94268-29-8|4-(Azetidin-3-yl)benzonitrile hydrochloride| Ambeed

Structure of 94268-29-8

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Quality Control of [ 94268-29-8 ] Purity: 95% SDS Specification

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Product Details of [ 94268-29-8 ]

CAS No. :	94268-29-8
Formula :	C₁₀H₁₁ClN₂
M.W :	194.66
SMILES Code :	N#CC1=CC=C(C2CNC2)C=C1.[H]Cl
MDL No. :	MFCD08460706
InChI Key :	OUCUIYOUNRIDRM-UHFFFAOYSA-N
Pubchem ID :	55254991

Safety of [ 94268-29-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of [ 94268-29-8 ]

* 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.

Downstream synthetic route of [ 94268-29-8 ]

[ 94268-29-8 ] Synthesis Path-Downstream 1~34

1
[ 1533440-48-0 ]
[ 94268-29-8 ]
[ 1533435-87-8 ]

Yield	Reaction Conditions	Operation in experiment
2.8 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 7. 4-(l-(3-(4-Chloro-2-methyI-lH-imidazol-5-yl)-4- methylbenzoyl)azetidin-3-yl)benzonitrile. A mixture of 3-(5-chloro-2-methyl-lH-imidazol- 4-yl)-4-methylbenzoic acid (compound 7.3, -0.038 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 8.6 mg, 0.044 mmol), EDCI (12 mg, 0.063 mmol), HOBt (8 mg, 0.044 mmol) and DIEA (28 mu, 0.16 mmol) in DMF (1 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with brine (how much), dried (MgS04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (8 % MeOH in DCM) to yield the title compound as a foam (2.8 mg, 19% over 2 steps), m/z (ES+) 391 (M+H)+. NMR (400 MHz, CDC13) delta 10.62 (s, 1H), 7.69 (d, J= 8.3 Hz, 2H), 7.54 - 7.40 (m, 3H), 7.37 (d, J= 1.9 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 4.80-4.58 (m, 2H), 4.41 - 4.19 (m, 2H), 4.03-3.92 (m, 1H), 2.49 (s, 3H), 2.32 (s, 3H).

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 78.

2
4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoic acid hydrochloride [ No CAS ]
[ 94268-29-8 ]
[ 1533436-77-9 ]

Yield	Reaction Conditions	Operation in experiment
2.2 mg	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4.0h;	Compound 82. 4-(l-(4-Cyclobutyl-2-methyl-5-(6-methyl-l,4,5,6,7,8- hexahydroimidazo[4,5-i ]azepin-2-yl)benzoyl)azetidin-3-yl)benzonitrile. Into a 100-mL round-bottom flask, was placed a mixture of 4-cyclobutyl-2-methyl-5-(6-methyl-l ,4,5,6,7,8- hexahydroimidazo[4,5-i ]azepin-2-yl)benzoic acid (compound 82.9, 40 mg, 0.12 mmol), EDC FontWeight="Bold" FontSize="10" HC1 (45.4 mg, 0.24 mmol, 2.00 equiv), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 23 mg, 0.12 mmol) in N,N- dimethylformamide (5 mL). The resulting solution was stirred for 4 h at room temperature then quenched by the addition of water/ice (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were washed with brine (2 x 10 mL). The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure to yield the crude product which was purified by Prep-HPLC using the following conditions (1-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP 18 OBD Column, 5 urn, 19* 150 mm; mobile phase, WATER WITH 0.03% NH40H and CH3CN (30% CH3CN up to 43% in 8 min, up to 100% in 4 min, down to 30% in 2 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing clean product were combined to yield 2.2 mg (4%) of the title compound as a white 480 (M+H)+.

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 154; 155.

3
[ 94268-29-8 ]
5-formyl-2,4-dimethylbenzoic acid [ No CAS ]
[ 1533441-23-4 ]

Yield	Reaction Conditions	Operation in experiment
54%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3.0h;	Compound 151.4. 4-(l-(5-Formyl-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. Into a 50-mL round-bottom flask, was placed a solution of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3, 500 mg, 2.81 mmol) in DCM (10 mL). <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 545 mg, 2.80 mmol), DIEA (1.4 mL, 8.41 mmol) and HBTU (1.60 g, 4.22 mmol) were added. The reaction mixture was stirred for 3h at room temperature. The reaction mixture was diluted with 150 mL of EtOAc, then washed with 2 x 50 mL of NH4C1 (sat.) and 1 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to furnish 480 mg (54%) of the title compound as a white solid.
54%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3.0h;	Compound 151.4. 4-(l-(5-Formyl-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile. Into a 50-mL round-bottom flask, was placed a solution of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3, 500 mg, 2.81 mmol) in DCM (10 mL). <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 545 mg, 2.80 mmol), DIEA (1.4 mL, 8.41 mmol) and HBTU (1.60 g, 4.22 mmol) were added. The reaction mixture was stirred for 3h at room temperature. The reaction mixture was diluted with 150 mL of EtOAc, then washed with 2 x 50 mL of NH4C1 (sat.) and 1 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to furnish 480 mg (54%) of the title compound as a white solid.

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 187.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 202.

4
[ 94268-29-8 ]
5-formyl-2,4-dimethylbenzoic acid [ No CAS ]
[ 1533437-35-2 ]

References: [1]Patent: WO2014/8197,2014,A1 .

5
[ 1533441-29-0 ]
[ 94268-29-8 ]
[ 1533437-50-1 ]

Yield	Reaction Conditions	Operation in experiment
22%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 159. 4-(l-(5-(2-Isopropyl-5-methyI-lH-imidazol-4-yl)-2,4- dimethylbenzoyl)azetidin-3-yl)benzonitrile. The mixture of 5 -(2-isopropy 1-5 -methyl- 1H- imidazol-4-yl)-2, 4-dimethylbenzoic acid (compound 159.3, 250 mg, 0.92 mmol), 4- (azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 195 mg, 1.0 mmol), EDCI (264 mg, 1.4 mmol), HOBt (170 mg, 1.0 mmol) and DIEA (640 mu, 3.7 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. The reaction was diluted with saturated NaHC03 and extracted with EtOAc (60 mL). The organic phase was washed with brine (3 X 20 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane and lyophilized to give 85 mg (22%) of the title compound as a white solid, m/z (ES+) 413 (M+H)+.
22%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 159. 4-(l-(5-(2-Isopropyl-5-methyl-lH-imidazol-4-yl)-2,4- dimethylbenzoyl)azetidin-3-yl)benzonitrile. The mixture of 5-(2-isopropyl-5-methyl-lH- imidazol-4-yl)-2, 4-dimethylbenzoic acid (compound 159.3, 250 mg, 0.92 mmol), 4- (azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 195 mg, 1.0 mmol), EDCI (264 mg, 1.4 mmol), HOBt (170 mg, 1.0 mmol) and DIEA (640 mu, 3.7 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. The reaction was diluted with saturated NaHCC>3 and extracted with EtOAc (60 mL). The organic phase was washed with brine (3 X 20 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane and lyophilized to give 85 mg (22%) of the title compound as a white solid m/z (ES+) 413 (M+H)+.

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 196.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 211.

6
[ 1533441-31-4 ]
[ 94268-29-8 ]
[ 1533437-53-4 ]

Yield	Reaction Conditions	Operation in experiment
42%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 164. 4-(l-(2,4-DimethyI-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitriIe. The mixture of 2,4-dimethyl-5-(5- methyl-2-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-4-yl)benzoic acid (compound 164.2, 157 mg, 0.5 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 126 mg, 0.65 mmol), EDCI (143 mg, 0.75 mmol), HOBt (93 mg, 0.55 mmol) and DIEA (345 xh, 2.00 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc (30 mL). The organic phase was washed with saturated NaHC03 (10 mL), brine (3 X 20 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by preparative TLC with 5% methanol in dichloromethane and lyophilized to give 95 mg (42%) of the title compound as a white solid. m/z
42%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 164. 4-(l-(2,4-Dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)- lH-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 2,4-dimethyl-5-(5- methyl-2-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-4-yl)benzoic acid (compound 164.2, 157 mg, 0.5 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 126 mg, 0.65 mmol), EDCI (143 mg, 0.75 mmol), HOBt (93 mg, 0.55 mmol) and DIEA (345 mu, 2.00 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc (30 mL). The organic phase was washed with saturated NaHCC>3 (10 mL), brine (3 X 20 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by preparative TLC with 5% methanol in dichloromethane and lyophilized to give 95 mg (42%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+.

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 197; 198.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 212; 213.

7
[ 1533441-32-5 ]
[ 94268-29-8 ]
[ 1533437-60-3 ]

Yield	Reaction Conditions	Operation in experiment
12%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 171. 4-(l-(2,4-Dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yI)-lH- imidazoI-4-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 2,4-dimethyl-5-(5- methyl-2-(tetrahydrofuran-3-yl)-lH-imidazol-4-yl)benzoic acid (compound 171.2, 100 mg, 0.30 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 71 mg, 0.37 mmol), EDCI (95 mg, 0.50 mmol), HOBt (20 mg, 0.10 mmol) and DIEA (207 mu,, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHC03 (10 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (3 X 10 mL), dried over MgS04 and concentrated under reduce pressure. The residue was purified by preparative TLC with 6 % methanol in dichloromethane and lyophilized to give 16 mg (12%) of the title compound as a white s .
12%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 171. 4-(l-(2,4-Dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yl)-lH- imidazol-4-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 2,4-dimethyl-5-(5- methyl-2-(tetrahydrofuran-3-yl)-lH-imidazol-4-yl)benzoic acid (compound 171.2, 100 mg, 0.30 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 71 mg, 0.37 mmol), EDCI (95 mg, 0.50 mmol), HOBt (20 mg, 0.10 mmol) and DIEA (207 mu, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHCC>3 (10 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (3 X 10 mL), dried over MgS04 and concentrated under reduce pressure. The residue was purified by preparative TLC with 6 % methanol in dichloromethane and lyophilized to give 16 mg (12%) of the title compound as a white solid. m/z (ES+) 441 (M+H)+.

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 201.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 216.

8
[ 1533441-45-0 ]
[ 94268-29-8 ]
[ 1533441-46-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 182.3. tert-Butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-l-carbonyl)-2- methylphenyl)-5-methyl-lH-imidazol-2-yI)piperidine-l-carboxylate. A mixture of 3-(2-(l- (tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-lH-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2, 506 mg), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 296 mg, 1.52 mmol), EDCI (315 mg, 1.65 mmol), HOBt (107 mg, 0.64 mmol) and DIEA (877 iL, 5.08 mmol) in DMF (25 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHC03 (20 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (3 X 10 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane to give 476 mg (69%) of the title
69%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 182.3. tert-Butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-l-carbonyl)-2- methylphenyl)-5-methyl-lH-imidazol-2-yl)piperidine-l-carboxylate. A mixture of 3 -(2-( 1 - (tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-lH-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2, 506 mg), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 296 mg, 1.52 mmol), EDCI (315 mg, 1.65 mmol), HOBt (107 mg, 0.64 mmol) and DIEA (877 mu, 5.08 mmol) in DMF (25 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHC( (20 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (3 X 10 mL), dried over MgS04 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane to give 476 mg (69%) of the title compound as a foam. m/z (ES+) 540 (M+H)+

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 210; 211.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 225; 226.

9
tert-butyl-3-(4-cyanophenyl)azetidine-1-carboxylate [ No CAS ]
[ 94268-29-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1.5h;	Compound 5.2. 4-(Azetidin-3-yl)benzonitriIe hydrochloride. tert-Butyl 3-(4- cyanophenyl)azetidine-l -carboxylate (compound 5.1, 100 mg, 0.387 mmol) was added to a 4-mL vial. HC1 in dioxane (4 M, 500 mu,, 2 mmol) was added and the unsealed mixture was stirred at room temperature for 1 .5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM and concentrated under reduced pressure. This was repeated with DCM twice to chase off any excess HC1 to yield the title compound as a white powder (80 mg, over theory), m/z (ES+) 159 (M+H)+.
	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1.5h;	Compound 5.2. 4-(Azetidin-3-yl)benzonitrile hydrochloride.tert-Butyl 3-(4- cyanophenyl)azetidine-l-carboxylate (compound 5.1, 100 mg, 0.387 mmol) was added to a 4-mL vial. HCI in dioxane (4 M, 500 mu, 2 mmol) was added and the unsealed mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM and concentrated under reduced pressure. This was repeated with DCM twice to chase off any excess HCl to yield the title compound as a white powder (80 mg, over theory), m/z (ES+)159 (M+H) .
800 mg	With hydrogenchloride; In ethyl acetate; at 26℃; for 2.0h;	To a solution of Intermediate 34 (1.1 g, 4.258 mmol) in EtOAc (8 mL) was added HCI 4M in EtOAc (SYMAX, 8 mL) at 0 C. The reaction mixture was allowed to 26 C and stirred for 2 h at the same temperature. The reaction mixture was concentrated under reduced pressure, the residue was washed with diethyl ether (50 mL) and dried under vacuum to yield the title compound (800 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-c/6) delta ppm: 9.45 (br s, 1 H), 9.18 (br s, 1 H), 7.88 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 4.34-4.20 (m, 3H), 4.13- 4.01 (m, 2H). [ES+ MS] m/z 159 (MH+).

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 70; 71.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 85; 86.
[3]Patent: WO2019/34702,2019,A1 .Location in patent: Page/Page column 45.

10
[ 126747-14-6 ]
[ 94268-29-8 ]

References: [1]Patent: WO2014/8197,2014,A1 .

11
[ 94268-29-8 ]
[ 1533437-71-6 ]

References: [1]Patent: WO2014/8197,2014,A1 .

12
[ 94268-29-8 ]
[ 1533441-47-2 ]

References: [1]Patent: WO2014/8197,2014,A1 .

13
[ 94268-29-8 ]
[ 1533437-72-7 ]

References: [1]Patent: WO2014/8197,2014,A1 .

14
[ 94268-29-8 ]
[ 1533437-73-8 ]

References: [1]Patent: WO2014/8197,2014,A1 .

15
[ 94268-29-8 ]
[ 1533440-44-6 ]
[ 1533435-85-6 ]

Yield	Reaction Conditions	Operation in experiment
45%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 5. 4-(l-(3-(2,4-Dimethyl-lH-imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile. To a mixture of 3-(2,4-dimethyl-lH-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7, 0.484 g, 2.10 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 0.41 g, 2.10 mmol), EtaOmicronBetaTau (0.085 g, 7.40 mmol) and EDCI (0.603 g, 3.15 mmol) in DMF (8 mL) was added DIEA (1.09 mL, 6.3 mmol). The mixture was stirred at room temperature for 16 hours, then partitioned between EtOAc (300 mL) and water (30 mL). The organic layer was washed with brine (3 x 30 mL) and the combined aqueous phases were back extracted with EtOAc (2 x 50 mL). All organic extracts were combined, dried (MgS04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc to 5% MeOH in EtOAc) to yield the title compound as a white solid (0.35g, 45%). m/z (ES+) 371 (M+H)+. NMR (400 MHz, CDC13) delta 7.66 (d with fine str., J = 8.4 Hz, 2H), 7.54-7.48 (m, 2H), 7.44 (d with fine str., J = 8.2 Hz, 2H), 7.30 (d, J = 7.9 Hz, 1 H), 4.77-4.56 (m, 2H), 4.35-4.18 (m, 2H), 3.97-3.87 (m, 1 H), 2.38 (s, 3H), 2.30 (s, 3H), 2.10 (s, 3H).
45%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 5. 4-(l-(3-(2,4-Dimethyl-lH-imidazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile. To a mixture of 3-(2,4-dimethyl-lH-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7, 0.484 g, 2.10 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 0.41 g, 2.10 mmol), EtaOmicronBetaTau (0.085 g, 7.40 mmol) and EDCI (0.603 g, 3.15 mmol) in DMF (8 mL) was added DIEA (1.09 mL, 6.3 mmol). The mixture was stirred at room temperature for 16 hours, then partitioned between EtOAc (300 mL) and water (30 mL). The organic layer was washed with brine (3 x 30 mL) and the combined aqueous phases were back extracted with EtOAc (2 x 50 mL). All organic extracts were combined, dried (MgS04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc to 5% MeOH in EtOAc) to yield the title compound as a white solid (0.35g, 45%). m/z (ES+) 371 (M+H)+. XH NMR (400 MHz, CDC13) delta 7.66 (d with fine str., J= 8.4 Hz, 2H), 7.54-7.48 (m, 2H), 7.44 (d with fine str., J= 8.2 Hz, 2H), 7.30 (d, J= 7.9 Hz, 1H), 4.77-4.56 (m, 2H), 4.35-4.18 (m, 2H), 3.97-3.87 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.10 (s, 3H).

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 73; 74.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 88; 89.

16
[ 1533440-45-7 ]
[ 94268-29-8 ]
[ 1533435-89-0 ]

References: [1]Patent: WO2014/8197,2014,A1 .

17
[ 1533440-45-7 ]
[ 94268-29-8 ]
[ 1533435-86-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-d6-formamide; at 20℃; for 18.0h;	Compound 6. 5-(3-(4-Cyanophenyl)azetidine-l-carbonyl)-2-cyclobutyl-4- methylbenzamide. To a 4-mL vial was added <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 27 mg, -90% pure, 0.13 mmol), HOBt (20 wt % H20)(22 mg, 0.13 mmol), EDC (27 mg, 0.14 mmol). A solution of 5-carbamoyl-4-cyclobutyl-2-methylbenzoic acid (compound 6.5, 28 mg, 0, 12 mmol) in DMF (500 mu,) was added followed by DIEA (83 mu,, 0.48 mmol). The mixture was sealed and stirred at room temperature for 18 hours. Additional amine (3 mg, ~0.015 mmol) and EDC (5 mg, -0.026 mmol) were added and the mixture was stirred at room temperature for an additional 27 hours. The mixture was diluted with ethyl acetate (5 mL) and washed with brine (8 mL). The aqueous was extracted with ethyl acetate (2 mL) and the combined organics was washed with brine, 1 M NaH2P04, saturated NaHC03 and brine (7 mL each). The product began precipitating out of solution after the final brine wash, so the organics was diluted with DCM (3 mL) and MeOH (-200 muL). The organics was dried (Na2S04), filtered, and concentrated under reduced pressure. The crude product was triturated with Et20 (1.5 mL), filtered, and washed with Et20 (0.5 mL) to yield the title compound as an off white powder (41.4 mg, 92%). m/z (ES+) 374 (M+H)+. NMR (400 MHz, CDC13): delta 7.67 (d with fine str., J= 8.4 Hz, 2H), 7.40 (d with fine str., J= 8.4 Hz, 2H), 7.32 (s, 1 H), 7.25 (s, 1H), 5.79 (br s, 1H), 5.70 (br s, 1H), 4.67-4.57 (m, 1H), 4.39-4.30 (m, 1 H), 4.28-4.18 (m, 1H), 4.00-3.86 (m, 3H), 2.46 (s, 3H), 2.42-2.31 (m, 2H), 2.19-1.96 (m,
92%	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; at 20℃; for 45.0h;Sealed tube;	Compound 6. 5-(3-(4-Cyanophenyl)azetidine-l-carbonyl)-2-cyclobutyl-4- methylbenzamide. To a 4-mL vial was added <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 27 mg, -90% pure, 0.13 mmol), HOBt (20 wt % H20)(22 mg, 0.13 mmol), EDC (27 mg, 0.14 mmol). A solution of 5-carbamoyl-4-cyclobutyl-2-methylbenzoic acid (compound 6.5, 28 mg, 0,12 mmol) in DMF (500 mu) was added followed by DIEA (83 mu, 0.48 mmol). The mixture was sealed and stirred at room temperature for 18 hours. Additional amine (3 mg, ~0.015 mmol) and EDC (5 mg, ~0.026 mmol) were added and the mixture was stirred at room temperature for an additional 27 hours. The mixture was diluted with ethyl acetate (5 mL) and washed with brine (8 mL). The aqueous was extracted with ethyl acetate (2 mL) and the combined organics was washed with brine, 1 M aH2P04, saturated aHC03 and brine (7 mL each). The product began precipitating out of solution after the final brine wash, so the organics was diluted with DCM (3 mL) and MeOH (~200 muKappa). The organics was dried ( a2S04), filtered, and concentrated under reduced pressure. The crude product was triturated with Et20 (1.5 mL), filtered, and washed with Et20 (0.5 mL) to yield the title compound as an off white powder (41.4 mg, 92%). m/z (ES+) 374 (M+H)+. XH NMR (400 MHz, CDC13): delta 7.67 (d with fine str., J= 8.4 Hz, 2H), 7.40 (d with fine str., J= 8.4 Hz, 2H), 7.32 (s, 1H), 7.25 (s, 1H), 5.79 (br s, 1H), 5.70 (br s, 1H), 4.67-4.57 (m, 1H), 4.39-4.30 (m, 1H), 4.28-4.18 (m, 1H), 4.00-3.86 (m, 3H), 2.46 (s, 3H), 2.42-2.31 (m, 2H), 2.19-1.96 (m, 3H), 1.88-1.77 (m, 1H)

References: [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 76.
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 91; 92.

18
[ 94268-29-8 ]
3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid [ No CAS ]
4-(1-(3-(2-((1R,4R)-4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile [ No CAS ]
4-(1-(3-(2-((1S,4S)-4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.2 mg; 18.4 mg	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Compounds 300.A and 300.B. 4-(l-(3-(2-(4-Methoxycyclohexyl)-4-methyl-lH- imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. Into a 50-mL round-bottom flask, was placed a solution of 3-(2-(4-methoxycyclohexyl)-4-methyl-lH-imidazol-5-yl)-4- methylbenzoic acid (compound 300.3, 140 mg, 0.43mmol) in N,N-dimethylformamide (3 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 82.8 mg, 0.43 mmol), HBTU (242.6 mg, 0.64 mmol) and DIEA (228 mu, 1.28 mmol) were added to the reaction. The reaction mixture was stirred for 1 overnight at room temperature, then diluted with 60 mL of EtOAc. The organic layer was washed with 3 x 20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5muiotaeta, 19* 100mm,; mobile phase, and (20.0% up to 27.0% in 10 min, up to 95.0% in 3 min, down to 20.0% in 1 min); Detector, Waters 2489 254 & 220nm. This resulted in 18.4 mg (9%) of compound 300.A as a white solid and 59.2 mg (30%) of compound 300.B as an off-white solid, m/z (ES+) 469 (M+H)+.

References: [1]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 356; 357.

19
[ 94268-29-8 ]
3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoic acid [ No CAS ]
[ 1533435-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Compound 7. 4-(l-(3-(4-Chloro-2-methyl-lH-imidazol-5-yl)-4- methylbenzoyl)azetidin-3-yl)benzonitrile. A mixture of 3-(5-chloro-2-methyl-lH-imidazol- 4-yl)-4-methylbenzoic acid (compound 7.3, -0.038 mmol), <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 8.6 mg, 0.044 mmol), EDCI (12 mg, 0.063 mmol), HOBt (8 mg, 0.044 mmol) and DIEA (28 mu, 0.16 mmol) in DMF (1 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with brine (how much), dried (MgSC ), filtered, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (8 % MeOH in DCM) to yield the title compound as a foam (2.8 mg, 19% over 2 steps), m/z (ES+) 391 (M+H)+. 'H NMR (400 MHz, CDC13) delta 10.62 (s, 1H), 7.69 (d, J= 8.3 Hz, 2H), 7.54 - 7.40 (m, 3H), 7.37 (d, J= 1.9 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 4.80-4.58 (m, 2H), 4.41 - 4.19 (m, 2H), 4.03-3.92 (m, 1H), 2.49 (s, 3H), 2.32 (s, 3H).

References: [1]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 93.

20
[ 94268-29-8 ]
4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoic acid hydrochloride [ No CAS ]
[ 1533436-77-9 ]

Yield	Reaction Conditions	Operation in experiment
2.2 mg	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4.0h;	Compound 82. 4-(l-(4-Cyclobutyl-2-methyl-5-(6-methyl-l,4,5,6,7,8- hexahydroimidazo[4,5-< \|azepin-2-yl)benzoyl)azetidin-3-yl)benzonitrile. Into a 100-mL round-bottom flask, was placed a mixture of 4-cyclobutyl-2-methyl-5-(6-methyl-l,4,5,6,7,8- hexahydroimidazo[4,5-i/]azepin-2-yl)benzoic acid (compound 82.9, 40 mg, 0.12 mmol), EDC'HCl (45.4 mg, 0.24 mmol, 2.00 equiv), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (compound 5.2, 23 mg, 0.12 mmol) in N,N- dimethylformamide (5 mL). The resulting solution was stirred for 4 h at room temperature then quenched by the addition of water/ice (10 niL). The resulting mixture was extracted with ethyl acetate (2 x 20 mL) and the combined organic layers were washed with brine (2 x 10 mL). The organic layer was dried ( a2S04), filtered, and concentrated under reduced pressure to yield the crude product which was purified by Prep-HPLC using the following conditions (1-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP 18 OBD Column, 5 urn, 19* 150 mm; mobile phase, WATER WITH 0.03% NH40H and CH3CN (30% CH3CN up to 43% in 8 min, up to 100% in 4 min, down to 30% in 2 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing clean product were combined to yield 2.2 mg (4%) of the title compound as a white solid, m/z (ES+) 480 (M+H)+.

References: [1]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 169; 170.

21
[ 94268-29-8 ]
3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoic acid [ No CAS ]
4-(1-(3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25℃; for 3.0h;	Compound 241. 4-(l-(3-(4-Chloro-2-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5- yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile. _:Into a 25-mL round-bottom flask, was placed a solution of 3-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-5-yl)-4- methylbenzoic acid (compound 241.4, 150 mg, 0.47 mmol) in N,N-dimethylformamide (3 niL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 91 mg, 0.47 mmol), EDOHC1 (180 mg, 0.94 mmol), 4-dimethylaminopyridine (114 mg, 0.93 mmol) were added to the reaction. The reaction mixture was stirred for 3 h at 25C, then diluted with 80 mL of EtOAc. The organic layer was washed with 3 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (1-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 muiotaeta, 19* 150 mm; mobile phase, WATER WITH 0.05% TFA and ACN (25.0% ACN up to 39.0% in 8 min, hold 39.0% in 1 min, up to 100.0% in 3 min, down to 25.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 133.3 mg (62%) of the title compound as a lightyellow solid. m/z (ES+) 461 (M+H)+.

References: [1]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 282; 283.

22
[ 94268-29-8 ]
3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoic acid [ No CAS ]
4-(1-(3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44.3 mg	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 2.0h;	Compound 244. 4-(l-(3-(4-Methoxy-lH-pyrazol-5-yl)-4-methylbenzoyl)azetidin- 3-yl)benzonitrile. Into a 25 -mL round-bottom flask, was placed a solution of 3-(4-methoxy- lH-pyrazol-5-yl)-4-methylbenzoic acid (compound 244.7, 60 mg, 0.26 mmol) in N,N- dimethylformamide (2 mL). 4-(Azetidin-3-yl)benzonitrile hydrochloride (75 mg, 0.39 mmol), EDC-HCl (99 mg, 0.52 mmol), and 4-dimethylaminopyridine (63 mg, 0.52 mmol) were added and the solution was stirred for 2 h at room temperature. The reaction was diluted with EtOAc (30 mL) and washed with brine (3 x 15 mL), dried (Na2S04), filtered and concentrated under reduced pressuer. The crude product (150 mg) was purified by Prep- HPLC with the following conditions (1-Pre-HPLC-010( Waters)): Column, SunFire Prep C18 OBD Column, 5 muiotaeta, 19* 150 mm; mobile phase, water with 0.05% TFA and CH3CN (35.0% CH3CN up to 50.0% in 10 min, up to 100% in 1 min, down to 35.0% in 2 min); Detector, UV 254 & 220nm. The fractions contained pure product were combined and lyophilized to obtain the title compound as an off-white solid (44.3 mg, 46%). m/z (ES+) 373 (M+H)+

References: [1]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 287; 288.

23
[ 94268-29-8 ]
5-(3-methoxy-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid [ No CAS ]
4-(1-[[5-(3-methoxy-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylphenyl]carbonyl]azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25℃;	To a solution of 5-(3-methoxy-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoic acid (500 mg, 1.92 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) was added . EDC HCl (738.5 mg, 3.85 mmol, 2.00 equiv), 4-dimethylaminopyridine (469.2 mg, 3.84 mmol, 2.00 equiv) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (447.7 mg, 2.30 mmol, 1.20 equiv). The resulting solution was stirred overnight at 25oC, then quenched with 10 mL of water. The aqueous phase was extracted with 3x50 mL of ethyl acetate and the combined organic layers were washed with 2x50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate as eluent to furnish 237.3 mg (31%) of 4-(1- [[5-(3-methoxy-4-methyl-1H-pyrazol-5-yl)-2,4-dimethylphenyl]carbonyl]azetidin-3- yl)benzonitrile (Compound 1) as a white solid. LC-MS: (ES, m/z): [M+H]+ 401. H- NMR: (400MHz, CD3OD, ppm): delta 7.768-7.748 (2H, m), 7.592-7.572 (2H, m), 7.300 (1H, s), 7.228 (1H, s), 4.661-4.616 (1H, m), 4.495-4.439 (1H, m), 4.250-4.210 (1H, m), 4.133-4.031 (2H, m), 3.933 (3H, s), 2.444 (3H, s), 2.244 (3H, s), 1.793 (3H, s).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 41.

24
[ 94268-29-8 ]
3-(3-(2-hydroxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid [ No CAS ]
4-(1-(3-(3-(2-hydroxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	3. To a solution of 3-(3-(2-hydroxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4- methylbenzoic acid (20.0 g, 72.5 mmol, 1.00 equiv) in DCM (500 mL) was added EDCI (16.7 g, 87.0 mmol, 1.20 equiv), 4-dimethylaminopyridine (1.77 g, 14.5 mmol, 0.20 equiv), DIEA (23.4 g, 181 mmol, 2.50 equiv) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (15.5 g, 79.7 mmol, 1.10 equiv). The resulting solution was stirred for overnight at room temperature. The resulting solution was diluted with 500 mL of H2O. The resulting solution was extracted with 3x500 mL of ethyl acetate and the combined organic layers were washed with 2x500 mL of NH4Cl ( sat.), 2x500 mL of brine and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel chromatography with CH2Cl2/MeOH (50/1-30/1) as eluent to furnish 21.0 g (67%) of 4-(1-(3-(3-(2-hydroxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4- methylbenzoyl)azetidin-3-yl)benzonitrile (Compound 2) as a white solid.

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 42.

25
[ 94268-29-8 ]
3-(3-(2-methoxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid [ No CAS ]
C₂₅H₂₆N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 2.0h;	To a solution of 3-(3-(2-methoxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4- methylbenzoic acid (100.0 mg, 0.34 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) was added <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (80.3 mg, 0.41 mmol, 1.20 equiv), EDCI (132.4 mg, 0.69 mmol, 2.00 equiv) and 4-dimethylaminopyridine (84.1 mg, 0.69 mmol, 2.00 equiv). The mixture was stirred for 2 h at room temperature. The resulting solution was diluted with 20 mL of H2O and extracted with 3x50 mL of ethyl acetate, then the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, Sunfire Prep C18 OBD Column, 19*150mm 5um 10nm; mobile phase, Water with 10mmol NH4HCO3 and ACN (35.0% ACN up to 65.0% in 8 min, up to 95.0% in 1 min,down to 35.0% in 1 min); Detector, waters2489 254&220nm. This resulted in 102.1 mg (69%) of 4-[1-([3- [1-(2-methoxyethyl)-4-methyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl]-4- methylphenyl]carbonyl)azetidin-3-yl]benzonitrile (Compound 3) as a white solid. LC- MS: (ES, m/z): [M+H]+ 431. H-NMR: (300 MHz, CD3OD, ppm): 7.64- 7.56 (3H, m), 7.49- 7.45 (3H, m), 7.34 (1H, d, J = 8.1Hz), 4.75- 4.68 (2H, m), 4.55- 4.49 (1H, m), 4.36- 3.92 (5H, m), 3.82- 3.56 (2H, m ), 3.20 (3H, m), 2.18 (3H, s), 1.70 (3H, s).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 44.

26
[ 94268-29-8 ]
3-(3-(2-ethoxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid [ No CAS ]
4-(1-(3-(3-(2-ethoxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 25℃; for 3.0h;	To a solution of 3-(3-(2-ethoxyethoxy)-4-methyl-1H-pyrazol-5-yl)-4- methylbenzoic acid (200 mg, 0.66 mmol, 1.00 equiv) in DMA (10 mL) was added EDCI (253 mg, 1.32 mmol, 2.00 equiv), 4-dimethylaminopyridine (12 mg, 0.10 mmol, 0.15 equiv), DIEA (254 mg, 1.97 mmol, 3.00 equiv) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (153 mg, 0.79 mmol, 1.20 equiv). The resulting solution was stirred for 3 h at 25oC, then quenched with 30 mL of NH4Cl(sat.). The aqueous phase was extracted with 3x30 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, then concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, Sunfire Prep C18 OBD Column, 19*150mm 5um 10nm; mobile phase, Water with 10mmol NH4HCO3 and ACN (25.0% ACN up to 75.0% in 8 min); Detector, Waters 2489 254&220 nm. This resulted in 142.1 mg (49%) of 4-(1-(3-(3-(2-ethoxyethoxy)-4- methyl-1H-pyrazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (Compound 4) as a white solid. LC-MS: (ES, m/z): [M+H]+ 445. H-NMR: (300Hz, CD3OD, ppm): 7.74 (2H, m), 7.76 (1H, d, J=8.4Hz), 7.75 (3H, m), 7.74 (1H, d, J=8.1Hz), 4.83 (1H, m), 4.43 (1H, m), 4.33 (1H, m), 4.23 (2H, m), 4.15 (1H, m), 4.06 (1H, m), 3.82 (2H, m), 3.62 (2H, m), 2.31 (3H, s), 1.83 (3H, s), 1.24 (3H, t).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 46.

27
[ 94268-29-8 ]
C₁₅H₁₈N₂O₄ [ No CAS ]
C₂₅H₂₆N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Into a 100-mL round-bottom flask, was placed 5-[1-(2-hydroxyethyl)-4- methyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl]-2,4-dimethylbenzoic acid (114 mg, 0.39 mmol, 1.00 equiv) in dichloromethane (10 mL). Then EDCI (149 mg, 1.01 mmol, 2.00 equiv), 4-dimethylaminopyridine (96 mg, 0.79 mmol, 2.00 equiv), DIEA (152 mg, 1.18 mmol, 3.00 equiv) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (92 mg, 0.47 mmol, 1.20 equiv) were added to the reaction. The resulting solution was stirred for 1 overnight at room temperature. The resulting solution was diluted with 20 mL of ethyl acetate. The resulting mixture was washed with 2x10 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 100 mg (59%) of 4-[1-([5-[1-(2-hydroxyethyl)-4-methyl-5-oxo-2,5-dihydro-1H- pyrazol-3-yl]-2,4-dimethylphenyl]carbonyl)azetidin-3-yl]benzonitrile (Compound 5) as a white solid. LC-MS: (ES, m/z): [M+H]+ 431. H-NMR: (300MHz, CD3OD, ppm): 7.768-7.740 (2H, d, J=8.4Hz), 7.591-7.563 (2H, d, J=8.4Hz), 7.295-7.225 (2H, d, J=21), 4.664-4.603 (1H, m), 4.499-4.424 (1H, m), 4.283-4.196 (3H, m), 4.112-4.011 (2H, m), 3.911-3.879 (2H, t), 2.438 (3H, s ), 2.239 (3H, s), 1.825 (3H, s).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 48-49.

28
[ 94268-29-8 ]
C₁₅H₁₈N₂O₄ [ No CAS ]
4-[1-([4-ethyl-3-[3-(2-hydroxyethoxy)-4-methyl-1H-pyrazol-5-yl]phenyl]carbonyl)azetidin-3-yl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 20℃;	Into a 25-mL round-bottom flask, was placed 4-ethyl-3-[3-(2-hydroxyethoxy)- 4-methyl-1 H-pyrazol-5-yl]benzoic acid (170 mg, 0.59 mmol, 1.00 equiv) in DMA (3 . mL). EDC HCl (225 mg, 1.17 mmol, 2.00 equiv), 4-dimethylaminopyridine (143 mg, 1.17 mmol, 2.00 equiv) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (227 mg, 1.17 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred for 1 overnight at room temperature, then diluted with 10 mL of ethyl acetate. The organic layer was washed with 2x10 mL of water and 1x10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, XBridge Prep Shield RP18 OBD Column, 19*150mm 5um 13nm; mobile phase, Water with 10mmolNH4HCO3 and ACN (20.0% ACN up to 52.0% in 8 min); Detector, Waters 2489 254&220 nm. This resulted in 45.1 mg (18%) of 4-[1-([4-ethyl-3-[3-(2- hydroxyethoxy)-4-methyl-1H-pyrazol-5-yl]phenyl]carbonyl)azetidin-3-yl]benzonitrile (Compound 6) as a white solid. LC-MS: (ES, m/z): [M+H]+ 431. H-NMR: (300MHz, CD3OD, ppm):delta 7.762-7.720 (3H, m), 7.608-7.485 (4H, m), 4.96-4.91 (1H, m), 4.665- 4.605 (1H, t), 4.459 (1H, m), 4.287-4.193 (3H, m), 4.138-4.057 (1H, m), 3.909-3.877 (2H, t), 2.673-2.597 (2H, m), 1.815 (3H, s), 1.122-1.071 (3H, t).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 52.

29
[ 94268-29-8 ]
4-methyl-3-[4-methyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]benzoic acid [ No CAS ]
4-[1-([4-methyl-3-[4-methyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenyl]carbonyl)azetidin-3-yl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 25℃; for 2.5h;	To a solution of 4-methyl-3-[4-methyl-3-(2,2,2-trifluoroethoxy)-1 H-pyrazol-5- yl]benzoic acid (250 mg, 0.80 mmol, 1.00 equiv) in DMA (10 mL) was added EDCI (305 mg, 1.59 mmol, 2.00 equiv), 4-dimethylaminopyridine (15 mg, 0.12 mmol, 0.15 equiv), DIEA (308 mg, 2.38 mmol, 3.00 equiv) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (185 mg, 0.95 mmol, 1.20 equiv). The resulting solution was stirred for 2.5 h at 25oC, then quenched with 20 mL of NH4Cl(sat). The aqueous phase was extracted with 4x20 mL of ethyl acetate and the combined organic layers were washed with 1x20 mL of brine, dried over anhydrous sodium sulfate. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, XBridge Prep BEH130 C18 Column, 19*100mm 5um 13nm; mobile phase, Water with 10mmolNH4HCO3 and MeCN (45.0% MeCN up to 70.0% in 8 min); Detector, Waters 2489 254&220nm. This resulted in 195.4 mg (54%) of 4-[1-([4- methyl-3-[4-methyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5- yl]phenyl]carbonyl)azetidin-3-yl]benzonitrile (Compound 9) as a white solid. LC-MS: (ES, m/z): [M+H]+ 455. H-NMR: (300Hz,CD3OD, ppm): 7.69 (3H,m), 7.56 (3H,d,J=8.1Hz), 7.43 (1H,d,8.1Hz), 4.75 (4H,m), 4.18 (1H,m), 4.15 (2H,m), 2.25 (3H,m), 1.80 (3H,m).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 58.

30
[ 94268-29-8 ]
3-(3-ethoxy-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid [ No CAS ]
4-(1-[[3-(3-ethoxy-4-methyl-1H-pyrazol-5-yl)-4-methylphenyl]carbonyl]azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 25℃; for 6.0h;	To a solution of 3-(3-ethoxy-4-methyl-1H-pyrazol-5-yl)-4-methylbenzoic acid (90 mg, 0.35 mmol, 1.00 equiv) in DMA (10 mL) was added EDCI (133 mg, 0.69 mmol, 2.00 equiv), 4-dimethylaminopyridine (84.5 mg, 0.69 mmol, 2.00 equiv), and 4- (azetidin-3-yl)benzonitrile hydrochloride (80.6 mg, 0.41 mmol, 1.20 equiv). The resulting solution was stirred for 6 h at 25oC, then quenched with 20 mL of water. The aqueous phase was extracted with 3x50 mL of ethyl acetate and the combined organic layers were washed with 1x30 mL of NH4Cl(sat) and 2x50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-006): Column, XBridge Prep C18 OBD Column, 19*150mm 5um 13nm; mobile phase, Water with 10mmol NH4HCO3 and ACN (39.0% ACN up to 57.0% in 8 min); Detector, Waters 2489 254&220nm. This resulted in 81.5 mg (59%) of 4-(1-[[3-(3-ethoxy-4-methyl-1H- pyrazol-5-yl)-4-methylphenyl]carbonyl]azetidin-3-yl)benzonitrile (Compound 10) as a white solid. LC-MS: (ES, m/z): [M+H]+ 401. H-NMR: (300MHz, CD3OD, ppm): 7.79 (2H, m), 7.71 (1H, m), 7.60(3H, m), 7.46 (1H, d, J=8.1), 4.82 (1H, m), 4.65 (1H, m), 4.46 (1H, m), 4.25 (3H, m), 4.10 (1H, m), 2.30 (3H, s), 2.00 (3H, s), 1.40 (3H, m).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 60.

31
[ 94268-29-8 ]
4-methyl-3-[4-methyl-3-(propan-2-yloxy)-1H-pyrazol-5-yl]benzoic acid [ No CAS ]
4-[1-([4-methyl-3-[4-methyl-3-(propan-2-yloxy)-1H-pyrazol-5-yl]phenyl]carbonyl)azetidin-3-yl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 25℃; for 4.0h;	To a solution of 4-methyl-3-[4-methyl-3-(propan-2-yloxy)-1 H-pyrazol-5- yl]benzoic acid (200 mg, 0.73 mmol, 1.00 equiv) in DMA (10 mL) was added EDCI (280.3 mg, 1.46 mmol, 2.00 equiv), 4-dimethylaminopyridine (178.1 mg, 1.46 mmol, 2.00 equiv) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (170 mg, 0.87 mmol, 1.20 equiv). The resulting solution was stirred for 4 h at 25oC, then quenched with 30 mL of water. The aqueous phase was extracted with 3x50 mL of ethyl acetate and the combined organic layers were washed with 1x100 mL of NH4Cl(sat) and 2x50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep- HPLC-006): Column, XBridge Prep C18 OBD Column, 19*150mm 5um 13nm; mobile phase, Water with 10mmol NH4HCO3 and ACN (43.0% ACN up to 59.0% in 8 min); Detector, Waters 2489 254&220nm. This resulted in 147.2 mg (49%) of 4-[1-([4- methyl-3-[4-methyl-3-(propan-2-yloxy)-1H-pyrazol-5-yl]phenyl]carbonyl)azetidin-3- yl]benzonitrile (Compound 11) as a white solid. LC-MS: (ES, m/z): [M+H]+ 415. H- NMR: (300MHz, CD3OD, ppm): delta 7.80 (2H, m), 7.70 (1H, m), 7.60 (3H, m), 7.45 (1H, d, J=7.8), 4.82 (1H, m), 4.65 (1H, m), 4.45 (1H, m), 4.22 (1H, m), 4.15 (1H, m) 2.30 (3H, s), 1.80 (3H, s), 1.35 (6H, m).

References: [1]Patent: WO2015/105860,2015,A9 .Location in patent: Page/Page column 62.

32
[ 406-93-9 ]
[ 94268-29-8 ]
4-(1-(4,4,4-trifluorobutanoyl)azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 26℃; for 16.0h;	General procedure: To a solution of Intermediate 75 (800 mg, 4.102 mmol) in DMF (15 mL) were added EDC.HCI (SILVARY, 1.95 g, 10.256 mmol), 4,4,4-trifluorobutanoic acid (OAKWOOD, 699 mg, 4.923 mmol) at 0 C, followed by the addition of DMAP (AVRA, 1.5 g, 12.307 mmol) at 0 C. The resultant reaction mixture was allowed to 26 C and stirred for 16 h at the same temperature. The reaction mixture was diluted with ice cold water (200 mL) and extracted with EtOAc (3 x 150 mL). Combined organic layers were washed with brine solution (100 mL), dried(anh) Na2S04, filtered and concentrated under reduced pressure. The crude was purified by silica chromatography column using a linear gradient of petroleum ether/EtOAc as eluents to yield the title compound (500 mg, 42%) as a colorless gum. 1H NMR (400 MHz, CDCI3) delta ppm: 7.71-7.65 (m, 2H), 7.45-7.39 (m, 2H), 4.64-4.42 (m, 2H), 4.20-4.05 (m, 2H), 3.94-3.87 (m, 1 H), 2.58-2.43 (m, 2H), 2.41-2.34 (m, 2H). [ES+ MS] m/z 283 (MH+).

References: [1]Patent: WO2019/34702,2019,A1 .Location in patent: Page/Page column 60.

33
[ 94268-29-8 ]
4-((4-(chloromethyl)-2-methylbenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]
4-(1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoliln-4-ylamino)methyl)-3-methylbenzyl)azetidin-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.9%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 15.0h;	To a mixture of 4-((4-(chloromethyl)-2-methylbenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.060 g, 0.141 mmol) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (0.027 mg, 0.141 mmol) in dry DMF (1.0 mL) was added DIEA (0.074 mL, 0.423 mmol) and the reaction mixture was stirred at 80 C. for 15 hours. The reaction was cooled to ambient temperature and quenched with 10% formic acid in DMSO (1.0 mL). The mixture was filtered through a membrane syringe filter (0.45 mum nylon) and the eluted solution was purified using standard methods to afford 2-(2,6-dioxopiperidin-3-yl)-4-((3-fluoro-4-((4-isopropylpiperidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (49.0 mg, 59.9% yield). LCMS (ESI) m/z 548.2 [M+H]+.

References: [1]Patent: US2019/322647,2019,A1 .Location in patent: Paragraph 0272; 0280.

34
[ 94268-29-8 ]
4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]
4-(1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)methyl)benzyl)azetidin-3-yl)benzonitrile hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.3%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24.0h;	To a solution of 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.062 g, 0.150 mmol) and <strong>[94268-29-8]4-(azetidin-3-yl)benzonitrile hydrochloride</strong> (0.031 g, 0.180 mmol) in dry DMF (0.30 mL) was added DIEA (0.079 mL, 0.450 mmol) and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was quenched with chilled 10% formic acid in DMSO (1.5 mL), filtered through a membrane syringe filter (0.45 mum nylon) and the solution was purified using standard methods to afford 4-(1-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl)azetidin-3-yl)benzonitrile hydrochloride (31.0 mg, 36.3% yield). LCMS (ESI) m/z 534.2 [M+H]+.

References: [1]Patent: US2019/322647,2019,A1 .Location in patent: Paragraph 0211; 0212.

Historical Records

Technical Information

• Benzylic Oxidation • Birch Reduction • Blaise Reaction • Blanc Chloromethylation • Catalytic Hydrogenation • Complex Metal Hydride Reductions • Friedel-Crafts Reaction • Hydride Reductions • Hydrogenolysis of Benzyl Ether • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Preparation of Amines • Reactions of Benzene and Substituted Benzenes • Ritter Reaction • Thorpe-Ziegler Reaction • Vilsmeier-Haack Reaction

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
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Response
Code	Phrase
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P321
P322
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P378
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Storage
Code	Phrase
P401
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Physical hazards
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H200	Unstable explosive
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H202	Explosive; severe projection hazard
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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

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CAS No.: 94268-29-8

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CAS No.: 94268-29-8

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[ 94268-29-8 ] Synthesis Path-Downstream 1~34

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