-(11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)azetidine-3-carboxylate [ No CAS ]
methyl 1-(11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)azetidine-3-carboxylate [ No CAS ]
methyl 1-(11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)azetidine-3-carboxylate [ No CAS ]
methyl 1-(11'H-spiro[cyclopentane-1,10'-dibenzo[b,f]oxepin]-3-yl)azetidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Compound 129: Methyl i-d i'H-spirorcvclopentane-I .I O'-dibenzorb/floxepinl-S-vD-S- azetidinecarboxylate31-1,11 'H-Spiro[cyclopentane-1 ,10'-dibenzo[b,f]oxepin]-3-one (Intermediate 20, 70 mg, 0.265 mmol) and <strong>[100202-39-9]methyl 3-azetidinecarboxylate hydrochloride</strong> (Intermediate 22, 48.2 mg, 0.318 mmol) in acetonitrile (4 ml) were stirred under nitrogen to give a colorless solution. After stirring for 30 min at room temperature NaBH(OAC)3 (84 mg, 0.397 mmol) was added and the reaction stirred overnight. Water was added, the solution concentrated under reduced pressure and the aqueous extracted with DCM. The phases were separated on a hydrophobic frit and the combined organic solvent was evaporated. The product was purified using a -NH2 5g column, eluting with EtOAc/cyclohexane 1 :9 to give the title compound (85 mg) as a mixture of two diastereoisomeric racemates. UPLC/MS Rf=0.65; m/z (ES): 364.06 [M+H]+The diastereomeric mixture was submitted for chiral HPLC purification (Preparative chromatographic conditions: Column = Chiralcel OJ-H; Mobile phase = n-Hexane/Ethanol 95/5% v/v; Flow rate = 13 mL/min; DAD= 215 nm) to give 1 single isomer and a mixture of other two:Compound 130: Methyl i-d i'H-spirorcvclopentane-I J O'-dibenzorb.floxepinl-S-vD-S- azetidinecarboxylate (isomer 1 ) retention time = 12.97 mins (21 mg); 1H NMR (400 MHz, CHLOROFORM-d) d ppm 7.30- 7.0 (m, 8 H); 3.73 (s, 3 H); 3.59-2.95 (m, 8 H); 2.22-1.59 (m, 6 H).The mixture of the two isomers: retention time = 14.95 mins (28 mg) was submitted to further chiral HPLC purification (Preparative chromatographic conditions: Column = Chiralcel AD-H (25x2 cm); Mobile phase = n-Hexane/2-Ethanol 90/10% v/v; Flow rate =13 mL/min; DAD = 225 nm) to obtain:Compound 131 : Methyl i-d i'H-spirorcvclopentane-I .I O'-dibenzorb/floxepinl-S-vD-S- azetidinecarboxylate (isomer 3) retention time = 7.5 mins (3 mg); m/z (ES): 364.06 [M+H]+ <n="121"/>Compound 132: Methyl i-d i'H-spirorcvclopentane-I .I O'-dibenzorb/floxepinl-S-vD-S- azetidinecarboxylate (isomer 2):retention time = 8.82 mins (19 mg); 1H NMR (400 MHz, CHLOROFORM-d) d ppm 7.29-7.00 (m, 8 H); 3.73 (s, 3 H); 3.58-2.94 (m, 8 H); 2.21-1.58 (m, 6 H).

Reference： [1]Patent: WO2009/16084,2009,A1 .Location in patent: Page/Page column 119-120

16
[ 868699-27-8 ]
[ 100202-39-9 ]
1-[2-(3-{4-[4-(cyclohexyloxy)butoxy]phenyl}propoxy)-5-(ethoxycarbonyl)phenyl]acetyl}-azetidine-3-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2005/103001,2005,A1 .Location in patent: Page/Page column 63-64

17
[ 100202-39-9 ]
4-nitrophenyl-4-cyclobutyl-1,4-diazepane-1-carboxylate [ No CAS ]
methyl 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; In methanol; isopropyl alcohol; at 85℃; for 72.0333h;	To a stirred solution of 4-nitrophenyl 4-cyclo butyl- 1,4-diazepane-l-carboxylate (2.4 g, 7.5 mmol) in isopropyl alcohol (6 ml) and methanol (3 ml) was added DIPEA (3.80 ml, 24 mmol) followed by <strong>[100202-39-9]methyl azetidine-3-carboxylate hydrochloride</strong> (1.70 g, 11 mmol) portion wise over 2 minutes. The resulting suspension was heated at 850C for 72 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with IM sodium carbonate solution (3 x 30 ml), dried (Na2SO4), filtered and evaporated at reduced pressure. Purification by FCC on silica provided the title compound as pale yellow oil (0.95 g, 43 %).LCMS data: Calculated MH+ (296); Found 100% (MH+) m/z 296, Rt = 3.53 min. NMR data: 1H NMR (500 MHz, CDCl3) delta ppm 4.17-4.10 (5H, m), 3.76 (3H, s), 3.50-3.36 (5H, m), 2.90-2.79 (IH, m), 2.57-2.38 (4H, m), 2.09-2.00 (2H, m), 1.96-1.78 (4H, m), 1.77- 1.57 (3H, m), 1.31-1.24 (2H, m).

Reference： [1]Patent: WO2009/135842,2009,A1 .Location in patent: Page/Page column 150-151

18
[ 100202-39-9 ]
[ 1220971-97-0 ]
[ 1220971-99-2 ]

Yield	Reaction Conditions	Operation in experiment
68%		A mixture the product of Example 1 , Step E (0.07 g; 0.85 mmol), azetidine-3-methylcarboxylate hydrochloride (0.03 g; 0.199 mmol) and DIPEA (0.035 ml, 0.2 mmol) in 1 ,2-dichloroethane (1 ml) and methanol (MeOH) (3 ml) was sonicated for 30 min at room temperature, then evaporated to dryness. The yellowish residue was suspended in 1 ,2- dichloroethane (1 ml) and NaBH(OAc)3 (0.12 g; 0.57 mmol) was added, followed by AcOH (0.01 ml). This was stirred for 1 h at room temperature and diluted to 15 ml with EtOAc, washed with 10% KOH (2 x 3 ml); brine, dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness. The residue was purified by FCC (SiO2, EtOAc) to give the title compound (0.06 g; 68%), as creamy syrup. 1H-NMR (CDCI3) 8.33 (d, 1 H, J = 3 Hz); 8.06 (dd, 1 H, 3, 9 Hz); 7.78 (dd, 1 H, J = 3, 9 Hz); 6.87 (d, 1 H, J = 2 Hz); 6.63 (s, 1 H); 4.14 - 4.22 (m, 4H); 3.6 - 3.7 (m, 5H); 3.48 - 3.34 (m, 2H); 1.49 (m, 6H).

Reference： [1]Patent: WO2010/43000,2010,A1 .Location in patent: Page/Page column 48

19
[ 100202-39-9 ]
[ 1226692-33-6 ]
[ 1226694-59-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	Step 7: l-(2-{6-Methyl-8-[4-(l-phenyl-lH-pyrazol-3-ylmethyl)-[l,4]diazepan-l-yl]-quinolin- 7-yloxy}-acetyl)-azetidine-3-carboxylic acid methyl ester[0188] A mixture of {6-Methyl-8-[4-(l-phenyl-lH-pyrazol-3-ylmethyl)-[l,4]diazepan-l- yl]-quinolin-7-yloxy} -acetic acid (100 mg, 0.21mmol), 3-Azetidinecarboxylic methyl ester HCl salt( 35.4 mg, 0.23 mmol) , HATU( 97 mg, 0.25 mmol) and DIEA (0.222 ml) in DMF (1 ml) was stirred at rt for 2 hrs. After an aqueous workup, the mixture was purified by flash chromatography to give a light yellow solid (70 mg, 59%). MS (ES) mlz 569.3 (M+ H+).

Reference： [1]Patent: WO2010/54006,2010,A1 .Location in patent: Page/Page column 73

20
1-{(2-bromoethoxy)[bis(4-methoxyphenyl)]methyl}-4-methoxybenzene [ No CAS ]
[ 100202-39-9 ]
[ 1229705-62-7 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2453 - 2466

21
[ 100202-39-9 ]
[ 6078-95-1 ]
[ 1229705-60-5 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2453 - 2466

22
[ 100202-39-9 ]
[ 109857-81-0 ]
[ 1229705-61-6 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2453 - 2466

23
[ 100202-39-9 ]
[ 105-07-7 ]
[ 1236148-78-9 ]

Yield	Reaction Conditions	Operation in experiment
		Int.3-B. Methyl l-(4-cyanobenzyl)azetidine-3-carboxylate: [00112] A mixture of 4-formylbenzonitrile (510 mg, 3.89 mmol), methyl azetidine- 3-carboxylate (590 mg, 3.89 mmol), acetic acid (0.245 mL, 4.28 mmol) and ~1 gm of powdered 4 Angstrom molecular sieves in DCE (15 mL) was stirred briskly at RT for 1 hr. At this time, sodium triacetoxyborohydride (907 mg, 4.28 mmol) was added and the reaction mixture was stirred at RT for 2 hr. After filtering through a sintered glass funnel, the filtrate was concentrated to a residue that was partitioned between EtOAc (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to afford a colorless oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100%EtOAc/Hex gradient. The essentially pure fractions were concentrated to afford methyl l-(4-cyanobenzyl)azetidine-3-carboxylate (765 mg, 3.32 mmol). HPLC retention time = 0.49 minutes [broad peak] (PHENOMENEX Luna 4.6 x 30 mm S- 5 ODS column) eluting with 10-90% aqueous methanol + 0.1% TFA over a 2 minute gradient. MS:(M+H)= 231.23. 1H NMR (400 MHz, CDCl3) delta ppm 3.32-3.36 (m, 3H) 3.49-3.58 (m, 2H) 3.67 (s, 2H) 3.72 (s, 3H), 7.39 (d, J= 8.6 Hz, 2H) 7.60 (d, J= 8.3 Hz, 2H).

Reference： [1]Patent: WO2010/85584,2010,A1 .Location in patent: Page/Page column 44

24
[ 100202-39-9 ]
[ 1160956-97-7 ]
[ 1160956-13-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of azetidine-2-carboxylic acid methyl ester hydrochloride (51 mg, 340 mumol) in methanol (1 mL), a solution of diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (30 mg, 68 mumol) in methanol (1 mL) followed by DIPEA (90 mg, 679 mumol) is added. The mixture is stirred at 70 C. for 22 h before it is cooled to rt and 3 M aq. NaOH (0.35 mL) is added. The mixture is stirred at rt for 18 h before it is separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 10 mum, eluting with a gradient of acetonitrile in water containing 0.5% of sat. aq. ammonia) to give the title compound (29 mg) as a resin; LC-MS*: tR=0.74 min; [M+1]+=543.09; 1H NMR (D6-DMSO): delta1.03 (t, J=7.0 Hz, 6H), 1.21 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.33 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 2.62-2.69 (m, 1H), 2.73 (q, J=7.3 Hz, 2H), 3.10-3.17 (m, 1H), 3.18-3.22 (m, 1H), 3.22-3.28 (m, 2H), 3.42-3.51 (m, 2H), 3.66-3.72 (m, 1H), 3.73 (s, 2H), 3.74-3.80 (m, 2H), 7.72 (s, 2H), 7.80 (s, 1H).

Reference： [1]Patent: US2010/261702,2010,A1 .Location in patent: Page/Page column 39

25
[ 100202-39-9 ]
[ 1257093-73-4 ]
[ 1257093-53-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 102 - 106

26
[ 100202-39-9 ]
[ 1202075-57-7 ]
[ 1202076-04-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 107 - 112

27
[ 100202-39-9 ]
[ 501-53-1 ]
[ 757239-60-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 18h;	A round bottomed flask containing <strong>[100202-39-9]methyl azetidine-3-carboxylate hydrochloride</strong>(3 g, 20 mmol), THF (30 mL) and H20 (30 mL) was added with an aqueous solution ofNaOH (4 M, 5 mL, 20 mmol) at 0 C, followed by benzyl chloroformate (2.84 mL, 20 mmol). The reaction was vigorously stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between Et20 (100 mL) and H20 (30 mL). The aqueous phase was back-extracted withEt20 (3 x 50 mL), the combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound (5 g, 99%) as a colourless oil, which was used in subsequent steps without further purification.?H NMR (400 MHz, CDC13): oe 7.43-7.25 (m, 5 H), 5.10 (s, 2 H), 4.23-4.13 (m, 4 H), 3.74 (s, 3 H), 3.38 (q, J = 7.2 Hz, 1 H).
	With triethylamine; In dichloromethane; at 20℃;	(i) 1-Benzyl 3-methyl 1,3-azetidinedicarboxylate 10 g of azetidine-3-carboxylic methyl ester hydrochloride and then 23 ml of triethylamine are added to 150 ml of CH2Cl2. The mixture is cooled and 13.5 g of benzyl chloroformate are added. After leaving overnight at AT, washing is carried out with water and then with HCl (N). After drying, concentrating to dryness and purifying by chromatography on silica (eluent: heptane-AcOEt (gradient from 0% to 50%)), 13.1 g of the expected compound are obtained.

Reference： [1]Patent: WO2016/177849,2016,A1 .Location in patent: Page/Page column 74; 75
[2]Patent: US2011/183960,2011,A1 .Location in patent: Page/Page column 27

28
[ 100202-39-9 ]
[ 1260024-00-7 ]
[ 1344997-80-3 ]

Yield	Reaction Conditions	Operation in experiment
		DESCRIPTION FOR D90methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D90)To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]acetaldehyde (D78) (160 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added <strong>[100202-39-9]methyl 3-azetidinecarboxylate hydrochloride</strong> (182 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D90) (200 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C27H31ClN2O3S requires 498. found 499.2 (M+H+).

Reference： [1]Patent: US2011/269738,2011,A1 .Location in patent: Page/Page column 38-39

29
[ 100202-39-9 ]
[ 1344997-64-3 ]
C₂₈H₃₂N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 301-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylic acid trifluoroacetate (E30)To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-(2-methylpropyl)benzonitrile (D62) (110 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (25.5 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (45.0 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (90 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.82 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)ethyl]-3-azetidinecarboxylic acid (E30) (24 mg) as a TFA salt. deltaH (DMSO-d6, 400 MHz): 0.86 (6H, d), 1.06 (3H, t), 1.92 (1H, m), 2.70 (2H, d), 2.84 (4H, m), 3.34 (2H, m), 3.55 (1H, m), 4.21 (4H, m), 7.29 (1H, t), 7.38 (1H, d), 7.63 (1H, d), 7.69 (1H, dd), 8.26 (1H, dd), 8.46 (1H, d). deltaF (DMSO-d6, 376 MHz): -73.6. MS (ES): C27H30N4O2S requires 474. found 475.1 (M+H+).
		To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1 ,2,4-thiadiazol-5-yl}-2-(2- methylpropyl)benzonitrile (D62) (110 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (25.5 mg), hydrogen chloride - methyl 3-azetidinecarboxylate (1 :1) (45.0 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (90 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1 :1), 0.5M sodium hydroxide (2.82 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1 -[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1 ,2,4-thiadiazol-3-yl}-2- ethylphenyl)ethyl]-3-azetidinecarboxylic acid (E30) (24 mg) as a TFA salt. deltaEta (DMSO-d6l 400MHz): 0.86 (6H, d), 1.06 (3H, t), 1.92 (1 H, m), 2.70 (2H, d), 2.84 (4H, m), 3.34 (2H, m), 3.55 (1 H, m), 4.21 (4H, m), 7.29 (1 H, t), 7.38 (1 H, d), 7.63 (1 H, d), 7.69 (1 H, dd), 8.26 (1 H, dd), 8.46 (1 H, d). 8F (DMSO-d6, 376MHz): -73.6. MS (ES): C27H3oN402S requires 474; found 475.1 (M+H+).

Reference： [1]Patent: US2011/269738,2011,A1 .Location in patent: Page/Page column 64-65
[2]Patent: WO2011/134280,2011,A1 .Location in patent: Page/Page column 135
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 4286 - 4296

30
[ 100202-39-9 ]
[ 1344997-65-4 ]
C₂₇H₃₀N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 271-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylic acid trifluoroacetate (E27)To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile (D63) (100 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (22.9 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (42.4 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (85 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.66 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylic acid (E27) (51 mg) as a TFA salt. deltaH (DMSO-d6, 400 MHz): 0.87 (6H, d), 1.04 (3H, t), 1.93 (1H, m), 2.71 (2H, d), 2.92 (2H, q), 3.58 (1H, m), 4.20 (4H, m), 4.51 (2H, s), 7.39 (1H, t), 7.52 (1H, d), 7.64 (1H, d), 7.84 (1H, d), 8.26 (1H, dd), 8.47 (1H, d). deltaF (DMSO-d6, 376 MHz): -73.5. MS (ES): C26H28N4O2S requires 460. found 461.1 (M+H+).
		To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1 ,2,4-thiadiazol-5-yl]-2-(2- methylpropyl)benzonitrile (D63) (100 mg) in dichloromethane (DCM) (15 mL) was added sodium acetate (22.9 mg), hydrogen chloride - methyl 3-azetidinecarboxylate (1:1) (42.4 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (85 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1 :1), 0.5M sodium hydroxide (2.66 mL) was added. The reaction solution was stirred at room temperature overnight. The isopropanol was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1 -[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1 ,2,4-thiadiazol-3-yl}-2-ethylphenyl)methyl]-3-azetidinecarboxylic acid (E27) (51 mg) as a TFA salt. deltaEta (DMSO-d6, 400MHz): 0.87 (6H, d), 1.04 (3H, t), 1.93 (1 H, m), 2.71 (2H, d), 2.92 (2H, q), 3.58 (1 H, m), 4.20 (4H, m), 4.51 (2H, s), 7.39 (1 H, t), 7.52 (1 H, d), 7.64 (1 H, d), 7.84 (1H, d), 8.26 (1 H, dd), 8.47 (1 H, d). 6F (DMSO-d6, 376MHz): - 73.5. MS (ES): C26H28N402S requires 460; found 461.1 (M+H+).

Reference： [1]Patent: US2011/269738,2011,A1 .Location in patent: Page/Page column 63-64
[2]Patent: WO2011/134280,2011,A1 .Location in patent: Page/Page column 132; 133
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 4286 - 4296

31
[ 100202-39-9 ]
[ 1344997-54-1 ]
C₂₆H₂₈F₃N₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 191-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E19)To a solution of 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}benzaldehyde (D47) (100 mg) in dichloromethane (DCM) (5 mL) and methanol (5.00 mL) was added sodium acetate (39.0 mg) and hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (72.1 mg). The reaction solution was stirred at room temperature for overnight. Sodium triacetoxyborohydride (101 mg) was added and the resulting solution was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the residue was dissolved in isopropanol/water (1:1, 5 mL), sodium hydroxide (2.378 mL) was added and the resulting solution was heated to 90 C. for 2 h. Isopropanol was removed in vacuo and the residue was acidified to pH=3-4, extracted with ethyl acetate (2*20 mL), the combined organic phases were dried over sodium sulphate and concentrated, the residue was purified by Mass Directed AutoPrep to afford 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E19) (44 mg) as a white solid. deltaH (DMSO-d6, 400 MHz): 1.06 (3H, t), 1.27 (6H, d), 2.87 (2H, q), 3.16 (4H, m), 3.34 (1H, m), 3.60 (2H, s), 4.89 (1H, m), 7.23 (1H, t), 7.38 (1H, dd), 7.45 (1H, d), 7.65 (1H, dd), 8.18 (1H, d), 8.25 (1H, dd). deltaF (DMSO-d6, 376 MHz): -61.4. MS (ES): C26H26F3N3O3S requires 505. found 506.1 (M+H+).
		To a solution of 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1 ,2,4- thiadiazol-3-yl}benzaldehyde (D47) (100 mg) in dichloromethane (DCM) (5 mL) and methanol (5.00 mL) was added sodium acetate (39.0 mg) and hydrogen chloride - methyl 3-azetidinecarboxylate (1 :1) (72.1 mg). The reaction solution was stirred at room temperature for overnight. Sodium triacetoxyborohydride (101 mg) was added and the resulting solution was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the residue was dissolved in isopropanol/water (1 :1 , 5 mL), sodium hydroxide (2.378 mL) was added and the resulting solution was heated to 90 C for 2 h. Isopropanol was removed in vacuo and the residue was acidified to pH=3-4, extracted with ethyl acetate (2*20 ml_), the combined organic phases were dried over sodium sulphate and concentrated, the residue was purified by Mass Directed AutoPrep to afford 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3- (trifluoromethyl)phenyl]-1 ,2,4-thiadiazol-3-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E19) (44 mg) as a white solid. deltaEta (DMSO-cfe, 400MHz): 1.06 (3H, t), 1.27 (6H, d), 2.87 (2H, q), 3.16 (4H, m), 3.34 (1 H, m), 3.60 (2H, s), 4.89 (1 H, m), 7.23 (1 H, t), 7.38 (1 H, dd), 7.45 (1 H, d), 7.65 (1 H, dd), 8.18 (1 H, d), 8.25 (1 H, dd). 8F (DMSO-oi6, 376MHz): -61.4. MS (ES): C25H26F3N303S requires 505; found 506.1 (M+H+).

Reference： [1]Patent: US2011/269738,2011,A1 .Location in patent: Page/Page column 61
[2]Patent: WO2011/134280,2011,A1 .Location in patent: Page/Page column 126; 127
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 4286 - 4296

32
[ 100202-39-9 ]
[ 1344997-59-6 ]
C₂₅H₂₈ClN₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 251-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid trifluoroacetate (E25)To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylbenzaldehyde (D53) (100 mg) in dichloromethane (DCM) (8 mL) and methanol (8.00 mL) was added sodium acetate (31.8 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (58.8 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (110 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (2.58 mL) was added, the reaction solution was heated to 80 C. for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=2-3. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (E25) (40 mg) as a TFA salt (white solid). deltaH (DMSO-d6, 400 MHz): 1.05 (3H, t), 1.28 (6H, d), 2.87 (2H, q), 3.19 (3H, m), 3.34 (2H, m), 3.60 (2H, s), 4.78 (1H, m), 7.23 (1H, t), 7.31 (1H, d), 7.38 (1H, d), 7.64 (1H, d), 7.94 (1H, dd), 8.07 (1H, d). deltaF (DMSO-d6, 376 MHz): -73.4. MS (ES): C24H26ClN3O3S requires 471. found 472.2 (M+H+).
		To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-thiadiazol-3-yl)-2- ethylbenzaldehyde (D53) (100 mg) in dichloromethahe (DCM) (8 mL) and methanol (8.00 mL) was added sodium acetate (31.8 mg), hydrogen chloride - methyl 3- azetidinecarboxylate (1 :1) (58.8 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (110 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1 :1), 0.5M sodium hydroxide (2.58 mL) was added, the reaction solution was heated to 80C for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=2-3. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-[3-(5-{3- chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3- azetidinecarboxylic acid (E25) (40 mg) as a TFA salt (white solid). 8H (DMSO-d6, 400MHz): 1.05 (3H, t), 1.28 (6H, d), 2.87 (2H, q), 3.19 (3H, m), 3.34 (2H, m), 3.60 (2H, s), 4.78 (1 H, m), 7.23 (1 H, t), 7.31 (1 H, d), 7.38 (1 H, d), 7.64 (1 H, d), 7.94 (1 H, dd), 8.07 (1 H, d). 6F (DMSO-d6, 376MHz): -73.4. MS (ES): C^H^CINaOaS requires 471 ; found 472.2 (M+H+).

Reference： [1]Patent: US2011/269738,2011,A1 .Location in patent: Page/Page column 63
[2]Patent: WO2011/134280,2011,A1 .Location in patent: Page/Page column 131
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 4286 - 4296

33
[ 100202-39-9 ]
[ 1344997-61-0 ]
C₂₇H₃₀N₄O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 261-{2-[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid trifluoroacetate (E26)To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile (D55) (150 mg) in dichloromethane (DCM) (7.5 mL) was added sodium acetate (31.4 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (58.1 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (122 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (3.83 mL) was added, the reaction solution was heated to 90 C. for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E26) (31 mg) as a TFA salt (white solid). deltaH (DMSO-d6, 400 MHz): 1.05 (3H, t), 1.31 (6H, d), 2.84 (4H, m), 3.35 (2H, m), 3.57 (1H, m), 4.20 (4H, m), 4.90 (1H, m), 7.28 (1H, t), 7.37 (1H, d), 7.44 (1H, d), 7.68 (1H, dd), 8.26 (1H, dd), 8.41 (1H, d). deltaF (DMSO-d6, 376 MHz): -73.5. MS (ES): C26H28N4O3S requires 476. found 477.2 (M+H+).
		To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1 ,2,4-thiadiazol-5-yl}-2-[(1- methylethyl)oxy]benzonitrile (D55) (150 mg) in dichloromethane (DCM) (7.5 mL) was added sodium acetate (31.4 mg), hydrogen chloride - methyl 3-azetidinecarboxylate (1 :1) (58.1 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (122 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1 :1), 0.5M sodium hydroxide (3.83 mL) was added, the reaction solution was heated to 90C for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5- {3-cyano-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3- azetidinecarboxylic acid (E26) (31 mg) as a TFA salt (white solid). deltaEta (DMSO-cfe, 400MHz): 1.05 (3H, t), 1.31 (6H, d), 2.84 (4H, m), 3.35 (2H, m), 3.57 (1H, m), 4.20 (4H, m), 4.90 (1 H, m), 7.28 (1 H, t), 7.37 (1 H, d), 7.44 (1 H, d), 7.68 (1 H, dd), 8.26 (1 H, dd), 8.41 (1 H, d). 5F (DMSO- /6l 376MHz): -73.5. MS (ES): C26H28N403S requires 476; found 477.2 (M+H+).

Reference： [1]Patent: US2011/269738,2011,A1 .Location in patent: Page/Page column 63
[2]Patent: WO2011/134280,2011,A1 .Location in patent: Page/Page column 131; 132

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[ 100202-39-9 ]
[ 1344706-06-4 ]
[ 1344707-41-0 ]

Yield	Reaction Conditions	Operation in experiment
39.9%	With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; for 1h;	(R/5)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- l,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), methyl azetidine-3-carboxylate-HCl (7.54 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge CI 8, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge CI 8, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)- methyl l-(3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- 1,2,4- oxadiazol-3-yl)phenyl)acetamido)propanoyl)azetidine-3-carboxylate (11.9 mg, 0.020 mmol, 39.9 % yield): LCMS = 600.2 [M+H]+; XH NMR (400 MHz, methanol-d4) delta ppm 8.14-8.26 (2 H, m), 7.54-7.77 (7 H, m), 5.12 (1 H, s), 4.00-4.34 (4 H, m), 3.73 (3 H, d, J=5.27 Hz), 3.39-3.56 (3 H, m), 2.36 (2 H, q, J=6.44 Hz); HPLC peak RT = 2.5 min (Method E).

Reference： [1]Patent: WO2011/133734,2011,A1 .Location in patent: Page/Page column 145-146

35
[ 872710-02-6 ]
[ 100202-39-9 ]
methyl 1-[(6-[(2R)-3-(4-fluorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 144 - 148

36
[ 872709-90-5 ]
[ 100202-39-9 ]
methyl 1-[(6-[(2S)-3-(4-fluorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 144 - 148

37
[ 100202-39-9 ]
[ 1355088-80-0 ]
methyl 1-[(6-[(2S)-2-(4-fluorobenzyl)butyl]oxy}-1-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 144 - 148

38
[ 100202-39-9 ]
[ 1355088-82-2 ]
methyl 1-[(6-[(2R)-2-(4-fluorobenzyl)-3-methylbutyl]oxy}-1-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 144 - 148

39
[ 872709-83-6 ]
[ 100202-39-9 ]
methyl 1-[(6-[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-3-azetidinecarboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 144 - 148

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[ 100202-39-9 ]
[ 1356679-12-3 ]
[ 1365925-92-3 ]

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[ 100202-39-9 ]
[ 1356679-13-4 ]
[ 1365926-42-6 ]

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[ 100202-39-9 ]
[ 1365927-96-3 ]
[ 1365942-27-3 ]

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[ 100202-39-9 ]
[ 1365928-39-7 ]
[ 1365942-49-9 ]

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[ 100202-39-9 ]
[ 1365942-61-5 ]
[ 1365942-73-9 ]

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[ 100202-39-9 ]
[ 1202077-27-7 ]
[ 1202077-28-8 ]

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[ 100202-39-9 ]
[ 1365943-04-9 ]
[ 1365997-14-3 ]

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[ 100202-39-9 ]
[ 1365909-62-1 ]
[ 1365916-79-5 ]

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[ 100202-39-9 ]
[ 1365909-74-5 ]
[ 1365916-84-2 ]

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[ 100202-39-9 ]
[ 1365909-79-0 ]
[ 1365916-90-0 ]

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[ 100202-39-9 ]
[ 1365911-25-6 ]
[ 1365916-97-7 ]

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[ 100202-39-9 ]
[ 1365911-43-8 ]
[ 1365917-07-2 ]

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[ 100202-39-9 ]
[ 1365997-38-1 ]
[ 1356679-58-7 ]

Yield	Reaction Conditions	Operation in experiment
0.5 g		Aqueous hydrochloric acid (5N, 3 ml, 15 mmol) was added to a solution of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazol-6-yl)(2-ethylthiazolidin-3-yl)methanone (0.65 g, 1.41 mmol) in THF (10 ml). The reaction mixture was stirred at 55 C for 4 hrs. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution, and diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated in vacuo to give aldehyde as a solid, which was taken to the next step without further characterization. Methyl azetidine-3-carboxylate hydrochloride (0.26 g, 170 mmol) was mixed with diisopropylethyl amine (0.30 mL, 1.70 mmol) in MeOH (1 mL). (2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazol-6-yl)(2-ethylthiazolidin-3-yl)methanone (obtained from the above reaction) was added as a solution in DCM (1 mL) and glacial acetic acid (0.12 mL, 2.12 mmol) was added. The mixture was stirred for 2 h at RT before sodium cyanoborohydride (0.045 g, 0.71 mmol) was added. The mixture was stirred for 1 h, saturated aqueous sodium bicarbonate solution was added, and the product was extracted into DCM. The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give product as a light yellow solid (0.50 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.36 (dd, J=7.8 Hz, 1 H), 8.05 - 8.15 (m, 2 H), 7.62 (d, J=8.5 Hz, 1 H), 7.18 - 7.26 (m, 2 H), 3.73 (s, 3 H), 3.69 (s, 2 H), 3.65 (br. s., 1 H), 3.59 (s, 2 H), 3.31 - 3.42 (m, 3 H), 3.00 (br. s., 2 H), 2.04 (br. s., 2 H), 1.65 - 1.82 (m, 2 H), 1.00 (br. s., 3 H); MS (ESI) m/z: calculated: 499.1; observed: 500.1 (M + H)+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 628 - 633

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[ 100202-39-9 ]
[ 1365911-51-8 ]
[ 1365917-11-8 ]

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[ 100202-39-9 ]
[ 1365911-70-1 ]
[ 1365917-18-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 628 - 633

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[ 100202-39-9 ]
C₁₈H₁₀BrF₃N₂OS₂ [ No CAS ]
C₂₃H₁₈F₃N₃O₃S₂ [ No CAS ]