[ CAS No. 57418-97-0 ] {[proInfo.proName]}

Name: 57418-97-0|4-Bromo-3-chlorobenzonitrile|98%
Brand: Ambeed
SKU: A109117
Price: 5.0 USD
Availability: InStock
Rating: 97 (35 reviews)

,{[proInfo.pro_purity]}

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

DV 2D 3D

3d Animation Molecule Structure of 57418-97-0

Structure of 57418-97-0 * 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 [ 57418-97-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 57418-97-0 ]

SDS Specification

Alternatived Products of [ 57418-97-0 ]

Product Details of [ 57418-97-0 ]

CAS No. :	57418-97-0	MDL No. :	MFCD09834777
Formula :	C₇H₃BrClN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YWTKUWXYQQZSIL-UHFFFAOYSA-N
M.W :	216.46	Pubchem ID :	16659395
Synonyms :

Calculated chemistry of [ 57418-97-0 ]

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) :	-5.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.03
Log Po/w (XLOGP3) :	3.14
Log Po/w (WLOGP) :	2.97
Log Po/w (MLOGP) :	2.79
Log Po/w (SILICOS-IT) :	3.12
Consensus Log Po/w :	2.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.6
Solubility :	0.0538 mg/ml ; 0.000249 mol/l
Class :	Soluble
Log S (Ali) :	-3.31
Solubility :	0.106 mg/ml ; 0.000491 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 :	1.63

Safety of [ 57418-97-0 ]

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

Application In Synthesis of [ 57418-97-0 ]

* 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 [ 57418-97-0 ]
Downstream synthetic route of [ 57418-97-0 ]

[ 57418-97-0 ] Synthesis Path-Upstream 1~3

1
[ 57418-97-0 ]
[ 120077-69-2 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 11, p. 3793 - 3816

2
[ 72635-78-0 ]
[ 57418-97-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2468 - 2485
[2] Patent: WO2005/82907, 2005, A2, . Location in patent: Page/Page column 56

3
[ 21803-75-8 ]
[ 57418-97-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 11, p. 3793 - 3816

[ 57418-97-0 ] Synthesis Path-Downstream 1~67

1
[ 72635-78-0 ]
[ 57418-97-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Patent: WO2005/82907,2005,A2 .Location in patent: Page/Page column 56

2
[ 57418-97-0 ]
[ 1066-54-2 ]
[ 914106-28-8 ]

Yield	Reaction Conditions	Operation in experiment
37%	With piperidine; copper(l) iodide; triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); at 90℃; for 1h;	3-chloro-4[(2-(trimethylsilyl)ethynyl]benzonitrile (61c). A mixture of aryl bromide 60c, (3.96 g, 18.2 mmol), (trimethylsilyl)acetylene (1.80 g, 18.23 mmol), PPh3 (0.24 g, 0.91 mol), Pd (PPh3)4 (0.11 g, 0.09 mmol), and Cul (0.17g, 0.91 mmol) in piperidine was stirred at 90 C for 1 h. The reaction mixture was poured into water and extracted into EtOAc. Column chromatography [hexanes/EtOAc (40:1)] gave a white solid (3.24 g, 37%); mp 82-83 C;1H NMR delta 8.27 (d, J = 1.9 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.3 and 1.9 Hz, 1H), 0.27 (s, 9H); HPLC (Method B) tR 9.41 min (100 area % at 265 nm). Anal. (C12H12ClNSi) C, H, N, Cl.; Reagents and conditions: (a) fuming HNO3, H2SO4; (b) Fe, AcOH, EtOH; (c) NaNO2, aq. HCl, then CuCl; (d) NalO4, l2, AcOH, AC2O, H2SO4; (e) NH2OH HCl, Py, EtOH (f) Ac2O; (g) TMSA, Pd2Cl2(PPh3)2, Cul, Et3N; (h) TMSA, PPh3, Pd(PPh3)4, Cul, piperidine; (j) 2-methyl-3-butyn-2-ol, Pd2Cl2(PPh3)2, Cul, Et3N; (k) 2-methyl-3-butyn-2-ol, 10% Pd/C, PPh3, Cul, aq. K2CO3/DME; (I) Cs2CO3, aq. CH3CN or MeOH; (m) NaH, toluene.; A second general method is depicted in Scheme 2 immediately hereinabove and comprises the cycloaddition of cyanophenylacetylenes 51 and benzaldehyde chlorooximes 52 in the presence of bis(tributyltin) oxide, see Moriya, O., et al., J. Chem. Soc., Perkin Trans., 1, 413-417 (1994); Moriya, O., et al., J. Chem. Soc., Chem. Commun., 17-18 (1991), or triethylamine, see Thomsen, l., et al., Acta Chem. Scand. (B), 319-313 (1988), in nonpolar solvents to give isoxazole dinitriles 53a-h,k-s and bromonitrile 53i. The latter was treated with copper(I) cyanide to give dinitrile 53j. See Friedman. L., et al., J. Org. Chem., 26, 2522-2524 (1961). This method also afforded alternate routes to dinitriles 50a,b,g, k prepared by the first method as provided in Scheme 1. The phenylacetylene synthons 51a-g were prepared as shown in Scheme 3 below. Starting materials 60a,e,g were commercially available. Nitration of 60a gave 60b. See Borsche, W., L., et al., Chem. Ber., 49, 2222-2243 (1916). The latter was reduced to aniline 56, see Blanksma, J. J., et al., Recl. Trav. Chim. Pays-Bas, 66, 365-373 (1947), which underwent diazotization followed by treatment with copper(l) chloride to give chlorobenzene 60c. Triflate 60d was prepared by treatment of 4-bromo-3-hydroxybenzonitrile with triflic anhydride. The preparation of aryl iodide 60f began with the known transformation of aldehyde 57 to iodo derivative 58. See Lulinski, P., et al., Bull. Chem. Soc. Jpn., 73(4), 951-956 (2000). Treatment of 58 with hydroxylamine hydrochloride gave aldoxime 59, which was dehydrated to give nitrile 60f using acetic anhydride. The aryl halides or triflates 60a-g were treated with (trimethylsilyl)acetylene, see Roesch. K. R., et al., J. Org. Chem., 66, 412-420 (2001), or with 2-methyl-3-butyn-2-ol, see Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998), to give intermediates 61a-f or 62a-f, respectively, of which 61a,d and 62a have been reported previously. See Dirk. S. M., et al., Tetrahedron, 59(3), 287-293 (2003); Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The acetylenes 51 (of which 51a,e were known previously), see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997); Dulog, L., et al., Liebigs Ann. Chem., 9, 1663-1671 (1995), were obtained by the treatment of intermediates 61 or 62 with cesium carbonate in acetonitrile or sodium hydride in toluene, respectively. See Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The use of cesium carbonate in acetonitrile was introduced for the deprotection of intermediates 61 after the treatment of compound 61b with potassium carbonate in methanol, see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997), failed to give product 51b. The pathway using 2-methyl-3-butyn-2-ol provided more economical preparations of all phenylacetylenes 51 except nitro analog 51b.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Patent: EP1719767,2006,A1 .Location in patent: Page/Page column 24-26; 40

3
[ 57418-97-0 ]
[ 115-19-5 ]
[ 914106-31-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With copper(l) iodide; potassium carbonate; triphenylphosphine;palladium 10% on activated carbon; In 1,2-dimethoxyethane; water;Heating / reflux;	3-Chloro-4-(3-hydroxy-3-methylbut-1-ynyl)benzonitrile (62b). 2-Methyl-3-butyn-2-ol (2.5 equiv) was added to a mixture of an aryl bromide 60c, K2CO3 (2.5 equiv), Cul (4 mol %), PPh3 (8 mol %), and 10% Pd/C (2 mol %) in DME and water. See Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The biphasic mixture was stirred at reflux under Ar overnight, and was then filtered (Celite) and partitioned between water and EtOAc. Column chromatography gave a white solid (4.25 g, 77%): mp 63-65 C (hexane); 1H NMR delta 8.18 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 8.1 and 1.6 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 5.68 (s, 1H), 1.50 (s, 6H); HPLC (Method B) tR 5.00 min (100 area % at 265 nm). Anal. (C12H10ClNO) C, H, N, Cl.; A second general method is depicted in Scheme 2 immediately hereinabove and comprises the cycloaddition of cyanophenylacetylenes 51 and benzaldehyde chlorooximes 52 in the presence of bis(tributyltin) oxide, see Moriya, O., et al., J. Chem. Soc., Perkin Trans., 1, 413-417 (1994); Moriya, O., et al., J. Chem. Soc., Chem. Commun., 17-18 (1991), or triethylamine, see Thomsen, l., et al., Acta Chem. Scand. (B), 319-313 (1988), in nonpolar solvents to give isoxazole dinitriles 53a-h,k-s and bromonitrile 53i. The latter was treated with copper(I) cyanide to give dinitrile 53j. See Friedman. L., et al., J. Org. Chem., 26, 2522-2524 (1961). This method also afforded alternate routes to dinitriles 50a,b,g, k prepared by the first method as provided in Scheme 1. The phenylacetylene synthons 51a-g were prepared as shown in Scheme 3 below. Starting materials 60a,e,g were commercially available. Nitration of 60a gave 60b. See Borsche, W., L., et al., Chem. Ber., 49, 2222-2243 (1916). The latter was reduced to aniline 56, see Blanksma, J. J., et al., Recl. Trav. Chim. Pays-Bas, 66, 365-373 (1947), which underwent diazotization followed by treatment with copper(l) chloride to give chlorobenzene 60c. Triflate 60d was prepared by treatment of 4-bromo-3-hydroxybenzonitrile with triflic anhydride. The preparation of aryl iodide 60f began with the known transformation of aldehyde 57 to iodo derivative 58. See Lulinski, P., et al., Bull. Chem. Soc. Jpn., 73(4), 951-956 (2000). Treatment of 58 with hydroxylamine hydrochloride gave aldoxime 59, which was dehydrated to give nitrile 60f using acetic anhydride. The aryl halides or triflates 60a-g were treated with (trimethylsilyl)acetylene, see Roesch. K. R., et al., J. Org. Chem., 66, 412-420 (2001), or with 2-methyl-3-butyn-2-ol, see Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998), to give intermediates 61a-f or 62a-f, respectively, of which 61a,d and 62a have been reported previously. See Dirk. S. M., et al., Tetrahedron, 59(3), 287-293 (2003); Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The acetylenes 51 (of which 51a,e were known previously), see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997); Dulog, L., et al., Liebigs Ann. Chem., 9, 1663-1671 (1995), were obtained by the treatment of intermediates 61 or 62 with cesium carbonate in acetonitrile or sodium hydride in toluene, respectively. See Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The use of cesium carbonate in acetonitrile was introduced for the deprotection of intermediates 61 after the treatment of compound 61b with potassium carbonate in methanol, see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997), failed to give product 51b. The pathway using 2-methyl-3-butyn-2-ol provided more economical preparations of all phenylacetylenes 51 except nitro analog 51b.; Reagents and conditions: (a) fuming HNO3, H2SO4; (b) Fe, AcOH, EtOH; (c) NaNO2, aq. HCl, then CuCl; (d) NalO4, l2, AcOH, AC2O, H2SO4; (e) NH2OH HCl, Py, EtOH (f) Ac2O; (g) TMSA, Pd2Cl2(PPh3)2, Cul, Et3N; (h) TMSA, PPh3, Pd(PPh3)4, Cul, piperidine; (j) 2-methyl-3-butyn-2-ol, Pd2Cl2(PPh3)2, Cul, Et3N; (k) 2-methyl-3-butyn-2-ol, 10% Pd/C, PPh3, Cul, aq. K2CO3/DME; (I) Cs2CO3, aq. CH3CN or MeOH; (m) NaH, toluene.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Patent: EP1719767,2006,A1 .Location in patent: Page/Page column 24-26; 41

4
[ 57418-97-0 ]
[ 914105-98-9 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

5
[ 57418-97-0 ]
[ 914106-08-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

6
[ 57418-97-0 ]
[ 914106-14-2 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

7
[ 57418-97-0 ]
5-(4-Amidino-2-chlorophenyl)-3-(4-amidinophenyl)isoxazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

8
[ 57418-97-0 ]
5-(4-Amidino-2-chlorophenyl)-3-(3-amidinophenyl)isoxazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

9
C₇H₃BrN₃⁽¹⁺⁾*Cl^(1-) [ No CAS ]
[ 57418-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; copper(l) chloride; In water; toluene; at 60 - 80℃; for 1h;	4-Bromo-3-chlorobenzonitrile (60c). Aniline 56 (5.19 g, 26.4 mmol) was added to conc. HCl maintained below 0 C. A solution of sodium nitrite (3.67 g, 53.2 mmol) in water (10 mL) was added dropwise such that the temperature of the reaction mixture did not exceed 5 C. The mixture was maintained for 1 h, then was added to a solution of CuCl (6.55 g, 66.2 mmol) in conc. HCl (20 mL). Toluene (200 mL) was added, and the biphasic mixture was stirred at 60-80 C for 1 h. Layers were separated, and the aqueous layer was extracted into toluene to afford a white solid (4.67 g, 82%); mp 80-81 C (hexane); 1H NMR delta 9.55 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 and 1.9 Hz, 1 H); HPLC (Method B) tR 3.96 min (100 area % at 265 nm). Anal. (C7H3BrClN) C, H, N, Br, Cl.; Reagents and conditions: (a) fuming HNO3, H2SO4; (b) Fe, AcOH, EtOH; (c) NaNO2, aq. HCl, then CuCl; (d) NalO4, l2, AcOH, AC2O, H2SO4; (e) NH2OH HCl, Py, EtOH (f) Ac2O; (g) TMSA, Pd2Cl2(PPh3)2, Cul, Et3N; (h) TMSA, PPh3, Pd(PPh3)4, Cul, piperidine; (j) 2-methyl-3-butyn-2-ol, Pd2Cl2(PPh3)2, Cul, Et3N; (k) 2-methyl-3-butyn-2-ol, 10% Pd/C, PPh3, Cul, aq. K2CO3/DME; (I) Cs2CO3, aq. CH3CN or MeOH; (m) NaH, toluene.; A second general method is depicted in Scheme 2 immediately hereinabove and comprises the cycloaddition of cyanophenylacetylenes 51 and benzaldehyde chlorooximes 52 in the presence of bis(tributyltin) oxide, see Moriya, O., et al., J. Chem. Soc., Perkin Trans., 1, 413-417 (1994); Moriya, O., et al., J. Chem. Soc., Chem. Commun., 17-18 (1991), or triethylamine, see Thomsen, l., et al., Acta Chem. Scand. (B), 319-313 (1988), in nonpolar solvents to give isoxazole dinitriles 53a-h,k-s and bromonitrile 53i. The latter was treated with copper(I) cyanide to give dinitrile 53j. See Friedman. L., et al., J. Org. Chem., 26, 2522-2524 (1961). This method also afforded alternate routes to dinitriles 50a,b,g, k prepared by the first method as provided in Scheme 1. The phenylacetylene synthons 51a-g were prepared as shown in Scheme 3 below. Starting materials 60a,e,g were commercially available. Nitration of 60a gave 60b. See Borsche, W., L., et al., Chem. Ber., 49, 2222-2243 (1916). The latter was reduced to aniline 56, see Blanksma, J. J., et al., Recl. Trav. Chim. Pays-Bas, 66, 365-373 (1947), which underwent diazotization followed by treatment with copper(l) chloride to give chlorobenzene 60c. Triflate 60d was prepared by treatment of 4-bromo-3-hydroxybenzonitrile with triflic anhydride. The preparation of aryl iodide 60f began with the known transformation of aldehyde 57 to iodo derivative 58. See Lulinski, P., et al., Bull. Chem. Soc. Jpn., 73(4), 951-956 (2000). Treatment of 58 with hydroxylamine hydrochloride gave aldoxime 59, which was dehydrated to give nitrile 60f using acetic anhydride. The aryl halides or triflates 60a-g were treated with (trimethylsilyl)acetylene, see Roesch. K. R., et al., J. Org. Chem., 66, 412-420 (2001), or with 2-methyl-3-butyn-2-ol, see Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998), to give intermediates 61a-f or 62a-f, respectively, of which 61a,d and 62a have been reported previously. See Dirk. S. M., et al., Tetrahedron, 59(3), 287-293 (2003); Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The acetylenes 51 (of which 51a,e were known previously), see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997); Dulog, L., et al., Liebigs Ann. Chem., 9, 1663-1671 (1995), were obtained by the treatment of intermediates 61 or 62 with cesium carbonate in acetonitrile or sodium hydride in toluene, respectively. See Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The use of cesium carbonate in acetonitrile was introduced for the deprotection of intermediates 61 after the treatment of compound 61b with potassium carbonate in methanol, see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997), failed to give product 51b. The pathway using 2-methyl-3-butyn-2-ol provided more economical preparations of all phenylacetylenes 51 except nitro analog 51b.

Reference： [1]Patent: EP1719767,2006,A1 .Location in patent: Page/Page column 24-26

10
[ 57418-97-0 ]
[ 180305-01-5 ]
[ 1034822-86-0 ]

Reference： [1]Patent: WO2008/76243,2008,A2 .Location in patent: Page/Page column 37
[2]Patent: WO2008/85316,2008,A1 .Location in patent: Page/Page column 33

11
[ 57418-97-0 ]
[ 108-59-8 ]
[ 863431-87-2 ]

Reference： [1]Patent: WO2005/82907,2005,A2 .Location in patent: Page/Page column 56-57

12
[ 57418-97-0 ]
[ 1308279-93-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

13
[ 57418-97-0 ]
[ 1261878-70-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

14
[ 57418-97-0 ]
[ 1308280-00-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

15
[ 57418-97-0 ]
[ 1308280-06-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

16
[ 57418-97-0 ]
[ 1308280-12-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

17
[ 57418-97-0 ]
[ 120077-69-2 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

18
[ 21803-75-8 ]
[ 57418-97-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 3793 - 3816

19
[ 57418-97-0 ]
[ 819057-45-9 ]
[ 1369584-77-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 3923 - 3933

20
[ 57418-97-0 ]
[ 1459254-68-2 ]
[ 1459254-71-7 ]

Yield	Reaction Conditions	Operation in experiment
171 mg	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 2-methyltetrahydrofuran; water; dimethyl sulfoxide; at 85℃; for 2.5h;Inert atmosphere;	A mixture of (Z)-4-(2-cyclobutyl-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(3- fluoro-1 -(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)benzaldehyde (303 mg, 0.59 mmol), <strong>[57418-97-0]4-bromo-3-chlorobenzonitrile</strong> (196 mg, 0.91 mmol), PdCl2(PPh3)2 (49 mg, 0.070 mmol), 2-methyl THF (1.2 mL), DMSO (1.2 mL), and 4M aq. K2CO3 (0.9 mL, 3.6 mmol) was degassed with three vacuum/N2 cycles and heated at 85 C for 2.5 h. The reaction was allowed to cool to rt, diluted with Et2O, washed with water (30 mL), and washed with brine (30 mL). Each aqueous layer was back extracted with Et20. The combined Et2O extracts were dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (0%-25% EtOAC in hexanes) to give (E)-3-chloro-4-(1-cyclobutyl-2-(3 -fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4-formylphenyl)vinyl)benzonitrile as a yellow foam (171 mg). 1H NMR (400MHz, DMSO-d6): oe 9.81 (s, 1H), 7.99 (d, 1H), 7.82-7.76 (m, 2H), 7.64-7.58 (m, 4H), 7.42-7.37 (m, 1H), 7.24 (d, 2H), 5.80 (d, 1H), 3.91-3.85 (m, 1H), 3.77-3.68 (m, 1H), 3.49-3.38 (m, 1H), 2.34-2.20 (m, 1H), 2.06-1.91 (m, 3H), 1.90-1.78 (m, 3H), 1.69-1.60 (m, 2H), 1.60-1.51 (m, 2H), 1.45-1.34 (m, 1H). LCMS: 540 (M+H).

Reference： [1]Patent: WO2013/142266,2013,A1 .Location in patent: Paragraph 00589

21
[ 57418-97-0 ]
[ 538-32-9 ]
[ 1616603-72-5 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 3844 - 3846

22
[ 57418-97-0 ]
ethyl 2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylate [ No CAS ]

Reference： [1]Patent: WO2014/160810,2014,A1

23
[ 57418-97-0 ]
[ 321745-86-2 ]
[ 1421620-42-9 ]

Yield	Reaction Conditions	Operation in experiment
39%	With bis(dibenzylideneacetone)-palladium(0); DavePhos; In tetrahydrofuran; at 65℃;Reflux;	Preparation 44 tert-butyl 2-(2-chloro-4-cyanophenyl)acetate [0223] Combined <strong>[57418-97-0]4-bromo-3-chlorobenzonitrile</strong> (0.600 g, 2.77 mmol) and (2-(tert-butoxy)-2- oxoethyl)zinc(II) chloride (8.32 mL, 4.16 mmol) in THF (5.54 mL), then Pd(dba)2 (0.080 g, 0.139 mmol) and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[l,l'-biphenyl]-2-amine (0.109 g, 0.277 mmol) were added and the reaction was refluxed overnight at 65C. The reaction was concentrated by rotary evaporation and purified on a silica gel column eluting with hexanes and EtOAc to give the title compound (274 mg, 39%) as a yellow oil. MS m/z [M+H]+ 252.

Reference： [1]Patent: WO2014/160810,2014,A1 .Location in patent: Paragraph 0222; 0223

24
[ 57418-97-0 ]
C₂₉H₃₅BN₂O₄ [ No CAS ]
C₃₀H₂₆ClN₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 4888 - 4904

25
[ 57418-97-0 ]
6-chloro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1H-indole [ No CAS ]
3-chloro-4-[6-chloro-2-(trifluoromethyl)-1H-indol-5-yl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Next, into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dioxane (5 mL), water (1 mL), 6-chloro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1H-indole (100 mg, 0.29 mmol, 1.00 equiv), <strong>[57418-97-0]4-bromo-3-chlorobenzonitrile</strong> (62.6 mg, 0.29 mmol, 1.00 equiv), (phosphoperoxy)potassium; dipotassium (184 mg, 0.866 mmol, 3.00 equiv), Pd(dppf)Cl2.CH2Cl2 (21 mg, 0.10 equiv). The resulting solution was stirred overnight at 80 C. in an oil bath. The reaction mixture was cooled. The crude product was purified by Prep-HPLC product was obtained. This resulted in 23.9 mg (23%) of 3-chloro-4-[6-chloro-2-(trifluoromethyl)-1H-indol-5-yl]benzonitrile as a off-white solid. (ES, m/z): 353 [M-H]-; (300 MHz, DMSO-d6, ppm): delta 12.64 (brs, 1H), 8.20 (s, 1H), 7.95-7.92 (m, 1H), 7.69 (s, 2H), 7.63-7.60 (d, J=8.1 Hz, 1H), 7.12 (s, 1H).

Reference： [1]Patent: US2015/366198,2015,A1 .Location in patent: Paragraph 0236; 0238

26
[ 57418-97-0 ]
[ 74-88-4 ]
5-(3-bromo-4-chlorophenyl)-2-methyl-2H-tetrazole [ No CAS ]
5-(3-bromo-4-chlorophenyl)-1-methyl-1H-tetrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		A solution of <strong>[57418-97-0]3-chloro-4-bromobenzonitrile</strong> (21.65 g, 0.1 mol, 1.0 eq.) in 100 mL DMF placed at 90 C. oil bath was treated with sodium azide (13.0 g, 0.2 mol, 2.0 eq.) and ammonium chloride (21.4 g, 0.4 mol) in two portions (for both reagents) over 15 minutes. The reaction mixture was stirred at 90 C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with 200 mL EtOAc, and passed through a filtration funnel to remove solid substances. The solution was concentrated on a rotary evaporator to remove EtOAc. To the resulting DMF solution was added K2CO3 (41.4 g, 0.3 mol), and the mixture was placed on a rotary evaporator at 50 C. for 1 hour to remove residual ammonium chloride and ammonia. The slurry was placed in an ice-water bath. Methyl iodide (6.4 g, 0.15 mol) was added in 4 portions over 1 hour. The reaction mixture was stirred for 48 hours while the ice-water bath was warmed up naturally to room temperature. Routine aqueous workup was performed, and the residue was purified by recrystallization to remove the region-isomer, yielding 5-(3-bromo-4-chlorophenyl)-2-methyl-2H-tetrazole (16.7 g, 61%) as an off-white solid.

Reference： [1]Patent: US9604978,2017,B2 .Location in patent: Page/Page column 184

27
[ 57418-97-0 ]
5-(2-chloro-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazin-2-amine [ No CAS ]

Reference： [1]Patent: US9604978,2017,B2

28
[ 57418-97-0 ]
C₁₄H₁₈BClN₄O₂ [ No CAS ]
C₈H₈BClN₄O₂ [ No CAS ]

Reference： [1]Patent: US9604978,2017,B2

29
[ 57418-97-0 ]
[ 1332076-55-7 ]
3-chloro-4-[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 5663 - 5672

30
[ 57418-97-0 ]
[ 1035235-28-9 ]
tert-butyl 4-(2-chloro-4-cyanophenyl)isoindoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 18h;Inert atmosphere; Reflux;	Step a. A mixture of <strong>[57418-97-0]4-bromo-3-chlorobenzonitrile</strong> (150 mg, 0.69 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (Intermediate 2, 287 mg, 0.83 mmol) and K2C03 (238 mg, 1.73 mmol) in 1,4-dioxane (5.4 ml) and water (0.6 ml) was degassed by nitrogen bubbling for 5 min. Pd(PPh3)4 (79 mg, 0.069 mmol) was then added. The mixture was heated at reflux for 18 h and then cooled to rt. The mixture was filtered on a silica pad and washed with EtOAc (200 ml). The filtrate was evaporated under reduced pressure. The residue (500 mg) was dissolved in DCM and purified by flash chromatography on silica gel using hexane/EtOAc (90: 10) to give tert-butyl 4- (2-chloro-4-cyanophenyl)isoindoline-2-carboxylate (242 mg, 99%) as a bright yellow solid. LCMS: Method I, 3.66 min, MS: ES+ 355, 357; NMR (400 MHz, CDC13) delta ppm 7.80 (m, 1H), 7.63 (m, 1H), 7.33-7.41 (m, 3 H), 7.14 (m, 1H), 4.77 (m, 2 H), 4.56 (m, 2 H), 1.49 (m, 9 H).

Reference： [1]Patent: WO2017/158388,2017,A1 .Location in patent: Page/Page column 95

31
[ 57418-97-0 ]
4-(2-chloro-4-cyanophenyl)isoindoline-2-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2017/158388,2017,A1

32
[ 57418-97-0 ]
3-chloro-4-(isoindolin-4-yl)benzonitrile trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2017/158388,2017,A1

33
[ 57418-97-0 ]
[ 1993-03-9 ]
2-chloro-2'-fluoro-[1,1'-biphenyl]-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; at 100℃; for 2h;Inert atmosphere; Microwave irradiation;	<strong>[57418-97-0]3-chloro-4-bromobenzonitrile</strong> (300 mg, 1.39 mmol 1.0 equiv), 2-fluorophenylboronic acid(194 mg, 1.39 mmol 1.0 equiv), Pd(PPh3)4 (0.05 equiv) and K2CO3 (2.0 equiv) were weighed into a microwave tube and solvated with DME (3.0 mL) and H2O (1.0 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 minutes and then heated to 100 C under microwave irradiation for 2 hours. The reaction was allowed to cool to room temperature, filtered through celite washing with Et2O and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2/H2O and extracted three times with CH2Cl2. The combined organic extracts were washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1:9 EtOAc:pet ether) to provide the title compound as a white solid (58 mg, 0.25 mmol, 18%)

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3016 - 3020

34
[ 57418-97-0 ]
[ 1993-03-9 ]
C₁₃H₁₁ClFN*ClH [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3016 - 3020

35
[ 57418-97-0 ]
[ 16419-60-6 ]
2-chloro-2'-methyl-[1,1'-biphenyl]-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; at 100℃; for 2h;Inert atmosphere; Microwave irradiation;	<strong>[57418-97-0]3-chloro-4-bromobenzonitrile</strong> (300 mg, 1.39 mmol, 1.0 equiv), o-tolylboronic acid(189 mg, 1.39 mmol, 1.0 equiv), Pd(PPh3)4 (80 mg, 0.07 mmol, 0.05 equiv) and K2CO3 (383 mg, 2.77 mmol, 2.0 equiv) were weighed into a microwave tube and solvated with DME (3.0 mL) and H2O (1.0 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 minutes and then heated to 100 C under microwave irradiation for 2 hours. The reaction was allowed to cool to room temperature, filtered through celite washing with Et2O and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2/H2O and extracted three times with CH2Cl2. The combined organic extracts were washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1:9 EtOAc:pet ether) to provide the title compound as a clear oil (300 mg, 1.32 mmol, 95%):

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3016 - 3020

36
[ 57418-97-0 ]
[ 16419-60-6 ]
(2-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)methanamine hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3016 - 3020

37
[ 57418-97-0 ]
[ 5720-06-9 ]
2-chloro-2'-methoxy-[1,1'-biphenyl]-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; at 100℃; for 2h;Inert atmosphere; Microwave irradiation;	<strong>[57418-97-0]3-chloro-4-bromobenzonitrile</strong> (300 mg, 1.39 mmol 1.0 equiv), 2-methoxyphenylboronic acid(211 mg, 1.39 mmol 1.0 equiv), Pd(PPh3)4 (0.05 equiv) and K2CO3 (2.0 equiv) were weighed into a microwave tube and solvated with DME (2 mL) and H2O (0.6 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 minutes and then heated to 100 C under microwave irradiation for 2 hours. The reaction was allowed to cool to room temperature, filtered through celite washing with Et2O and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2/H2O and extracted three times with CH2Cl2. The combined organic extracts were washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1:9 EtOAc:pet ether) to provide the title compound as a white solid (228 mg, 0.94 mmol, 67%)

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3016 - 3020

38
[ 57418-97-0 ]
[ 1208076-65-6 ]