[ CAS No. 189680-06-6 ] {[proInfo.proName]}

Name: 189680-06-6|2-Bromo-5-hydroxybenzonitrile|98%
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Quality Control of [ 189680-06-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 189680-06-6 ]

Product Details of [ 189680-06-6 ]

CAS No. :	189680-06-6	MDL No. :	MFCD08061922
Formula :	C₇H₄BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IXJNUEMHAJZKFW-UHFFFAOYSA-N
M.W :	198.02	Pubchem ID :	15323111
Synonyms :

Calculated chemistry of [ 189680-06-6 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.88
TPSA :	44.02 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 :	Yes
Log Kp (skin permeation) :	-6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.45
Log Po/w (XLOGP3) :	1.98
Log Po/w (WLOGP) :	2.03
Log Po/w (MLOGP) :	1.55
Log Po/w (SILICOS-IT) :	2.0
Consensus Log Po/w :	1.8

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.76
Solubility :	0.345 mg/ml ; 0.00174 mol/l
Class :	Soluble
Log S (Ali) :	-2.53
Solubility :	0.584 mg/ml ; 0.00295 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.77
Solubility :	0.34 mg/ml ; 0.00172 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.4

Safety of [ 189680-06-6 ]

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

Application In Synthesis of [ 189680-06-6 ]

* 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 [ 189680-06-6 ]
Downstream synthetic route of [ 189680-06-6 ]

[ 189680-06-6 ] Synthesis Path-Upstream 1~3

1
[ 873-62-1 ]
[ 189680-06-6 ]

Yield	Reaction Conditions	Operation in experiment
22%	at 20℃; for 18 h;	Step 1 : 4-Bromo-3-cyanophenolTo a mixture of 3-cyanophenol (3.2 g, 26.8 mmol) in glacial acetic acid (20 ml) was added a solution of bromine (4.2 g, 23.3 mmol) in acetic acid (5 ml) dropwise over 5 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was filtered. The filtrate was added to water (100 ml) containing a few mg of sodium thiosulfate. The insoluble material was collected and the filter cake was added to warm methanol (15 ml) and was filtered through celite. The filtrate was slowly diluted with water and the precipitate was collected and dried to give the title compound, 183-5°C, mp (1.0 g, 22percent).

Reference： [1] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 2, p. 120 - 124
[2] Patent: WO2011/34828, 2011, A1, . Location in patent: Page/Page column 80
[3] Patent: WO2004/35556, 2004, A1, . Location in patent: Page 95

2
[ 873-62-1 ]
[ 189680-06-6 ]

Reference： [1] Molecules, 2014, vol. 19, # 3, p. 3401 - 3416
[2] Synthetic Communications, 2004, vol. 34, # 5, p. 751 - 758
[3] Heterocyclic Communications, 2011, vol. 17, # 1-2, p. 10 - 16

3
[ 873-62-1 ]
[ 54582-94-4 ]
[ 189680-06-6 ]

Reference： [1] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[2] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506

[ 189680-06-6 ] Synthesis Path-Downstream 1~54

1
[ 873-62-1 ]
[ 54582-94-4 ]
4-bromo-3-hydroxybenzonitrile [ No CAS ]
2-bromo-3-hydroxybenzonitrile [ No CAS ]
[ 189680-06-6 ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 4504 - 4506
[2]Journal of Organic Chemistry,1997,vol. 62,p. 4504 - 4506

2
[ 873-62-1 ]
2-bromo-3-hydroxybenzonitrile [ No CAS ]
[ 189680-06-6 ]

Reference： [1]Molecules,2014,vol. 19,p. 3401 - 3416
[2]Synthetic Communications,2004,vol. 34,p. 751 - 758
[3]Heterocyclic Communications,2011,vol. 17,p. 10 - 16

3
[ 6482-24-2 ]
[ 189680-06-6 ]
2-bromo-5-(2-methoxy-ethoxy)-benzonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 3670 - 3674

4
[ 189680-06-6 ]
[ 862168-56-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 3670 - 3674

5
[ 189680-06-6 ]
2-{4-[3-(5-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-<i>c</i>]pyrimidin-7-yl)-benzyl]-piperazin-1-yl}-5-(2-methoxy-ethoxy)-benzonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 3670 - 3674

6
[ 873-62-1 ]
[ 189680-06-6 ]

Yield	Reaction Conditions	Operation in experiment
22%	With bromine; acetic acid; at 20℃; for 18.0h;	Step 1 : 4-Bromo-3-cyanophenolTo a mixture of 3-cyanophenol (3.2 g, 26.8 mmol) in glacial acetic acid (20 ml) was added a solution of bromine (4.2 g, 23.3 mmol) in acetic acid (5 ml) dropwise over 5 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was filtered. The filtrate was added to water (100 ml) containing a few mg of sodium thiosulfate. The insoluble material was collected and the filter cake was added to warm methanol (15 ml) and was filtered through celite. The filtrate was slowly diluted with water and the precipitate was collected and dried to give the title compound, 183-5C, mp (1.0 g, 22%).
	With N-Bromosuccinimide; tetrafluoroboric acid diethyl ether complex; In acetonitrile; at -20 - 20℃; for 5.0h;	3-Hydroxybenzonitrile (2. 0g, 16. [8MMOL)] was dissolved in acetonitrile [(20ML)] and cooled [TO-20C.] [TETRAFLUOROBORIC] acid diethyl ether complex (2. [3ML,] 16. [8MMOL)] followed by N- bromosuccinimide (3. 0g, 16. [8MMOL)] were added and the mixture allowed to warm to ambient temperature. The resulting mixture was stirred for 5 hours, treated with aqueous sodium hydrogen sulfate solution (38%, [10MI)] and extracted with methyl 2-methylpropyl ether (x2). The organic extracts were combined, washed with water (x2) and brine, dried under magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of methyl 2-methylpropyl ether/dichloromethane (2: 98) to give the title compound (1.58g). MS (ES+) m/e 197 [M- [H]]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 120 - 124
[2]Patent: WO2011/34828,2011,A1 .Location in patent: Page/Page column 80
[3]Patent: WO2004/35556,2004,A1 .Location in patent: Page 95

8
[ 189680-06-6 ]
[ 183158-34-1 ]
[ 1279015-56-3 ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; for 6.0h;Reflux;	Step 2: 2-Cyano-2',3'-dimethyl-biphenyl-4-olA mixture of <strong>[189680-06-6]4-bromo-3-cyanophenol</strong> (1.0 g, 5 mmol), 2,3-dimethylphenylboronic acid (1.1 g, 8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmol) and a 2M sodium carbonate solution (5 ml ) in 50 ml of 1 ,2-dimethoxyethane was heated at reflux for 6 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 0-10% ethyl acetate/heptane to provide the title compound, 133-7C, mp (0.33 g, 30%).

Reference： [1]Patent: WO2011/34828,2011,A1 .Location in patent: Page/Page column 80-81

9
[ 189680-06-6 ]
[ 1279014-68-4 ]

Reference： [1]Patent: WO2011/34828,2011,A1

10
[ 100-39-0 ]
[ 189680-06-6 ]
5-(benzyloxy)-2-bromobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.0h;Inert atmosphere;	Step A: 5-(benzyloxy)-2-bromobenzonitrile<strong>[189680-06-6]4-bromo-3-cyanophenol</strong> (lg, 5.05 mmol) was dissolved in DMF (10 ml) and 2C03 (1.40 g, 10.10 mmol) and benzyl bromide (0.66 ml, 5.56 mmol) added. The mixture was stirred under Nu2 for 1 hr at RT. The mixture was diluted with water (15mL) and extracted with EtOAc (2 x lOmL). The organic fractions were combined, washed with brine (saturated, 1 x 8 mL), dried over MgS04, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 289 (Mu+Eta)+·
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.0h;Inert atmosphere;	<strong>[189680-06-6]4-bromo-3-cyanophenol</strong> (lg, 5.05 mmol) was dissolved in DMF (10 ml) and K2C03 (1.40 g, 10.10 mmol) and benzyl bromide (0.66 ml, 5.56 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15mL) and extracted with EtOAc (2 x lOmL). The organic fractions were combined, washed with brine (saturated, 1 x 8 mL), dried over MgS04, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 289 (Mu+Eta)+·

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 120 - 124
[2]Patent: WO2012/138845,2012,A1 .Location in patent: Page/Page column 50
[3]Patent: WO2013/74388,2013,A1 .Location in patent: Page/Page column 57

11
[ 189680-06-6 ]
[ 1402554-82-8 ]

Reference： [1]Patent: WO2012/138845,2012,A1
[2]Patent: WO2013/74388,2013,A1

12
[ 189680-06-6 ]
[ 1402554-83-9 ]

Reference： [1]Patent: WO2012/138845,2012,A1
[2]Patent: WO2013/74388,2013,A1

13
[ 189680-06-6 ]
[ 1402554-84-0 ]

Reference： [1]Patent: WO2013/74388,2013,A1

14
[ 189680-06-6 ]
[ 1402554-85-1 ]

Reference： [1]Patent: WO2013/74388,2013,A1

15
[ 189680-06-6 ]
[ 1437776-45-8 ]

Reference： [1]Patent: WO2013/74388,2013,A1

16
[ 161975-39-9 ]
[ 189680-06-6 ]
tert-butyl 4-((4-bromo-3-cyanophenoxy)methyl)piperidin-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5.0h;	tert-butyl 4-((methylsulfonyloxy)methyl)piperidin-1-carboxylate ( 2.00 g, 6.81 mmol), 2-bromo-5- hydroxybenzonitrile (1.35 g, 6.87 mmol) and K2CO3 (1.88 g, 13.63 mmol) were dissolved in DMF (50 mL) at 80 C, following with stirring at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH4Cl aqueous solution, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to yield the title compound as white solid (1.90 g, 70%).
70%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5.0h;	tert-Butyl 4-((methylsulfonyloxy)methyl)piperidin-l-carboxylate (Step 2 of Intermediate 1, 2.00 g, 6.81 mmol), <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (1.35 g, 6.87 mmol) and K2C03 (1.88 g, 13.63 mmol) were dissolved in DMF (50 mL) at 80C. The solution was stirred at the same temperature for 5 h. To the reaction mixture, water was added, and the mixture was extracted with EtOAc. The organic layer was washed with saturated NH4C1 aqueous solution, dried with anhydrous MgS04, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 12 g cartridge; EtOAc / hexane = 0 % to 30 %), and concentrated to obtain the desired compound (1.90 g, 70%) as white solid .
70%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5.0h;	t-butyl 4-((methylsulfonyloxy)methyl)piperidin-1-carboxylate (2.00 g, 6.81 mmol), <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (1.35 g, 6.87 mmol) and K2CO3 (1.88 g, 13.63 mmol) were dissolved in DMF (50 mL) at 80 C., following with stirring at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH4Cl aqueous solution, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; EtOAchexane=0% to 30%), and concentrated to yield the title compound as white solid (1.90 g, 70%)

Reference： [1]Patent: WO2013/187646,2013,A1 .Location in patent: Page/Page column 150
[2]Patent: WO2015/80446,2015,A1 .Location in patent: Page/Page column 28; 29
[3]Patent: US2015/166480,2015,A1 .Location in patent: Paragraph 0903

17
[ 4333-56-6 ]
[ 189680-06-6 ]
[ 1594130-69-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16.0h;	To a stirred mixture of 2.50 g (13 mmol) <strong>[189680-06-6]2-bromo-5-hydroxy-benzonitrile</strong> in 100 mL DMF are added 5.23 g (38 mmol) K2CO3 and 3.05 g (25 mmol) cyclopropylbromide. The reaction mixture is stirred for 16 h at 120 C. Afterwards the reaction is quenched by the addition of ice water and extracted with EtOAc. The org. layers are combined, washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc). [0425] C10H8BrNO (M=238.1 g/mol) [0426] Rf (TLC): 0.8 (silica gel, PE/EtOAc 9/1))
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16.0h;	Example XVIII 2-Bronno-5-cvclopropoxy-benzonitrile To a stirred mixture of 2.50 g (13 mmol) <strong>[189680-06-6]2-bromo-5-hydroxy-benzonitrile</strong> in 100 mL DMF are added 5.23 g (38 mmol) K2CO3 and 3.05 g (25 mmol) cydopropylbromide. The reaction mixture is stirred for 16 h at 120 C. Afterwards the reaction is quenched by the addition of ice water and extracted with EtOAc. The org. layers are combined, washed with sat. aq. NaCI solution, dried over Na2SO4 , filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc). CioH8BrNO (M= 238.1 g/mol) Rf (TLC): 0.8 (silica gel, PE/EtOAc 9/1 ))

Reference： [1]Patent: US2014/100211,2014,A1 .Location in patent: Paragraph 0424-0426
[2]Patent: WO2014/56771,2014,A1 .Location in patent: Page/Page column 85

18
[ 189680-06-6 ]
[ 1610416-54-0 ]

Reference： [1]Patent: WO2014/78331,2014,A1

19
[ 75-03-6 ]
[ 189680-06-6 ]
[ 1353776-83-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16.0h;Inert atmosphere;	1006201 Step A: Preparation of 2-bromo-5-ethoxybenzonitrile: A round bottom flask and nitrogen inlet was charged with <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (1.50 g, 7.58 mmol) and dry DMF (30 mL). To this was added cesium carbonate (4.94 g, 15.2 mmol) followed by ethyl iodide (1.77 g, 11.4 mmol) and the mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with water and extracted two times with diethyl ether. The extracts were washed two times with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-bromo-5-ethoxybenzonitrile (1.72 g, 100%) as a white solid.

Reference： [1]Patent: WO2014/78331,2014,A1 .Location in patent: Paragraph 00620

20
[ 189680-06-6 ]
[ 1609577-20-9 ]

Reference： [1]Patent: WO2014/72881,2014,A1

21
[ 189680-06-6 ]
[ 1609581-14-7 ]

Reference： [1]Patent: WO2014/72881,2014,A1

22
[ 189680-06-6 ]
C₁₉H₂₅N₃OSi [ No CAS ]

Reference： [1]Patent: WO2014/72881,2014,A1

23
[ 189680-06-6 ]
[ 1609259-82-6 ]

Reference： [1]Patent: WO2014/72881,2014,A1
[2]Patent: WO2015/166370,2015,A1
[3]Patent: WO2015/162515,2015,A1

24
[ 18162-48-6 ]
[ 189680-06-6 ]
[ 1609581-12-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole; In tetrahydrofuran; at 20℃; for 2.0h;	1H-lmidazole (2.14 g, 31.4 mmol) was added portion-wise to a 000 solution of 2- bromo-5-hydroxybenzonitrile (5.65 g, 28.5 mmol) and teit-butyldimethylsilyl chloride (4.52 g, 30.0 mmol) in tetrahydrofuran (56.5 mL). The reaction mixture was allowed to stir at room temperature for 2 hours, whereupon it was filtered. The filtrate was washedwith water and with saturated aqueous sodium chloride solution. The aqueous layer was extracted with diethyl ether, and the combined organic layers were concentrated in vacuo to afford the product as an orange oil. Yield: 8.87 g, 28.4 mmol, quantitative. 1H NMR (400 MHz, ODd3) oe 7.50 (d, J=8.8 Hz, 1H), 7.08-7.12 (m, 1H), 6.90-6.95 (m, 1H), 0.98 (5, 9H), 0.22 (5, 6H).
99.6%	With 1H-imidazole; In tetrahydrofuran; at 0 - 20℃; for 2.0h;	1H-lmidazole (2.14 g, 31.4 mmol) was added portion-wise to a 000 solution of <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (5.65 g, 28.5 mmol) and tert-butyldimethylsilyl chloride (4.52 g, 30.0 mmol) in tetrahydrofuran (56.5 mL). The reaction mixture was allowed to stir at room temperature for 2 hours, and was then filtered. The filtrate was washed with water and withsaturated aqueous sodium chloride solution. The aqueous layer was extracted with diethyl ether, and the combined organic layers were concentrated in vacuo to afford the product as an orange oil. Yield: 8.87 g, 28.4 mmol, 99.6%. 1H NMR (400 MHz, ODd3) oe 7.50 (d, J=8.8 Hz, 1H), 7.08-7.12 (m, 1H), 6.90-6.95 (m, 1H), 0.98 (s, 9H), 0.22 (s, 6H).

Reference： [1]Patent: WO2015/166370,2015,A1 .Location in patent: Page/Page column 114
[2]Patent: WO2014/72881,2014,A1 .Location in patent: Page/Page column 83; 84

25
[ 189680-06-6 ]
C₁₀H₈BrF₂NO [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

26
[ 189680-06-6 ]
C₁₂H₁₁F₂NO [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

27
[ 189680-06-6 ]
C₁₇H₂₂F₂N₂O₄ [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

28
[ 189680-06-6 ]
C₁₃H₁₂F₂N₂O₃ [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

29
[ 189680-06-6 ]
C₁₉H₁₈F₂N₄O₃ [ No CAS ]

Reference： [1]Patent: WO2014/140279,2014,A1

30
[ 78-95-5 ]
[ 189680-06-6 ]
C₁₀H₈BrNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.86%	With potassium carbonate; In acetonitrile; for 2.0h;Reflux;	Step 1 (ME-Si):A mixture of <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (12 g, 60.61 mmol), chloroacetone (5.85 mL,72.73 mmol) and potassium carbonate (16.75 g, 121 mmol)) in acetonitrile (100 mL) wasrefluxed for 2 h. The reaction mass was cooled to room temperature, filtered and washed with ethyl acetate. The combined filtrate was concentrated in vacuum and the resulting mas was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to affordthe crude intermediate. Purification by column chromatography over silica gel (60-l20mesh) and using 15-20% ethyl acetate in pet ether as the eluent afforded 6.75 g (43.86%) of MF-S1 as a off white solid.

Reference： [1]Patent: WO2014/140279,2014,A1 .Location in patent: Page/Page column 70; 128

31
[ 189680-06-6 ]
2-(4,6-dimethylpyrimidin-5-yl)-5-(pyrrolo[1,2-a]pyrazin-1-yloxy)benzonitrile [ No CAS ]

Reference： [1]Patent: WO2015/166370,2015,A1

32
[ 189680-06-6 ]
2-(4,6-dimethylpyrimidin-5-yl)-5-(pyrazolo[1,5-a]pyrazin-4-yloxy)benzonitrile [ No CAS ]

Reference： [1]Patent: WO2015/166370,2015,A1

33
[ 18162-48-6 ]
[ 189680-06-6 ]
[ 1609581-14-7 ]

Reference： [1]Patent: WO2015/166370,2015,A1
[2]Patent: WO2015/162515,2015,A1

34
[ 288-32-4 ]
[ 18162-48-6 ]
[ 189680-06-6 ]
[ 1609581-12-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran; at 0 - 20℃; for 2.0h;	1H-lmidazole (2.14 g, 31.4 mmcl) was added portion-wise to a 000 solution of 2- bromo-5-hydroxybenzonitrile (5.65 g, 28.5 mmol) and teit-butyldimethylsilyl chloride (4.52 g, 30.0 mmol) in tetrahydrofuran (56.5 mL). The reaction mixture was allowed to stir at room temperature for 2 hours, and was then filtered; the filtrate was washed with water and with saturated aqueous sodium chloride solution. The aqueous layer wasextracted with diethyl ether, and the combined organic layers were concentrated in vacuo to afford the product as an orange oil. Yield: 8.87 g, 28.4 mmol, quantitative. 1H NMR (400 MHz, ODd3) o 7.50 (d, J=8.8 Hz, 1H), 7.08-7.12 (m, 1H), 6.90-6.95 (m, 1H), 0.98 (5, 9H), 0.22 (5, 6H).

Reference： [1]Patent: WO2015/162515,2015,A1 .Location in patent: Page/Page column 141

35
[ 189680-06-6 ]
2-(4,6-dimethylpyrimidin-5-yl)-5-([1,3]thiazolo[5,4-c]pyridin-4-yloxy)benzonitrile [ No CAS ]

Reference： [1]Patent: WO2015/162515,2015,A1

36
[ 73789-86-3 ]
[ 189680-06-6 ]
C₁₇H₁₆BrNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 18.0h;	a- Synthesis of Int. 88: A sol. of <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (6.29 g, 31.8 mmol) in ACN (90 mL) and DMF (10 mL) was treated with K2C03 (4.83 g, 34.9 mmol) and 8 (7.11 g, 33.4 mmol) at rt. The r.m. was stirred for 18 h at r.t. Then, water and EtOAc were added, and the organic layer was washed with brine, separated, dried over MgS04, filtered and concentrated in vacuo to afford 11.4 of Int. 88, white solid (quant.).
100%	With potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 18.0h;	a- Synthesis of intermediate 13: A solution of <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (6.29 g, 31.8 mmol) in ACN (90 mL) and DMF (10 mL) was treated with K2C03 (4.83 g, 34.9 mmol) and 4-isopropylbenzyl bromide (7.11 g, 33.4 mmol) at r.t. The reaction mixture was stirred for 18 hours at r.t. Then, water and EtOAc were added, and the organic layer was washed with brine,separated, dried over MgSO4, filtered and concentrated in vacuo to afford 11.4 g of intermediate 13, white solid (quantitative).

Reference： [1]Patent: WO2015/144799,2015,A1 .Location in patent: Page/Page column 126
[2]Patent: WO2015/144801,2015,A1 .Location in patent: Page/Page column 77; 78

37
[ 189680-06-6 ]
C₂₃H₂₈BNO₃ [ No CAS ]

Reference： [1]Patent: WO2015/144799,2015,A1
[2]Patent: WO2015/144801,2015,A1

38
[ 189680-06-6 ]
C₃₆H₄₃N₅O₃Si [ No CAS ]

Reference： [1]Patent: WO2015/144799,2015,A1

39
[ 189680-06-6 ]
C₃₀H₂₉N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2015/144799,2015,A1

40
[ 189680-06-6 ]
C₂₇H₂₅N₅O [ No CAS ]

Reference： [1]Patent: WO2015/144801,2015,A1

41
[ 762-51-6 ]
[ 189680-06-6 ]
2-bromo-5-(2-fluoroethoxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.69 g	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;	Step A: 2-bromo-5-(2-fluoroethoxy)benzonitrile. To <strong>[189680-06-6]2-bromo-5-hydroxybenzonitrile</strong> (1.5 g, 7.6 mmol) in DMF (5 mL) was added Cs2CO3 (3.7 g, 11.4 mmol) and 1-iodo-2-fluoroethane (1.23 mL, 15.1 mmol) and the mixture was left to stir at room temperature. Upon completion the reaction mixture was diluted with H2O and the aqueous layer extracted with EtOAc (3*). The combined organics were washed with 5% LiCl solution, brine, dried with MgSO4, filtered and concentrated. Purification via silica gel chromatography (0-30% EtOAc in hexanes) gave the title compound (1.69 g) as a light yellow oil. 1H NMR (500 MHz, Chloroform-d) delta 7.56 (d, J=8.9 Hz, 1H), 7.18 (d, J=3.0 Hz, 1H), 7.05 (dd, J=8.9, 3.0 Hz, 1H), 4.87-4.63 (m, 2H), 4.30-4.14 (m, 2H).

Reference： [1]Patent: US2016/75696,2016,A1 .Location in patent: Paragraph 0253; 0254

42
[ 189680-06-6 ]
5-(2-bromoethoxy)-2-(2H-1,2,3-triazol-2-yl)benzoic acid [ No CAS ]

Reference： [1]Patent: US2016/75696,2016,A1

43
[ 189680-06-6 ]
5-(2-bromoethoxy)-2-(2H-1,2,3-triazol-2-yl)benzonitrile [ No CAS ]

Reference： [1]Patent: US2016/75696,2016,A1

44
[ 189680-06-6 ]
2,2-bis-(3-phenyl-prop-2-ynyl)-malonic acid dimethyl ester [ No CAS ]
dimethyl 2-cyano-4-oxo-1',3'-diphenyl-4'H-spiro[cyclohexane-1,2'-pentalene]-2,5-diene-5',5'(6'H)-dicarboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 6946 - 6950
Angew. Chem.,2016,vol. 128,p. 7060 - 7064,5

45
1-{2-(bromomethyl)-3-methylphenyl}-4-methyl-1,4-dihydro-5H-tetrazol-5-one [ No CAS ]
[ 189680-06-6 ]
1-[2-(4-bromo-3-cyanophenoxymethyl)-3-methylphenyl]-4-methyl-1,4-dihydrotetrazol-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.94 g	With potassium carbonate; In acetonitrile; at 80℃; for 4.0h;	A mixture of 1.42g of 14A (mentioned in the Reference Preparation Example 14), 1.00g of <strong>[189680-06-6]4-bromo-3-cyanophenol</strong>, 1.38g of potassium carbonate, and 20mL of acetonitrile was heated and stirred at 80C for 4 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue thus obtained was washed with methyl tert-butyl ether and hexane to obtain 1.94g of 1-[2-(4-bromo-3-cyanophenoxymethyl)-3-methylphenyl]-4-methyl-1,4-dihydrotetrazol-5-one (Referred to as 41A).
1.94 g	With potassium carbonate; In acetonitrile; at 80℃; for 4.0h;	Reference Production Example 41 (0699) A mixture of 1.42 g of 14A mentioned in Reference Production Example 14, 1.00 g of <strong>[189680-06-6]4-bromo-3-cyanophenol</strong>, 1.38 g of potassium carbonate, and 20 mL of acetonitrile was stirred with heating at 80 C. for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue thus obtained was washed with hexane and methyl tert-butyl ketone to obtain 1.94 g of 1-[2-(4-bromo-3-cyanophenoxymethyl)-3-methylphenyl]-4-methyl-1,4-dihydrotetrazol-5-one (referred to as 41A). (0700) 1H-NMR (CDCl3) delta: 7.53 (1H, d, J=8.9 Hz), 7.46 (1H, t, J=7.6 Hz), 7.43-7.39 (1H, m), 7.30 (1H, dd, J=7.6, 1.1 Hz), 7.14 (1H, d, J=3.0 Hz), 6.97 (1H, dd, J=8.9, 3.0 Hz), 5.01 (2H, s), 3.67 (3H, s), 2.48 (3H, s).

Reference： [1]Patent: CN105392779,2016,A .Location in patent: Paragraph 1335; 1336; 1337; 1338
[2]Patent: US2016/159755,2016,A1 .Location in patent: Paragraph 0699; 0700

46
1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrrole-2-carbonitrile [ No CAS ]
[ 189680-06-6 ]
5-(2-cyano-4-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 6451 - 6457

47
[ 189680-06-6 ]
5-(benzyloxy)-2-isobutylbenzonitrile [ No CAS ]