[ CAS No. 345954-83-8 ] {[proInfo.proName]}

Name: 345954-83-8|Azetidine-3-carbonitrile hydrochloride|97%
Brand: Ambeed
SKU: A147240
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Quality Control of [ 345954-83-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 345954-83-8 ]

Product Details of [ 345954-83-8 ]

CAS No. :	345954-83-8	MDL No. :	MFCD09749828
Formula :	C₄H₇ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MJZQSPDYIKSJCN-UHFFFAOYSA-N
M.W :	118.56	Pubchem ID :	45072465
Synonyms :

Calculated chemistry of [ 345954-83-8 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	32.66
TPSA :	35.82 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 :	Yes
Log Kp (skin permeation) :	-6.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.1
Log Po/w (WLOGP) :	0.15
Log Po/w (MLOGP) :	-0.31
Log Po/w (SILICOS-IT) :	0.57
Consensus Log Po/w :	0.1

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.64
Solubility :	27.3 mg/ml ; 0.23 mol/l
Class :	Very soluble
Log S (Ali) :	-0.41
Solubility :	46.4 mg/ml ; 0.392 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.5
Solubility :	37.3 mg/ml ; 0.315 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.29

Safety of [ 345954-83-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 345954-83-8 ]

* 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 [ 345954-83-8 ]
Downstream synthetic route of [ 345954-83-8 ]

[ 345954-83-8 ] Synthesis Path-Upstream 1~4

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
[ 36476-86-5 ]
[ 345954-83-8 ]

Reference： [1] Patent: WO2006/15854, 2006, A2, . Location in patent: Page/Page column 17
[2] Patent: WO2011/61214, 2011, A1, . Location in patent: Page/Page column 49-50
[3] Patent: EP1942109, 2008, A1, . Location in patent: Page/Page column 16

3
[ 142253-54-1 ]
[ 345954-83-8 ]

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

4
[ 142253-54-1 ]
[ 345954-83-8 ]

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

[ 345954-83-8 ] Synthesis Path-Downstream 1~45

1
[ 345954-83-8 ]
[ 18880-04-1 ]
[ 876385-07-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 2h;	l-(3.4-Dichloro-benzyl)-azetidine-3-carbonitrile:A solution of l-Benzhydryl-azetidine-3-carbonitrile (0.25 g, 1.0 mmol) in dichloromethane(2ml) is treated with 1-chloroethylchloroformate (0.12 ml, 1.1 mmol). The reaction mixtureis stirred at room temperature for 3 hours, the solvent evaporated and the residue taken-upin methanol and refluxed for 1 hour. The reaction mixture is cooled to room temperatureand stirred for a further 18 hours. The solvent is evaporated to afford crude <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong>. The crude azetidine-3-carbonitrile is dissolved indichloromethane (3 ml) and treated with triethylamine (0.25 ml, 2.0 mmol) and 3,4-dichlorobenzylbromide (0.24 g, 1.0 mmol). The reaction mixture is stirred at ambienttemperature for 2 hours, then washed with water, the organic phase dried over magnesiumsulphate and evaporated. The crude product is purified by chromatography over flash silicausing hexanetethylacetate 2:1 as eluent to afford l-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile. [MH]+ 240.97

Reference： [1]Patent: WO2006/15854,2006,A2 .Location in patent: Page/Page column 17

2
[ 36476-86-5 ]
[ 345954-83-8 ]

Yield	Reaction Conditions	Operation in experiment
		1-(3.4-Dichloro-benzyl)-azetidine-3-carbonitrile:A solution of l-Benzhydryl-azetidine-3-carbonitrile (0.25 g, 1.0 mmol) in dichloromethane(2ml) is treated with 1-chloroethylchloroformate (0.12 ml, 1.1 mmol). The reaction mixtureis stirred at room temperature for 3 hours, the solvent evaporated and the residue taken-upin methanol and refluxed for 1 hour. The reaction mixture is cooled to room temperatureand stirred for a further 18 hours. The solvent is evaporated to afford crude azetidine-3-carbonitrile hydrochloride. The crude azetidine-3-carbonitrile is dissolved indichloromethane (3 ml) and treated with triethylamine (0.25 ml, 2.0 mmol) and 3,4-dichlorobenzylbromide (0.24 g, 1.0 mmol). The reaction mixture is stirred at ambienttemperature for 2 hours, then washed with water, the organic phase dried over magnesiumsulphate and evaporated. The crude product is purified by chromatography over flash silicausing hexanetethylacetate 2:1 as eluent to afford l-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile. [MH]+ 240.97
	With carbonochloridic acid 1-chloro-ethyl ester; In 1,2-dichloro-ethane; at 70℃; for 1.5h;	Step 1: Azetidine-3-carbonitrile hydrochlorideA 50 ml_ flask was charged with l-benzhydrylazetane-3-carbonitrile (500 mg, 2.01 mmol) and 1,2-dichloroethane (8.9 ml_). 1-chloroethyl chloroformate (285 muIota_, 2.61 mmol) was added and the reaction mixture was stirred at 70 C for 1.5 h. After cooling to room temperature, methanol (8.9 ml_) was added and the reaction mixture was stirred at 70 C for 1.5h. The reaction mixture was concentrated to dryness. The crude mixture was triturated in pentane to give a dark solid (250 mg, quantitative) which was used without further purification.
		[Reference Example 7]; 3-Azetidinecarbonitrile hydrochloride; [Show Image] [Show Image] 1,2-Dichloroethane (16 ml) was added with 1-benzhydrylazetidine-3-carbonitrile (1.24 g), and added with 1-chloroethyl chloroformate (0.82 ml) at room temperature, and the mixture was refluxed for 0.5 hour by heating. The reaction mixture was concentrated, then the resulting residue was added with methanol (16 ml), and the mixture was refluxed for 1 hour by heating, and left to cool. The mixture was concentrated again, and then the resulting residue was added with ethyl acetate, and the deposited solid was collected by filtration, and dried to obtain the title compound (360 mg) as colorless solid. 1H-NMR (400MHz, d6-DMSO) delta : 3.94-4.02 (1H, m), 4.14 (2H, s), 4.16 (2H, s), 9.61 (2H, br). EI-MS; m/z: 82 (M+).

Reference： [1]Patent: WO2006/15854,2006,A2 .Location in patent: Page/Page column 17
[2]Patent: WO2011/61214,2011,A1 .Location in patent: Page/Page column 49-50
[3]Patent: EP1942109,2008,A1 .Location in patent: Page/Page column 16

3
[ 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

4
[ 345954-83-8 ]
[ 1258066-99-7 ]
[ 1258065-56-3 ]

Yield	Reaction Conditions	Operation in experiment
13.7%	With 4-methyl-morpholine; dmap; HATU; In tetrahydrofuran; at 25℃; for 1h;Inert atmosphere;	EXAMPLE 41 : (i?)-l-(2-(6-chloro-3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin- 4(lH,3H,5H)-yl)-3,3-dimethylbutanoyl)azetidine-3-carbonitrile[0384] To an 8 niL scintillation vial equipped for stirring was added (i?)-2-(6-chloro-3- oxopyrrolo[4,3,2-(ie][2,6]naphthyridin-4(lH,3H,5H)-yl)-3,3-dimethylbutanoic acid (25 mg, 0.078 mmol) under nitrogen. THF (0.5 mL), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (18.45 mg, 0.155 mmol), HATU and 4-methylmorpholine (11.79 mg, 0.117 mmol) were added and the solution was stirred at 25C for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCNZH2O, 15-40%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow semi-solid (4.1 mg, 13.7%). 1H NMR (400 MHz, CD3OD) delta 1.17 (s, 9 H) 3.50 - 3.78 (m, 1 H) 4.17 (br. s., 1 H) 4.25 - 4.37 (m, 1 H) 4.41 - 4.69 (m, 2 H) 5.17 - 5.30 (m, 2 H) 5.44 (s, 1 H) 7.87 (br. s., 1 H) 8.25 (s, 1 H). [M+H] calc'd for Ci9H20ClN5O2, 386; found, 386.4.

Reference： [1]Patent: WO2010/144486,2010,A1 .Location in patent: Page/Page column 83-84

5
[ 345954-83-8 ]
[ 1258067-03-6 ]
[ 1258065-57-4 ]

Yield	Reaction Conditions	Operation in experiment
34.4%	With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 25℃; for 4h;	EXAMPLE 42: (i?)-l-(2-(6-fluoro-3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(lH,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile[0406] To an 8 rnL scintillation vial equipped for stirring was added (i?)-2-(6-fluoro-3- oxopyrrolo[4,3,2-fe][2,6]naphthyridin-4(l/f,3/f,5H)-yl)-3-methylbutanoic acid (60 mg, 0.206 mmol). DMF (0.5 mL), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.309, 36.6 mg), HOBt (47.3 mg, 0.309 mmol), EDC (59.2 mg, 0.309 mmol) and JV,JV-dimethylpyridin-4- amine (37.7 mg, 0.309 mmol) were added and the solution was stirred at 25C for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCNZH2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a TFA salt. The residue was further purified using silica column chromatography (MeOH/DCM, 0-10%) which gave the title compound as a white solid (free base, 25.2 mg, 34.4%). 1H NMR (400 MHz, DMSO-Je) delta 0.78 (dd, J=6.57, 3.79 Hz, 3 H) 0.95 (dd, J=13.01, 6.44 Hz, 3 H) 1.09 (t, J=6.95 Hz, 1 H) 3.53 - 3.86 (m, 1 H) 3.94 - 4.10 (m, 1 H) 4.10 - 4.29 (m, 2 H) 4.29 - 4.48 (m, 1 H) 4.87 (dd, J=18.82, 8.21 Hz, 1 H) 4.96 - 5.14 (m, 2 H) 7.99 (dd, J=5.43, 2.40 Hz, 1 H) 8.25 (t, J=2.78 Hz, 1 H) 12.39 (br. s., 1 H). [M+H] calc'd for Ci8Hi8FN5O2, 356; found, 356.5.

Reference： [1]Patent: WO2010/144486,2010,A1 .Location in patent: Page/Page column 89

6
[ 345954-83-8 ]
[ 1258067-15-0 ]
[ 1258066-14-6 ]

Yield	Reaction Conditions	Operation in experiment
28%	With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; for 2h;	EXAMPLE 81 : (i?)-l-(3-methyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin- 4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile[0519] (i?)-3-Methyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(l/f,3H,5H)- yl)butanoic acid (80 mg, 0.29 mmol), HOBt (54 mg, 0.35 mmol) and EDC (84 mg, 0.44 mmol) were combined in DMF (2 rnL). Azetidine-3-carbonitrile HCl salt (52 mg, 0.44 mmol) and JV-methylmorpholine (130 muL, 1.17 mmol) were added, and the solution was stirred at room temperature for 2 h. Purification by preparative HPLC (10-45% AcCN/water with 0.035% TFA) followed by purification by silica gel chromatography (8% MeOH/DCM) gave the title compound as a white solid (28 mg, 28%). 1H NMR (500 MHz, DMSO-J6) delta 0.90 (dd, J=6.5, 2.0 Hz, 3H), 1.06 (dd, J=6.5, 2.0 Hz, 3H), 2.42-2.51 (m, IH), 3.61-3.75 (m, IH), 4.15-4.68 (m, 4H), 4.95-5.21 (m, 3H), 7.09 (t, J=5.0 Hz, IH), 7.81 (d, J=12.5 Hz, IH), 8.27 (t, J=5.0 Hz, IH). [M+H] calc'd for Ci8Hi9N5O2, 338; found, 338.

Reference： [1]Patent: WO2010/144486,2010,A1 .Location in patent: Page/Page column 118-119

7
[ 345954-83-8 ]
[ 1258067-21-8 ]
[ 1258066-15-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 2h;	EXAMPLE 82: (i?)-l-(3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(lH,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile[0528] (i?)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-Je][2,6]naphthyridin-4(l/f,3/f,5H)- yl)butanoic acid (80 mg, 0.278 mmol), HOBt hydrate (51.2 mg, 0.334 mmol), and EDC hydrochloride (80 mg, 0.418 mmol) were combined in DMF (2 mL). Azetidine-3- carbonitrile hydrochloride (49.5 mg, 0.418 mmol) and 4-methylmorpholine (0.124 mL, 1.114 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and purified by flash column chromatography (8% MeOH/DCM) to afford the title compound (38 mg, 39%). 1H NMR (500 MHz, CD3OD) delta 1.17 (s, 9H), 3.58-3.72 (m, IH), 4.13-4.65 (m, 4H), 5.35-5.45 (m, 3H), 7.28-7.38 (m, IH), 7.95 (d, J=15.5 Hz, IH), 8.33-8.40 (m, IH). [M+H] calc'd for Ci9H2IN5O2, 352; found, 352.

Reference： [1]Patent: WO2010/144486,2010,A1 .Location in patent: Page/Page column 118-119

8
[ 345954-83-8 ]
[ 1258067-29-6 ]
[ 1258066-20-4 ]

Yield	Reaction Conditions	Operation in experiment
12%	With 4-methyl-morpholine; dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	EXAMPLE 87: (i?)-l-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2- fe][2,6]naphthyridin-4(l/f,3/f,5H)-yl)butanoyl)azetidine-3-carbonitrile[0543] (i?)-3,3-Dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-fe][2,6]naphthyridin- 4(l/f,3/f,5H)-yl)butanoic acid (10 mg, 0.033 mmol), DMAP (6 mg, 0.05 mmol), 4- methylmorpholine (0.015 niL, 0.13 mmol), EDC hydrochloride (10 mg, 0.050 mmol), HOBt hydrate (8 mg, 0.050 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (6 mg, 0.050 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred under nitrogen at room temperature for 3 h. The solution was concentrated and purified by preparative HPLC (10-30% AcCN/H2O with 0.035% TFA) to give the title compound (1.4 mg, 12%). 1H NMR (500 MHz, CD3OD) delta 1.18 (s, 9H), 2.35 (d, J=8.8 Hz, 3H) 4.17-4.18 (m, IH), 4.29-4.31 (m, 2H), 4.52-4.62 (m, IH), 4.64-4.69 (m, IH), 5.19-5.23 (m, 2H), 5.45 (s, IH), 7.83 (d, J=16.1 Hz, 3H), 8.19 (s, IH). [M+H] calc'd for C20H23N5O2, 366; found, 366

Reference： [1]Patent: WO2010/144486,2010,A1 .Location in patent: Page/Page column 125-126

9
[ 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

10
[ 345954-83-8 ]
[ 3744-87-4 ]
[ 1334674-98-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;Product distribution / selectivity;	Step 1 In a round-bottomed flask were combined Boc-D-alanine (500 mg, 2.64 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (376 mg, 3.17 mmol), HOBT (445 mg, 2.91 mmol) and HATU (1.11 g, 2.91 mmol). Then added DMF (5 mL) followed by N,N-diisopropylethylamine (1.38 mL, 7.93 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with water and extracted with EtOAc (3). The combined organics were washed with water (3) dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes) to afford 493 mg (74%) of [(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a white solid.
74%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	Step 4[(R)-2-(3-Cyanoazetidin-l-yl)-l-methyl-2-oxo-ethyl]-carbamic acid tert-butyl esterIn a round-bottomed flask were combined Boc-D-alanine (500 mg, 2.64 mmol), azetidine-3- carbonitrile hydrochloride (376 mg, 3.17 mmol), HOBT (445 mg, 2.91 mmol) and HATU (1.11 g, 2.91 mmol). Then added DMF (5 mL) followed by N,N-diisopropylethylamine (1.38 mL, 7.93 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with water and extracted with EtOAc (3x). The combined organics were washed with water (3x) dried over MgSC^ and concentrated. The residue was purified by Si02 chromatography (50% to 100% EtOAc/hexanes) to afford 493 mg (74%) of [( )-2-(3 -cyanoazetidin- 1 -yl)- 1 -methyl-2- oxo-ethyl]-carbamic acid tert-butyl ester as a white solid.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 94
[2]Patent: WO2013/30138,2013,A1 .Location in patent: Page/Page column 66

11
[ 345954-83-8 ]
[ 54256-41-6 ]
[ 1334675-66-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 5h;	Step 1 (R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (2.25 g, 10.5 mmol) and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (3.69 g, 11.5 mmol) were dissolved in dichloromethane (105 mL). 3-Cyanoazetidine hydrochloride (1.36 g, 11.5 mmol) and then N,N-diisopropylethylamine (4.5 mL, 26.1 mmol) were added and the mixture was stirred at room temperature for 5 h. Water, dilute HCl and more dichloromethane were added, the layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 2.45 g (83%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester.
59%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Example 21.2- (6-Chloro-l-methyl-lH-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3- cyano-azetidin- 1 -yl)- 1 -cyclopropyl-2-oxo-ethyl]-amide Step 1[(R)-2-(3-C ano-azetidin-l-yl)-l-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl esterIn a round-bottomed flask Boc-D-cyclopropylglycine (500 mg, 2.32 mmol) and azetidine-3- carbonitrile hydrochloride (441 mg, 3.72 mmol) were dissolved in DMF (10 ml). N,N- Diisopropylethylamine (1.2 ml, 6.87 mmol) was added followed by HATU (972 mg, 2.56 mmol). The reaction mixture was stirred at room temperature ovemight then quenched with water and extracted with diethyl ether (2x). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 384 mg (59%) of [(R)-2-(3-cyano-azetidin-l-yl)-l- cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as an off-white solid.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 108
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 345 - 356
[3]Patent: WO2013/30138,2013,A1 .Location in patent: Page/Page column 94

12
[ 345954-83-8 ]
[ 1334675-93-2 ]
2-(7-methoxythieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyanoazetidin-1-yl)-1-cyclopropyl-2-oxoethyl]amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Step 2 To a solution of (R)-cyclopropyl-[2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-acetic acid (27 mg, 0.049 mmol) in DMF (2 mL) at room temperature was added triethylamine (34.0 muL, 0.24 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (6 mg, 0.049 mmol and PyBOP (31 mg, 0.059 mmol). The reaction mixture was stirred for 16 h at the same temperature then poured into EtOAc (25 mL) and washed with water (4×30 mL). The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 23 g, hex:EtOAc, 9:1 to 100% in 30 min) to give 26 mg (64%) of 2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 120

13
[ 345954-83-8 ]
[ 22838-58-0 ]
[ 1380740-57-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h;Product distribution / selectivity;	EXAMPLE 2: (R)-ierf-Butyl 1 -(3 -cyanoazetidin-l-yl)-3 -methyl- l-oxobutan-2- ylcarbamate; Method A:; To (i~)-2-(tert-Butoxycarbonylamino)-3-methylbutanoic acid (100 g, 460 mmol) in DCM (1.08 L) was added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (54.6 g, 46 mmol), lH-benzo[d][l,2,3]triazol-l-ol (6.22 g, 46.0 mmol), Et3N (64.2 mL, 460 mmol), and -((ethylimino)methylene)-N3,N3-dimethylpropane- 1 ,3 -diamine hydrochloride (97 g, 506 mmol). The resulting white suspension was stirred at room temperature for 3 hours. The reaction was subsequently quenched with water (360 mL). The organic layer was washed with water (360 mL), concentrated, and dried in a vacuum oven at 40C for 16 hours. The crude material was suspended in isopropyl acetate (360 mL) at 65C for 90 minutes. The suspension was cooled and stirred at room temperature for 1 hour. Hexanes (180 mL) were added to the suspension over a 15 minute period, and the reaction mixture was stirred for 2 hours at 0C. The solid was filtered and washed with isopropyl acetate/hexanes (1 :1, 100 mL) and dried in a vacuum oven at 40C for 16 hours to give the title compound as a white solid (119.2 g, 92%). 1H NMR (400 MHz, DMSO-d6) delta ppm 0.75-0.94 (m, 6H), 1.30-1.47 (m, 9H), 1.74-1.95 (m, 1H), 3.64 (m, J=8.0 Hz, 1H), 3.73-3.89 (m, 1H), 4.00 (ddd, J=12.3, 9.7, 6.1 Hz, 1H), 4.15 (dt, J=18.6, 9.3 Hz, 1H), 4.34 (dd, J=8.5, 5.9 Hz, 1H), 4.40-4.60 (m, 1H), 7.05 (dd, J=12.9, 8.3 Hz, 1H). [M+H] calc'd for C14H23N3O3, 282; found, 282.

Reference： [1]Patent: WO2012/78802,2012,A1 .Location in patent: Page/Page column 24-25

14
[ 345954-83-8 ]
[ 1382995-45-0 ]
[ 1382995-46-1 ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	Step 2. 1-[(3'-Acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-yl)carbonyl]azetidine-3-carbonitrile To a solution of 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylic acid (70 mg, 0.2 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (30 mg, 0.25 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.25 mmol) in N,N-dimethylformamide (0.42 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol). After being stirred at room temperature for 2 h, the mixture was diluted with ethyl acetate, washed with water, brine, dried and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (25 mg, 30% in 3 steps). LCMS calculated for C21H19ClFN2O3 (M+H)+: m/z=401.1. found: 401.1.

Reference： [1]Patent: US2012/157430,2012,A1 .Location in patent: Page/Page column 55

15
[ 345954-83-8 ]
[ 16937-99-8 ]
[ 1415969-22-0 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 345 - 356

16
[ 345954-83-8 ]
[ 91103-47-8 ]
[ 1334674-98-4 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 345 - 356

17
[ 345954-83-8 ]
[ 109-70-6 ]
[ 1422772-92-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1677 - 1692

18
[ 345954-83-8 ]
(3RS,4SR)-3-(3H-imidazo-[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanecarbaldehyde [ No CAS ]
[ 1428242-02-7 ]
[ 1428242-03-8 ]

Yield	Reaction Conditions	Operation in experiment
15%; 17%		To a vial charged with a scalemic mixture enriched, in (1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanecarbaldehyde and (1R,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanecarbaldehyde (0.350 g, 1.304 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.309 g, 2.61 mmol) was added MeOH (9 mL). The mixture was stirred at rt for about 1 h. Sodium cyanoborohydride (0.246 g, 3.91 mmol) was added in one portion. The mixture was stirred at rt for about 1 h. Solvent was removed under reduced pressure. The residue was purified by mass triggered HPLC (Table 1, method f). The desired fractions were concentrated under reduced pressure and the residue was purified by chiral chromatography (Table 2, Method 5) Detection methods were evaporative light scattering (ELSD) detection and optical rotation. The desired fractions were combined and concentrated under reduced pressure to yield 1-(((1R,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)methyl)azetidine-3-carbonitrile (0.0675 g, 15%). LC/MS (Table 1, Method b) Rt=1.40 min; MS m/z: 335 (M+H)+) and 1-(((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)methyl)azetidine-3-carbonitrile (0.0764 g, 17%) both as white solids. LC/MS (Table 1, Method b) Rt=1.38 min; MS m/z: 335 (M+H)+. Jak3 IC50=C

Reference： [1]Patent: US2013/72470,2013,A1 .Location in patent: Paragraph 0422-0424

19
[ 345954-83-8 ]
[ 45121-22-0 ]
[ 1426421-08-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;	Example 20.2-(6-Chloro-l -methyl- 1 H-indazol-3 -yl)-5H-pyrrolo [2,3 -b]pyrazine-7-carboxylic acid [(R)- 1 -(3 - cyano-azetidine- 1 -carbonyl)-prop l]-amideStep 1[(R)-l -(3 -C ano-azetidine- l-carbonyl)-propyl]-carbamic acid tert-butyl esterIn a round-bottomed flask Boc-D-2-aminobutyric acid (400 mg, 1.97 mmol) and azetidine-3- carbonitrile hydrochloride (373 mg, 3.15 mmol) were dissolved in DMF (9 ml). N,N- Diisopropylethylamine (1.0 ml, 5.73 mmol) was added followed by HATU (823 mg, 2.16 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2x). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to provide 410 mg (70%) of [(R)-l-(3-cyano-azetidine-l-carbonyl)-propyl]-carbamic acid tert-butyl ester white solid.

Reference： [1]Patent: WO2013/30138,2013,A1 .Location in patent: Page/Page column 92; 93

20
[ 345954-83-8 ]
[ 124655-17-0 ]
[ 1415969-22-0 ]

Yield	Reaction Conditions	Operation in experiment
458 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;	Example 43.2-(6-Chloro-l -methyl- 1 H-indazol-3 -yl)-5H-pyrrolo [2,3 -b]pyrazine-7-carboxylic acid [(R)- 1 -(3 - cyano-azetidine-1 -carbonyl)-2,2-dimethyl-propyl]-amideStep 1[(R)-l-(3-C ano-azetidine-l-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl esterA round-bottomed flask was charged with Boc-D-tert-leucine (300 mg, 1.3 mmol) and azetidine- 3-carbonitrile hydrochloride (231 mg, 1.95 mmol). DMF (6 ml) was added followed by N,N- diisopropylethylamine (0.68 ml, 3.9 mmol) and HATU (543 mg, 1.43 mmol). The light yellow solution was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2x). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 458 mg of [(R)-l-(3- cyano-azetidine-l-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a light yellow oil.

Reference： [1]Patent: WO2013/30138,2013,A1 .Location in patent: Page/Page column 133; 134

21
[ 345954-83-8 ]
C₂₄H₂₀ClN₅O₄ [ No CAS ]
C₂₈H₂₆ClN₇O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 100℃; for 18h;	Step 4: Intermediate 6009C (50 mg, 0.1 1 mmol) is charged in a round-bottom flask and suspended in EtOH (1 .0 mL). Diisopropylethylamine (48 mg, 0.26 mmol, 2.5 eq) and azetidine- 3-carbonitrile hydrochloride (Fluorochem) (19 mg, 0.16 mmol, 1 .5 eq) are added and the solution is heated at 100 C for 18 h. The solution is diluted with EtOAc and washed with brine (3x). The organic layer is dried over MgS04, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (EtOAc/hexanes) to provide intermediate 6009D.

Reference： [1]Patent: WO2013/152063,2013,A1 .Location in patent: Page/Page column 127-128

22
[ 345954-83-8 ]
C₃₄H₄₃F₃N₈O₅SSi [ No CAS ]
1-[2-[(1-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)pyridin-4-yl]methyl}azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.5 mg		Prepared according to the method of Example 1 using <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (13 mg, 0.1 1 mmol, Oakwood) and N,N-diisopropylethyamine (23 , 0.13 mmol) in the displacement step which was carried out at room temperature overnight, and the product was afforded as the free base (7.5 mg, 55%). 'H NMR (400 MHZ, d6-DMSO) delta 12.1 1 (br s, 1 H), 8.83 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.60 (d, = 3.6 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J= 3.6 Hz, 1H), 6.96 (s, 1H), 5.28 - 4.71 (m, 1 H), 3.66 (s, 2H), 3.56 - 3.46 (m, 3H), 3.42 (s, 2H), 3.38 - 3.24 (m, 2H), 3.09 - 2.95 (m, 2H), 2.81 (p, 7= 7.4 Hz, 1H), 2.73 - 2.56 (m, 2H), 2.40 - 2.27 (m, 2H), 2.23 - 2.08 (m, 2H), 2.08 - 1.93 (m, 2H), 1.76 - 1.59 (m, 2H). 19F NMR (376 MHz, de-DMSO) delta -67.38 (s). LCMS (M+H)+: 617.3.

Reference： [1]Patent: WO2013/173720,2013,A1 .Location in patent: Page/Page column 73; 74

23
[ 345954-83-8 ]
[ 1578244-55-9 ]
[ 1578244-83-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 135℃; for 8h;	The following Examples were prepared according to Method 5 (Example 54) above using 8-chloro-A/-(2-methoxy-4-(1 -methyl-1 H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidin-2-amine (Example 94) and the appropriate amine as described. The crude reaction residues were purified as above or according to one of the following methods: Method A: Silica gel column chromatography eluting with 0-5% or 0-10% MeOH in DCM. Method B: Silica gel column chromatography eluting with 0-5% MeOH in EtOAc. Method C: Silica gel column chromatography eluting with 0-70% EtOAc in cyclohexane followed by reverse phase preparative HPLC eluting with 10-90% MeOH in water (0.1 % formic acid). Method D: Silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane followed by a second chromatography eluting with either 0-5% or 0-20% MeOH in either DCM or EtOAc. Method E: Silica gel column chromatography eluting with between 0-20% MeOH in DCM. Method F: Elution through an SCX-2 column followed by silica gel column chromatography eluting with 0-5% MeOH in EtOAc. Method G: Elution through an SCX-2 column followed by silica gel column chromatography eluting with 1 -10% MeOH/aq NH3 (10/1 ) in DCM. Method I: Elution through an SCX-2 column using 1 M followed by 7M methanolic ammonia followed by trituration with MeOH. Method J: Elution through an SCX-2 column followed by silica gel column chromatography eluting with 0-10% EtOH in DCM. Method K: Trituration with ether. Method L: Elution thorugh an SCX column using 50% MeOH in chloroform followed by 50% chloroform in 7N NH3/MeOH.

Reference： [1]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 00387

24
[ 345954-83-8 ]
[ 108-12-3 ]
C₉H₁₄N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - 20℃;	To a stirred solution of isovaleric acid (0.90 g, 8.85 mmol) in DCM (20 mL) was added 0.1 mL of N,N-Dimethylformamide. The solution was cooled to 0C, followed by the addion of oxalyl chloride (1.45 g, 1 1.5 mmol). The reaction mixture was warmed to room temperature and stirred for 4.0 h. Then the solution was evaporated to remove the solvent at below 50C. The residue and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.94 g, 7.96 mmol) were dissolved in 20 mL DCM. The solution was cooled to -20C, followed by the addion of DIPEA (3.83 mL, 26.55 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The resultant was quenched by addition of saturated aqueous NaHC03. The mixture was extracted with DCM (3 X 100 mL), and the combined extracts were washed with brine, dried by Na2S04 and filtered, concentrated under vacuum at below 40C. The crude product was purified by flash chromatography (20% Petrolium ether/ethyl acetate) to give 833 mg of Compound 9a (Yield: 63%) as a light yellow oil. [M+H] found 167.

Reference： [1]Patent: WO2015/57695,2015,A1 .Location in patent: Paragraph 0271; 0272

25
[ 345954-83-8 ]
[ 106-93-4 ]
1-(2-bromoethyl)azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.2%	With caesium carbonate; In acetonitrile; at 20℃; for 18h;	A mixture of <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (1.51 g, 12.7 mmol) , 1, 2-dibromoethane (9 mL, 8.20 mmol) and cesium carbonate (8 g, 104 mmol) in acetonitrile (15 mL) was stirred at rt for 18 h. The reaction mixture was diluted with water (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM/MeOH (v/v) 40/1 to give a light yellow liquid product (1.16 g, 48.2) .[1878]MS (ESI, pos. ion) m/z: 189.05 [M+1]+.

Reference： [1]Patent: WO2016/615,2016,A1 .Location in patent: Paragraph 00745

26
[ 345954-83-8 ]
[ 589-87-7 ]
1-(4-bromophenyl)azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23.86%	With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In dimethyl sulfoxide; at 70℃; for 5h;	To a solution of 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol) in DMSO (16 mL) were added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (420 mg, 3.54 mmol) , cesium carbonate (1.7 g, 5.2 mmol) , N, N-dimethylglycine (400 mg, 3.80 mmol) and cuprous iodide (675 mg, 3.54 mmol) in turn. The mixture was stirred at 70 for 5 h and quenched with water (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 3/1 to give a light yellow solid product (200 mg, 23.86) .[1006]MS (ESI, pos. ion) m/z: 237.1, 238.9 [M+1]+.

Reference： [1]Patent: WO2016/615,2016,A1 .Location in patent: Paragraph 00537

27
[ 345954-83-8 ]
[ 640-68-6 ]
[ 479553-01-0 ]
(R)-N-(1-(3-cyanoazetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2%		The 1H- pyrrolo [2,3-b] pyridine-4-carboxylic acid (250mg, 1.54mmol) was dissolved in N, N- dimethylformamide (5mL) added successively HATU (879.6mg, 2.31mmol), diisopropylethyl amine (403muL, 2.3mmol) and D- valine (270.9mg, 2.31mmol), stirred at rt for 12h, and then continue to add HATU (879.6mg, 2.31mmol), DIPEA (403muL, 2.31mmol) and 3-cyano-ring butylamine hydrochloride (273mg, 2.31mmol), stirred at room temperature 12h, was added a saturated brine (10 mL) quenched and extracted with dichloromethane (15mL × 3), dried, concentrated and subjected to column chromatography separation (eluent: CH2Cl2/ MeOH (v / v) = 30/1), and then by preparative thin layer chromatography to give 10mg of white solid, yield: 2.0%.

Reference： [1]Patent: CN105566321,2016,A .Location in patent: Paragraph 0304; 0305; 0306; 0307; 0308

28
[ 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

29
[ 345954-83-8 ]
[ 1382981-73-8 ]
C₁₄H₁₅ClN₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃; for 16h;	Example 110 l-(2 3-chloro-lH^yrrolo[2,3-b]pyridin-5-yl)-6,6-dimethyl-8,9-dihydro-6H-[l,4]oxazino[4,3- e]purin-4-yl)azetidine-3-carbonitrile To a solution of 2,4-dichloro-6,6-dimethyl-8,9-dihydro-6H-[l,4]oxazino[4,3-e]purine (80.0 mg, 0.293 mmol) in N,N-dimethylformaldehyde (1 mL) was added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (34.7 mg, 0.293 mmol) and N,N-diisopropylethylamine (0.153 mL, 0.879 mmol). The reaction mixture was shaken at 70 C for 16 h and concentrated to dryness in vacuo.

Reference： [1]Patent: WO2016/142310,2016,A1 .Location in patent: Page/Page column 143

30
[ 345954-83-8 ]
[ 100-39-0 ]
[ 94985-26-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In acetonitrile; at 20℃;	To a solution of azetidine-3-carbonitrile, HC1 (1.5 g, 12.65 mmol) and (bromomethyl)benzene (1.503 mL, 12.65 mmol) in ACN (20 mL) was added TEA (5.29 mL, 38.0 mmol) and stirred at ft for overnight. The reaction mixture was thenconcentrated under vacuum and diluted with EtOAc (15 mL). The organic layer is then washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography afforded 1-benzylazetidine-3-carbonitrile (2.01 g, 92% yield) as a pale yellow solid. MS (ESI) m/z: 201.1 (M+H)t

Reference： [1]Patent: WO2017/19819,2017,A1 .Location in patent: Page/Page column 123

31
[ 345954-83-8 ]
4,6-diiodo-2-methoxypyrimidine [ No CAS ]
1-(6-iodo-2-methoxypyrimidin-4-yl)azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1h;	A solution of 4,6-diiodo-2-methoxypyrimidine (1.00 g, 2.76 mmol), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.52 g, 4.42 mmcl) and DIPEA (1.78 g, 13.8 mmcl) in NMP (5 mL) was heated to 100 C and stirred for 1 h. The mixture was partitioned with EtOAc (100 mL) and water (100 mL). The organic layer was washed with water (100 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by column (DCM) to give thetitle compound (600 mg, yield 69%) as a white solid.1H NMR (300 MHz, CDCI3): 6 6.36 (s, 1 H), 4.40-4.27 (m, 4H), 3.91 (s, 3H), 3.66-3.58 (m,1 H).

Reference： [1]Patent: WO2017/12576,2017,A1 .Location in patent: Page/Page column 133

32
[ 345954-83-8 ]
[ 58885-60-2 ]
tert-butyl 3-(3-cyanoazetidin-1-yl)propylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;Inert atmosphere;	Step 1 : tert-butyl 3-(3-cyanoazetidin-l-yl)propylcarbamate [00286] To a solution of tert-butyl 3 -oxopropyl carbamate (0.30 g, 1.73 mmol) in 1,2- dichloroethane (19 mL) was added <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (0.205 g, 1.73 mmol), followed by addition of NaBH(OAc)3 (0.55 g, 2.6 mmol). The reaction mixture was stirred at room temperature under argon overnight and a solution of saturated NaHC03 (20 mL) added. The organic phase was separated, and the aqueous phase was further extracted with CH2C12 (20 mL x 2). The combined organic phase was washed with saturated NaHC03 (20 mL) and brine (20 mL), dried over MgS04, and finally was concentrated under reduced pressure. Purification by silica-gel column chromatography with CH3OH/CH2Cl2/NH4OH (180:9: 1) yielded the desired product (0.24 g, 58 %) as a colorless oil.

Reference： [1]Patent: WO2016/196393,2016,A2 .Location in patent: Paragraph 00286

33
[ 345954-83-8 ]
[ 79099-07-3 ]
tert-butyl 4-(3-cyanoazetidin-1-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (1.00 g, 5.02 mmol) in methanol (10 mL) was added NaOAc (412 mg, 5.02 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (714 mg, 6.02 mmol). The mixture was stirred overnight at room temperature, then NaBH3CN (315 mg, 5.02 mmol) was added. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The residue was dissolved in EtOAc and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloride methane /methanol (95/5). This resulted in 1.41 g (crude) of tert-butyl 4- (3- cyanoazetidin-l-yl)piperidine- l-carboxylate as a white solid. LC/MS (Method I, ESI): [M+H]+= 266.4, RT= 0.71 min.

Reference： [1]Patent: WO2017/89390,2017,A1 .Location in patent: Page/Page column 103; 104

34
[ 345954-83-8 ]
[ 108-36-1 ]
1-(3-bromophenyl)azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 95℃; for 3h;Inert atmosphere;	To a degassed (argon, 10 mm) suspension of 1,3-dibromobenzene (2.98 g, 12.65 mmol, 1.5mL), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (1.0 g, 8.43 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.49 g, 0.84 mmol) and sodium tert-butoxide (3.2 g, 33.70mmol) in dry 1 ,4-dioxane (70 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.39 g,0.42 mmol). The reaction mixture was stirred at 95C for 3 h and was allowed to cool to room temperature. Water (20 mL) and ethyl acetate (100 mL) were added. Layers were separated and aqueous layer was extracted with ethyl acetate (2x50 mL). Combined organic extracts were dried with sodium sulfate and solvents were removed in vacuo. Purification by flashcolumn chromatography (Method L7; 500 g; heptane, 10%-30% ethyl acetate) afforded 1.25 g(5.28 mmol; 62% of theory) of 1-(3-bromophenyl)azetidine-3-carbonitrile.GC-MS (Method A) R1 = 4.87 mm; m/z = 236/238 M1H NMR (300 MHz, DMSO-d6, Method M2) 67.14 (t, J = 8.0 Hz, 1H), 6.97-6.82 (m, 1H), 6.66(t, J = 2.0 Hz, 1H), 6.51 -6.42 (m, 1H), 4.10 (dd, J = 8.4, 7.5 Hz, 2H), 3.99 (dd, J = 7.5, 5.4 Hz,2H), 3.90-3.77 (m, 1H).

Reference： [1]Patent: WO2017/178416,2017,A1 .Location in patent: Page/Page column 118; 119

35
[ 345954-83-8 ]
octan-3-yl 3-((3-chloro-2-fluoropyridin-4-yl)thio)propanoate [ No CAS ]
octan-3-yl 3-((3-chloro-2-(3-cyanoazetidin-1-yl)pyridin-4-yl)thio)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 60℃; for 6h;Sealed tube;	To a solution of octan-3-yl 3-((3-chloro-2-fluoropyridin-4-yl)thio)propanoate in DMA (862 mu.), was added <strong>[345954-83-8]3-azetidinecarbonitrile hydrochloride</strong> (152 mg, 1.29 mmol) and DIPEA (298 mu^, 1.72 mmol). Reaction mixture was stirred in a capped vial at 60 C for 6 hours. The resulting reaction mixture was concentrated in vacuo and the residue, octan-3-yl 3- ((3-chloro-2-(3-cyanoazetidin-l-yl)pyridin-4-yl)thio)propanoate, was carried onto the next step without any further purification and assuming quantitative yield. LC-MS (ESI) m/z: [M + H] calculated for C20H28CIN3O2S : 410.17; found 409.9

Reference： [1]Patent: WO2018/13597,2018,A1 .Location in patent: Paragraph 0629

36
[ 345954-83-8 ]
(R)-2-(7,8-dimethoxy-5-oxo-1,5-dihydro-4H-benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-4-yl)butanoic acid [ No CAS ]
(R)-1-(2-(7,8-dimethoxy-5-oxo-1,5-dihydro-4H-benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-4-yl)butanoyl)azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		Compound 17k (30 mg, 0.08 mmol) was added to a solution of HATU (30 mg, 0.08 mmol) and DIPEA (30 mg 0.24 mmol) in DMF (4 mL). After stirring for 5 min, <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (13 mg, 0.09 mmol) was added to the mixture. The mixture was stirred at room temperature for 24 h and then the reaction was quenched with saturated ammonium chloride (15 mL). The solution was extracted with EtOAc (3*15 mL). The combined organic layer was washed with saturated sodium bicarbonate (15 mL), water and brine and dried using anhydrous sodium sulfate. The residue obtained after evaporation of the organic layer was purified using silica gel column chromatography (CH2Cl2:MeOH 9.8:0.2) to give compound 20a as a white solid (28 mg, 60%): mp 257-260 C. IR (thin film) 3313, 2957, 1649, 1609, 1572, 1514, 1464, 1421, 1385, 1310, 1262, 1209, 1152, 1040 cm-1; 1H NMR (500 MHz, DMSO) delta 12.26 (s, 1H), 9.47 (s, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.06 (s, 1H), 5.77 (s, 1H), 4.08 (s, 3H), 3.99 (t, J=8.9 Hz, 1H), 3.94 (s, 3H), 3.88 (d, J=8.4 Hz, 1H), 3.54 (s, 1H), 2.47-2.36 (m, 2H), 2.21 (d, J=7.6 Hz, 1H), 0.81 (t, J=7.6 Hz, 3H); MALDIMS m/z (rel intensity) 446 (MH)+; HRESIMS calcd for C24H23N5O4 (MH)+ 446.1823, found 446.1828; C18 HPLC purity, 96.72% (MeOH-H2O, 85:15).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 10440 - 10462
[2]Patent: US2019/127377,2019,A1 .Location in patent: Paragraph 0183

37
[ 345954-83-8 ]
(R)-2-(7,8-dimethoxy-5-oxo-1,5-dihydro-4H-benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-4-yl)-3-methylbutanoic acid [ No CAS ]
(R)-1-(2-(7,8-dimethoxy-5-oxo-1,5-dihydro-4H-benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-4-yl)-3-methylbutanoyl)-azetidine-3-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 10440 - 10462

38
[ 345954-83-8 ]
[ 4025-64-3 ]
3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
475 g	With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;	Step 2: Preparation of 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic Acid, Intermediate 3.1 To a suspension of <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (275 g, 2.32 mol) in DCM (2.8 L) at 0 C. was added triethylamine (1.3 L, 9.28 mol). The mixture was stirred for 10 min at 0 C. then 3-(chlorosulfonyl)benzoic acid (563 g, 2.56 mol, Arbor Chemicals) was slowly added in portions over the period of 1 h (Caution: Exotherm). The reaction mixture was stirred at rt for 3 h and then cooled to 0 C. and quenched with 1N aqueous HCl (4 L). The precipitate was collected by filtration, washed with water (2 L) and dried under vacuum to give 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid (475 g) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 13.65 (bs, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.26 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.1, 7.8 Hz, 1H), 4.02 (dd, J=8.5, 5.8 Hz, 2H), 3.89 (dd, J=8.5, 5.8 Hz, 2H), 3.68-3.60 (m, 1H). LCMS-ESI (NEG) m/z: 265.0 (M-H)-.

Reference： [1]Patent: US2019/77793,2019,A1 .Location in patent: Paragraph 0205

39
[ 345954-83-8 ]
[ 912577-43-6 ]
3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
349 mg	With triethylamine; In dichloromethane; at 20℃; for 2h;	3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic Acid, Intermediate 6.0 A 40 mL pressure vial was charged with 3-(chlorosulfonyl)-5-fluorobenzoic acid (500 mg, 2.10 mmol, Enamine) and <strong>[345954-83-8]3-cyanoazetidine hydrochloride</strong> (497 mg, 4.19 mmol, Synthonix, Inc.). To that mixture was added DCM (10.5 mL) followed by triethylamine (1.17 mL, 8.38 mmol). After 2 hours at rt, the mixture was transferred to a separatory funnel and the pH was adjusted to ?10 using saturated aqueous solution NaHCO3. The layers were separated and the aqueous was carefully acidified with concentrated HCl (pH=3) upon which a white solid precipitated from the solution. The solid was collected by filtration and lyophilized to give 3-((3-cyanoazetidin-1-yl)sulfonyl)-5-fluorobenzoic acid (349 mg) as a white solid. 1H NMR (500 MHz, DMSO-d6) delta ppm 3.64 (tt, J=8.94, 5.86 Hz, 1H) 3.96 (dd, J=8.69, 5.84 Hz, 2H) 4.06 (t, J=8.82 Hz, 2H) 8.03 (dt, J=7.85, 1.98 Hz, 1H) 8.07-8.11 (m, 2H) 13.92 (br s, 1H). LCMS-ESI (POS.) m/z: 285.2 (M+H)+.

Reference： [1]Patent: US2019/77793,2019,A1 .Location in patent: Paragraph 0214-0215

40
[ 345954-83-8 ]
2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole [ No CAS ]
1-[7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); caesium carbonate; at 90℃; for 16h;Inert atmosphere;	A mixture of (5S,7S)-2-bromo-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole (200 mg, 0.71 mmol), [2-(2-aminophenyl)phenyl]palladium; dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane; methanesulfonate (60 mg, 0.07 mmol), cesiumcarbonate (693 mg, 2.13 mmol) and <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (168 mg, 1.42 mmol) was stirred at 90 C for 16 h under nitrogen atmosphere. The mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by RP-HPLC (acetonitrile 30-60% / 0.05% ammonia hydroxide in water) to afford l-[(5S,7S)-7-fluoro- 5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]azetidine-3-carbonitrile (15.3 mg, 8%) as a red solid. XH NMR (400 MHz, CDCI3) delta 7.42 - 7.35 (m, 3H), 7.23 - 7.21 (m, 2H), 5.98 - 5.81 (m, 1H), 5.30 - 5.29 (m, 1H), 4.35 - 4.22 (m, 4H), 3.63 - 3.51 (m, 2H), 2.81 - 2.70 (m, 1H). LCMS RT = 1.852 min, m/z = 283.9 [M+H]+. LCMS (10 to 80% acetonitrile in water + 0.03% trifluoacetic acid over 7 mins) retention time 1.852 min, ESI+ found [M+H] = 283.9.

Reference： [1]Patent: WO2019/72942,2019,A1 .Location in patent: Page/Page column 125

41
[ 345954-83-8 ]
2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-difluoro-1-H-benzo[d]imidazol-1-yl)acetic acid [ No CAS ]
tert-butyl ((3R,4R)-1-(1-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dimethyl sulfoxide; at 20℃;	A solution of 2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-d^ benzo d\|imidazol-1-yl)acetic acid (0.015 g, 0.035 mmol), <strong>[345954-83-8]3-cyanoazetidine hydrochloride</strong> (4.15 mg, 0.035 mmol) and 2-(1H-benzotriazole-1-yl)-l,l,3,3-tetramethyluronium hexaflurophosphate (0.013 g, 0.035 mmol) in dimethyl sulfoxide (0.117 ml) and DIPEA (0.024 ml, 0.140 mmol) was shaken at ambient temperature. The reaction mixture was purified by reverse phase HPLC to obtain tert-butyl {( 3 .. R - j -i j -(2-(3-cyanoazetidin-1-yl -2-oxoethyl)-5,6-diyl)carbamate. MS: (ESI pos. ion) m/z: 493.2 fM+1].

Reference： [1]Patent: WO2019/79578,2019,A1 .Location in patent: Page/Page column 286

42
[ 345954-83-8 ]
N-[(1R)-8-[8-(2,3-dichlorophenyl)-7-methylimidazo[1,2-c]pyrimidin-5-yl]-3-oxo-8-azaspiro[4.5]decan-1-yl]-2-methylpropane-2-sulfinamide [ No CAS ]
N-[(1R)-3-(3-cyanoazetidin-1-yl)-8-[8-(2,3-dichlorophenyl)-7-methylimidazo[1,2-c]pyrimidin-5-yl]-8-azaspiro[4.5]decan-l-yl]-2-methylpropane-2-sulfinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	To a solution of N-[(li?)-8-[8-(2,3-dichlorophenyl)-7-methylimidazo[l,2- c]pyrimidin-5-yl]-3-oxo-8-azaspiro[4.5]decan-l-yl]-2-methydpropane-2-sulfinamide (20 mg, 36 mhio, 1 eq.), N,N-diisopropylethylamine (7 mg), and azetidine-3-carbonitriie hydrochloride (6 mg, 47 umol, 1.3 eq.) in DMC (0.3 mL) was added sodium triacetoxyborohydnde (12 rng, 55 mhio) at room temperature. The reaction was stirred at room temperature for 2 h and then filtered. The filtrate was concentrated under reduced pressure and the remaining residue was purified by column chromatography to afford crude N-[(ii?)-3-(3-cyanoazetidin-l-yl)~8-[8-(2,3- dichlorophenyl)-7-methylimidazo[l ,2-c]pyrimidin-5-yl]-8-azaspiro[4.5]decan-l -yl]-2- methylpropane-2-sulfinamide. To a solution of this material in MeOH (0.3 mL) was added HCL (4M solution in dioxane, 0.1 mL) dropwise at room temperature. The mixture was let stirred at room temperature for 2 h. The solution was concentrated under reduced pressure and purified by reverse phase HPLC to afford l-[(4R)-4-amino-8-[8-(2,3-dichlorophenyl)-7-methylimidazo[l ,2- c]pyrimidin-5-yl]-8-azaspiro[4.5]decan-2-yl]azetidine-3-carbonitrile (3 mg) as a white solid.jH NMR (500 MHz, Methanol-A) d 8.36 (s, 3H), 7.74 - 7.70 (m, 1 1 1 ). 7.68 (dd, .1 8 1. 1.5 Hz,1 1 1 ). 7.48 (d, J = 1.5 Hz, i l l ). 7.45 (t, J = 7.9 Hz, 1 I ) 7 33 (dd, I = 7 7, 1.6 Hz, i l l ). 3.95 (d, .1 = 10.3 Hz, I I I). 3.88 (d, J = 9.0 Hz, 1 1 1). 3.62 Lid. J = 19.9, 6.5 Hz, 21 1 ). 3.49 - 3.38 (m, 31 1 ). 3.24 (t, J = 12.6 Hz, 3H), 3.12 (dq, J = 6.7, 3.3 Hz, I I I). 2.26 (dd, J = 14.0, 6.5 Hz, }. 2.21 (s, 3H), 1.99 (dtd, J = 36.6, 13.2, 12.5, 5.7 Hz, 31 1). 1.83 (d, J = 12.8 Hz, H i ). 1.76 (d, J = 13.8 Hz, 1 1 1 ). 1.70 (d, J = 14.0 Hz, 21 1). LC-MS (ESI): m/z [M + i f ] calculated for C26H30CI2N? 510.2; found 510.5.

Reference： [1]Patent: WO2019/118909,2019,A1 .Location in patent: Paragraph 00435

43
[ 345954-83-8 ]
2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzoic acid [ No CAS ]
1-[2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzoyl]azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of Int 94 (43 mg, 0.090 mmol, 1 eq.) in dry DMSO (0.5 mL) is added HATU (41 mg, 0.179 mmol, 2 eq.) and DIPEA (47 pL, 0.269 mmol, 3 eq.). The mixture is stirred at RT for 5 min and then <strong>[345954-83-8]3-cyanoazetidine hydrochloride</strong> (CAS 345954-83-8; 21 mg, 0.178 mmol, 2.0 eq.) is added. The mixture is stirred at RT for 2 h and then purified by preparative HPLC to afford Cpd 357.

Reference： [1]Patent: WO2019/238424,2019,A1 .Location in patent: Paragraph 0346; 0347

44
[ 345954-83-8 ]
5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one [ No CAS ]
1-[1-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]-6-oxo-pyridazin-4-yl]azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium carbonate; In dimethyl sulfoxide; acetonitrile; at 70℃; for 18h;	General procedure: To a stirred suspension of 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4- yl]methyl]pyridazin-3-one (building block A, 300 mg, 0.947 mmol) and (R)-3- hydroxypyrrolidine (0.14 mL, 1.73 mmol) in DMSO (0.5 mL) and acetonitrile (3 mL) was added potassium carbonate (393 mg, 2.84 mmol) Then the reaction mixture was stirred at 70 C for 18 h. After cooling to room temperature the reaction mixture was diluted with EtOAc (80 mL) was washed three times with water (10 mL) and brine (10 mL). The aqueous layers were back extracted twice with EtOAc (80 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2CI2) afforded the title compound (341 mg, 93 %) as an off-white foam. MS (ESI): 368.2 ([M+H]+).

Reference： [1]Patent: WO2019/238633,2019,A1 .Location in patent: Page/Page column 142; 178

45
[ 6945-67-1 ]
[ 345954-83-8 ]
1-(4-nitropyridin-2-yl)azetidine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1,4-dioxane; at 100℃;	The <strong>[6945-67-1]2-bromo-4-nitropyridine</strong> (1.00g, 4.93mmol),3-acetonitrile cyclobutylamine hydrochloride(759.30mg, 6.40mmol) and cesium carbonate (4.82g, 14.78mmol) were placed in the reaction flask,50mL 1,4-dioxane was added, and the reaction was carried out at 100C overnight.After LC-MS detection, the reaction was completed, cooled to room temperature, filtered to obtain a filtrate, concentrated under reduced pressure, and purified by column chromatography to obtain the title compound.

Reference： [1]Patent: CN111196804,2020,A .Location in patent: Paragraph 0545; 0547-0549

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Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 345954-83-8 ] {[proInfo.proName]}

Quality Control of [ 345954-83-8 ]

Related Doc. of [ 345954-83-8 ]

Product Details of [ 345954-83-8 ]

Calculated chemistry of [ 345954-83-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 345954-83-8 ]

Application In Synthesis of [ 345954-83-8 ]

[ 345954-83-8 ] Synthesis Path-Upstream 1~4

[ 345954-83-8 ] Synthesis Path-Downstream 1~45

Similar Product of [ 345954-83-8 ]

Related Functional Groups of [ 345954-83-8 ]

Nitriles

Related Parent Nucleus of [ 345954-83-8 ]

Aliphatic Heterocycles

Azetidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Similar Product of
[ 345954-83-8 ]

Related Functional Groups of
[ 345954-83-8 ]

Related Parent Nucleus of
[ 345954-83-8 ]