[ CAS No. 142253-54-1 ] {[proInfo.proName]}

Name: 142253-54-1|tert-Butyl 3-cyanoazetidine-1-carboxylate|97%
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SKU: A125916
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Quality Control of [ 142253-54-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 142253-54-1 ]

SDS Specification

Alternatived Products of [ 142253-54-1 ]

Product Details of [ 142253-54-1 ]

CAS No. :	142253-54-1	MDL No. :	MFCD06796640
Formula :	C₉H₁₄N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WEFREESWPHICPL-UHFFFAOYSA-N
M.W :	182.22	Pubchem ID :	10631283
Synonyms :

Calculated chemistry of [ 142253-54-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.78
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.53
TPSA :	53.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.1
Log Po/w (XLOGP3) :	0.61
Log Po/w (WLOGP) :	1.0
Log Po/w (MLOGP) :	0.45
Log Po/w (SILICOS-IT) :	0.48
Consensus Log Po/w :	0.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.16
Solubility :	12.7 mg/ml ; 0.0698 mol/l
Class :	Very soluble
Log S (Ali) :	-1.3
Solubility :	9.05 mg/ml ; 0.0496 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.8
Solubility :	28.8 mg/ml ; 0.158 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.22

Safety of [ 142253-54-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 142253-54-1 ]

* 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 [ 142253-54-1 ]
Downstream synthetic route of [ 142253-54-1 ]

[ 142253-54-1 ] Synthesis Path-Upstream 1~11

1
[ 345954-83-8 ]
[ 24424-99-5 ]
[ 142253-54-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine In dichloromethane for 16 h;	Step 1 3-Cyanoazetidine hydrochloride (3.64 g, 30.7 mmol) was suspended in 77 mL of dichloromethane. Triethylamine (4.3 mL, 30.7 mmol) was added, followed by portionwise addition of di-tert-butyl dicarbonate (8.0 g, 36.8 mmol). The reaction mixture was stirred for 16 h then diluted with aqueous hydrochloric acid and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 5.5 g (98percent) of tert-butyl 3-cyanoazetidine-1-carboxylate.

Reference： [1] Patent: US2011/230462, 2011, A1, . Location in patent: Page/Page column 64-65
[2] Patent: WO2011/61214, 2011, A1, . Location in patent: Page/Page column 50
[3] Patent: WO2013/152065, 2013, A2, . Location in patent: Page/Page column 27

2
[ 773837-37-9 ]
[ 254454-54-1 ]
[ 142253-54-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	at 130℃; for 6 h;	To a 100 mL round bottom flask was added tert-butyl 3-iodoazetidine-1-carboxylate (6) (6.54 g, 0.0231 mol, 1 equiv.) and DMSO (25 mL). NaCN (2.3 g, 0.0462 mol, 2equiv.) was added to the solution in one portion and stirred at 130 oC for 6 h. The resulting mixture was cooledto rt, poured into water (200 mL), and extracted with diethyl ether (5 x 200 mL). The combined organicextracts were washed with brine (50 mL), dried over Na2SO4 and concentrated. The crude compound waspurified by flash chromatography (silica gel, 5–50percent EtOAc in hexanes) to give the desired product 22 (3.27 g,78percent). Physical State: off-white solid (mp 78–80 oC); Rf = 0.40 (2:8 EtOAc/hexanes, vis. KMnO4); 1H NMR (500MHz, CDCl3): δ 4.23 – 4.11 (m, 4H), 3.38 (tt, J 8.9, 6.3 Hz, 1H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3): δ 155.6,119.6, 80.8, 52.6 (br, 2C), 28.4 (3C), 17.2.

Reference： [1] Arkivoc, 2018, vol. 2018, # 4, p. 195 - 214

3
[ 773837-37-9 ]
[ 124-63-0 ]
[ 141699-55-0 ]
[ 142253-54-1 ]

Reference： [1] Patent: US2003/229226, 2003, A1, . Location in patent: Page 20

4
[ 773837-37-9 ]
[ 141699-58-3 ]
[ 142253-54-1 ]

Reference： [1] Patent: WO2010/131145, 2010, A1, . Location in patent: Page/Page column 85-86
[2] Patent: WO2016/206101, 2016, A1, . Location in patent: Page/Page column 89

5
[ 143-33-9 ]
[ 141699-58-3 ]
[ 142253-54-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 1, p. 94 - 104

6
[ 141699-55-0 ]
[ 142253-54-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 1, p. 94 - 104
[2] Patent: WO2016/206101, 2016, A1,

7
[ 142253-54-1 ]
[ 325775-44-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 1, p. 94 - 104
[2] Patent: US2003/229226, 2003, A1, . Location in patent: Page 20

8
[ 142253-54-1 ]
[ 142253-55-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide In methanol; water for 4 h; Reflux	To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate 22 (3.7 g, 0.0202 mol, 1 equiv.) in MeOH (35 mL) was added a solution of NaOH (4.03 g, 0.101 mol,5 equiv.) in H2O (35 mL) and refluxed until the reaction was complete by TLC (ca. 4 h). The resulting reactionmixture was cooled to rt and concentrated to remove the MeOH. The mixture was neutralized with 10 percent aq.citric acid (200 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed withbrine (50 mL), dried over Na2SO4, and concentrated to give the desired product 23 (3.72 g, 92percent). PhysicalState: white solid (mp 106–107 oC); 1H NMR (500 MHz, CDCl3): δ 4.13 (d, J 7.5 Hz, 4H), 3.41 – 3.35 (m, 1H), 1.44(s, 9H); 13C NMR (126 MHz, CDCl3): δ 177.4, 155.3, 80.3, 51.8 (br, 2C), 32.0, 28.5 (3C); HRMS (ESI-TOF): calc’dfor C9H14NO4 [M-H] 200.0928; found 200.0923.
80.8%	Stage #1: With water; sodium hydroxide In methanol for 5 h; Reflux Stage #2: With citric acid In water	Preparation 831 -(tert-ButoxycarbonvDazetidine-S-carboxylic acid; A solution of sodium hydroxide (27.5 g) in water (30OmL) was added to solution of tert-butyl 3- cyanoazetidine-1-carboxylate (Preparation 82, 25.1 g, 0.138 mol) in methanol (30OmL). The mixture was heated at reflux for 5 hours. The methanol was evaporated and the residuary aqueous solution was neutralized with 10percent citric acid and extracted with dichloromethane (2.1 L). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white crystalline solid (22.3 g, 80.8percent). 1H NMR (400 MHz, DMSO-d₆): δ = 4.01-3.97 (m, 2H), 3.87-3.84 (m, 2H), 3.36-3.28 (m, 1 H), 1.37 (s, 9H) ppm.

Reference： [1] Arkivoc, 2018, vol. 2018, # 4, p. 195 - 214
[2] Patent: WO2010/131145, 2010, A1, . Location in patent: Page/Page column 86

9
[ 142253-54-1 ]
[ 345954-83-8 ]

Reference： [1] Patent: WO2010/60952, 2010, A1, . Location in patent: Page/Page column 107-108

10
[ 142253-54-1 ]
[ 345954-83-8 ]

Reference： [1] Patent: CN105732602, 2016, A, . Location in patent: Paragraph 0458; 0459; 0460; 0461; 0462; 0463

11
[ 142253-54-1 ]
[ 887591-62-0 ]

Reference： [1] Arkivoc, 2018, vol. 2018, # 4, p. 195 - 214

[ 142253-54-1 ] Synthesis Path-Downstream 1~88

1
[ 142253-54-1 ]
[ 325775-44-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; hydrogen;nickel; In methanol; at 20℃; under 30402.0 Torr; for 3.5h;	[0182] To a stirred solution of the nitrile (47) (728 mg, 1 equiv.) in MeOH (5 mL) was added NH3 (2M in MeOH, 10 mL) and raney nickel (1 mL). The solution was evacuated, placed under a H2 atmosphere (40 atm) and stirred at rt for 3.5 h. The suspension was then filtered through celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the desired primary amine (48).

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 94 - 104
[2]Patent: US2003/229226,2003,A1 .Location in patent: Page 20

2
[ 142253-54-1 ]
[ 1009367-63-8 ]

Yield	Reaction Conditions	Operation in experiment
77.6%	With azidotrimethyltin; In toluene; at 100℃; for 18h;	Compound 28A. tert-Butyl 3-(2H-tetrazol-5-yl)azetidine-l-carboxylateHN-N. . N,N>~VNBoc <n="106"/>[00190] Tert-butyl 3-cyanoazetidine-l-carboxylate (493.8 mg, 2.713 mmol) and azidotrimethyltin (920 mg, 4.34 mmol) in dry toluene (13 mL) were placed in sealed tube and heated in 100 0C oil bath for 18 hours. Solvent was removed under reduced pressure and the residue was purified via Prep HPLC to provide compound 28A as a light yellow oil (474 mg, 77.6% yield). 1H NMR (400 MHz, CDCl3) delta ppm 4.42 - 4.52 (m, 2 H), 4.28 - 4.35 (m, 2 H), 4.18 - 4.28 (m, 1 H), 1.43 - 1.49 (s, 9 H).

Reference： [1]Patent: WO2008/24892,2008,A2 .Location in patent: Page/Page column 104-105

3
[ 141699-55-0 ]
[ 142253-54-1 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 94 - 104
[2]Patent: WO2016/206101,2016,A1

4
[ 142253-54-1 ]
[ 1028286-25-0 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 94 - 104

5
[ 142253-54-1 ]
[ 1026942-02-8 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 94 - 104

6
[ 142253-54-1 ]
[ 1026576-25-9 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 94 - 104

7
[ 372-48-5 ]
[ 142253-54-1 ]
[ 869811-51-8 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 6h;	A solution of 2-fluoropyridine (2.6 mL, 30.2 mmol) and tert-butyl 3-cyanoazetidine-l- carboxylate (I-1,5.0 g, 27.5 mmol) in THF (200 mL) at room temperature was treated with LHMDS (55 mL of a 1.0 M solution in THF, 55 mmol). After 6 h, the reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic extracts were dried (Na2S04) and concentrated under reduced pressure to afford tert-butyl 3-cyano-3-pyridin-2- ylazetidine-1-carboxylate (1-2) as a yellow-brown oil. Analytical LCMS: single peak (214 nm), 3.004 min. This material was used in subsequent reactions without further purification.

Reference： [1]Patent: WO2005/110983,2005,A1 .Location in patent: Page/Page column 30

8
[ 17282-04-1 ]
[ 142253-54-1 ]
[ 895132-49-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hexamethylsilazane; In toluene; at -10 - 20℃; for 2.5h;	To a stirred suspension of tert-butyl 3-cyanoazetidine-l-carboxylate (5g ; 27.43mmol) and 2-chloro-3- fluoropyridine (5.05g ; 38.41mmol) in toluene (100 ml) cooled in an acetone/ice bath under an atmosphere OfN2 , was added a solution of potassium bis(trimethylsilyl)amide (0.5M solution in toluene ; 71.34ml ; 35.67mmol) over 30 minutes keeping the internal temperature below -1O0C . The reaction mixture was allowed to warm to ambient temperature, then stirred an additional 2 hours. The reaction was poured into brine (150 ml) and extracted with EtOAc (3 x 100ml). The combined organic phase was washed with brine (100 ml), dried (MgSO4), filtered and evaporated to give a brown oil. The crude product was chromatographed on silica gel eluted with 5% EtOAc in DCM to give the desired product as colourless oil (2.67 g).1H NMR (ppm)(CDCl3): 8.45 (1 H, dd, J = 1.1, 4.6 Hz), 7.55-7.49 (1 H, m), 7.43-7.39 (1 H, m), 4.66 (2H, d, J = 8.9 Hz), 4.57 (2 H, d, J = 8.8 Hz), 1.45 (9 H, s).

Reference： [1]Patent: WO2006/67529,2006,A1 .Location in patent: Page/Page column 46

Yield	Reaction Conditions	Operation in experiment
		4. 1-t-Butyloxycarbonyl-3-cyanoazetidine A stirred, cooled (5 C.) solution of the foregoing alcohol (25 g, 0.144 mol) in dichloromethane (600 ml) was treated with triethylamine (32 ml, 0.23 mol) followed by dropwise addition of methanesulphonyl chloride (16.7 ml, 0.216 mol). After addition the cooling bath was removed and the reaction mixture stirred at room temperature for 2 hours. The solution was washed with water (2200 ml), dried (sodium sulphate) and evaporated to give the mesylate as a gum (36 g). This mesylate in toluene (800 ml) was treated with tetrabutylammonium cyanide (55 g, 0.20 mol) and the reaction mixture was stirred under a nitrogen atmosphere, whilst heating at reflux, for 18 hours. Water (200 ml) was added to the cooled reaction mixture and the organic layer was separated. The aqueous was extracted with ethyl acetate (4200 ml) then the combined organics were evaporated. The crude product was purified using column chromatography eluding with dichloromethane?10% methanol in dichloromethane. The title compound was obtained (14.7 g, 56%) as a gum. delta (360 MHz, d6 -DMSO) 1.39 (9H, s), 3.65-3.78 (1H, m), 3.99 (2H, dd, J1 =6, J2 =9 Hz), 4.12 (2H, dd, J1 =J2 =9 Hz).
		b N-tert-Butyloxycarbonyl-3-cyanoazetidine Methane sulphonyl chloride (4.7 ml, 60 mmol) was added slowly to a stirred solution of the preceding alcohol (7.0 g, 40 mmol) in dry pyridine (40 ml) at +20 C. The mixture was stirred for 4 h and the solvent then removed under vacuum. The residue was partitioned between EtOAc/H2 O and the aqueous was extracted with EtOAc (2). The combined extracts were dried (Na2 SO4) and evaporated to give the desired mesylate (10.2 g, 100%). A mixture of the mesylate (2.5 g, 10 mmol) and tetra-n-butylammonium cyanide (8.0 g, 30 mmol), in anhydrous toluene (80 ml) was heated at reflux for 64 h. The mixture was cooled to room temperature and partitioned between EtOAc/H2 O. The aqueous was extracted with EtOAc (2), the combined extracts dried (Na2 SO4) and evaporated and the residue chromatographed on silica gel eluding with 40% EtOAc/petroleum ether to give the title nitrile (1.15 g, 80%). delta (250 MHz, CDCl3) 1.45 (9H, s (Me)3), 3.33-3.46 (1H, m, CH), 4.11-4.25 (4H, m, 2 of CH2).

10
[ 2937-50-0 ]
[ 142253-54-1 ]
1-allyloxycarbonyl-3-carboxyazetidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; acetic acid; In tetrahydrofuran; hydrogenchloride; water; ethyl acetate;	PREPARATION 19 A solution of <strong>[142253-54-1]N-tert-butoxycarbonyl-3-cyanoazetidine</strong> (205 g) in conc. hydrochloric acid (100 ml) and acetic acid (1000 ml) was stirred at 130 C. for 6 hours. The solvent was removed by evaporation, and to the residue were added tetrahydrofuran (1000 ml) and water (1000 ml). To the solution was added allyl chloroformate (167 ml) at 5-10 C., keeping the pH between 9.5 and 10.5 with 4N aqueous sodium hydroxide. The aqueous layer was separated, washed with ethyl acetate (500 ml). To the aqueous solution was added ethyl acetate (2000 ml) and the solution was adjusted to pH 1.5 with conc. hydrochloric acid with stirring. The organic layer was extracted with ethyl acetate (1000 ml) and evaporated to give 1-allyloxycarbonylazetidine-3-carboxylic acid (215 g). NMR (CDCl3, delta): 3.26-3.65 (1H, m), 4.22 (4H, d, J=6 Hz), 4.57 (2H, m), 5.10-5.43 (2H, m), 5.67-6.17 (1H, m), 7.33 (1H, s).

Reference： [1]Patent: US5102877,1992,A

11
[ 773837-37-9 ]
[ 124-63-0 ]
[ 141699-55-0 ]
[ 142253-54-1 ]

Yield	Reaction Conditions	Operation in experiment
		[0181] Following general procedure 4, to a cold (0 C.), stirred solution of the alcohol (46) (1.23 g, 1 equiv.) in EtOAc (10 mL) was added Et3N (1.28 mL, 1.3 equiv.) followed by MsCl (0.66 mL, 1.2 equiv.). The resultant suspension was stirred at 0 C. for 1 h. The undissolved material (Et3N.HCl) was filtered off and washed with EtOAc. The organic filtrate was concentrated under reduced pressure to afford an oil. This crude oil (mesylate) was dissolved in DMSO (5 mL) and NaCN (0.696 g, 2 equiv.) was added. The resultant reaction mixture was stirred at 130 C. for 2 days. The reaction mixture was then poured into H2O and extracted with Et2O (2×). The combined organic extracts were washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to afford a residue which was purified by flash chromatography (gradient elution: 25% EtOAc in hexane to 33% EtOAc in hexane) to yield the desired nitrile (47).

Reference： [1]Patent: US2003/229226,2003,A1 .Location in patent: Page 20

12
[ 142253-54-1 ]
[ 345954-83-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2h;	To 0.3 g (1.64 mmol) 1-N-boc-3-cyanoazetidine, was added 8.23 ml. (32.9 mmol) HCI in dioxane (4 M), and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated to give the desired product as a HCI salt, which was used in the next step without further purification.
195 g	With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 4h;	Step 1: Preparation of azetidine-3-carbonitrile Hydrochloride To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (300 g, 1.65 mol, Pharma Blocks) in 1,4-dioxane (300 mL) at 0 C. was added 4M HCl in dioxane (1.25 L, 5.0 mol). The mixture was allowed to warm to rt and stirred for an additional 4 h. The reaction mixture was then concentrated under reduced pressure and azeotroped with toluene (3*250 mL). The residue was slurried with hexanes (500 mL) and dried under high vacuum to give azetidine-3-carbonitrile hydrochloride (195 g) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 9.87 (bs, 2H), 4.22-4.08 (m, 4H), 4.05-3.95 (m, 1H).

Reference： [1]Patent: WO2010/60952,2010,A1 .Location in patent: Page/Page column 107-108
[2]Patent: US2019/77793,2019,A1 .Location in patent: Paragraph 0204

13
[ 183013-57-2 ]
[ 142253-54-1 ]
[ 875454-95-8 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of tert-butyl 3-cyanoazetidine-l-carboxylate (0.4g, 2.2 mmol) and TFA (3mL) was aged in CH2Cl2 (5mL) for 4h and then concentrated. To a solution of this crude residue in dichloroethane (1OmL) was added 3-[(4-acetyl-3-hydroxy-2- propylphenoxy)methyl]benzaldehyde and NaBH(OAc)3 (0.47 g, 2.2 mmol) and HOAc (0. ImL). The mixture was stirred at rt for 12h, diluted with EtOAc and brine, and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and concentrated. The crude residue was purified chromatography on silica gel (EtOAc/hexanes) to give the title compound as a pale yellow oil. MS (ESI+) 379.4 (M++l).

Reference： [1]Patent: WO2006/14918,2006,A2 .Location in patent: Page/Page column 52

14
[ 100-58-3 ]
[ 142253-54-1 ]
tert-butyl 3-benzoylazetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%		To a solution of l-JV-Boc-3-cyanoazetidine (5.0 g, 27.5 mmol) in THF (150 mL) was added a solution of PhMgBr (3.0M, 11.0 mL, 32.9 mmol) and stirred at room temperature for 3h. The reaction was diluted with EtOAc (200 mL), washed with 0.05N HCl (120 mL), dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography (silica gel) using 0 to 40% EtOAc in hexanes to afford 1 as a clear colorless oil (1.10 g, 15%); Eta-nmr (400 MHz, CDCl3) delta 7.83 (dd, J= 8, 4 Hz, 2H), 7.60-7.56 (m, IH), 7.52-7.44 (m, 2H), 4.25-4.09 (m, 5H), 1.44 (s, 9H); LC-MS (214) 99%, 3.16 min, m/z 206.0 (M - 1Bu), 283.9 (MNa+).

Reference： [1]Patent: WO2010/114907,2010,A1 .Location in patent: Page/Page column 53; 86

15
[ 142253-54-1 ]
[ 732976-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; water; for 2h;	To a solution of l-<strong>[142253-54-1]N-Boc-3-cyanoazetidine</strong> (5.0 g, 27.5 mmol) in 1,4- dioxane (50 mL) was added 4 N HCl (50 mL) and stirred for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in CH2Cl2 (60 mL) and DIPEA (10.6 mL, 60.4 mmol) and added l-methylimidazole-4-sulfonyl chloride (4.94 g, 27.5 mmol) and stirred at room temperature for 20 h. The reaction mixture was washed with 2 N NaOH (50 mL), dried over MgSO4 and concentrated under vacuum to afford 8 as a white crystalline solid (4.97 g, 80%); ; Eta-nmr (300 MHz, CDCl3) delta 7.06 (s, IH), 7.56 (s, IH), 4.27-4.19 (m, 4H), 3.82 (s, 3H), 3.43-3.31 (m, IH); LC-MS (214) 99%, 0.93 min, m/z 227 '.1 (M+H).
	With trifluoroacetic acid; In dichloromethane; at 20℃;	and 1-(t-butoxycarbonyl) -3-Shianoazechijin 216mg was dissolved in methylene chloride 2.5 ml, was added trifluoroacetic acid 1 ml, and stirred at room temperature overnight.Under reduced pressure, the solvent was concentrated to give a brown pale oil.This was dissolved in degassed 1,4-dioxane 4 ml, triethylamine 302mg, (S) -6- chloro-N2 - [1-(4- fluorophenyl) ethyl] -N4- (pyrazin-2-yl ) pyrimidine-2,4-diamine 205mg, 2- dicyclohexylphosphino-2 ', 4', 6'-triisopropyl biphenyl 57mg, sodium t- butoxide 229mg and tris (dibenzylideneacetone) and (chloroform) dipalladium 62mg sequentially was added, under an argon atmosphere, the mixture was stirred for 3 hours at 90 .The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried with magnesium sulfate.Under reduced pressure, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to give the title compound 58mg as a pale yellow powder.

Reference： [1]Patent: WO2010/114907,2010,A1 .Location in patent: Page/Page column 91
[2]Patent: JP5668756,2015,B2 .Location in patent: Paragraph 0139

16
[ 142253-54-1 ]
[ 142253-55-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide; In methanol; water; for 4h;Reflux;	To a solution of <strong>[142253-54-1]tert-butyl 3-cyanoazetidine-1-carboxylate</strong> 22 (3.7 g, 0.0202 mol, 1 equiv.) in MeOH (35 mL) was added a solution of NaOH (4.03 g, 0.101 mol,5 equiv.) in H2O (35 mL) and refluxed until the reaction was complete by TLC (ca. 4 h). The resulting reactionmixture was cooled to rt and concentrated to remove the MeOH. The mixture was neutralized with 10 % aq.citric acid (200 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed withbrine (50 mL), dried over Na2SO4, and concentrated to give the desired product 23 (3.72 g, 92%). PhysicalState: white solid (mp 106-107 oC); 1H NMR (500 MHz, CDCl3): delta 4.13 (d, J 7.5 Hz, 4H), 3.41 - 3.35 (m, 1H), 1.44(s, 9H); 13C NMR (126 MHz, CDCl3): delta 177.4, 155.3, 80.3, 51.8 (br, 2C), 32.0, 28.5 (3C); HRMS (ESI-TOF): calc?dfor C9H14NO4 [M-H] 200.0928; found 200.0923.
80.8%		Preparation 831 -(tert-ButoxycarbonvDazetidine-S-carboxylic acid; A solution of sodium hydroxide (27.5 g) in water (30OmL) was added to solution of tert-butyl 3- cyanoazetidine-1-carboxylate (Preparation 82, 25.1 g, 0.138 mol) in methanol (30OmL). The mixture was heated at reflux for 5 hours. The methanol was evaporated and the residuary aqueous solution was neutralized with 10% citric acid and extracted with dichloromethane (2.1 L). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white crystalline solid (22.3 g, 80.8%). 1H NMR (400 MHz, DMSO-d6): delta = 4.01-3.97 (m, 2H), 3.87-3.84 (m, 2H), 3.36-3.28 (m, 1 H), 1.37 (s, 9H) ppm.

Reference： [1]Arkivoc,2018,vol. 2018,p. 195 - 214
[2]Patent: WO2010/131145,2010,A1 .Location in patent: Page/Page column 86

17
[ 773837-37-9 ]
[ 141699-58-3 ]
[ 142253-54-1 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 100 - 105℃; for 100h;	Preparation 82 tert-Butyl 3-cvanoazetidine-1 -carboxylate; Sodium cyanide (47.3 g, 0.966 mol) was added to a stirred solution of tert-butyl 3- (methylsulfonyloxy)azetidine-i-carboxylate (Preparation 57, 121.4 g, 0.483 mol) in dimethylsulfoxide (17OmL). The reaction mixture was heated to 100-1050C and stirred at this temperature for 100 hours. The reaction mixture was diluted with water (1.5L) and extracted with ether (2.4L). The combined organic extracts were washed with water (1 L) and brine (0.6L), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane:ethyl acetate (3:1 ) to afford the title compound as a white crystalline solid (61.5 g, 70.0%). 1H NMR (400 MHz, CDCI3): delta = 4.20-4.10 (m, 4H), 3.40-3.32 (m, 1 H), 1.41 (s, 9H) ppm.
	In dimethyl sulfoxide; at 140℃;Inert atmosphere;	Into a 5000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl 3-(methanesulfonyloxy)azetidine-1- carboxylate (350 g, 1.39 mol, 1.00 equiv) in DMSO (2500 mL). This was followed by the addition of NaCN (140 g, 2.86 mol, 2.00 equiv) in several batches. The resulting solution was stirred overnight at 140C. The reaction mixture was cooled and then quenched by the addition of 3 L of aqueous Fe2504. The solid was filtered out. The filtrate was extracted with 3x2000 mL of ethyl acetate. The organic layers were combined,dried and concentrated under vacuum. The residue was applied onto a silica gel columnand eluted with ethyl acetate/petroleum ether (1:3) to give the title compound as a solid.

Reference： [1]Patent: WO2010/131145,2010,A1 .Location in patent: Page/Page column 85-86
[2]Patent: WO2016/206101,2016,A1 .Location in patent: Page/Page column 89

18
[ 142253-54-1 ]
[ 74-88-4 ]
[ 936850-09-8 ]

Yield	Reaction Conditions	Operation in experiment
89%		Step 1 In a 100 mL 2-neck round-bottomed flask, <strong>[142253-54-1]tert-butyl 3-cyanoazetidine-1-carboxylate</strong> (1.5 g, 8.2 mmol) was dissolved in THF (30 mL). The colorless solution was cooled to -76 C. and lithium bis(trimethylsilyl)amide (1.0M solution in THF, 9.0 mL, 9.0 mmol) was added dropwise over 25 min. The yellow solution was stirred at -76 C. for 30 min then iodomethane (0.78 mL, 12.5 mmol) was slowly added. The reaction mixture was stirred at -76 C. for 30 min and then warmed to room temperature over 1 h. The reaction mixture was quenched with 10 mL of saturated NH4Cl and diluted with 10 mL of water then extracted with ~100 ml EtOAc (2*). The combined organic layers were washed with ~10 mL water and ~10 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 40 g silica gel with EtOAc/hexanes, (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated to afford 1.44 g (89%) of 3-cyano-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as a yellow solid.
69%		To a solution of <strong>[142253-54-1]tert-butyl 3-cyanoazetidine-1-carboxylate</strong> (22) (50 mg, 0.275 mmol, 1 equiv.) in THF (1.0 mL) was added LiHMDS (1M in THF, 0.302 mL, 0.302mmol, 1.1 equiv.) at -78 oC and stirred for 30 min. at the same temperature. Methyl iodide (25.7 muL, 0.411mmol, 1.5 equiv.) was added via syringe and stirred at -78 oC for 45 min. followed by stirring at rt for 1 h. Theresulting mixture was quenched with NH4Cl (1 mL) and extracted with ethyl acetate (3 x 2 mL). The combinedorganic extracts were washed with brine (2 mL), dried over Na2SO4, and concentrated. The crude material waspurified by flash chromatography (silica gel, 5-40% EtOAc in hexanes) to give the desired product 26 (37.4 mg,69%, caution: product can be lost through sublimation under high vacuum.). Physical State: yellow crystallinesolid (mp 57 oC); Rf = 0.53 (3:7 EtOAc/hexanes, vis. KMnO4); 1H NMR (500 MHz, CDCl3): delta 4.29 (d, J 8.6 Hz, 2H),3.80 (d, J 8.6 Hz, 2H), 1.67 (s, 3H), 1.45 (s, 9H); 13C NMR (126 MHz, CDCl3): delta 155.7, 122.2, 80.7, 59.3 (br, 2C),28.3 (3C), 26.0, 23.5; HRMS (ESI-TOF): calc?d for C10H16N2NaO2 [M+Na+] 219.1109; found 219.1087.
32%		PREPARATION S: 3-cyano-3-methylazetidine, TFA salt[0438] STEP A: tert-butyl 3-cyano-3-methylazetidine-l-carboxylate[0439] To an oven-dried 25 mL round bottom flask equipped for stirring was added diisopropylamine (1.318 mL, 9.33 mmol) under nitrogen. THF (10 mL) was added and the colorless solution was cooled to 00C. n-BuLi in hexanes (1.6N, 5.83 mL, 9.33 mmol) was added dropwise and the solution was stirred at 00C for 30 min. The solution was cooled to -78C and a solution of tert-butyi 3-cyanoazetidine-l-carboxylate (1 g, 5.49 mmol) in THF (3 mL) was added and the solution was stirred at -78C for 30 min. Iodomethane (0.445 mL, 7.13 mmol) was added dropwise at -78C. The reaction mixture was stirred for 30 min; it was then allowed to slowly warm up to 25C and was stirred for 16 h. The reaction mixture was quenched at 00C with aqueous ammonium chloride (5 mL) and was extracted with DCM (3 times). The extracts were dried over Na2SO4. Purification by silica column chromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.35 g, 32%). 1H NMR (500 MHz, CDCl3) delta 1.45 (s, 9 H) 1.67 (s, 3 H) 3.80 (d, J=8.30 Hz, 2 H) 4.29 (d, J=8.79 Hz, 2 H).

Step 2: To a stirred solution of 8004A (50.0 g, 0.274 mol) in THF (500 mL) at -78 C is added a LiHMDS solution in THF (1 M; 330 mL, 0.330 mol, 1 .2 eq). The mixture is stirred for 30 min, then methyliodide (122g, 0.860 mol, 3.1 eq) is added and the mixture is stirred at RT for 60 min. The reaction mixture is neutralized at 0 C by adding a saturated aqueous NH4CI solution (500 ml_) and the aqueous layer is extracted with EtOAc (3 x 250 ml_). The organic layers are combined, washed with brine, dried over Na2S04, filtered and concentrated. The crude residue is purified by silica gel flash chromatography (eluent: petroleum ether / EtOAc, 10% to 15%) to afford intermediate 8004B.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 89-90
[2]Arkivoc,2018,vol. 2018,p. 195 - 214
[3]Patent: WO2010/144486,2010,A1 .Location in patent: Page/Page column 97-98
[4]Patent: WO2013/152065,2013,A2 .Location in patent: Page/Page column 27; 28

19
[ 373-52-4 ]
[ 142253-54-1 ]
[ 1228581-11-0 ]

Yield	Reaction Conditions	Operation in experiment
94%		PREPARATION R: 3-(fiuoromethyl)azetidine-3-carbonitrile, TFA salt[0431] STEP A: tert-butyl 3-cyano-3-(fluoromethyl)azetidine-l-carboxylate[0432] To an oven-dried 25 mL round bottom flask equipped for stirring was added diisopropylamine (0.659 mL, 4.66 mmol) under nitrogen. THF (5 mL) was added and the colorless solution was cooled to 00C. To this solution was added n-BuLi (2.92 mL, 4.66 mmol) and the solution was stirred at 00C for 30 min. The solution was cooled to -78C and a solution of tert-butyl 3-cyanoazetidine-l-carboxylate (0.5 g, 2.74 mmol) in THF (3 mL) was added and the solution was stirred at -78C for 30 min. Bromofluoromethane (0.403 g, 3.57 mmol) was added at -78C dropwise. The reaction mixture was stirred for 30 min and then allowed to warm to 25C and stirred for 16 h. The reaction mixture was quenched at 00C with aqueous NH4Cl (5 mL) and extracted with DCM (3 x). The extracts were dried over Na2SO4. Purification by silica column chromatography (MeOH/DCM, 0- 5%) afforded the title compound as a yellow oil (0.52 g, 94%).

Reference： [1]Patent: WO2010/144486,2010,A1 .Location in patent: Page/Page column 96

20
[ 1118-03-2 ]
[ 142253-54-1 ]
[ 1009367-63-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	In toluene; at 100℃;	PREPARATION 32 tert-Butyl 3-(1 H-tetrazol-5-yl)azetidine-1-carboxylate In a Schlenk tube, tert-Butyl 3-cyanoazetidine-1-carboxylate (250 mg, 1.37 mmol) and azidotrimethylstannane (452 mg, 2.20 mmol) were dissolved in toluene (6.5 ml) and stirred at 100 C overnight. Solvent was removed and the solid obtained purified according to purification method A. 173 mg (56% yield) of the title product were obtained. LRMS: m/z 226 (M+1)+ Retention time: 4.63 min (method B)

Reference： [1]Patent: EP2305660,2011,A1 .Location in patent: Page/Page column 31

21
[ 142253-54-1 ]
[ 1009367-63-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With azidotrimethyltin; In toluene; at 100℃;	In a Schlenk tube, tert-Butyl 3-cyanoazetidine-1-carboxylate (250 mg, 1.37 mmol) and azidotrimethylstannane (452 mg, 2.20 mmol) were dissolved in toluene (6.5 ml) and stirred at 100 C overnight. Solvent was removed and the solid obtained purified according to purification method A. 173 mg (56% yield) of the title product were obtained.LRMS: m/z 226 (M+1)+ Retention time: 4.63 min (method B)

Reference： [1]Patent: WO2011/35900,2011,A1 .Location in patent: Page/Page column 49

22
[ 345954-83-8 ]
[ 24424-99-5 ]
[ 142253-54-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In dichloromethane; for 16h;	Step 1 3-Cyanoazetidine hydrochloride (3.64 g, 30.7 mmol) was suspended in 77 mL of dichloromethane. Triethylamine (4.3 mL, 30.7 mmol) was added, followed by portionwise addition of di-tert-butyl dicarbonate (8.0 g, 36.8 mmol). The reaction mixture was stirred for 16 h then diluted with aqueous hydrochloric acid and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 5.5 g (98%) of tert-butyl 3-cyanoazetidine-1-carboxylate.
	With triethylamine; In dichloromethane; at 5 - 20℃;	Step 2: tert- Butyl 3-cyanoazetidine-l-carboxylateTo a solution of <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (250 mg, 2.01 mmol theoretical; which may be prepared as described in Step 1) and triethylamine (1.12 ml_, 8.04 mmol) in dichloromethane (10.2 mL) was added di-tert-butyldicarbonate (482 mg, 2.21 mmol) portionwise at 5 C. After stirring at room temperature for 16 h, the reaction mixture was washed with HCI 0.5N and brine then dried over Na2S04. The solvent was removed under reduced pressure and the crude mixture purified on column chromatography (eluent: Pentane/EtOAc 95/5 to 4/1) to give the compound (190 mg, 52%) as a clear oil.*H NMR (CDCIs, 300 MHz) : delta (ppm) : 4.29-4.05 (m, 4H), 3.48-3.29 (m, 1H), 1.44 (s, 9H).
	With triethylamine; In tetrahydrofuran; at 20℃; for 4h;	Step 1 : To a stirred solution of 3-cyano azetidine hydrochloride (Oakwood) (10.0 g, 0.084 mol) in THF (100 mL) containing Et3N (25.5 g, 0.252 mol, 3.0 eq) is added di-tert-butyl dicarbonate (27.6 g, 0.126 mol, 1 .5 eq). The mixture is stirred at RT for 4 h, then water (100 mL) is added followed by EtOAc (50 mL). The aqueous phase is extracted with EtOAc (3 x 50 mL). The organic layers are combined and washed with brine, dried over Na2S04, filtered and concentrated. The crude residue is purified by silica gel flash chromatography (eluent: petroleum ether / EtOAc, 10%) to afford intermediate 8004A.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 64-65
[2]Patent: WO2011/61214,2011,A1 .Location in patent: Page/Page column 50
[3]Patent: WO2013/152065,2013,A2 .Location in patent: Page/Page column 27

23
[ 142253-54-1 ]
[ 1309207-05-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	With hydroxylamine hydrochloride; triethylamine; In ethanol; for 3h;Reflux;	Step 3: tert-Butyl 3-[(Z)-amino(hydroxyimino)methyl]azetidine-l- carboxylateIn a 16 mL vial, terf-butyl 3-cyanoazetidine-l-carboxylate (190 mg, 1.04 mmol; which may be prepared as described in Step 2) was dissolved in ethanol (2.9 mL), then hydroxylamine hydrochloride (101 mg, 1.46 mmol) and triethylamine (247 pL,1.77 mmol) were added. The reaction mixture was stirred at reflux for 3 h, cooled and concentrated. The residue was taken up in EtOAc and water, the aqueous layer extracted with EtOAc, dried over Na2S04 and concentrated to give the product as a white solid (170 mg, 76%).*H NMR (DMSO-c/e, 300 MHz) delta (ppm) : 9.10 (s, 1H), 5.54-5.43 (br s, 2H), 4.00-3.78 (m, 4H), 3.23-3.08 (m, 1H), 1.37 (s, 9H).

Reference： [1]Patent: WO2011/61214,2011,A1 .Location in patent: Page/Page column 50

24
[ 142253-54-1 ]
[ 1309207-08-6 ]

Reference： [1]Patent: WO2011/61214,2011,A1

25
[ 28539-02-8 ]
[ 142253-54-1 ]
[ 1228581-13-2 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation Example 24 To a solution of N-isopropylpropan-2-amine (11.54 mL) in THF (50 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 51.45 mL) at -78C. The reaction mixture was warmed to 0C and then stirred for 30 minutes. The reaction mixture was cooled to -78C again, and then a solution of <strong>[142253-54-1]tert-butyl 3-cyanoazetidine-1-carboxylate</strong> (5.0 g) in THF (30 mL) was added dropwise, followed by stirring at -78C for 1 hour. To the reaction mixture was added dropwise a solution of 1H-benzotriazol-1-yl-methanol (8.19 g) in THF (20 mL) at -78C, followed by stirring at -78C for 3 hours. To the reaction mixture was added a saturated aqueous NH4Cl solution (100 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 50:50) to obtain tert-butyl 3-cyan-3-(hydroxymethyl)azetidine-1-carboxylate (5.68 g) as a white solid.

Reference： [1]Patent: EP2354134,2011,A1 .Location in patent: Page/Page column 23-24

26
[ 142253-54-1 ]
[ 1228581-11-0 ]

Reference： [1]Patent: EP2354134,2011,A1

27
[ 142253-54-1 ]
[ 1228581-12-1 ]

Reference： [1]Patent: EP2354134,2011,A1

28
[ 75-03-6 ]
[ 142253-54-1 ]
[ 1334675-26-1 ]

Yield	Reaction Conditions	Operation in experiment
91%		Step 1 In a 100 mL 2-neck round-bottomed flask, <strong>[142253-54-1]tert-butyl 3-cyanoazetidine-1-carboxylate</strong> (0.80 g, 4.4 mmol) was dissolved in THF (16 mL). The colorless solution was cooled to -76 C. and lithium bis(trimethylsilyl)amide (1.0M solution in THF, 4.8 mL, 4.8 mmol) was added dropwise over 20 min. The yellow solution was stirred at -76 C. for 30 min then iodoethane (0.50 mL, 6.2 mmol) was slowly added. The reaction mixture was stirred at -76 C. for 30 min and then warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with 10 mL of saturated NH4Cl and diluted with 10 mL of water then extracted with ~100 ml EtOAc (2*). The combined organic layers were washed with ~10 mL water and ~10 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 40 g silica gel with EtOAc/hexanes, (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated to afford 0.84 g (91%) of 3-cyano-3-ethyl-azetidine-1-carboxylic acid tert-butyl ester as a light yellow oil.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 93

29
[ 925-90-6 ]
[ 142253-54-1 ]
[ 1352012-69-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 12 (compound No. 220)2,2,2-Trifluoro-1 -(trifluoromethyl)ethyl 3-[1 -(4-chlorobenzenesulphonylamino)cyclopropyl]-12.1 . ie f-Butyl 3-(1 -aminocyclopropyl)azetidine-1 -carboxylate; 10.5 ml (35 mmol) of titanium tetraisopropoxide (Ti(OiPr)4) and then, dropwise, 21 ml (63 mmol) of a 3M solution of ethylmagnesium bromide in diethyl ether are added, under a nitrogen atmosphere, to a solution of 4.8 g (26.34 mmol) of ie f-butyl 4-cyanoazetidine- 1 -carboxylate in 150 ml of diethyl ether. The mixture is stirred for 40 minutes and then 9 ml (71 mmol) of the boron trifluoride etherate complex (BF3.Et20) are added dropwise. The reaction mixture is stirred for 5 hours. 100 ml of a 2M aqueous sodium hydroxide solution and 150 ml of dichloromethane are added. The mixture is filtered through celite. The organic phase is separated by settling. It is dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, elution being carried out with a 90:10 mixture of dichloromethane and methanol, in order to obtain 1.91 g (9.0 mmol) of product in the form of a colourless oil which slowly solidifies. 1H NMR (CDCIs, delta ppm, 200 MHz): 3.65 (t, 2H), 3.35 (m, 2H), 2.30-2.20 (m, 1 H), 1 .45 (s, 2H), 1 .15 (s, 9H), 0.35 (m, 2H), 0.20 (m, 2H).

Reference： [1]Patent: WO2011/151808,2011,A1 .Location in patent: Page/Page column 36-37

30
[ 142253-54-1 ]
[ 1352012-70-4 ]

Reference： [1]Patent: WO2011/151808,2011,A1

31
[ 1239358-93-0 ]
[ 142253-54-1 ]
[ 1239361-85-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example 178 (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carbonitrile 216 mg of <strong>[142253-54-1]1-(t-butoxycarbonyl)-3-cyanoazetidine</strong> was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain brown oil. The obtained oil was dissolved in 4 ml of degassed 1,4-dioxane, and 302 mg of triethylamine, 205 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 57 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 229 mg of sodium t-butoxide and 62 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 90 C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 58 mg of the objective compound as pale yellow powder. MS (ESI) m/z 391 (M+H)

Reference： [1]Patent: US2011/288065,2011,A1 .Location in patent: Page/Page column 54

32
[ 100-48-1 ]
[ 142253-54-1 ]
[ 1416149-25-1 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 762 - 769

33
[ 142253-54-1 ]
[ 1360451-55-3 ]

Reference： [1]Patent: US2013/158005,2013,A1

34
[ 142253-54-1 ]
[ 1360451-26-8 ]

Reference： [1]Patent: US2013/158005,2013,A1

35
[ 142253-54-1 ]
[ 1360451-28-0 ]

Reference： [1]Patent: US2013/158005,2013,A1

36
[ 142253-54-1 ]
[ 1360451-54-2 ]

Reference： [1]Patent: US2013/158005,2013,A1

37
[ 142253-54-1 ]
[ 1360451-30-4 ]

Reference： [1]Patent: US2013/158005,2013,A1

38
[ 113975-22-7 ]
[ 142253-54-1 ]
[ 1360451-25-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 0.75h;Inert atmosphere;	1) tert-Butyl 3-cyano-3-(3-iodopyridin-2-yl)azetidine-1-carboxylate The cyanoazetidine (70 mg, 0.4 mmol) and 2-fluoro-3-iodopyridine (93 mg, 0.4 mmol) is dissolved in dry THF (18 ml) under nitrogen. LiHMDS (lithium hexamethyldisilazide) in THF (0.7 ml, 0.7 mmol) is added to the solution at RT and stirred for a further 45 min. The batch is then added to saturated aqueous ammonium chloride solution and extracted to exhaustion with ethyl acetate. Drying of the organic phase over sodium sulfate and chromatography of the organic residue on silica gel (petroleum ether/ethyl acetate=8:2) gives the product with a yield of 76% (110 mg); 1H NMR (DMSO-d6) delta [ppm] J [Hz]: ppm 8.65 (dd, 1H) 8.44 (dd, 1H) 7.27 (dd, 1H) 4.63 (d, 2H) 4.49 (d, 2H) 1.39 (s, 9H).

Reference： [1]Patent: US2013/158005,2013,A1 .Location in patent: Paragraph 0203; 0204; 0205; 0206

39
[ 142253-54-1 ]
[ 1581683-56-8 ]

Reference： [1]Patent: WO2014/43272,2014,A1

40
[ 142253-54-1 ]
[ 1581683-57-9 ]

Reference： [1]Patent: WO2014/43272,2014,A1

41
[ 142253-54-1 ]
[ 1581683-58-0 ]

Reference： [1]Patent: WO2014/43272,2014,A1

42
[ 109-70-6 ]
[ 142253-54-1 ]
[ 1384165-00-7 ]

Yield	Reaction Conditions	Operation in experiment
84%		Exam le lv - Preparation of R4: tert-butyl 3-(3-chloropropyl)-3-cyanoazetidine-l-carboxylate: [0287] A solution of tert-butyl 3-cyanoazetidine-l-carboxylate (3.15g, 17.3 mmol), in THF (70 ml), at -78C, was treated with lithium bis(trimethylsilyl)amide 1M (19.0 mL, 19.0 mmol). After 30 min l-bromo-3-chloropropane (3.40 mL, 34.6 mmol) was added. The mixture was slowly warmed to RT. After lhr the reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl ether, dried over sodium sulfate, concentrated, purified by flash chromatography with ethyl acetate/hexanes, yielding 3.75g (84% yield) of mmolthe product as a colorless oil. LCMS m/z: 259.7 (M+l). tert-butyl 3-cyano-3-(3-iodopropyl)azetidine-l-carboxylate: [0288] A solution of tert-butyl 3-(3-chloropropyl)-3-cyanoazetidine-l- carboxylate (3.75g, 14.5 mmol), in acetone (60 ml), was treated with sodium iodide (6.52g, 43.5 mmol), then refluxed overnight. The reaction was diluted with ether, washed with water, dried over sodium sulfate, concentrated, and purified by flash chromatography with ethyl acetate/hexanes, yielding 4.68g (92% yield) of the product as a colorless oil. LCMS m/z: 351.2 (M+l). tert-butyl 5-oxo-2-azaspiro [3.4] octane-2-carboxylate : [0289] A solution of tert-butyl 3-cyano-3-(3-iodopropyl)azetidine-l-carboxylate (4.68g, 13.4 mmol), in dry THF (54 ml), was cooled to -78C, then slowly treated with n- butyllithium 2.5M in hexanes (10.7 mL, 26.7 mmol). TLC after 15 minutes shows no starting material. The reaction was quenched with acetic acid (1.53 mL, 26.7 mmol), warmed to room temperature, diluted with ether, washed with brine, dried over sodium sulfate, concentrated, and purified by flash chromatography with ethyl acetate/hexanes, yielding 2.61g (87% yield) of product . LCMS m/z: 226.3 (M+l). tert-butyl 5-(benzylamino)-2-azaspiro [3.4] octane-2-carboxylate 2,2,2-trifluoroacetate : [0290] A solution of tert-butyl 5-oxo-2-azaspiro[3.4]octane-2-carboxylate (0.243g, 1.08 mmol), and benzylamine (0.139g, 1.29 mmol) in dry methylene chloride (4.3 ml), was cooled to 0C, then slowly treated with titanium tetrachloride(0.102g, 0.539 mmol), then heated to reflux. After 3h the reaction was cooled to room temperature, diluted with ether (white ppt forms), and filtered with the aid of celite. The light yellow filtrate was concentrated to an oil, dissolved in MeOH (5mL), cooled to 0C with an ice bath, then treated with sodium borohydride (0.041g,1.08 mmol ). LCMS after lhr shows a major peak corresponding to product. The reaction was diluted with DMF (0.75 mL), concentrated, and purified by reverse phase liqud chromatography (5-95% acetonitrile/water), giving the title compound as a light yellow solid (420 mg, 90% yield) after concentration by rotary evaporator. LCMS m z: 317.4 (M+l). N-benzyl-2-azaspiro [3.4] octan-5-amine dihydrochloride : [0291] A flask charged with methanol (5 mL) was treated with acetyl chloride (0.5 mL), followed by tert-butyl 5-(benzylamino)-2-azaspiro[3.4]octane-2-carboxylate 2,2,2- trifluoroacetate (0.420 mg, 0.98 mmol). After 30 min the mixture is stripped of solvent giving product as a white powder (280 mg, quantitavive yield). LCMS m/z: 217.3 (M+l). 2-azaspiro[3.4]octan-5-amine dihydrochloride: [0292] A Parr shaker flask was charged with N-benzyl-2-azaspiro[3.4]octan-5- amine dihydrochloride (286mg, 0.99 mmol), 10% Pd/C (300 mg), and methanol (10 mL), then shook under a hydrogen atmosphere at 60 psi. After 24h the mixture was filtered through celite, giving product as a white powder (197 mg, quantitavive yield ). LCMS m/z: 127.2 (M+l).

Reference： [1]Patent: WO2014/43272,2014,A1 .Location in patent: Paragraph 0286; 0287

43
[ 624-92-0 ]
[ 142253-54-1 ]
tert-butyl 3-cyano-3-(methylsulfonyl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To B1 (4.0 g, 22 mmol) and dimethyldisulfide (2.5 mL, 27 mmol) in THF (88 mL) at -78 C was added LHMDS (1.0 M in THF, 27 mL, 27 mmol) dropwise. The reaction was stirred at - 78 C for 2 h and then saturated NH4Cl(aq) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc. The combined organic layerswere washed with water and brine, dried (MgS04), filtered, and concentrated in vacuo to provide an oil that was used directly in the next step. The oil was taken up into MeOH (88 mL) and Oxone (27.0 g, 44 mmol) in water (88 mL) was added at room temperature. The heterogeneous mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with EtO Ac. The combined organic layers were washed with water and brine, dried (MgS04), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 35 minutes) to provide the title compound B2.

Reference： [1]Patent: WO2014/150344,2014,A1 .Location in patent: Page/Page column 61; 62

44
[ 142253-54-1 ]
tert-butyl 3-cyano-3-(((R)-2-((R)-1,1-dimethylethylsulfinamido)-2-(2-fluoro-5-nitrophenyl)propyl)sulfonyl)azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

45
[ 142253-54-1 ]
1-methyl-3-(methylsulfonyl)azetidine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

46
[ 142253-54-1 ]
(R)-N-((R)-1-((3-cyano-1-methylazetidin-3-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

47
[ 142253-54-1 ]
(R)-3-((2-amino-2-(2-fluoro-5-nitrophenyl)propyl)sulfonyl)-1-methylazetidine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

48
[ 142253-54-1 ]
(R)-7-(2-fluoro-5-nitrophenyl)-9-imino-2,7-dimethyl-5-thia-2,8-diazaspiro[3.5]nonane 5,5-dioxide [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

49
[ 142253-54-1 ]
(R)-di-tert-butyl (7-(2-fluoro-5-nitrophenyl)-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-8-en-9-yl)imidodicarbonate [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

50
[ 142253-54-1 ]
(R)-di-tert-butyl (7-(5-amino-2-fluorophenyl)-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]non-8-en-9-yl)imidodicarbonate [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

51
[ 142253-54-1 ]
(R)-di-tert-butyl (7-(5-(5-cyanopicolinamido)-2-fluorophenyl)-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]non-8-en-9-yl)imidodicarbonate [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

52
[ 142253-54-1 ]
(R)-5-cyano-N-(4-fluoro-3-(9-imino-2,7-dimethyl-5,5-dioxido-5-thia-2,8-diazaspiro[3.5]nonan-7-yl)phenyl)picolinamide [ No CAS ]

Reference： [1]Patent: WO2014/150344,2014,A1

53
[ 142253-54-1 ]
tert-butyl 3-picolinoyl-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 4926 - 4947

54
[ 142253-54-1 ]
[ 1432049-21-2 ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 4926 - 4947

55
[ 402-44-8 ]
[ 142253-54-1 ]
tert-butyl 3-cyano-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 4926 - 4947

56
[ 142253-54-1 ]
azetidine-3-carboxamide hydrochloride [ No CAS ]
[ 345954-83-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 2h;	Compound BB-30-1 (0.200g, 1.10mmol) was dissolved in dichloromethane (2mL), followed by addition of hydrogen chloride in dioxanesix rings solution (1mL, 4M).The reaction was stirred at 20 2 hours.The reaction mixture was concentrated to give the title compound BB-30-30a and the BB(white solid, 0.130 g, yield: 99%), was used directly in the next step synthesis without isolation.

Reference： [1]Patent: CN105732602,2016,A .Location in patent: Paragraph 0458; 0459; 0460; 0461; 0462; 0463

57
[ 611-17-6 ]
[ 142253-54-1 ]
tert-butyl 3-(2-chlorobenzyl)-3-cyanoazetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
457 mg		To a solution of DIPA (2.366 mL) in THF (40 mL), n-butyllithium (1.6 M solution in hexane, 9.98 mL) was added, and the mixture was stirred at 0C for 30 minutes. In an Ar atmosphere, a solution of <strong>[142253-54-1]tert-butyl 3-cyanoazetidine-1-carboxylate</strong> (2.5 g) in THF (10 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was cooled to -78C. Then, 1-(bromomethyl)-2-chlorobenzene (3.07 g) was added thereto, and the mixture was stirred overnight in an Ar atmosphere while the temperature was gradually raised to room temperature. The reaction solution was poured to a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (457 mg). 1H NMR (300 MHz, CDCl3) delta 1.44 (9H, s), 3.39 (2H, s), 4.04-4.11 (2H, m), 4.21-4.32 (2H, m), 7.24-7.33 (2H, m), 7.34-7.40 (1H, m), 7.41-7.47 (1H, m).

Reference： [1]Patent: EP3118200,2017,A1 .Location in patent: Paragraph 0268; 0389

58
[ 766-11-0 ]
[ 142253-54-1 ]
tert-butyl 3-(5-bromopyridin-2-yl)-3-cyanoazetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Into a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of LDA (1 M, 18 mL, 1.25 equiv) in tetrahydrofuran (100 mL). This was followed by the addition of a solution of tert-butyl 3- cyanoazetidine-1-carboxylate (2.7 g, 14.8 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at -78C over 45 mm. The reaction mixture was stirred for 45 mm at-78C, then a solution of 5-bromo-2-fluoropyridine (2.6 g, 14.77 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was added dropwise with stirring at -78C over 45 mm. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 200 mL of water, then extracted with 3x200 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (20:1-5:1) to give the title compound as a solid.

Reference： [1]Patent: WO2016/206101,2016,A1 .Location in patent: Page/Page column 89

59
[ 142253-54-1 ]
C₅₂H₅₉N₉O₁₁S₂ [ No CAS ]

Reference： [1]Patent: WO2016/206101,2016,A1

60
[ 142253-54-1 ]
tert-butyl 3-cyano-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/206101,2016,A1

61
[ 773837-37-9 ]
[ 254454-54-1 ]
[ 142253-54-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	In dimethyl sulfoxide; at 130℃; for 6h;	To a 100 mL round bottom flask was added tert-butyl 3-iodoazetidine-1-carboxylate (6) (6.54 g, 0.0231 mol, 1 equiv.) and DMSO (25 mL). NaCN (2.3 g, 0.0462 mol, 2equiv.) was added to the solution in one portion and stirred at 130 oC for 6 h. The resulting mixture was cooledto rt, poured into water (200 mL), and extracted with diethyl ether (5 x 200 mL). The combined organicextracts were washed with brine (50 mL), dried over Na2SO4 and concentrated. The crude compound waspurified by flash chromatography (silica gel, 5-50% EtOAc in hexanes) to give the desired product 22 (3.27 g,78%). Physical State: off-white solid (mp 78-80 oC); Rf = 0.40 (2:8 EtOAc/hexanes, vis. KMnO4); 1H NMR (500MHz, CDCl3): delta 4.23 - 4.11 (m, 4H), 3.38 (tt, J 8.9, 6.3 Hz, 1H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3): delta 155.6,119.6, 80.8, 52.6 (br, 2C), 28.4 (3C), 17.2.