[ CAS No. 57381-37-0 ] {[proInfo.proName]}

Name: 57381-37-0|2-Bromo-5-chlorobenzonitrile|98%
Brand: Ambeed
SKU: A170262
Price: 6.0 USD
Availability: InStock
Rating: 97 (35 reviews)

,{[proInfo.pro_purity]}

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

DV 2D 3D

3d Animation Molecule Structure of 57381-37-0

Structure of 57381-37-0 * 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 [ 57381-37-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 57381-37-0 ]

SDS Specification

Alternatived Products of [ 57381-37-0 ]

Product Details of [ 57381-37-0 ]

CAS No. :	57381-37-0	MDL No. :	MFCD08445660
Formula :	C₇H₃BrClN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CTSHRMBLMKPDAG-UHFFFAOYSA-N
M.W :	216.46	Pubchem ID :	10330944
Synonyms :

Calculated chemistry of [ 57381-37-0 ]

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 :	1.69

Safety of [ 57381-37-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H312-H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 57381-37-0 ]

* 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 [ 57381-37-0 ]
Downstream synthetic route of [ 57381-37-0 ]

[ 57381-37-0 ] Synthesis Path-Upstream 1~4

1
[ 925-90-6 ]
[ 57381-37-0 ]
[ 22246-02-2 ]

Yield	Reaction Conditions	Operation in experiment
34.6%	Stage #1: at 0 - 5℃; for 5 h; Inert atmosphere Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃; for 16 h; Inert atmosphere	To a stirred solution of 2-bromo-5-chlorobenzonitrile (80 g, 370 mmol) in THF (1000 mL) at 0°C was added EtMgBr (370 mL, 1110 mmol) dropwise. The reaction mixture was stilTed at 0-5°C for 5 hours before MeOH (500 mL) was added dropwise. After the solution was stilTed for another 15 mm, NaBH4 (28 g, 740 mmol) was added carefully and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then poured into water and exacted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crudeproduct, which was purified by column chromatography (petroleum ether: EtOAc =3: 1) to afford the title compound (30 g, 34.6percent) as yellowish oil. MS: 235.5 [M+H’i.

Reference： [1] Patent: WO2014/191340, 2014, A1, . Location in patent: Page/Page column 37; 38

2
[ 766-84-7 ]
[ 57381-37-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid In trifluoroacetic acid at 24 - 31℃; for 6.13333 h;	An alternative synthesis of compound 1-2 follows: To a solution of 3-chlorobenzonitrile 1-1 (50 g, 360 mmol) in trifluoroacetic acid (180 mL) was added sulfuric acid (24 mL) and then 1,3-dibromo-5,5-dimethylhydantoin (67 g, 234 mmol) in portions over 8 minutes. The reaction temperature was allowed to reach 31° C. and then cooling was applied to bring the temperature to 24° C. After a 6 hour age, the heterogeneous reaction was cooled to 10° C. and water (250 mL) was added. Following a 10 minute age, the reaction was filtered and the product cake was washed twice with water (250 and 100 mL) to afford a white solid (52.4 g, 63percent). 1H NMR (CDCl3, 400 MHz) 6 7.64-7.62 (m, 2H), 7.44 (dd, J=8.6, 2.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ134.2, 134.1, 133.9, 133.8, 123.3, 117.2, 115.8

Reference： [1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 9, p. 3026 - 3035
[2] Tetrahedron, 2004, vol. 60, # 50, p. 11367 - 11374
[3] Organic Letters, 2006, vol. 8, # 18, p. 3903 - 3906
[4] Patent: US2004/181070, 2004, A1, . Location in patent: Page 11
[5] Patent: US2004/181070, 2004, A1, . Location in patent: Page 11

3
[ 21739-93-5 ]
[ 124-63-0 ]
[ 57381-37-0 ]

Reference： [1] Patent: US5130318, 1992, A,

4
[ 174265-12-4 ]
[ 57381-37-0 ]

Reference： [1] Tetrahedron Letters, 2018, vol. 59, # 29, p. 2844 - 2847
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 42, p. 7959 - 7963

[ 57381-37-0 ] Synthesis Path-Downstream 1~87

1
[ 57381-37-0 ]
N-[1-(5-chloro-2-(pyridin-4-yl)phenyl)vinyl]acetamide [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 3903 - 3906

2
[ 57381-37-0 ]
[ 304462-63-3 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374
[2]Tetrahedron,2004,vol. 60,p. 11367 - 11374

3
[ 57381-37-0 ]
[ 256951-72-1 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374
[2]Tetrahedron,2004,vol. 60,p. 11367 - 11374

4
[ 57381-37-0 ]
[ 732275-75-1 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374
[2]Tetrahedron,2004,vol. 60,p. 11367 - 11374
[3]Tetrahedron,2004,vol. 60,p. 11367 - 11374
[4]Tetrahedron,2004,vol. 60,p. 11367 - 11374
[5]Tetrahedron,2004,vol. 60,p. 11367 - 11374

5
[ 57381-37-0 ]
[ 819070-54-7 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374

6
[ 57381-37-0 ]
[ 819070-55-8 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374

7
[ 57381-37-0 ]
[ 757976-80-0 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374

8
[ 57381-37-0 ]
[ 757976-86-6 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374

9
[ 57381-37-0 ]
5-chloro-2-piperidin-4-ylbenzonitrile [ No CAS ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 11367 - 11374
[2]Tetrahedron,2004,vol. 60,p. 11367 - 11374

10
[ 541-41-3 ]
[ 57381-37-0 ]
[ 220269-80-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	for 5h;Heating / reflux;	A suspension of <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (58.5 g, 297 mmol) in ethyl chloroformate (141 mL, 1.48 mol) was heated at reflux for 5 h. The excess ethyl chloroformate (99 mL) was distilled off and toluene (96 mL) was added. Slow addition of cyclohexane (228 mL) induced crystallization. The resulting solid was collected by filtration and rinsed with cyclohexane. Drying in vacuo afforded the title compound (54.3 g, 68%) as an orange solid. MS: m/e=267.1/269.2 (M-H-).

Reference： [1]Patent: US2006/84642,2006,A1 .Location in patent: Page/Page column 9

11
[ 21739-93-5 ]
[ 124-63-0 ]
[ 57381-37-0 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; thionyl chloride; ammonia; In dichloromethane; chloroform;	(ii) Methanesulphonyl chloride (0.85 ml) was added to a solution of 2-bromo-5-chlorobenzoic acid (2.55 g) and pyridine (1.3 ml) in dichloromethane (5 ml) under an atmosphere of argon. The mixture was stirred for 1.5 hours and then gaseous ammonia was bubbled through for 5 minutes. Volatile material was removed by evaporation and the residue was suspended in chloroform (5 ml). Thionyl chloride (3 ml) was added and the mixture was heated under reflux for 20 hours. Volatile material was removed by evaporation and the residue was partitioned between dichloromethane (50 ml) and water (30 ml). The organic layer was separated, washed with water (30 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue recrystallized from ethyl acetate/hexane (1:1 v/v) to give 2-bromo-5-chlorobenzonitrile (B) (1.64 g), m.p. 135-137 C.; NMR (CDCl3): 7.4(dd,1H), 7.6(d,1H), 7.65(d,1H).

Reference： [1]Patent: US5130318,1992,A

12
[ 616-45-5 ]
[ 57381-37-0 ]
[ 942317-48-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 10 - 35℃;Inert atmosphere; Reflux;	Example 35; 5-chloro-1-[5-chloro-2-(2-oxopyrrolidin-1-yl)benzyl]-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride; (Step 1); To a solution (139 ml) of <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (15.0 g), pyrrolidin-2-one (7.90 ml) and cesium carbonate (45.2 g) in 1,4-dioxane were added tris(dibenzylideneacetone)dipalladium (1.59 g) and 4,5-bis(biphenylphosphino)-9,9-dimethylxanthine (2.0 g) at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 3 hr. The mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The organic layer was filtered through celite, and washed with ethyl acetate. The filtrate was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate:hexane=1:10?1:1) to give 5-chloro-2-(2-oxopyrrolidin-1-yl)benzonitrile (12.5 g) as yellow crystals. 1H NMR (400 MHz, CD3OD) delta ppm 2.24-2.31 (2H, m) 2.62 (2H, t, J=8.0 Hz), 3.94 (2H, t, J=6.8 Hz) 7.39 (1H, d, J=9.2 Hz) 7.60 (1H, dd, J=2.4, 8.8 Hz) 7.67 (1H, d, J=2.4 Hz).

Reference： [1]Patent: US2009/270393,2009,A1 .Location in patent: Page/Page column 44

13
[ 939052-79-6 ]
[ 57381-37-0 ]
[ 1227700-96-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3026 - 3035

14
[ 1765-93-1 ]
[ 57381-37-0 ]
[ 1227701-05-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3026 - 3035

15
[ 1692-25-7 ]
[ 57381-37-0 ]
[ 1227701-06-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3026 - 3035

16
[ 98-80-6 ]
[ 57381-37-0 ]
[ 37863-79-9 ]

Yield	Reaction Conditions	Operation in experiment
73.6%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 70℃; for 40h;Inert atmosphere;	2-Bromo-5-chloro-benzonitrile (297.0 g, 1.372 mol), phenyl boronic acid (184.0 g,1.509 mol), sodium carbonate (436.3 g, 4.116 mol), 1,2-dimethoxyethane (4455 mL) and water (1485 mL) were added to a vessel under nitrogen. The flask was degassed three times with nitrogen and tetrakis(triphenylphosphine)palladium(0) (79.3 g, 0.069 mol) wasadded. The flask was degassed three times with nitrogen and was stirred and heated to70C and then stirred at that temperature for 24 h. Further phenyl boronic acid (36.8 g,0.302 mol), sodium carbonate (87.3 g, 0.824 mol) and tetrakis(triphenylphosphine)palladium (15.9 g, 0.014 mol) were added and the mixture stirred for a further 16 h. Thereaction was cooled to room temperature and the suspension was filtered and the solidwashed with ethyl acetate (2 x 2000 mL). The combined filtrates were separated and theorganic layer was washed with saturated brine (2 x 2000 mL). The organic layer was dried over anhydrous magnesium sulphate, filtered and the solid washed with ethyl acetate (1000 mL). The combined filtrates were concentrated whilst absorbing onto silica gel (600 g). The crude material was purified on silica gel (6 Kg) eluting with 25-50%toluene in heptane. The pure fractions were combined and concentrated to give a whitesolid. The solid was azeotroped with heptane (8 x 800 mL) to remove any residualtoluene and give the target compound. Yield = 215.9 g (73.6 %).1H NMR (270 MHz, DMSO d6) O 8.18- 8.12 (m, 1 H), 7.86 (dd, J = 8.4 Hz, 2.4 Hz, 1H),7.7 - 7.45 (m, 6 H).

Reference： [1]Patent: WO2014/207445,2014,A1 .Location in patent: Page/Page column 61
[2]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3026 - 3035

17
[ 1341204-97-4 ]
[ 57381-37-0 ]
2-(5-(4'-chloro-2'-cyanobiphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 85℃; for 21h;	2-{5-[4-(4,4,5,5-Tetramethyl-[l ,3,2]dioxaborolan-2-yl)-phenyl]-l H-imidazol- 2-yl} -pyrrolidine- 1-carboxylic acid fer/-butyl ester (2 g, 4.55 mmol), 2-Bromo-5-chloro- benzonitrile (985 mg, 4.55 mmol), Pd(PPh3)4 (263 mg, 0.228 mmol) and a 2 M aqueous solution of potassium carbonate (4.6 mL, 9.2 mmol) were suspended in 1 ,2-methoxyethane (20 mL) and degassed for 10 min. The stirred reaction mixture was heated to 85 C for 21 hours then poured into a saturated aqueous solution OfNaHCO3 (250 mL). The aqueous phase was extracted 3 times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (65% to 90% EtOAc/hexanes) to afford 2-[5-(4'-Chloro-2'-cyano-biphenyl-4-yl)-1H-irnidazol-2-yl]- pyrrolidine- 1-carboxylic acid tert-butyl ester (1.65 g, 81%).

Reference： [1]Patent: WO2010/132601,2010,A1 .Location in patent: Page/Page column 618

18
[ 1338326-89-8 ]
[ 57381-37-0 ]
[ 1338326-45-6 ]

Yield	Reaction Conditions	Operation in experiment
44.1%	With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; water; at 100℃; for 0.666667h;Sealed tube; Microwave irradiation; Inert atmosphere;	Example 22: 4'-( -Amino-5-oxo-7,8-dihvdropyrimidor5.,4-H [l,41oxazepin-6(5H)-vD-4- chlorobiphenyl-2-carbonitrile; 4-Amino-6-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)-7,8- dihydropyrimido[5,4-f][l ,4]oxazepin-5(6H)-one (Intermediate 8; 250 mg, 0.65 mmol), 2- bromo-5-chlorobenzonitrile (156 mg, 0.72 mmol), (l , l'-bis(diphenylphosphino)ferrocene)- dichloropalladium(II) (DCM adduct) (26.7 mg, 0.03 mmol) and tripotassium phosphate (167 mg, 0.78 mmol) were suspended in DME (3 mL), ethanol (1.5 mL) and water (0.75 mL) and sealed into a microwave tube. The mixture was degassed under vacuum and the atmosphere replaced with nitrogen. The reaction was heated to 1 10 C for 40 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with methyl THF (60 mL), and washed sequentially with water (30 mL) and saturated brine (30 mL), filtered then evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 1 to 6% MeOH in DCM. Pure fractions were evaporated to dryness and triturated with ether to afford 4'-(4-amino-5-oxo-7,8- dihydropyrimido[5,4-f][l ,4]oxazepin-6(5H)-yl)-4-chlorobiphenyl-2-carbonitrile (1 13 mg, 44.1 %) as a white solid. 1H NMR (400 MHz, DMSO) delta 4.05 - 4.10 (2H, m), 4.60 - 4.66 (2H, m), 7.55 - 7.60 (2H, m), 7.63 (2H, s), 7.65 - 7.69 (3H, m), 7.88 (1H, dd), 8.15 (1H, d), 8.18 (1H, s). m z (ES+) (M+H)+ = 392

Reference： [1]Patent: WO2011/121350,2011,A1 .Location in patent: Page/Page column 71-72

19
[ 1338327-38-0 ]
[ 57381-37-0 ]
[ 1338326-72-9 ]

Yield	Reaction Conditions	Operation in experiment
24.94%	With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; ethanol; water; at 130℃; for 1.5h;Sealed tube; Microwave irradiation; Inert atmosphere;	Example 50 : (R)-4 '-( 4-Amino-8-methyl-5-oxo-7,8-dihvdropyrimido [5,4- f\| [ 1 ,41 oxazepin-6( 5H)-yl)-4-chloro-2 '-fluor obiphenyl-2-carbonitrile; (i~)-4-Amino-6-(3-fluoro-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)-8- methyl-7,8-dihydropyrimido[5,4-f][l ,4]oxazepin-5(6H)-one (Intermediate 51 ; 290 mg, 0.70 mmol), PdCl2(dppf)-DCM adduct (28.6 mg, 0.04 mmol), potassium phosphate (0.07 mL, 0.84 mmol) and <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (182 mg, 0.84 mmol) were suspended in DME (3 mL), ethanol (1.5 mL) and water (0.75 mL) and sealed into a microwave tube, degassed under vacuum and the atmosphere replaced with nitrogen. The reaction was heated to 130 C for 90 minutes in the microwave reactor and cooled to RT. The reaction mixture was evaporated to dryness and redissolved in methyl THF (25 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over Na2SC"4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep CI 8 OBD column, 5mu silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (74.0 mg, 24.94 %) as a white solid. 1H NMR (400 MHz, CDC13, 30C) 2.61 (3H, s), 3.89 - 4.00 (2H, m), 4.86 - 5.08 (1H, m), 5.51 - 5.74 (1H, m), 7.22 (1H, d), 7.49 (2H, dd), 7.66 (1H, dd), 7.78 (1H, d), 7.82 - 8.07 (1H, m), 8.33 (1H, s). m/z (ES+), (M+H)+ = 424

Reference： [1]Patent: WO2011/121350,2011,A1 .Location in patent: Page/Page column 83-84

20
[ 57381-37-0 ]
[ 1394908-05-4 ]

Reference： [1]Patent: WO2012/113850,2012,A2

21
[ 57381-37-0 ]
[ 1394908-06-5 ]

Reference： [1]Patent: WO2012/113850,2012,A2

22
[ 57381-37-0 ]
[ 1394909-43-3 ]

Reference： [1]Patent: WO2012/113850,2012,A2

23
[ 57381-37-0 ]
[ 1394909-44-4 ]

Reference： [1]Patent: WO2012/113850,2012,A2

24
[ 141-91-3 ]
[ 57381-37-0 ]
[ 1394910-02-1 ]

Yield	Reaction Conditions	Operation in experiment
39%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 145℃; for 5h;Inert atmosphere; Sealed tube; Microwave irradiation;	5-chloro-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-benzonitrile (Intermediate 54)(Intermediate 54)A mixture of Xantphos [161265-03-8] (294 mg, 0.51 mmol) and Pd2(dba)3 (211 mg, 0.23 mmol) in dry 1,4-dioxane (75 mL) was degassed for 5 min. Cis-2,6- dimethylmorpholine (1.5 mL, 12.13 mmol), <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (2.5 g,11.55 mmol) and cesium carbonate (7.52 g, 23.10 mmol) were added and the mixture was further degassed with nitrogen for 5 min. The tube was sealed and the reaction mixture was stirred at 145 C for 5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent gradient DCM/heptanes 0/100 to 100/0). The desired fractions were collected and evaporated, yielding 1.39 g (39 %) of Intermediate 54 as a yellow oil.

Reference： [1]Patent: WO2012/113850,2012,A2 .Location in patent: Page/Page column 55

25
[ 325142-95-8 ]
[ 57381-37-0 ]
[ 1394909-42-2 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	5-chloro-2-(2,6-dimethyl-4-pyridinyl)-benzonitrile (Intermediate 1)(Intermediate 1)A mixture of <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (10.03 g, 46.33 mmol), 2,6- dimethylpyridine-4-boronic acid, pinacol ester ([325142-95-8], 16.20 g, 69.50 mmol), tetrakis(triphenylphosphine)palladium (3.21 g, 2.78 mmol), 1,4-dioxane (50 mL), and sodium carbonate (14.73 g, 139.00 mmol) in water (50 mL) was stirred and heated under nitrogen atmosphere at 100 C for 2 h. The reaction was diluted with CH2CI2 and water and the layers were separated. The organic layer was dried with MgS04, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 98/2 DCM/MeOH). The desired fractions were collected and evaporated, yielding 8.73 g (77 %) of Intermediate 1, after drying overnight under vacuum at 50 C.

Reference： [1]Patent: WO2012/113850,2012,A2 .Location in patent: Page/Page column 34

26
[ 57381-37-0 ]
[ 1440519-72-1 ]

Reference： [1]Patent: WO2013/79452,2013,A1

27
[ 57381-37-0 ]
[ 1396777-82-4 ]

Reference： [1]Patent: WO2013/79452,2013,A1
[2]Patent: WO2016/55394,2016,A1

28
[ 23719-80-4 ]
[ 57381-37-0 ]
[ 1270382-70-1 ]

Yield	Reaction Conditions	Operation in experiment
34%		To a solutionof <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (20 g, 93 mmol) in THF (200 mL) was added cyclopropylmagnesiumbromide (558 mL, 279 mmol) at 0 C. The resulting reaction - 151 -mixture was stirred at 0-5 C for 5 hours before MeOH (100 mL) was added and stirring continued at room temperature for 15 min. NaBH4 (7.1 g, 186 mmol) was added subsequently and the reaction mixture was stirred at room temperature overnight. Water was added and reaction mixture was exacted with AcOEt (300 mL x 3). The combined organic layers were concentrated in vacuo to give a crude product which was then purified by chromatography to give (2-bromo-5-chlorophenyl)(cyclopropyl)methanamine (8.2 g, yield 34%).

Reference： [1]Patent: WO2013/79452,2013,A1 .Location in patent: Page/Page column 150; 155

29
[ 925-90-6 ]
[ 57381-37-0 ]
[ 1260841-26-6 ]

Yield	Reaction Conditions	Operation in experiment
17.6%		To a stirred solution of <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (10 g, 46 mmol) and Ti(Oi-Pr)4 (16.64 mL, 55 mmol) in THF (200 mL) at -78 C was added EtMgBr (138 mL, 138 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred - 168 -for 2 hours. BF3-Et20 (17.2 mL) was added, and the solution was stirred for another 16 hours before it was quenched with aq. HCl solution and washed with EtOAc. The aqueous phase was adjusted to pH ~ 10 with aq. NaOH solution, and exacted with EtOAc (3 x). The combined organic layers were concentrated to give a crude product which was purified by chromatography to afford title compound (2 g, yield 17.6%). MS: 246.7 (M+H+, lCl) as oil.
17.6%		GammaAlpha1 l-(2-Bromo-5-chloro-phenyl)cvclopropanamine To a stirred solution of <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (10 g, 46 mmol) and Ti(Oi-Pr)4 (16.64 mL, 55 mmol) in THF (200 mL) at -78C was added EtMgBr (138 mL, 138 mmol) drop wise. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. BF3-Et20 (17.2 mL) was added, and the solution was stirred for another 16 hours before it was quenched with aq. HCl solution and washed with EtOAc. The aqueous phase was adjusted to pH - 10 with aq. NaOH solution, and exacted with EtOAc three times. The combined organic layers were concentrated to give a crude product which was purified by silica gel flash chromatography to afford title compound (2 g, 17.6%). MS: 246.7 (M+H+, 1C1) as oil.

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 19000 - 19006
Angew. Chem.,2019,vol. 131,p. 19176 - 19182,7
[2]Patent: WO2013/79452,2013,A1 .Location in patent: Page/Page column 167; 168
[3]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 47; 48

30
7,7-diethyl-4-methoxy-2,2,5-trimethyl-3,6-dioxa-2,7-disilanon-4-ene [ No CAS ]
[ 57381-37-0 ]
methyl 3-(4-chloro-2-cyanophenyl)-2-((triethylsilyl)oxy)propanoate [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5056 - 5059

31
[ 57381-37-0 ]
[ 1609162-48-2 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 5641 - 5643

32
[ 768-60-5 ]
[ 57381-37-0 ]
[ 1609162-62-0 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 5641 - 5643
[2]Chemical Communications,2017,vol. 53,p. 6828 - 6831

33
[ 107-19-7 ]
[ 57381-37-0 ]
[ 1609162-66-4 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 5641 - 5643

34
[ 57381-37-0 ]
[ 1440519-59-4 ]

Reference： [1]Patent: WO2014/191336,2014,A1
[2]Patent: WO2014/191338,2014,A1
[3]Patent: WO2016/55394,2016,A1

35
[ 925-90-6 ]
[ 57381-37-0 ]
1-(2-bromo-5-chloro-phenyl)-ethylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		To a stirred solution of <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (80 g, 370 mmol) in THF (1000 mL) at 0C was added EtMgBr (370 mL, 1110 mmol) drop wise. The reaction mixture was stilTed at 0-5C for 5 hours before MeOH (500 mL) was added drop wise. After thesolution was stilTed for another 15mm, NaBH4 (28 g, 740 mmol) was added carefully and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then poured into water, exacted with EtOAc (3 x). The organic combined layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by column (petroleum ether: EtOAc =3: 1) to afford title compound (30 g,35%) as yellowish oil. MS: 235.5 (M+H).
34.6%		To a stirred solution of <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (80 g, 370 mmol) in THF (1000 mL)at 0C was added EtMgBr (370 mL, 1110 mmol) dropwise. The reaction mixture wasstuffed at 0-5C for 5 hours before MeOH (500 mL) was added dropwise. After the solution was stuffed for another 15 mi NaBH4 (28 g, 740 mmol) was added carefully and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then poured into water and exacted with EtOAc (3 x). The combined organic layerswere dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by column chromatography (petroleum ether: EtOAc =3: 1) to afford the title compound (30 g, 34.6%) as yellowish oil. MS: 235.5 [M+Hj.

Reference： [1]Patent: WO2014/191336,2014,A1 .Location in patent: Page/Page column 40
[2]Patent: WO2014/191338,2014,A1 .Location in patent: Page/Page column 38; 39

36
[ 75-16-1 ]
[ 57381-37-0 ]
1-(2-bromo-5-chloro-phenyl)-1-methyl-ethylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of <strong>[57381-37-0]2-bromo-5-chloro-benzonitrile</strong> (10 g, 46 mmol) in THF (200 mL)at 0C, was added MeMgBr (77 mL, 230 mmol) drop wise. The reaction mixture wasallowed to warm up to room temperature and stuffed for 2 hours. Ti(Oi-Pr)4 (13 g, 46 mmol) was added and the solution was stuffed for another 16 hours before it was quenched with aq. HC1 solution and washed with EtOAc. The aqueous phase was adjusted to pH 10 with aq. NaOH solution, and exacted with EtOAc (3x). The combined organic layers were concentrated to give a crude title product (3.8 g, 33%) as oil, which was used directly in the next step without further purification. MS: 249.30 (M+H).
		To a stirred solution of <strong>[57381-37-0]2-bromo-5-chloro-benzonitrile</strong> (10 g, 46 mmol) in THF (200 mL)at 0C, was added MeMgBr (77 mL, 230 mmol) dropwise. The reaction mixture wasallowed to warm up to room temperature and stuffed for 2 hours. Ti(Oi-Pr)4 (13 g, 46mmol) was added and the solution was stuffed for another 16 hours before it was quenchedwith aq. HC1 solution and washed with EtOAc. The aqueous phase was adjusted to pH 10 with aq. NaOH solution, and exacted with EtOAc (3 x 100 mL). The combined organic layers were concentrated to give a crude title product (3.8 g, yield 33%) as oil, which was used directly in the next step without further purification. MS: 249.30 (M+Hj
		To a stirred solution of <strong>[57381-37-0]2-bromo-5-chloro-benzonitrile</strong> (10 g, 46 mmol) in THF (200 mL) at 0C, was added MeMgBr (77 mL, 230 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stuffed for 2 hours. Ti(Oi-Pr)4 (13 g, 46 mmol) was added and the solution was stuffed for another 16 hours before it was quenchedwith aq. HC1 solution and washed with EtOAc. The aqueous phase was adjusted to pH10 with aq. NaOH solution, and exacted with EtOAc (3 x). The combined organic layers were concentrated to give a crude title product (3.8 g, yield 33%) as oil, which was used directly in the next step without further purification. MS: 249.30 (M+H]

GammaAlpha1 l-(2-Bromo-5-chloro-phenyl)- 1-methyl-ethylamine To a stirred solution of <strong>[57381-37-0]2-bromo-5-chloro-benzonitrile</strong> (10 g, 46 mmol) in THF (200 mL) at 0 C, was added MeMgBr (77 mL, 230 mmol) drop wise. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Ti(Oi-Pr)4 (13 g, 46 mmol) was added and the solution was stirred for another 16 hours before it was quenched with aq. HC1 solution and washed with EtOAc. The aqueous phase was adjusted to pH ~ 10 with aq. NaOH solution, and exacted with EtOAc (3x). The combined organic layers were concentrated to give a crude title product (3.8 g, 33%) as oil, which was used directly in the next step without further purification. MS: 249.30 (M+H)+.

Reference： [1]Patent: WO2014/191336,2014,A1 .Location in patent: Page/Page column 41; 42
[2]Patent: WO2014/191340,2014,A1 .Location in patent: Page/Page column 38; 39
[3]Patent: WO2014/191338,2014,A1 .Location in patent: Page/Page column 39; 40
[4]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 39; 40

37
[ 57381-37-0 ]
4’-chloro-2’-cyano-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)biphenyl-4-sulfonamide [ No CAS ]

Reference： [1]Patent: WO2014/207445,2014,A1

38
[ 57381-37-0 ]
4-(4-chloro-2-cyanophenyl)benzene-1-sulfonyl chloride [ No CAS ]

Reference： [1]Patent: WO2014/207445,2014,A1

39
[ 57381-37-0 ]
4-(4-chloro-2-cyanophenyl)benzene-1-sulfonic acid [ No CAS ]

Reference： [1]Patent: WO2014/207445,2014,A1

40
N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ No CAS ]
[ 57381-37-0 ]
4’-chloro-2’-cyano-N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)[1,1‘-biphenyl]-4-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.8 g	With dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 6h;Inert atmosphere;	A solution of N-(( 1 s,4s)-4-hydroxy-4-methylcyclohexyl)-4-(4,4, 5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzenesulfonamide (17 g, 43.0 mmol), <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong>(14 g, 64.7 mmol), and sodium carbonate (9.lg, 86 mmol) in dioxane : water (240 mL,9:1) was degassed using argon for 10 mi [1,1-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (3.14 g, 4.3 mmol) was added and the reaction mixture was degassed for another 10 mm. The reaction mixture was heated at 110C for 6 hours. Solvent was evaporated under reduced pressure, water was added, and the compoundwas extracted in ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 100-200 mesh silica gel using 20-40% ethyl acetate in hexane as eluent. The fractions were concentrated to 1/1Qth the volume (85 mL) and then filtered. The residue obtained was washed with 20% ethyl acetate in hexane followed by n-pentane to afford the title compound. Yield: 5.8 g, 33% (over 2 steps).1H NMR (400 MHz, Chloroform-d) O 8.04-7.97 (m, 2H), 7.79 (d, J= 2.2 Hz, 1H), 7.69-7.64 (m, 3H), 7.48 (d, J= 8.4 Hz, 1H), 4.45 (d, J= 8Hz, 1H), 3.3-3.15 (br, 1H), 1.74-1.51 (m, 6H), 1.45-1.35 (m, 2H), 1.20 (5, 3H), 1.00 (5, 1H).LCMS: mobile phase A: 5 mM ammonium formate in water + 0.1% ammonia, mobile phase B: acetonitrile + 5% mobile phase A + 0.1% ammonia; Column: YMC Triart, C18(50X4.6 mm) 3uM; Flow rate: 1.4 mL/min. Run time: 4.5 mins - starting solvent 30:70 B:A is increased linearly to 95:5 B:A over the first 2 mins, held at 95:5 B:A for 1.5 mm, reduced linearly to 30:70 B:A over 0.5 mm and held at 30:70 B:A for the final 0.5 mm. Retention time 2.62 mm m/z403.30 [M-1].

Reference： [1]Patent: WO2014/207445,2014,A1 .Location in patent: Page/Page column 54; 55

41
N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [ No CAS ]
[ 57381-37-0 ]
4’-chloro-2’-cyano-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)biphenyl-4-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.5%	With dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 6h;Inert atmosphere;	A stirred solution of dioxane : water (9:1; 100 mL), N-((lr,4r)-4-hydroxy-4- methylcyclohexyl)-4-(4,4, 5, 5-tetramethyl- 1, 3,2-dioxaborolan-2-yl)benzenesulfonamide (12 g, 30.4 mmol), <strong>[57381-37-0]2-bromo-5-chlorobenzonitrile</strong> (9.86 g, 45.5 mmol) and sodium carbonate (6.44 g, 60.8 mmol) was degassed using argon for 10 minutes. [1,1- Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (2.21 g, 3.0 mmol) was added andthe reaction mixture was degassed for another 10 minutes and stirred at 11000 for 6 hours. The solvent was evaporated under reduced pressure and the compound was extracted into ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure followed by washing with n-pentane (twice) and dried under vacuum at 45-50C to give the title compound (5.7 g, 46.5%).1H NMR (400 MHz, methanol-d4) O 8.01 (d, J= 8.1 Hz, 2H), 7.95 (m, 1H), 7.83-7.74 (m,3H), 7.64(d, J= 8.5 Hz, 1H), 3.25-3.17(m, 1H), 1.8-1.54(m, 4H), 1.47-1.34(m, 4H),1.18 (5, 3H).LCMS: mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia, mobile phase B: acetonitrile + 5% mobile phase A + 0.1% ammonia; Column: YMC Triart, 018 (50X4.6 mm) 3uM; Flow rate: 1.4 mL/min. Run time: 4.5 mins - starting solvent 30:70 B:A is increased linearly to 95:5 B:A over the first 2.5 mins, held at 95:5 B:A for 0.5 mm, reduced linearly to 30:70 B:A over 1 mm and held at 30:70 B:A for the final 0.5 mm.Retention time 2.167 mi m/z403 (M-H).

Reference： [1]Patent: WO2014/207445,2014,A1 .Location in patent: Page/Page column 49

42
[ 98-86-2 ]
[ 57381-37-0 ]
7-chloro-3-phenylisoquinolin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With copper(I) oxide; caesium carbonate; In ethanol; at 60℃; for 12h;Schlenk technique; Inert atmosphere;	A mixture of <strong>[57381-37-0]5-chloro-2-bromobenzonitrile</strong> (107.5mg, 0.5mmol), cuprous oxide (36.0mg, 0.25mmol), cesium carbonate (489.3mg, 1.5mmol), methyl phenyl ketone (60.0mg, 0.5 after mmol) were added to a Schlenk reaction flask, vacuum, purged with nitrogen three times, in a nitrogen atmosphere, 10.0 mL of ethanol was added, the reaction 60 12 hours. after completion of the reaction, the solvent under reduced pressure, was removed by column chromatographic separation (elution with petroleum ether: ethyl acetate = 20: 1, V: V ), to give the product as a white solid 0.127g, 99%.

Reference： [1]Patent: CN104628643,2016,B .Location in patent: Paragraph 0061-0063
[2]Journal of Organic Chemistry,2015,vol. 80,p. 3998 - 4002

43
[ 105-36-2 ]
[ 57381-37-0 ]
diethyl (Z,Z)-3,3'-[4,4'-dichlorobiphenyl-2,2'-diyl]bis(3-aminoprop-2-enoate) [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 7824 - 7829

44
[ 100-52-7 ]
[ 57381-37-0 ]
4-amino-6-chloro-2-phenyl-quinazoline [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4236 - 4239

45
[ 62-53-3 ]
[ 57381-37-0 ]
5-chloro-2-(phenylamino)benzonitrile [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2017,vol. 2017,p. 6604 - 6608
[2]Organic Letters,2016,vol. 18,p. 1690 - 1693

46
[ 57381-37-0 ]
[ 1246849-56-8 ]

Reference： [1]Organic Letters,2016,vol. 18,p. 1690 - 1693

47
[ 57381-37-0 ]
C₁₉H₁₅ClN₂ [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 1690 - 1693
[2]European Journal of Organic Chemistry,2017,vol. 2017,p. 6604 - 6608

48
[ 57381-37-0 ]
2-(5-bromo-3-pyridyl)-5-chloro-3-methyl-isoindolin-1-one [ No CAS ]