[ CAS No. 174913-09-8 ] {[proInfo.proName]}

Name: 174913-09-8|1-Bromo-4-chloro-2-methoxybenzene|98%
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Quality Control of [ 174913-09-8 ]

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Product Details of [ 174913-09-8 ]

CAS No. :	174913-09-8	MDL No. :	MFCD03790889
Formula :	C₇H₆BrClO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CQGYLDZGJLVLMK-UHFFFAOYSA-N
M.W :	221.48	Pubchem ID :	17984845
Synonyms :

Calculated chemistry of [ 174913-09-8 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.64
TPSA :	9.23 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) :	-5.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.48
Log Po/w (XLOGP3) :	3.41
Log Po/w (WLOGP) :	3.11
Log Po/w (MLOGP) :	3.15
Log Po/w (SILICOS-IT) :	3.14
Consensus Log Po/w :	3.06

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.74
Solubility :	0.0404 mg/ml ; 0.000182 mol/l
Class :	Soluble
Log S (Ali) :	-3.28
Solubility :	0.115 mg/ml ; 0.00052 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.0
Solubility :	0.0221 mg/ml ; 0.0001 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 174913-09-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 174913-09-8 ]

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

Upstream synthesis route of [ 174913-09-8 ]
Downstream synthetic route of [ 174913-09-8 ]

[ 174913-09-8 ] Synthesis Path-Upstream 1~7

1
[ 174913-09-8 ]
[ 68-12-2 ]
[ 53581-86-5 ]

Reference： [1] Organic Letters, 2016, vol. 18, # 15, p. 3630 - 3633

2
[ 174913-09-8 ]
[ 13659-23-9 ]

Yield	Reaction Conditions	Operation in experiment
32%	With boron tribromide In dichloromethane at -40 - 20℃; for 12.33 h;	To a solution of 1-bromo-5-chloro-2 methoxyphenyl 275 (2.5 g, 11 mmol, 1 eq) in DCM (100 mL) was added dropwise BBr₃(1 M solution in DCM, 38.5 mmol, 3.5 eq) over 20 min at -40 C. The solution was warmed to rt and stirred for 12 h. TLC (3:2 Hexane:DCM) showed complete consumption of 275. The solution was quenched with NaHCO₃and stirred until two phases appeared. The organic was separated, washed with brine, dried, filtered and concentrated in vacuo to afford 0.80 g of 276 as a white solid which was used without purification. Yield 32percent

Reference： [1] Patent: US2008/114167, 2008, A1, . Location in patent: Page/Page column 208
[2] Patent: US2007/265332, 2007, A1, . Location in patent: Page/Page column 20

3
[ 13659-23-9 ]
[ 74-88-4 ]
[ 174913-09-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide for 2 h;	Preparation Example 27 Synthesis of 1-bromo-4-chloro-3-(4-ethoxybenzyl)-6-methoxybenzene; A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-BU₄NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily 2-bromo-5-chloroanisole (2.94 g, 97percent). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at -10°C over five minutes. After stirred at 5°C for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31percent) as a colorless crystal. Then, Et₃SiH (1.62 mL, 10.1 mmol) and BF₃*Et₂O (0.772 mL, 6.09 mmol) were added sequentially to a chloroform - acetonitrile (1:1; 16 mL) solution of (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.50 g, 4.06 mmol) at -5°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain a colorless oily title compound (1.48 g, 99percent). ¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.0 Hz, 3 H) 3.87 (s, 3 H) 3.93 (s, 2 H) 4.01 (q, J=7.0 Hz, 2 H) 6.77 - 6.87 (m, 2 H) 6.90 (s, 1 H) 7.03 - 7.12 (m, 2 H) 7.29 (s, 1 H). EI 354(M⁺), 356(M+2), 358(M+4).

Reference： [1] Patent: EP1845095, 2007, A1, . Location in patent: Page/Page column 41-42
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3247 - 3261

4
[ 57479-70-6 ]
[ 174913-09-8 ]

Reference： [1] Chemical Science, 2018, vol. 9, # 15, p. 3860 - 3865

5
[ 13659-23-9 ]
[ 77-78-1 ]
[ 174913-09-8 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 9, p. 2450 - 2454[2] Angew. Chem., 2018, vol. 130, # 9, p. 2475 - 2479,5

6
[ 174913-09-8 ]
[ 121-43-7 ]
[ 762287-57-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.666667 h; Inert atmosphere Stage #2: at 20℃; for 3 h; Inert atmosphere	Synthesis of Intermediate I-1 10262] 22.1 g (100 mmol) of 2-bromo-5-chioroanisole was dissolved in 500 ml of THF, and stirred in a N2 atmosphere at—78° C. for 10 minutes. Then, 44 mL of 2.5 M n-BuLi was slowly added thereto by using a dropping funnel, and the mixture was additionally stirred for 30 minutes. 10.4 g (110 mmol) of trimethyl borate was slowly and dropwisely added thereto by using a dropping flannel, and the mixture was additionally stirred for 3 hours at room temperature. Next, an organic layer was extracted therefrom once by using 300 ml of 1 M HC1 and three times by using water and diethylether. The organic layer was dried using magnesium sulfate, and a solvent was removed thereform by evaporation. The residue was separated and purified through a silica gel chromatography to obtain 13.61 g of Intermediate 1-1 (73 mmol, yield:73percent). The compound thus obtained was confirmed by usingMS/FAB.10263] C7H8BC103 Cal. 186.40. Found. 186.47.
50%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 20℃; for 24 h;	10272] 5.2 g (23.6 mmol) of 2-bromo-5-chloroanisole was dissolved in 100 mE of tetrahydroffiran (THF). 10 mE (25.0 mmol) of n-l3uEi (2.5M in hexane) was slowly added drop- wise thereto at —78° C. The result was stirred at the same temperature for 1 hour. Then, 9.3 mE (50.0 mmol) of trim- ethyl borate was slowly added dropwise thereto, and stirred for 24 hours at room temperature. Once the reaction was complete, 10percent aqueous HC1 solution was added thereto to adjust pH to about 5. Then, an organic layer was extracted three times therefrom by using diethylether. The obtained organic layer was dried by using magnesium sulfate (Mg504). Then, a solvent was removed therefrom by evaporation. The obtained residue was purified by recrystallization, thereby obtaining 3.15 g of Intermediate 1-1 (yield: 50percent).

Reference： [1] Organic Letters, 2016, vol. 18, # 15, p. 3630 - 3633
[2] Patent: US2016/190448, 2016, A1, . Location in patent: Paragraph 0261; 0262; 0263
[3] Patent: US2016/190449, 2016, A1, . Location in patent: Paragraph 0271; 0272

7
[ 174913-09-8 ]
[ 762287-57-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6626 - 6637

[ 174913-09-8 ] Synthesis Path-Downstream 1~88

1
[ 174913-09-8 ]
[ 16331-46-7 ]
[ 898538-43-7 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminum (III) chloride; In chloroform; at -10 - 20℃; for 14.0833h;	Preparation Example 27 Synthesis of 1-bromo-4-chloro-3-(4-ethoxybenzyl)-6-methoxybenzene; A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-BU4NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily <strong>[174913-09-8]<strong>[174913-09-8]2-bromo-5-chloroanisol</strong>e</strong> (2.94 g, 97%). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of <strong>[174913-09-8]<strong>[174913-09-8]2-bromo-5-chloroanisol</strong>e</strong> (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at -10C over five minutes. After stirred at 5C for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31%) as a colorless crystal. Then, Et3SiH (1.62 mL, 10.1 mmol) and BF3·Et2O (0.772 mL, 6.09 mmol) were added sequentially to a chloroform - acetonitrile (1:1; 16 mL) solution of (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.50 g, 4.06 mmol) at -5C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain a colorless oily title compound (1.48 g, 99%). 1H NMR (200 MHz, CHLOROFORM-d) delta ppm 1.40 (t, J=7.0 Hz, 3 H) 3.87 (s, 3 H) 3.93 (s, 2 H) 4.01 (q, J=7.0 Hz, 2 H) 6.77 - 6.87 (m, 2 H) 6.90 (s, 1 H) 7.03 - 7.12 (m, 2 H) 7.29 (s, 1 H). EI 354(M+), 356(M+2), 358(M+4).

Reference： [1]Patent: EP1845095,2007,A1 .Location in patent: Page/Page column 41-42

2
[ 174913-09-8 ]
[ 375853-82-0 ]
[ 607744-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃;	2-Bromo-5-chloroanisole (5.54 g), 1-(2(H)-pyridine-carboxylic acid-3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-tert.-butyl ester (7.73 g), dichloro(1,1'-bis(diphenyl-phosphino)-ferrocene)palladium(II) DCM adduct (1.22 g) and K2CO3 (10.36 g) were dissolved in degassed DMF in a dry apparatus under argon and the mixture was degassed again by evacuation followed by refilling with argon. The resulting suspension was heated in an oil bath at 85 C overnight. The mixture was cooled, filtered through Celite and evaporated to dryness. The crude product was purified by flash chromatography to yield a clear yellowish oil.
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃;	Intermediate 1a): [Show Image] 2-Bromo-5-chloroanisole (5.54 g), 1-(2(H)-pyridine-carboxylic acid-3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-tert.-butyl ester (7.73 g), dichloro(1,1'-bis(diphenyl-phosphino)-ferrocene)palladium(II) DCM adduct (1.22 g) and K2CO3 (10.36 g) were dissolved in degassed DMF in a dry apparatus under argon and the mixture was degassed again by evacuation followed by refilling with argon. The resulting suspension was heated in an oil bath at 85C overnight. The mixture was cooled, filtered through Celite and evaporated to dryness. The crude product was purified by flash chromatography to yield a clear yellowish oil.
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃;	2-Bromo-5-chloroanisole (5.54 g), 1-(2(H)-pyridine-carboxylic acid-3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-tert.-butyl ester (7.73 g), dichloro(1,1'-bis(diphenylphosphino)-ferrocene)palladium(II) DCM adduct (1.22 g) and K2CO3 (10.36 g) were dissolved in degassed DMF in a dry apparatus under argon and the mixture was degassed again by evacuation followed by refilling with argon. The resulting suspension was heated in an oil bath at 85C overnight. The mixture was cooled, filtered through Celite and evaporated to dryness. The crude product was purified by flash chromatography to yield a clear yellowish oil.

Reference： [1]Patent: EP1842846,2007,A1 .Location in patent: Page/Page column 43
[2]Patent: EP2020405,2009,A1 .Location in patent: Page/Page column 53-54
[3]Patent: EP1826201,2007,A1 .Location in patent: Page/Page column 26

3
[ 174913-09-8 ]
[ 16331-45-6 ]
[ 1036955-11-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With aluminum (III) chloride; In dichloromethane; at 20℃; for 19h;Heating / reflux;	Example 3; Synthesis of (2'R,3tR,4lS,5'S,6'R)-6-chloro-5-(4-ethylbenzyl)-6'-(hydroxymethyl)- 3I,4',5',6'-tetrahydro-2H-spiro[benzofuran-3,2'-pyran]-3',4',51-triol (Compound 30):; Part A: Synthesis of l-bromo-4-chloro-5-(4-ethylbenzyl)-2-methoxybenzene (22).; The overall synthetic scheme for 22 is depicted in Scheme 3 A (see Figure 13).; Synthesis of (5-bromo-2-chloro-4-methoxyphenyl)(4-ethylphenyl)methanone (21):; To a solution of l-<strong>[174913-09-8]bromo-4-chloro-2-methoxybenzene</strong> (5.1 g, 23 mmol) and 4- ethylbenzoyl chloride (4.1 g, 24 mmol) in 15 mL of anhydrous dichloromethane (DCM) was added aluminum trichloride (3.2 g, 24 mmol). The mixture was stirred at room temperature for 1 hour, followed by heating at reflux for 18 hours. The mixture was poured into 100 mL of ice-cold water and the organic layer was isolated. The aqueous solution was extracted with 25 mL DCM. The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and evaporated. Recrystallization from petroleum ether gave the intermediate (5-bromo-2-chloro-4-methoxyphenyl)(4-ethylphenyl)methanone 21 (5.6 g, 69%).
	With aluminum (III) chloride; In dichloromethane; at -5 - 20℃; for 4h;	To a solution of 4-ethyl benzoic acid (AQ) (0.50 g, 3.33 mmol) in dry dichloromethane (20 mL) was added dropwise oxalyl chloride (0.32 mL, 3.68 mmol) followed by N,N-dimethylformamide (0.1 mL). After being stirred for 2 h at room temperature, the reaction mixture was evaporated and the residue was dissolved in dry dichloromethane (20 mL) at room temperature under agron. After cooling to -5 C., <strong>[174913-09-8]1-<strong>[174913-09-8]bromo-4-chloro-2-methoxybenzene</strong></strong> (0.6 g, 2.78 mmol) was added. Then AlCl3 (0.43 g, 3.33 mmol) was added portionwise and the reaction temperature was kept between -5 C. and 0 C. After being stirred at room temperature for four hours, the reaction mixture was poured onto ice water and extracted with dichloromethane (80 mL). The combined organic layers were washed with 1 M HCl (10 mL), water (10 mL) and brine (10 mL), and then dried over anhydrous Na2SO4 Concentration under reduced pressure gave AR as a white solid. Yield: 0.5 g (52.3%). 1H-NMR (CDCl3, 400 MHz): delta 7.75 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 6.98 (s, 1H), 3.99 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H).

Reference： [1]Patent: WO2008/83200,2008,A2 .Location in patent: Page/Page column 57-58
[2]Patent: US2008/242596,2008,A1 .Location in patent: Page/Page column 28
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 3247 - 3261

4
[ 174913-09-8 ]
[ 107-13-1 ]
[ 942268-21-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; triphenylphosphine;palladium diacetate; In N,N-dimethyl-formamide; at 90℃; for 96h;	(i) (2E)-3-(4-chloro-2-methoxyphenyl)acrylonitrile 1-Bromo-4-chloro-2-methoxybenzene (1 g), acrylonitrile (0.45 ml), DMF (4 ml), palladium acetate (0.1 g), triphenylphosphine (0.24 g) and triethylamine (0.9 g) were charged to a flask and heated at 90 C. for 4 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and then evaporated under reduced pressure. The residue was purified using flash column chromatography (eluent 1:4 ethyl acetate/hexane) to give the subtitle compound as a yellow oil (0.31 g).

Reference： [1]Patent: US2008/293775,2008,A1 .Location in patent: Page/Page column 18

5
[ 174913-09-8 ]
[ 1191-95-3 ]
[ 1095544-56-1 ]

Yield	Reaction Conditions	Operation in experiment
38.8%		l-(4-Chloro-2-methoxyphenyl)cyclobutanol To a slurry of <strong>[174913-09-8]<strong>[174913-09-8]2-bromo-5-chloroanisol</strong>e</strong> (7.07 g, 31.9 mmol) in THF (50 mL) at -78 0C under an atmosphere of argon was added n-butyllithium (12.8 ml, 31.9 mmol), dropwise keeping the temperature below -60 0C. The reaction was stirred at -78 0C for 1 hour and then cyclobutanone (2.46 g, 35.1 mmol) added dropwise. The reaction was stirred at -78 0C and then allowed to warm to ambient temperature over 2 hours. The reaction was poured into saturated NH4Cl (100 mL) and washed with EtOAc (2 x 10OmL), the comined organic extracts were washed with saturated brine (100 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% Et2O in isohexane. Pure fractions were evaporated to dryness to afford l-(4-chloro-2-methoxyphenyl)cyclobutanol (2.63 g, 38.8 %) as a yellow oil.1R NMR (400.132 MHz, CDC13) delta 1.64 (IH, m), 2.05 (IH, m), 2.34 (2H, m), 2.47 (2H, m), 3.88 (3H, s), 6.89 (IH, d), 6.94 (IH, m), 7.22 (IH, d)

Reference： [1]Patent: WO2009/1127,2008,A1 .Location in patent: Page/Page column 273

6
[ 174913-09-8 ]
[ 411235-57-9 ]
[ 1095539-56-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium phosphate;palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 3h;	4-Chloro-l-cyclopropyl-2-methoxybenzene2-Bromo-5-chloroanisole (1.77 g, 8.00 mmol), potassium phosphate (5.94 g, 28.0 mmol), tricyclohexylphosphine (0.224 g, 0.800 mmol) and cyclopropylboronic acid (0.893 g, 10.4 mmol) were suspended in toluene (32 mL) and water (1.6 mL) added followed by palladium(II) acetate (0.090 g, 0.40 mmol). The mixture was heated to 100 0C for 3 hours and then allowed to cool. Poured into water (100 mL) and extracted with EtOAc (3 x 50 mL), the combined organics layers were dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% Et20 in isohexane. Pure fractions were evaporated to dryness to afford 4-chloro-l-cyclopropyl- 2-methoxybenzene (1.380 g, 94 %) as a yellow oil.1H NMi? (400.132 MHz, CDC13) delta 0.57 - 0.64 (2H, m), 0.86 - 0.95 (2H, m), 2.03 - 2.13(IH, m), 3.85 (3H, s), 6.74 (IH, d), 6.79 - 6.85 (2H, m)

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8827 - 8837,11
[2]Patent: WO2009/1127,2008,A1 .Location in patent: Page/Page column 118

7
[ 174913-09-8 ]
[ 691-64-5 ]
[ 1193444-53-9 ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 8708 - 8713

8
[ 174913-09-8 ]
[ 927-74-2 ]
[ 1208265-64-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With pyrrolidine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); at 80℃; for 6h;	Preparation of 4-(4-Chloro-2-methoxy-phenyl)-butyric acid (IXa)-Prepared as described in Scheme 2; 4-(4-Chloro-2-methoxy-phenyl)-but-3-yn-1-ol; To a stirred solution of <strong>[174913-09-8]<strong>[174913-09-8]2-bromo-5-chloroanisol</strong>e</strong> (2 g, 9 mmol), Pd(PPh3)4 (520 mg, 0.45 mmol), and CuI (400 mg) in pyrrolidine (20 mL) was added a solution of 3-butyn-1-ol (1.26 g, 18 mmol) in pyrrolidine (30 mL). The reaction mixture was stirred at 80 C. for 6 h, and then concentrated in vacuo. The resulting residue was extracted with ethyl acetate and the organic phase was washed with 1N hydrochloric acid, followed by water, then brine, and dried over sodium sulfate. Upon removal of the solvent under reduced pressure, the crude product was subjected to column chromatography on silica gel (gradient elution with 0%-40% EtOAc/hexane) to give 4-(4-chloro-2-methoxy-phenyl)-but-3-yn-1-ol as a colorless oil (1.46 g, 76.7%). 1H NMR (300 MHz, CDCl3) delta ppm 7.29 (d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 1.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 3.87 (s, 3H), 3.82 (t, J=6.2 Hz, 2H), 2.73 (t, J=6.2 Hz, 2H), 1.92 (br. s, 1H).

Reference： [1]Patent: US2010/41713,2010,A1 .Location in patent: Page/Page column 12; 16-17

9
[ 174913-09-8 ]
[ 1227402-29-0 ]
[ 1227402-31-4 ]

Reference： [1]Nature Chemistry,2010,vol. 2,p. 313 - 318

10
[ 617-35-6 ]
[ 174913-09-8 ]
C₁₂H₁₅ClO₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2806 - 2811

11
[ 174913-09-8 ]
[ 1310041-44-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2806 - 2811

12
[ 174913-09-8 ]
[ 1310041-47-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2806 - 2811

13
[ 174913-09-8 ]
C₁₅H₁₅Cl₄NO₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2806 - 2811

14
[ 174913-09-8 ]
[ 1310041-95-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2806 - 2811

15
[ 174913-09-8 ]
[ 20201-24-5 ]
C₂₃H₂₅NO₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2806 - 2811

16
[ 174913-09-8 ]
[ 1095539-58-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8827 - 8837,11
[2]Patent: WO2009/1127,2008,A1

17
[ 174913-09-8 ]
[ 1095539-61-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8827 - 8837,11
[2]Patent: WO2009/1127,2008,A1

18
[ 174913-09-8 ]
[ 1095535-39-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8827 - 8837,11

19
[ 174913-09-8 ]
[ 105942-08-3 ]
4'-chloro-3-fluoro-2'-methoxybiphenyl-4-carbonitrile [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11157 - 11161,5
Angewandte Chemie,2012,vol. 124,p. 11319 - 11323,5

20
[ 174913-09-8 ]
[ 7439-95-4 ]
[ 1213256-49-5 ]

Reference： [1]Organometallics,2013,vol. 32,p. 4516 - 4522

21
[ 174913-09-8 ]
[ 1449700-84-8 ]

Reference： [1]Organometallics,2013,vol. 32,p. 4516 - 4522

22
[ 174913-09-8 ]
bis{N,N’-{(κ2-P,O)-2-[di-(2-methoxy-4-chloro-phenyl)-phosphine]benzenesulfonate} palladium(II)-methyl}-N,N,N’,N’-tetramethylethylenediamine dihydrate [ No CAS ]

Reference： [1]Organometallics,2013,vol. 32,p. 4516 - 4522

23
[ 174913-09-8 ]
[ 1448857-84-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6626 - 6637

24
[ 174913-09-8 ]
[ 762287-57-0 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6626 - 6637

25
[ 174913-09-8 ]
[ 480-97-7 ]
4-(4-chloro-2-methoxyphenoxy)benzofuran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate; In 1,4-dioxane; at 90 - 100℃; for 24h;Inert atmosphere; Sealed tube;	To a solution of benzofuran-4-ol (2.0 mmol), <strong>[174913-09-8]<strong>[174913-09-8]2-bromo-5-chloroanisol</strong>e</strong> (2.6 mmol), Cs2CO3 (3.0 mmol), CuI (0.2 mmol) and N,N-dimethylglycine hydrochloride (0.6 mmol) in dry dioxane were stirred at 90-100 C. under N2 atmosphere for 24 h. The reaction was cooled down, quenched with brine, and extracted with ethyl acetate (3×10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The product was purified by column chromatography to give 47f. [0376] 4-(4-chloro-2-methoxyphenoxy)Benzofuran (47f) (33) 1H NMR (400 MHz, CDCl3) delta 7.54 (d, J=2.0 Hz, 1H), 7.24 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.08 (t, J=1.2 Hz, 1H), 6.89-6.88 (m, 2H), 6.72-6.71 (m, 1H), 6.62 (d, J=7.6 Hz, 1H), 3.84 (s, 3H). GC-MS (ES) for C15H11ClO3 [M]+=274.

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16705 - 16713
[2]Patent: US2015/105351,2015,A1 .Location in patent: Paragraph 0375

26
[ 174913-09-8 ]
[ 4790-81-2 ]
7-(4-chloro-2-methoxyphenoxy)benzofuran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate; In 1,4-dioxane; at 90℃; for 24h;Inert atmosphere; Sealed tube;	Synthesis of 7-(4-chloro-2-methoxyphenoxy)Benzofuran (52). Following step A2 in the synthetic scheme 1.2 from 51 to give 52 (20) 1H NMR (500 MHz, CDCl3) delta 7.62 (d, J=2.0 Hz, 1H), 7.32 (dd, J=8.0, 1.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.88-6.85 (m, 2H), 6.80 (d, J=2.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 3.85 (s, 3H). GC-MS (ES) for C15H11ClO3 [M]+=274.

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16705 - 16713
[2]Patent: US2015/105351,2015,A1 .Location in patent: Paragraph 0381

27
[ 174913-09-8 ]
rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
rac-1-((2S,3R,4R)-4-((4-chloro-2-methoxyphenyl)amino)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.2%	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 100℃; for 1.5h;Inert atmosphere;	To a greenhouse test tube was added rac-I-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin- I(2H)-yl)ethanone (for a preparation see Intermediate 6, 39.0 mg, 0.179 mmol), I-bromo-4-chloro-2- methoxybenzene (47.5 mg, 0.214 mmol), Pd2(dba)3 (17.4 mg, 0.019 mmol, DavePhos (7.4 mg,0.019 mmol), sodium tert-butoxide (26.1 mg, 0.272 mmol) and 1,4-dioxane (2 mL). The reactionmixture was heated under nitrogen at 100 C using a greenhouse reactor for I h 30 mm. The reaction mixture was allowed to cool to rt and filtered through a celite cartridge, washing with ethyl acetate. The filtrate was evaporated in vacuo and the residue dissolved in a mixture of methanol:DMSO (2 mL, 1:1) and purified by MDAP (Formic). The required fractions were combined and evaporated in vacuo. Not all of the sample was injected into the MDAP, hence the residueswere combined, diluted in methanol (1 mL) and purified by MDAP (Formic). The required fraction was added to the previous fractions and evaporated in vacuo to give the required product as a yellow solid (30.9 mg, 0.086 mmol, 48.2 % yield). This was impure so the product was dissolved in DCM (1 mL) and purified on a 5 g silica cartridge eluting with 20% ethyl acetate in cyclohexane. The required fractions were combined and evaporated under a stream of nitrogen to give the requiredproduct as a yellow solid (20 mg, 0.056 mmol, 31.2%). LCMS (2 mm Formic): Rt = 1.26 mi [MH] = 359.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 244; 245

28
[ 174913-09-8 ]
4-(2,2-dioxido-3,4,7,8-tetrahydro-6,9-ethanopyrido[2,1-c][1,2,4]thiadiazin-9(6H)-yl)phenol [ No CAS ]
9-(4-(4-chloro-2-methoxyphenoxy)phenyl)-3,4,6,7,8,9-hexahydro-6,9-ethanopyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.6 mg	With 2-Picolinic acid; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 130℃;Inert atmosphere;	To a mixture of 2-picolinic acid (16 mg), tripotassium phosphate (208 mg), <strong>[174913-09-8]1-<strong>[174913-09-8]bromo-4-chloro-2-methoxybenzene</strong></strong> (108 mg), 4-(2,2-dioxido-3,4,7,8-tetrahydro-6,9-ethanopyrido[2,1-c][1,2,4]thiadiazin-9(6H)-yl)phenol (100 mg) and DMSO (3 ml) was added copper(I) iodide (25 mg), and the mixture was stirred under a nitrogen atmosphere at 130C overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Silica gel was added to the organic layer, and the mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate), and crystallized from THF/IPE to give the title compound (24.6 mg) as white crystals. MS (API+), found: 447.1. 1H NMR (300 MHz, DMSO-d6) delta 1.73-1.83 (2H, m), 1.86-1.99 (4H, m), 2.02-2.17 (2H, m), 3.18-3.24 (2H, m), 3.70-3.83 (4H, m), 3.87-3.96 (2H, m), 6.81 (2H, d, J = 9.1 Hz), 7.12 (1H, d, J = 2.5 Hz), 7.16-7.31 (4H, m).

Reference： [1]Patent: EP2813508,2014,A1 .Location in patent: Paragraph 0509

29
[ 174913-09-8 ]
7-chloro-5-hydroxy-2-naphthonitrile [ No CAS ]
7-chloro-5-(4-chloro-2-methoxyphenoxy)-2-naphthonitrile [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 1259 - 1262

30
[ 174913-09-8 ]
7-chloro-5-(4-chloro-2-hydroxyphenoxy)-2-naphthonitrile [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 1259 - 1262

31
[ 174913-09-8 ]
C₃₀H₁₉Cl₂N₃O₅ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 1259 - 1262

32
[ 174913-09-8 ]
7-chloro-5-(4-chloro-2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)-2-naphthonitrile [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 1259 - 1262

33
[ 174913-09-8 ]
[ 1257213-52-7 ]
1-(4'-chloro-2'-methoxy-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 2.0h;Inert atmosphere;	A solution of 2.0 g (9.0 mmol) of <strong>[174913-09-8]1-<strong>[174913-09-8]bromo-4-chloro-2-methoxybenzene</strong></strong> (Tokyo Chemical Industry Co., Ltd.), 2.6 g (8.2 mmol) of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl]cyclopropanecarboxylic acid ethyl ester (synthesized according to a process described in WO 12/078593) and 2.7 g (25 mmol) of sodium carbonate in 1,4-dioxane (20 ml)-water (20 ml) was degassed and subjected to nitrogen replacement. Then, 0.21 g (0.25 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride methylene chloride adduct was added, and the mixture was heated and stirred under a nitrogen atmosphere at 80C for 2 hours. After completion of the reaction, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, subsequently dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the fraction having Rf = 0.5 (developing solvent; hexane:ethyl acetate = 90:10 (V/V)) was concentrated under reduced pressure to obtain 2.46 g (7.4 mmol, yield 90%) of the title compound as a white solid. Mass spectrum (EI, m/z): 330 [M]+. 1 H-NMR spectrum (400 MHz, CDCl3) delta : 7.45-7.41 (2H, m), 7.39-7.35 (2H, m), 7.25 (1H, d, J = 8.2 Hz), 7.00 (1H, dd, J = 8.2, 2.0 Hz), 6.96 (1H, d, J = 2.0 Hz), 4.12 (2H, q, J = 7.1 Hz), 3.81 (3H, s), 1.61 (2H, dd, J = 6.9, 3.9 Hz), 1.22 (2H, dd, J = 7.0, 4.0 Hz), 1.19 (3H, t, J = 7.1 Hz).
90%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 2.0h;Inert atmosphere;	(Reference Example 5) 1-(4'-chloro-2'-methoxy-[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid ethyl ester A 1,4-dioxane (20 ml)-water (20 ml) solution of 2.0 g (9.0 mmol) of <strong>[174913-09-8]1-<strong>[174913-09-8]bromo-4-chloro-2-methoxybenzene</strong></strong> (Tokyo Chemical Industry Co., Ltd.), 2.6 g (8.2 mmol) of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylic acid ethyl ester (synthesized in accordance with the process described in ) and 2.7 g (25 mmol) of sodium carbonate was degassed and was purged with nitrogen. Next, 0.21 g (0.25 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride methylene chloride adduct was added. The mixture was stirred in a nitrogen atmosphere for 2 hours while performing heating at 80C. After the completion of the reaction, water was added to the reaction mixture liquid, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction having Rf= 0.5 (developing solvent: hexane:ethyl acetate = 90:10 (V/V)) was concentrated under reduced pressure and was dried by vacuum heating to give the title compound weighing 2.46 g (7.4 mmol, yield 90%) as a white solid. Mass spectrum (EI, m/z): 330 [M]+. 1H-NMR spectrum (400MHz, CDCl3) delta: 7.45-7.41 (2H, m), 7.39-7.35 (2H, m), 7.25 (1H, d, J = 8.2 Hz), 7.00 (1H, dd, J = 8.2, 2.0 Hz), 6.96 (1H, d, J = 2.0 Hz), 4.12 (2H, q, J = 7.1 Hz), 3.81 (3H, s), 1.61 (2H, dd, J = 6.9, 3.9 Hz), 1.22 (2H, dd, J = 7.0, 4.0 Hz), 1.19 (3H, t, J = 7.1 Hz).

Reference： [1]Patent: EP2940013,2015,A1 .Location in patent: Paragraph 0521
[2]Patent: EP3162801,2017,A1 .Location in patent: Paragraph 0153; 0154

34
[ 174913-09-8 ]
1-[4'-(3-carbamoyl-5-chlorothiophen-2-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl]cyclopropane-1-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Patent: EP2940013,2015,A1
[2]Patent: EP3162801,2017,A1

35
[ 174913-09-8 ]
(R)-1-[4'-(5-chloro-3-[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl]cyclopropane-1-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Patent: EP2940013,2015,A1
[2]Patent: EP3162801,2017,A1

36
[ 174913-09-8 ]
(R)-1-[4'-(5-chloro-3-[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl]cyclopropane-1-carboxylic acid [ No CAS ]

Reference： [1]Patent: EP2940013,2015,A1
[2]Patent: EP3162801,2017,A1

37
[ 174913-09-8 ]
(R)-1-{4'-[5-chloro-3-([1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid ethyl ester [ No CAS ]