sales@ambeed.com

Structure Search

List Search MOL Search Structure Search

Hello, Sign in

Home Cart 0 Sign in

X

[ CAS No. 154607-01-9 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

DV 2D 3D

3d Animation Molecule Structure of 154607-01-9

Chemical Structure| 154607-01-9

Chemical Structure| 154607-01-9

Structure of 154607-01-9 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 154607-01-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 154607-01-9 ]

SDS Specification

Alternatived Products of [ 154607-01-9 ]

Product Details of [ 154607-01-9 ]

CAS No. :	154607-01-9	MDL No. :	MFCD00040883
Formula :	C₇H₃BrClN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AYQBMZNSJPVADT-UHFFFAOYSA-N
M.W :	216.46	Pubchem ID :	7010420
Synonyms :

Calculated chemistry of [ 154607-01-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.87
TPSA :	23.79 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.05
Log Po/w (XLOGP3) :	2.96
Log Po/w (WLOGP) :	2.97
Log Po/w (MLOGP) :	2.79
Log Po/w (SILICOS-IT) :	3.12
Consensus Log Po/w :	2.78

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.49
Solubility :	0.0699 mg/ml ; 0.000323 mol/l
Class :	Soluble
Log S (Ali) :	-3.12
Solubility :	0.163 mg/ml ; 0.000754 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.96
Solubility :	0.0238 mg/ml ; 0.00011 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.72

Safety of [ 154607-01-9 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405	UN#:	3439
Hazard Statements:	H301+H311+H331-H315-H319	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 154607-01-9 ]

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

Upstream synthesis route of [ 154607-01-9 ]
Downstream synthetic route of [ 154607-01-9 ]

[ 154607-01-9 ] Synthesis Path-Upstream 1~9

1
[ 154607-01-9 ]
[ 20925-27-3 ]

Reference： [1] Organic Letters, 2002, vol. 4, # 26, p. 4689 - 4692

2
[ 20925-27-3 ]
[ 154607-01-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃; Stage #2: at 0 - 20℃; for 2 h;	General procedure: 4-Cyano-3-(substituted) aniline 4a or 4b (38 mmol) was dissolved in conc. HCl (27 ml). After cooling to 0 C, sodium nitrite (39 mmol, 1.5 eq) was added very slowly to the stirred solution with the temperature being kept within (0 and 5 °C). This diazonium salt solution was then poured into a flask containing CuBr (53 mmol, 1.4 eq) and 22 ml of conc. HCl. The solution was stirred for 2 h, and then, the reaction mixture was poured into ice water (50 ml) extracted with Ethyl acetate (100 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with saturated aqueous NaHCO3 solution (1 x 150 ml), brine (3 x 100 ml) and dried over Na2SO4. The resulting material was concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate, 10:1) to afford the title compound (5a or 5b) as white solid (72–75 percent yield).

Reference： [1] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 539 - 552

3
[ 623-00-7 ]
[ 154607-01-9 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 6, p. 2786 - 2791

4
[ 108-42-9 ]
[ 154607-01-9 ]

Reference： [1] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 539 - 552

5
[ 21402-26-6 ]
[ 154607-01-9 ]

Reference： [1] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 539 - 552

6
[ 62473-92-1 ]
[ 10026-13-8 ]
[ 154607-01-9 ]

Reference： [1] American Chemical Journal, 1903, vol. 30, p. 508

7
[ 154607-01-9 ]
[ 158435-41-7 ]

Reference： [1] Patent: WO2008/59335, 2008, A1, . Location in patent: Page/Page column 28-29
[2] Patent: WO2009/30962, 2009, A1, . Location in patent: Page/Page column 14

8
[ 154607-01-9 ]
[ 73183-34-3 ]
[ 945391-06-0 ]

Yield	Reaction Conditions	Operation in experiment
20%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 12 h; Inert atmosphere	Under N₂ atmosphere, bis(pinacolato)diboron (391mg, 1.54mmol), potassium acetate (412mg, 4.5mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (102mg, 0.14mmol) were respectively added to a solution of 2-chloro-4-bromobenzonitrile (300mg, 1.4mmol) in dioxane (15mL). The mixture was stirred at 80°C for 12hrs, cooled to room temperature, filtered through celite, washed with EA (50mL). The filtrate was evaporated under reduced pressure, and the residue was purified by silica preparative plate to give white solid 23-b (73mg, yield 20percent). ¹H-NMR (400MHz, CDCl₃) δ: 7.78 (d, J=7.6 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.52 (dd, J=7.6 Hz, 1.2 Hz, 1H), 1.37 (s, 12H) ppm.

Reference： [1] Patent: EP3275867, 2018, A1, . Location in patent: Paragraph 0206; 0207

9
[ 154607-01-9 ]
[ 1297538-32-9 ]

Reference： [1] Patent: WO2016/162604, 2016, A1,

[ 154607-01-9 ] Synthesis Path-Downstream 1~19

1
[ 62473-92-1 ]
[ 10026-13-8 ]
[ 154607-01-9 ]

Reference： [1]American Chemical Journal,1903,vol. 30,p. 508

2
[ 154607-01-9 ]
[ 20925-27-3 ]

Reference： [1]Organic Letters,2002,vol. 4,p. 4689 - 4692

3
[ 154607-01-9 ]
[ 874482-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-bromo-2-chlorobenzonitrile With borane-THF In tetrahydrofuran at 0℃; for 1h; Heating / reflux; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃; for 1h; Heating / reflux; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/8046, 2006, A1 Location in patent: Page/Page column 50-51

4
[ 154607-01-9 ]
[ 14394-70-8 ]
[ 1210806-72-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 4h;Heating / reflux;	[0141] To a solution of <strong>[14394-70-8]2-chloro-5-methylpyrimidin-4-amine</strong> (144 mg, 1.0 mmol) in 1,4- dioxane (20 mL) was added 4-bromo-2-chlorobenzonitrile (217 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9- dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 26, was used for next reaction without further purification.

Reference： [1]Patent: WO2007/53452,2007,A1 .Location in patent: Page/Page column 91

5
[ 154607-01-9 ]
[ 158435-41-7 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of Intermediate 4-Bromo-2-chloro-benzaldehvde (l-3a):The 4-Bromo-2-chloro-benzaldehyde was prepared using procedures described in J. Med. Chem. 1981, 24, 1155-1161.4-bromo-2-chloro-benzonitrile (7.05g, 32.5 mmol) was dissolved in toluene (60 mL) and dichloromethane (1OmL) and cooled to -600C as a 1.5M solution of diisobutylaluminum hydride in toluene (33.4 ml, 49.8 mmol) was added dropwise over 30 minutes keeping the temperature between -60 and - 500C. The reaction was allowed to warm slowly to room temperature and stirred for an additional 3 hours. The reaction was quenched using ethyl acetate and stirred for 20 minutes before the addition of 1 N hydrochloric acid at O0C. The reaction was then allowed to warm slowly to room temperature. The reaction was extracted using ethyl acetate (2 times). Removal of the solvent provided the title compound (l-3a). <n="30"/>1H NMR (CDCI3): delta 7.52 (dd, 1H), 7.64 (d, 1H), 7.77 (d, 1H), 10.4 (s, 1 H)
		To 4-bromo-2-chlorobenzonitrile (2.Og, 9.2mmol) in toluene (5OmL) at -780C under argon was added DIBAL (IM solution in toluene, 13.9mL, 13.9mmol). The mixture was allowed to warm to -5O0C over 4 h. MeOH (4.5mL) and water (4.5mL) were added and the mixture stirred for 10 min at -5O0C. The mixture was allowed to warm to rt, acidified with 2N HCl (pH <7) and extracted with EtOAc (20OmL) and water (10OmL). The aqueous was further extracted with EtOAc (2x50mL), the combined organics were then washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (25%DCM: /so-hexane) to give 4-bromo-2-chlorobenzaldehyde. To a solution of 4-bromo-2-chlorobenzaldehyde (750mg, 3.4mmol) in DME (22mL) and EtOH (15mL) was added 3-carboxamidobenzene boronic acid (676mg, 4.1mmol) and 2M Na2CO3 solution (15mL). Argon was bubbled through the mixture for 15 min. ife(triphenylphosphino) palladium dichloride (120mg, 0.17mmol) was added and the reaction heated to 750C for 6.5 h before cooling to rt. The mixture was partitioned between water (20OmL) and EtOAc (20OmL), the aqueous was extracted with EtOAc (2x50mL) and the combined organics dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography(50%EtOAc: Iso-hexane to 100%EtOAc) to give the title compound: RT = 3.19min; m/z (ES+) = 301.0 [M + H + MeCN]+.

Reference： [1]Patent: WO2008/59335,2008,A1 .Location in patent: Page/Page column 28-29
[2]Patent: WO2009/30962,2009,A1 .Location in patent: Page/Page column 14

6
[ 154607-01-9 ]
[ 73183-34-3 ]
[ 548797-51-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 115℃; for 12h;	Under N2 atmosphere, bis(pinacolato)diboron (391mg, 1.54mmol), potassium acetate (412mg, 4.2mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (102mg, 0.14mmol) were respectively added to a solution of 2-chloro-4-bromobenzonitrile (300mg, 1.4mmol) in dioxane (15mL). The mixture was stirred at 115C for 12hrs, cooled to room temperature, filtered through celite, washed with EA (50mL). The filtrate was evaporated under reduced pressure to give compound 22-c (620mg, yield 100%). The product was directly used for the next step without further purification. LC-MS (ESI): m/z = 182 [M+H]+.
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 14h;	Reference Example 25; 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 4-Bromo-2-chlorobenzonitrile (19.43 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolan (25.08 g), potassium acetate (26.5 g), and 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (1:1) (2.20 g) were dissolved in DMSO (300 mL), and the mixture was stirred at 80 C. for 14 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was suspended in diisopropyl ether-hexane and filtrated to give the title compound (17.74 g) as a brown powder.1H-NMR (CDCl3) δ: 1.35 (12H, s), 7.63-7.68 (1H, m), 7.72-7.80 (1H, m), 7.91 (1H, s).
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 4.5h;	Example 15: Synthesis of 2-Chloro-4-(5-fluoro-4-hydroxymethyl-pyridin-3-yl)- benzonitrileStep 1: 2-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (15a)A mixture of 4-bromo-2-chlorobenzonitrile (15 g, 69.3 mmol), 4,4,4' ,4', 5,5,5', 5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) (17.60 g, 69.3 mmol), potassium acetate (13.60 g, 139 mmol) and PdCI2(dppf).CH2CI2 adduct (2.83 g, 3.46 mmol) in 1 ,4-dioxane (100 mL) was heated to 80 C for 4.5 hr. After filtration and concentration, the residue was dissolved into CH2CI2 and mixed with celite. After concentration, the residue was loaded to column (120g ISCO) and flushed with ethyl acetate / heptane (v/v, 0%-5%) and resulted colorless solid 16.4 g. 1H NMR (400.3 MHz, CDCI3): 6 1.35 (s, 12H), 7.61 (d, J = 7.6 Hz, 1H), 7.70 (d, J =7.6 Hz, 1 H), 7.87 (s, 1 H).

	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 4.5h;	A mixture of 4-bromo-2-chlorobenzonitrile (15 g, 69.3 mmol), 4,4,44',5,5,5',5'- octamethyl-2.2'-bi(1,3,2-dioxaborolane) (17.6O g, 69.3 mmol). potassium acetate (13.60 g, 139 mmof) and PdCI2(dppf).CH2CI2 addυct (2.83 g, 3.46 mmol) in 1,4-dioxane (100 mL) was heated to 800C for 4.5 h. After filtration and concentration, the residue was dissolved into CH2Ci2 and mixed with celite. After concentration, the residue was loaded to column (12Og isco) and flushed with ethyl acetate / heptane (v/v, 0%-5%) and resulted in a colorless solid 16.4 g. 1H NMR (400 MHz1 CDCI3)'. δ 1.35 (s. 12H), 7.61 (d, J = 7.6 Hz. 1H), 7.70 (d, J «7.6 Hz. 1H), 7.87 (s. 1H).
0.850 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 4h;	The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-bromo-2-chlorobenzonitrile (1.0 g, 4.61 mmo), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (1.29 g, 4.33 mmol), potassium acetate (0.9063 g, 9.23 mmol),Pd(dppf)C12 (0.190 g, 0.23 mmol) in 1,4-dioxane to afford 0.850 g of title compound. ‘HNMR (300 MHz, DMSO-d6): 7.99-7.91 (d, J = 7.8Hz, 1H), 7.82 (s, 1H), 7.75-7.73 (d, J =7.2 Hz, 1H), 1.31 (s, 12H):_To a solution of ethyl 4-amino-3-bromobenzoate (5.0 g, 20.66 mmol), (4- cyanophenyl)boronic acid (3.33 g, 22.72 mmol) and Pd(dppf)C12 (0.843 g, 1.03 mmoi) indiglyme (10 mL) was added K2C03 (4.27 g, 30.99 mmol). The reaction mixture was heated at80C for 4 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 2.7 g of title product. ‘H NMR (300 MHz, DMSO-d6): 7.92-7.89 (d, J = 7.8 Hz, 2H), 7.69-7.67 (d, J = 8.7 Hz, 1H), 7.63-7.60 (d, J = 7.8 Hz, 2H),7.56 (s, 1H), 6.8 1-6.78 (d, J = 8.4Hz, 1H), 5.83 (br s, 2H), 4.22-4.20 (q, J = 6.9 Hz, 2H),1.28-1.23 (t, J= 7.5 Hz, 3H).

Reference： [1]Patent: EP3275867,2018,A1 .Location in patent: Paragraph 0201; 0202
[2]Journal of Heterocyclic Chemistry,2021,vol. 58,p. 2280 - 2286
[3]Patent: US2009/270359,2009,A1 .Location in patent: Page/Page column 39
[4]Patent: WO2011/61168,2011,A1 .Location in patent: Page/Page column 60-61
[5]Patent: WO2010/130796,2010,A1 .Location in patent: Page/Page column 57
[6]Patent: WO2016/55947,2016,A1 .Location in patent: Page/Page column 76; 77; 86; 87

7
[ 1073354-70-7 ]
[ 154607-01-9 ]
[ 1126779-15-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 4.0h;	Reference Example 42-chloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)benzonitrile (Synthesis method 1) A mixture of <strong>[1073354-70-7]tert-butyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate</strong> (1.70 g) synthesized in Reference Example 1, 4-bromo-2-chlorobenzonitrile (1.14 g), tetrakis(triphenylphosphine)palladium(0) (0.58 g), sodium carbonate (1.4 g), 1,2-dimethoxyethane (40 mL) and water (7 mL) was stirred at 90 C. for 4 hr. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (hexane-ethyl acetate), and each fraction was suspended in diisopropyl ether and collected by filtration to give the title compound (193 mg) and tert-butyl 4-(3-chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylate (620 mg) as a solid. A mixture of tert-butyl 4-(3-chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylate (600 mg) and TFA was stirred at room temperature for 3 hr, neutralized with saturated aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was washed with diisopropyl ether to give the title compound (328 mg) as colorless crystals

Reference： [1]Patent: US2009/270359,2009,A1 .Location in patent: Page/Page column 34

8
[ 1126779-11-0 ]
[ 154607-01-9 ]
[ 1126779-17-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran; water for 24h; Inert atmosphere; Reflux;	4.2 (Synthesis method 2) 3,5-Dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (28.3 g) synthesized in Reference Example 3, 4-bromo-2-chlorobenzonitrile (22.9 g) and triethylamine (25.8 mL) were dissolved in THF-water (6:1) (217 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (1:1) (2.26 g) was added under a nitrogen atmosphere. The reaction mixture was stirred with heating under reflux for 24 hr, and concentrated. The obtained residue was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography to give 2-chloro-4-[3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]benzonitrile (20.0 g) as colorless crystals. A mixture of the obtained 2-chloro-4-[3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]benzonitrile (18.7 g) and 10% hydrochloric acid methanol solution (180 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into ice-cooled 1 mol/L aqueous sodium hydroxide solution to quench the reaction, methanol was evaporated and the obtained aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was washed with diisopropyl ether-hexane to give the title compound (13.7 g) as colorless crystals. 1H-NMR (DMSO-d6) δ: 2.33 (6H, s), 7.24-7.30 (1H, m), 7.42 (1H, d), 7.70 (1H, d).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2009/270359, 2009, A1 Location in patent: Page/Page column 34

9
[ 154607-01-9 ]
[ 1297537-41-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: anhydrous sodium carbonate / [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / lithium hydroxide monohydrate; tetrahydrofuran / 2.5 h / 35 °C 2.1: hydrogenchloride / ethanol / 1 h / 30 °C / Inert atmosphere 3.1: sodium hydroxide / lithium hydroxide monohydrate; methanol / 2 h / 25 °C / Inert atmosphere 4.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 18 h / 20 °C / Inert atmosphere 4.2: 20 h / 20 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile; lithium hydroxide monohydrate / 0.5 h / Inert atmosphere; Reflux 1.2: 2.5 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / lithium hydroxide monohydrate / 2 h / 10 °C 2.2: 4 h / 0 - 5 °C 3.1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: trans-bis(triphenylphosphine)palladium(II) dichloride; anhydrous sodium carbonate / lithium hydroxide monohydrate; tetrahydrofuran / 40 °C 2.1: hydrogenchloride / ethanol / Reflux 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 3.2: 24 h / 20 °C

	Multi-step reaction with 3 steps 1: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous sodium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 45 °C 2: hydrogenchloride / lithium hydroxide monohydrate; ethanol / Reflux 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 4 h / 20 °C
	Multi-step reaction with 3 steps 1.1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 3 h / 40 °C / Inert atmosphere 2.1: hydrogenchloride / ethanol / 2 h / 30 °C / Inert atmosphere 3.1: triphenylphosphine / ethyl acetate / 0.5 h / Inert atmosphere 3.2: 3 h / 20 °C / Inert atmosphere 3.3: 1 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: potassium carbonate; palladium diacetate; triphenylphosphine / acetonitrile; lithium hydroxide monohydrate / 3.5 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / lithium hydroxide monohydrate; methanol / 2.5 h / 10 °C 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 3.2: 35 - 45 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile / Inert atmosphere; Reflux 2.1: hydrogenchloride / ethanol / Reflux 3.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 3.2: Reflux
	Multi-step reaction with 4 steps 1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile; lithium hydroxide monohydrate / Inert atmosphere; Reflux 2: hydrogenchloride; lithium hydroxide monohydrate; ethanol / Reflux 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 4: hydrogenchloride; lithium hydroxide monohydrate / acetonitrile / Reflux

Reference： [1]Current Patent Assignee: ORION OYJ - WO2011/51540, 2011, A1
[2]Current Patent Assignee: ORION OYJ - WO2016/162604, 2016, A1
[3]Yu, Jiang; Zhou, Peiting; Hu, Mingxing; Yang, Liuqing; Yan, Guoyi; Xu, Ruixue; Deng, Yufang; Li, Xinghai; Chen, Yuanwei [European Journal of Medicinal Chemistry, 2019, vol. 182]
[4]Current Patent Assignee: SICHUAN UNIVERSITY - CN110669049, 2020, A
[5]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116476, 2020, A
[6]Current Patent Assignee: SHENZHEN TARGETRX INC - EP3932908, 2022, A1
[7]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN113861115, 2021, A
[8]Bao, Qiqi; Han, Xiaoli; Huang, Chenchao; Li, Xiaoyu; Wu, Meng; Xiao, Xiaohui; Xu, Qian; Zhang, Rongyu; Zhang, Zixiong; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]

10
[ 903550-26-5 ]
[ 154607-01-9 ]
[ 1297537-35-9 ]

Yield	Reaction Conditions	Operation in experiment
92.3%		Acetonitrile (50 ml), water (50 ml), potassium carbonate * H20 (2i .7 g, 2.07 eqv.) and 4-bromo-2-chlorobenzonitrile (II) (14.0 g, 1.00 eqv.) were charged. The mixture was refluxed under nitrogen atmosphere for about 0.5 h. The mixture was cooled to 60-70 C under nitrogen protection. Palladium(II)acetate Pd(OAc)2 (0.10 g,0.007 eqv.) and triphenylphosphine (0.40 g, 0024 eqv.) were added under nitrogen protection. 1 -(Tetrahydro-2H-pyran-2-yl)-5 -(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan- 2-yl)-1H-pyrazole (I) (21.0 g, 1.17 eqv.) was dissolved in acetonitrile (30 ml). Air was removed by vacuum and replaced by nitrogen. This solution was added to the reaction mixture in about 0.5 h at 70 ± 3 C. The reaction mixture was stirred for 2 hat 70 ± 3 C. The water phase was separated off and removed from the reaction mixture at 65-70 C. 2 nil of ammonia water (25 %) was added to the reaction mixture which was then cooled to 20 ± 5 C. Water (80 nil) was added gradually at 20 ± 5 C. The mixture was stirred overnight at 20 ± 5 C. The crystalline product was filtered and washed twice with acetonitrile:water 1:1(20 nil). The product was dried under reduced pressure at 50-60 C. Yield 17.18 g (92.3 %). HPLC-purity 99.8%.
83.3%	With trans-bis(triphenylphosphine)palladium dichloride; sodium carbonate; In tetrahydrofuran; water; at 40℃;	<strong>[903550-26-5]1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.6 g,5.8 mmol) and commercially available 4-bromo-2-chlorobenzonitrile (1.0 g, 4.6 mmol) were dissolved in THF(16.0 ml). To this mixture bis(triphenylphosphine) palladium (II)chloride (162.5 mg, 0.23 mmol), sodium carbonate (1.2 g,11.1 mmol) and 4.5 ml of water were added and the reactionmixture was stirred at 40 C overnight. The solvent was distilledunder vacuum. The resulting mixture was diluted with ethylacetate and washed twice with water. The organic layer wasdried over anhydrous Na2SO4, filtered and concentrated undervacuum. The crude product was purified by column chromatographyon silica gel using a solvent of 10% ethyl acetate inhexanes to give intermediate 7 as a yellow solid (1.1 g, yield83.3%).
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; at 35℃; for 2.5h;	1 -(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- lH-pyrazole (6.5 g; 23.28 mmol) and 4-bromo-2-chlorobenzonitrile (4 g; 18.48 mmol) were dissolved in THF (65 ml). To this mixture bis(triphenylphosphine)- palladium(II) chloride (0.65 g; 0.92 mmol), sodium carbonate (4.7 g; 44.3 mmol) and 18 ml of water were added and the reaction mixture was stirred at 35 C for 2.5 h. The solvents were distilled to almost dryness and water (48 ml) was added. After 30 min of stirring the precipitated product was filtered and 32 ml of ethanol was added to the precipitation. The suspension was stirred for 15 min at RT and 30 min at -10 C before filtering to give 3.7 g of the product. -NMR (400MHz; d6-DMSO): delta 1.63-1.54 (m, 3H), 1.84-1.80 (m, 1H), 1.97-1.94 (m, 1H), 2.39-2.35 (m, 1H), 3.63- 3.57 (m, 1H), 3.99 (m, 1H), 5.32-5.27 (m, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (m, 1H), 7.92 (d, 1H), 8.14 (d, 1H).

	With tetrabutylammomium bromide; sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; toluene; at 42℃; for 2h;Inert atmosphere;	a) 2-Chloro-4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)benzonitrile4-Bromo-2-chlorobenzonitrile (30 g, 139 mmol), 90 ml of THF and 360 ml of toluene were placed in reaction vessel under nitrogen athmosphere. Bis(triphenyl- phosphine)-palladium(II) chloride (4.57g, 6.51 mmol), Na2C03 (33.1 g, 312 mmol), 180 ml of water and tetrabutylammonium bromide (0.894 g, 2.77 mmol) were added. The reaction mixture was heated up to 42 C. l-(Tetrahydro-2H-pyran-2-yl)-lH- pyrazole-5-boronic acid pinacol ester (42.4 g; 152 mmol) was added in three portions within one hour. The reaction was agitated at 42 C for one hour followed with addition of 180 ml of water and cool down. The reaction mixture was filtered and layers separated. Organic phase was washed with 400 ml of water. The layers were separated and the toluene phase was distilled close to dryness. 180 ml of ethanol was added to the warm residue and the mixture was cooled down to 5 C for three hours. The precipitate was filtered and washed with cold ethanol. 36.4 g of the title compound was obtained after vacuum drying. -NMR (400 MHz, DMSO-i 6): delta 1.48-1.70 (m, 3H), 1.78-1.86 (m, IH), 1.90-2.00 (m, IH), 2.29-2.46 (m, IH), 3.55- 3.68 (m, IH), 3.93-4.04 (m, IH), 5.29 (dd, IH), 6.72 (d, IH), 7.65 (d, IH), 7.72 (dd, IH), 7.92 (d, IH), 8.13 (d, IH).
2.4 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In tetrahydrofuran; water; at 45℃;	4-bromo-2-chlorophenyl-carbonitrile (2g, 8mol) and 1- (tetrahydro -2H- pyran-2-yl) lH-pyrazole-5-boronic acid pinacol ester (4.45g, 16mmol) was dissolved in THF (22ml).Was added bis (triphenylphosphine) palladium (II) dichloride (281mg, 0.4mmol), sodium carbonate (2g, 19.2mmol) and water (6ml), N swap2three times.The mixture was heated to 45 , stirred overnight.The solvent was evaporated, the insolubles were removed by filtration through Celite, diluted with water and extracted twice with ethyl acetate, dried over anhydrous sodium sulfate and concentrated, purified by silica gel column (PE: EA = 5: 1) to give a pale yellow solid 2.4g.

Reference： [1]Patent: WO2016/162604,2016,A1 .Location in patent: Page/Page column 14; 15
[2]European Journal of Medicinal Chemistry,2019,vol. 182
[3]Patent: WO2011/51540,2011,A1 .Location in patent: Page/Page column 50
[4]Patent: WO2012/143599,2012,A1 .Location in patent: Page/Page column 69-70
[5]Patent: CN110669049,2020,A .Location in patent: Paragraph 0102; 0104-0106

11
[ 2591-86-8 ]
[ 154607-01-9 ]
[ 101048-77-5 ]

Yield	Reaction Conditions	Operation in experiment
73.1%		(1) Intermediate I-1 (X = Cl): 4-Bromo-2-chlorobenzonitrile (10.0 g, 46.20 mmol) was dissolved in an appropriate amount of 240 mL of anhydrous tetrahydrofuran, Under ice bath conditions, A 2N solution of isopropylmagnesium chloride in tetrahydrofuran (30 ml, 40.06 mmol) was added dropwise. After reaction for 1 h, 3 equivalents of N-formylpiperidine were added under ice-cooling and the reaction was continued for 2 h. The reaction was quenched and extracted with ethyl acetate. The organic layers were combined, washed with water and dried. Column chromatography, eluent: petroleum ether:ethyl acetate=4:1, to obtain 5.6 g of a white solid, yield 73.1%.
65.9%		General procedure: To a solution of 4-halogen-2-chlorobenzonitrile (23.10mmol) in dry 35 THF under Argon at 0C was added 36 isopropyl magnesium chloride (30.03mmol, 2M solution in ether) dropwise during 20min, and the reaction mixture was stirred for 2h, keeping the temperature around 0C. Then 37 1-formyl piperidine (30.03mmol) was added dropwise at 0C and stirred for additional 2h at 0C. The reaction mixture was quenched with saturated 38 NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=3:1) to afford 39 compound 10a and 10b. 4.1.2.1 39 2-Chloro-4-formylbenzonitrile (10a) (0020) Yield:65.9%; White solid; Mp: 114-115C; 1H NMR (400MHz, DMSO-d6) delta 10.07 (s, 1H), 8.23-8.22 (m, 2H), 8.02 (d, J=7.6Hz, 1H); MS (ESI) m/z 166.0 (M+H)+.
65.9%		2-Chloro-4-bromobenzonitrile (5.0 g, 23.10 mmol) was dissolved in 120 mL of anhydrous tetrahydrofuran, and a solution of 2N isopropylmagnesium chloride in tetrahydrofuran (15.0 ml, 30.03 mmol) was added dropwise. The reaction mixture was reacted under argon at 0 C for 2 hours.Thereafter, N-formylpiperidine (3.33 ml, 30.03 mmol) was added at 0 C and the reaction was continued at 0 C for 2 hours.The reaction was quenched with saturated ammonium chloride solution, 3 times (3 × 50mL), combined organic layers were extracted with ethyl acetate, washed twice with distilled water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate.Concentrated and separated by column chromatography, eluent petroleum ether: ethyl acetate = 3: 1, to give 2.52 g of a white solid, a yield of 65.9%.

		Intermediate 2b 2-Chloro-4-formylbenzonitrile In a 25 mL three-necked flask, isopropylmagnesium chloride 2M in THF (751 mu, 1.5 mmol, Eq: 1.3) was combined with THF (10 ml) under Ar to give a colorless solution. The reaction mixture was cooled down to 0C and 4-bromo-2-chlorobenzonitrile (0.250 g, 1.15 mmol, Eq: 1.00), dissolved in THF (2.5 ml), was added dropwise during 10 min keeping the temperature below 2C (yellow solution). The metallation was allowed to proceed at 0C for additional 2 hours. A solution of N-formylpiperidine (170 mg, 167 mu, 1.5 mmol, Eq: 1.3) in THF (2.5 ml) was added, and the reaction was stirred at 0C for 2 hours (yellow solution). Work up: The reaction mixture was poured into 10 mL 1 M HC1 and extracted with EtOAc (1 x 20 mL). The organic layers were combined, washed with water, dried over Na2S04, and concentrated i. V. Purification : The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 50% EtOAc in heptane) to yield 82mg of the desired title product as white solid. MS (GC-EI): 165 [M]+.
82 mg		In a 25 mL three-necked flask, isopropylmagnesium chloride 2M in THF (751 mul, 1.5 mmol, Eq: 1.3) was combined with THF (10 ml) under Ar to give a colorless solution. The reaction mixture was cooled down to 0 C. and 4-bromo-2-chlorobenzonitrile (0.250 g, 1.15 mmol, Eq: 1.00), dissolved in THF (2.5 ml), was added dropwise during 10 min keeping the temperature below 2 C. (yellow solution). The metallation was allowed to proceed at 0 C. for additional 2 hours. A solution of N-formylpiperidine (170 mg, 167 mul, 1.5 mmol, Eq: 1.3) in THF (2.5 ml) was added, and the reaction was stirred at 0 C. for 2 hours (yellow solution). Work up: The reaction mixture was poured into 10 mL 1 M HCl and extracted with EtOAc (1*20 mL). The organic layers were combined, washed with water, dried over Na2SO4, and concentrated i. V. Purification: The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 50% EtOAc in heptane) to yield 82 mg of the desired title product as white solid. MS (GC-EI): 165 [M]+.

Reference： [1]Patent: CN107857760,2018,A .Location in patent: Paragraph 0077-0079
[2]Bioorganic Chemistry,2019,vol. 82,p. 41 - 57
[3]Patent: CN109956912,2019,A .Location in patent: Paragraph 0032-0038
[4]Patent: WO2013/120771,2013,A1 .Location in patent: Page/Page column 50-51
[5]Patent: US2014/128429,2014,A1 .Location in patent: Paragraph 0032; 0333

12
[ 154607-01-9 ]
[ 62673-31-8 ]
4-benzyl-2-chlorobenzonitrile [ No CAS ]
[ 1068162-79-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In tetrahydrofuran at 57℃;

Reference： [1]Karlsson, Staffan; Sörensen, Henrik; Andersen, Sören M.; Cruz, Angele; Ryberg, Per [Organic Process Research and Development, 2016, vol. 20, # 2, p. 262 - 269]

13
[ 615-16-7 ]
[ 154607-01-9 ]
2-(chloro)-4-(1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With caesium carbonate In N,N-dimethyl-formamide at 110℃; for 12h;	General procedure for the synthesis of compounds (7a, b) General procedure: 4-Bromo-2-(substituted) benzonitrile 5a or 5b (5 mmol) was added to a mixture of 1H-benzo[d]imidazol-2(3H)-one (6) (10 mmol) and Cs2CO3 (10 mmol) in DMF (25.0 ml). After 12 h, 50 ml of ice water was added dropwise. The resulting suspension was filtered, and the filter cake was dried in a vacuum oven. The solid was purified by flash chromatography (50 % ethyl acetate in hexane) to afford 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-(substituted) benzonitrile (7a or 7b).

Reference： [1]Elancheran; Saravanan; Choudhury, Bhaswati; Divakar; Kabilan; Ramanathan; Das, Babulal; Devi; Kotoky, Jibon [Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 539 - 552]

14
[ 20925-27-3 ]
[ 154607-01-9 ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: 4-Cyano-3-(substituted) aniline 4a or 4b (38 mmol) was dissolved in conc. HCl (27 ml). After cooling to 0 C, sodium nitrite (39 mmol, 1.5 eq) was added very slowly to the stirred solution with the temperature being kept within (0 and 5 C). This diazonium salt solution was then poured into a flask containing CuBr (53 mmol, 1.4 eq) and 22 ml of conc. HCl. The solution was stirred for 2 h, and then, the reaction mixture was poured into ice water (50 ml) extracted with Ethyl acetate (100 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with saturated aqueous NaHCO3 solution (1 x 150 ml), brine (3 x 100 ml) and dried over Na2SO4. The resulting material was concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate, 10:1) to afford the title compound (5a or 5b) as white solid (72-75 % yield).

Reference： [1]Medicinal Chemistry Research,2016,vol. 25,p. 539 - 552

15
[ 154607-01-9 ]
[ 1297537-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile; lithium hydroxide monohydrate / 0.5 h / Inert atmosphere; Reflux 1.2: 2.5 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / lithium hydroxide monohydrate / 2 h / 10 °C 2.2: 4 h / 0 - 5 °C
	Multi-step reaction with 2 steps 1: trans-bis(triphenylphosphine)palladium(II) dichloride; anhydrous sodium carbonate / lithium hydroxide monohydrate; tetrahydrofuran / 40 °C 2: hydrogenchloride / ethanol / Reflux
	Multi-step reaction with 2 steps 1: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous sodium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 45 °C 2: hydrogenchloride / lithium hydroxide monohydrate; ethanol / Reflux

	Multi-step reaction with 2 steps 1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 3 h / 40 °C / Inert atmosphere 2: hydrogenchloride / ethanol / 2 h / 30 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: palladium diacetate; potassium carbonate 2: ammonia
	Multi-step reaction with 2 steps 1: potassium carbonate; palladium diacetate; triphenylphosphine / acetonitrile; lithium hydroxide monohydrate / 3.5 h / 60 - 70 °C / Inert atmosphere 2: hydrogenchloride / lithium hydroxide monohydrate; methanol / 2.5 h / 10 °C
	Multi-step reaction with 2 steps 1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile / Inert atmosphere; Reflux 2: hydrogenchloride / ethanol / Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile; lithium hydroxide monohydrate / Inert atmosphere; Reflux 2: hydrogenchloride; lithium hydroxide monohydrate; ethanol / Reflux

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/162604, 2016, A1
[2]Yu, Jiang; Zhou, Peiting; Hu, Mingxing; Yang, Liuqing; Yan, Guoyi; Xu, Ruixue; Deng, Yufang; Li, Xinghai; Chen, Yuanwei [European Journal of Medicinal Chemistry, 2019, vol. 182]
[3]Current Patent Assignee: SICHUAN UNIVERSITY - CN110669049, 2020, A
[4]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116476, 2020, A
[5]Current Patent Assignee: SHENZHEN TARGETRX INC - EP3932908, 2022, A1
[6]Current Patent Assignee: SHENZHEN TARGETRX INC - EP3932908, 2022, A1
[7]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN113861115, 2021, A
[8]Bao, Qiqi; Han, Xiaoli; Huang, Chenchao; Li, Xiaoyu; Wu, Meng; Xiao, Xiaohui; Xu, Qian; Zhang, Rongyu; Zhang, Zixiong; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]

16
[ 154607-01-9 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile; lithium hydroxide monohydrate / 0.5 h / Inert atmosphere; Reflux 1.2: 2.5 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / lithium hydroxide monohydrate / 2 h / 10 °C 2.2: 4 h / 0 - 5 °C 3.1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / ethyl acetate / 10 - 20 °C / Inert atmosphere 5.1: sodium tetrahydridoborate; ethanol / ethanol
	Multi-step reaction with 5 steps 1.1: trans-bis(triphenylphosphine)palladium(II) dichloride; anhydrous sodium carbonate / lithium hydroxide monohydrate; tetrahydrofuran / 40 °C 2.1: hydrogenchloride / ethanol / Reflux 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 3.2: 24 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 5.1: sodium tetrahydridoborate / tetrahydrofuran; methanol / 20 °C
	Multi-step reaction with 4 steps 1.1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 3 h / 40 °C / Inert atmosphere 2.1: hydrogenchloride / ethanol / 2 h / 30 °C / Inert atmosphere 3.1: triphenylphosphine / ethyl acetate / 0.5 h / Inert atmosphere 3.2: 3 h / 20 °C / Inert atmosphere 3.3: 1 h / 20 °C / Inert atmosphere 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere

	Multi-step reaction with 5 steps 1.1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile / Inert atmosphere; Reflux 2.1: hydrogenchloride / ethanol / Reflux 3.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 3.2: Reflux 4.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 5.1: sodium tetrahydridoborate; ethanol
	Multi-step reaction with 6 steps 1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile; lithium hydroxide monohydrate / Inert atmosphere; Reflux 2: hydrogenchloride; lithium hydroxide monohydrate; ethanol / Reflux 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 4: hydrogenchloride; lithium hydroxide monohydrate / acetonitrile / Reflux 5: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 6: sodium tetrahydridoborate; ethanol

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/162604, 2016, A1
[2]Yu, Jiang; Zhou, Peiting; Hu, Mingxing; Yang, Liuqing; Yan, Guoyi; Xu, Ruixue; Deng, Yufang; Li, Xinghai; Chen, Yuanwei [European Journal of Medicinal Chemistry, 2019, vol. 182]
[3]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116476, 2020, A
[4]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN113861115, 2021, A
[5]Xu, Qian; Zhang, Zixiong; Huang, Chenchao; Bao, Qiqi; Zhang, Rongyu; Wu, Meng; Xiao, Xiaohui; Han, Xiaoli; Li, Xiaoyu; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]

17
[ 154607-01-9 ]
[ 73183-34-3 ]
[ 945391-06-0 ]

Yield	Reaction Conditions	Operation in experiment
20%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80.0℃; for 12.0h;Inert atmosphere;	Under N2 atmosphere, bis(pinacolato)diboron (391mg, 1.54mmol), potassium acetate (412mg, 4.5mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (102mg, 0.14mmol) were respectively added to a solution of 2-chloro-4-bromobenzonitrile (300mg, 1.4mmol) in dioxane (15mL). The mixture was stirred at 80C for 12hrs, cooled to room temperature, filtered through celite, washed with EA (50mL). The filtrate was evaporated under reduced pressure, and the residue was purified by silica preparative plate to give white solid 23-b (73mg, yield 20%). 1H-NMR (400MHz, CDCl3) delta: 7.78 (d, J=7.6 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.52 (dd, J=7.6 Hz, 1.2 Hz, 1H), 1.37 (s, 12H) ppm.

Reference： [1]Patent: EP3275867,2018,A1 .Location in patent: Paragraph 0206; 0207

18
[ 154607-01-9 ]
[ 652148-92-0 ]
2-chloro-4-(6-chloropyridin-2-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); triethylamine In tetrahydrofuran; water at 20℃; for 18h; Inert atmosphere; chemoselective reaction;

Reference： [1]Guo, Pengfei; Zhang, Hao; Zhou, Jianguang; Gallou, Fabrice; Parmentier, Michael; Wang, Hui [Journal of Organic Chemistry, 2018, vol. 83, # 14, p. 7523 - 7527]

19
[ 154607-01-9 ]
[ 175883-60-0 ]
C₁₄H₉Cl₂NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: A reaction mixture of 2a-e (5.0 mmol, 1.0 equiv.), differentsubstituted 4-bromobenzonitrile (6.0 mmol, 1.2 equiv.) and potassiumcarbonate (12.5 mmol, 2.5 equiv.) in PEG400/H20 (10 mL/10 mL) was stirred at room temperature for 15 min, and PdCl2(0.05 mmol, 0.01 equiv.) was subsequently added. Stirring wascontinued for an additional 15 h until complete consumption ofstarting material as judged by TLC. Then the reaction mixture waspoured into water (80 mL) and extracted with ethyl acetate(30 mL*3). The organic layers were washed with brine, dried overanhydrous Na2SO4, filtered and condensed under reduced pressure.The residuewas then purified via column chromatography on silicagel, eluting with EtOAc/petroleum ether to 3a-r as white solid.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 182
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 11430 - 11436

Same Skeleton Products

Related Products

Historical Records

Related Functional Groups of
[ 154607-01-9 ]

Aryls

[ 99835-27-5 ]

4-Bromo-2,6-dichlorobenzonitrile

Similarity: 0.92

[ 914250-82-1 ]

3-Bromo-2-chlorobenzonitrile

Similarity: 0.92

[ 57381-49-4 ]

2-Bromo-4-chlorobenzonitrile

Similarity: 0.88

[ 57418-97-0 ]

4-Bromo-3-chlorobenzonitrile

Similarity: 0.86

[ 304854-55-5 ]

3-Bromo-5-chlorobenzonitrile

Similarity: 0.86

Bromides

[ 99835-27-5 ]

4-Bromo-2,6-dichlorobenzonitrile

Similarity: 0.92

[ 914250-82-1 ]

3-Bromo-2-chlorobenzonitrile

Similarity: 0.92

[ 57381-49-4 ]

2-Bromo-4-chlorobenzonitrile

Similarity: 0.88

[ 57418-97-0 ]

4-Bromo-3-chlorobenzonitrile

Similarity: 0.86

[ 304854-55-5 ]

3-Bromo-5-chlorobenzonitrile

Similarity: 0.86

Chlorides

[ 99835-27-5 ]

4-Bromo-2,6-dichlorobenzonitrile

Similarity: 0.92

[ 914250-82-1 ]

3-Bromo-2-chlorobenzonitrile

Similarity: 0.92

[ 57381-49-4 ]

2-Bromo-4-chlorobenzonitrile

Similarity: 0.88

[ 57418-97-0 ]

4-Bromo-3-chlorobenzonitrile

Similarity: 0.86

[ 304854-55-5 ]

3-Bromo-5-chlorobenzonitrile

Similarity: 0.86

Nitriles

[ 99835-27-5 ]

4-Bromo-2,6-dichlorobenzonitrile

Similarity: 0.92

[ 914250-82-1 ]

3-Bromo-2-chlorobenzonitrile

Similarity: 0.92

[ 57381-49-4 ]

2-Bromo-4-chlorobenzonitrile

Similarity: 0.88

[ 57418-97-0 ]

4-Bromo-3-chlorobenzonitrile

Similarity: 0.86

[ 304854-55-5 ]

3-Bromo-5-chlorobenzonitrile

Similarity: 0.86

Ghs Precautionary Statements

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
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

Ghs Hazard Statements

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