[ CAS No. 77771-03-0 ] {[proInfo.proName]}

Name: 77771-03-0|3-Bromo-4-fluorobenzyl alcohol|98%
Brand: Ambeed
SKU: A968991
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2D 3D

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Quality Control of [ 77771-03-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 77771-03-0 ]

Product Details of [ 77771-03-0 ]

CAS No. :	77771-03-0	MDL No. :	MFCD00143093
Formula :	C₇H₆BrFO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HNVVROFWONXXGO-UHFFFAOYSA-N
M.W :	205.02	Pubchem ID :	2773351
Synonyms :

Calculated chemistry of [ 77771-03-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.23
TPSA :	20.23 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) :	-6.25 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.06
Log Po/w (XLOGP3) :	1.83
Log Po/w (WLOGP) :	2.35
Log Po/w (MLOGP) :	2.72
Log Po/w (SILICOS-IT) :	2.77
Consensus Log Po/w :	2.35

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.64
Solubility :	0.467 mg/ml ; 0.00228 mol/l
Class :	Soluble
Log S (Ali) :	-1.88
Solubility :	2.73 mg/ml ; 0.0133 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.36
Solubility :	0.0887 mg/ml ; 0.000433 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.44

Safety of [ 77771-03-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313	UN#:	N/A
Hazard Statements:	H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 77771-03-0 ]

* 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 [ 77771-03-0 ]
Downstream synthetic route of [ 77771-03-0 ]

[ 77771-03-0 ] Synthesis Path-Upstream 1~5

1
[ 77771-03-0 ]
[ 78239-71-1 ]

Reference： [1] Patent: US4792563, 1988, A,
[2] Patent: US4326087, 1982, A,
[3] Patent: WO2007/61670, 2007, A1, . Location in patent: Page/Page column 176-177
[4] Patent: WO2017/37146, 2017, A1, . Location in patent: Page/Page column 219; 220

2
[ 77771-03-0 ]
[ 77771-02-9 ]

Reference： [1] Synthetic Communications, 2009, vol. 39, # 2, p. 366 - 370
[2] Patent: US4626601, 1986, A,
[3] Patent: US4626601, 1986, A,
[4] Patent: US4626601, 1986, A,

3
[ 77771-03-0 ]
[ 74-88-4 ]
[ 887268-22-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Stage #2: at 0 - 20℃; for 1 h;	To a solution of (3-bromo-4-fluorophenyl)methanol (5.00 g, 24.4 mmol) in N,N-anhydrous N,N-dimethylformamide (50 mL) was added a 60percent suspension of sodium hydride in mineral oil (1.37 g, 34.2 mmol) in portions at 0° C., and the mixture was stirred at 0° C. for 30 minutes. To it was then added iodomethane (4.15 g, 29.3 mmol) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction was quenched by addition of water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 2 to 5percent of ethyl acetate in petroleum ether, afforded the title compound as a colorless oil (4.50 g, 84percent yield): ¹H NMR (400 MHz, CDCl₃) δ7.57 (dd, J=6.4, 2.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 4.42 (s, 2H), 3.41 (s, 3H).

Reference： [1] Patent: US2018/162868, 2018, A1, . Location in patent: Paragraph 1534-1535
[2] Patent: US2004/220194, 2004, A1, . Location in patent: Page 23
[3] Patent: US2005/239795, 2005, A1, . Location in patent: Page/Page column 20

4
[ 77771-03-0 ]
[ 887268-22-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7299 - 7317

5
[ 77771-03-0 ]
[ 501420-63-9 ]

Reference： [1] Patent: WO2011/71565, 2011, A1,
[2] Patent: WO2010/93845, 2010, A1,

[ 77771-03-0 ] Synthesis Path-Downstream 1~55

1
[ 77771-03-0 ]
[ 74-88-4 ]
[ 887268-22-6 ]

Yield	Reaction Conditions	Operation in experiment
84%		To a solution of <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (5.00 g, 24.4 mmol) in N,N-anhydrous N,N-dimethylformamide (50 mL) was added a 60% suspension of sodium hydride in mineral oil (1.37 g, 34.2 mmol) in portions at 0 C., and the mixture was stirred at 0 C. for 30 minutes. To it was then added iodomethane (4.15 g, 29.3 mmol) at 0 C. The mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction was quenched by addition of water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 2 to 5% of ethyl acetate in petroleum ether, afforded the title compound as a colorless oil (4.50 g, 84% yield): 1H NMR (400 MHz, CDCl3) delta7.57 (dd, J=6.4, 2.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 4.42 (s, 2H), 3.41 (s, 3H).
	With sodium hydride; In tetrahydrofuran; at 0℃; for 3h;	Step 2: Cool a solution of the product of Step 1 (1.20 g, 5.9 mmol) in THF (50 ml) in ice and add NaH (60% in oil, 0.33 g, 8.2 mmol), then CH3I (1.00 ml, 7.1 mmol). Stir 3 h and partition between ether and water. Dry (MgSO4) and concentrate to obtain the crude methyl ether as a yellow oil.
	With sodium hydride; In tetrahydrofuran; for 3h;	Cool a solution of the product of Step 1 (1.20 g, 5.9 mmol) in THF (50 ml) in ice and add NaH (60% in oil, 0.33 g, 8.2 mmol), then CH3l (1.00 ml, 7.1 mmol). Stir 3 h and partition between ether and water. Dry (MgSO4) and concentrate to obtain the crude methyl ether as a yellow oil.

Reference： [1]Patent: US2018/162868,2018,A1 .Location in patent: Paragraph 1534-1535
[2]Patent: US2004/220194,2004,A1 .Location in patent: Page 23
[3]Patent: US2005/239795,2005,A1 .Location in patent: Page/Page column 20

2
[ 77771-03-0 ]
[ 18162-48-6 ]
[ 655237-57-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;	General procedure: <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (7.0 g, 34.14 mmol) was dissolved in DMF (60mL), to this was added imidazole (2.79 g, 40.97 mmol) and TDBMSCl (6.18 g, 40.97mmol). The mixture was stirred overnight, the reaction mixture was quenched withwater (100 mL), extracted with heptane (2 x 75 mL), the organic layer was dried overMgSO4, filtered and evaporated to afford colourless liquid. The crude product was purified by distillation at 0.097 mBar, collecting fractions that distilled at 75C to afford ((3-bromo-4-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (10.30 g, 94 %) as acolourless liquid.
	With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 0℃; for 2h;	Step 1: To the product of Preparation 33, Step 1 (5.4 g, 26 mmol) in DMF (20 ml) at 0 C. add t-butyldimethylsilyl chloride (4.17 g, 28 mmol) and imidazole (2.69 g, 40 mmol). Stir 2 h and partition between 1:1 ether-hexane and water. Wash with brine, dry (MgSO4) and concentrate to obtain the product as a colorless oil
	With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 0℃; for 2h;	To the product of Preparation 22, Step 1 (5.4 g, 26 mmol) in DMF (20 ml) at 0 C. add t-butyidimethylsilyl chloride (4.17 g, 28 mmol) and imidazole (2.69 g, 40 mmol). Stir 2 h and partition between 1:1 ether-hexane and water. Wash with brine, dry (MgSO4) and concentrate to obtain the product as a colorless oil.

With 1H-imidazole; In N,N-dimethyl-formamide; at 0℃; for 2h;

Step 2: To the product of Step 1 (5.4 g, 26 mmol) in DMF (20 ml) at 0 C. add t-butyldimethylsilyl chloride (4.17 g, 28 mmol) and imidazole (2.69 g, 40 mmol). Stir 2 h and partition between 1:1 ether-hexane and water. Wash with brine, dry (MgSO4) and concentrate to obtain the product as a colorless oil.

Reference： [1]Synlett,2014,vol. 25,p. 123 - 127
[2]Patent: US2004/220194,2004,A1 .Location in patent: Page 28
[3]Patent: US2005/239795,2005,A1 .Location in patent: Page/Page column 24
[4]Patent: US2007/66620,2007,A1 .Location in patent: Page/Page column 11-12

3
[ 77771-02-9 ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With methanol; sodium tetrahydroborate; at 20℃;	(3-bromo-4-fluoro-phenyl)-methanol; A solution of 5 g (24.6 mmol) 3-bromo-4-fluoro-benzaldehyde in 20 ml anhydrous methanol is mixed in portions with 1.38 g (36.58 mmol) sodium borohydride while stirring and stirred for another hour at room temperature. After adding water, an extraction is carried out using diethyl ether, and the organic phase is dried over sodium sulfate. After the solvent is removed under vacuum, the appropriate alcohol is obtained. The product is obtained in pure form and can be used for further reactions.Form: colorless crystalsYield: 4.68 g (22.9 mmol; 93%)Rf: 0.41 (diethyl ether/n-hexane=1:1)
	With sodium tetrahydroborate; In ethanol; for 2h;	Step 1: To a solution of 3-bromo-4-fluorobenzaldehyde (1.20 g, 5.9 mmol) in EtOH (20 ml) add NaBH4 (0.103 g, 2.7 mmol). Stir 2 h, concentrate, and partition between ether and water, with NH4Cl (0.6 g) added. Dry (MgSO4) and concentrate to obtain the alcohol as a colorless oil
	With sodium tetrahydroborate; In ethanol; for 2h;	To a solution of 3-bromo-4-fluorobenzaldehyde (1.20 g, 5.9 mmol) in EtOH (20 ml) add NaBH4 (0.103 g, 2.7 mmol). Stir 2 h, concentrate, and partition between ether and water, with NH4Cl (0.6 g) added. Dry (MgSO4) and concentrate to obtain the alcohol as a colorless oil.

	In tetrahydrofuran;	Stage 2: 3-Bromo-4-fluorobenzyl alcohol Lithium aluminium hydride (0.075 g) was added to a stirred solution of 3-bromo-4-fluorobenzaldehyde (1.2 g) in dry tetrahydrofuran (20 cm3), the temperature being maintained below 5 C. by external cooling. The temperature of the reaction mixture was then allowed to rise to the ambient value (ca 20 C.) and the mixture was stirred for 2 hours; GLC analysis of a withdrawn sample indicated 82% conversion at this time, and further lithium aluminium hydride (0.025 g) was therefore added to the mixture. After a further 1.5 hours GLC analysis indicated that the reaction was complete. The mixture aas poured into water (20 cm3) and the products extracted into diethyl ether (3*20 cm3). The combined ethereal extracts were washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave the title compound in high purity. 1 H NMR (CDCl3): 1.78 (1H,t); 4.65 (2H,d); 7.1-7.7 (3H,m) IR (liquid film): 3347 cm-1 (OH, broad)
		Step 1: To a solution of 3-bromo-4-fluorobenzaldehyde (1.20 g, 5.9 mmol) in EtOH (20 ml) add NaBH4 (0.103 g, 2.7 mmol). Stir 2 h, concentrate, and partition between ether and water, with NH4Cl (0.6 g) added. Dry (MgSO4) and concentrate to obtain the alcohol as a colorless oil.
		Step 1: To 3-bromo-4-fluorobenzaldehyde (3.50 g, 17.2 mmol) in THF (25 ml) add NaBH4 (0.65 g, 17 mmol). Stir 2 h and add water (5 ml), then 1N NaOH (50 ml). Extract with ether, dry (MgSO4), and concentrate to obtain the alcohol as a yellow oil.
	With methanol; sodium tetrahydroborate; for 3h;	3-Bromo-4-fluorobenzaldehyde (0.300 g, 1.48 mmol) was dissolved in methanol (3 mL). Sodium borohydride (0.0671 g, 1.77 mmol) was added. After 3 h, the reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was taken up in 2:1 EtOAc-hexane (60 mL). The organic layer was extracted with dilute NaHCO3 (6 mL) then half-saturated brine (6 mL), then was dried over sodium sulfate and concentrated. The material was purified through silica gel (45 mL) using 30% to 40% EtOAc-hexane to afford the title compound.
	With sodium tetrahydroborate; In methanol; at 0℃; for 1h;	To a solution of 3-bromo-4-fluorobenzaldehyde (50 g, 0.246 mol) in MeOH (500 mL) at 0 C was added NaBH4 (9.3 g, 0.246 mol) portionwise. After 1 h, the reaction was concentrated in vacuo, diluted with water and extracted with DCM. The combined extracts were dried over MgS04 and concentrated in vacuo to give (3-bromo-4-fluorophenyl)methanol (53 g). 1H NMR (400 MHz, CDC13) delta 7.58-7.56 (m, 1H), 7.28-7.25 (m, 1H), 7.09 (t, J=4.4 Hz, 1H), 4.65 (d, J=5.2 Hz, 2H), 1.82 (t, J=5.6 Hz, 1H).
		To a solution of 3-bromo-4-fluorobenzaldehyde (50 g, 0.246 mol) in MeOH (500 niL) at 0 0C was added NaBH4 (9.3 g, 0.246 mol) portionwise. After 1 h, the reaction was concentrated in vacuo, diluted with water and extracted with DCM. The combined extracts were dried over MgSO4 and concentrated in vacuo to give (3-bromo-4-fluorophenyl)methanol (53 g). 1H NMR (400 MHz, CDCl3) delta 7.58-7.56 (m, IH), 7.28-7.25 (m, IH), 7.09 (t, J=4.4 Hz, IH), 4.65 (d, J=5.2 Hz, 2H), 1.82 (t, J=5.6 Hz, IH).
		General procedure: To a solution of benzaldehyde (3.18 g, 30.0 mmol) inmethanol (20 mL) was added sodium borohydride (1.37g, 36.0 mmol) in portions inice-water bath. The mixture was stirred at room temperature, and after 2.0 hquenched with diluted HCl (1M). The resulting aqueous solution was then extracted with CH2Cl2 (10 mL×3).The organic phase was combined, dried over anhydrous MgSO4, filteredand concentrated reduced pressure by a rotary evaporator to provide the crude product. The crude product was purified by column chromatography on silica gelusing EtOAc-petroleumether (1:20, v/v) as eluentto give the corresponding phenylmethanol
15.1 g	With sodium tetrahydroborate; In methanol; for 1h;Cooling with ice;	Dissolve 3-bromo-4-fluorobenzaldehyde (15.0 g, 7.4 mmol, CAS: 77771-02-9)Sodium borohydride (3.4 g, 89.9 mmol) was added to the reaction solution in 100 mL of methanol under ice bath.After stirring for 1 h, water was added and extracted with ethyl acetate.Washed three times with saturated brine, dried over anhydrous sodium sulfate and evaporated in vacuo.Intermediate M-29-1 (15.1 g) was obtained.

Reference： [1]Patent: US2010/256389,2010,A1 .Location in patent: Page/Page column 4
[2]Patent: US2004/220194,2004,A1 .Location in patent: Page 23
[3]Patent: US2005/239795,2005,A1 .Location in patent: Page/Page column 20
[4]Patent: US4792563,1988,A
[5]Patent: US2007/66620,2007,A1 .Location in patent: Page/Page column 11-12
[6]Patent: US2007/66620,2007,A1 .Location in patent: Page/Page column 26
[7]Patent: WO2007/61670,2007,A1 .Location in patent: Page/Page column 176
[8]Patent: WO2011/71565,2011,A1 .Location in patent: Page/Page column 158-159
[9]Patent: WO2010/93845,2010,A1 .Location in patent: Page/Page column 147-148
[10]Tetrahedron Letters,2014,vol. 55,p. 4458 - 4462
[11]Patent: CN110041333,2019,A .Location in patent: Paragraph 0817-0820

4
[ 77771-03-0 ]
[ 6482-24-2 ]
[ 1248085-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; potassium carbonate; potassium iodide; In DMF (N,N-dimethyl-formamide); at 0 - 100℃; for 36.17h;	To the product of Preparation 22, Step 1 (1.50 g, 7.3 mmol) in DMF (20 ml) at 0 C. add NaH (60% in oil, 0.35 g, 0.21 g NaH, 8.8 mmol). Stir 10 min. and add 2-bromoethyl methyl ether (1.22 g, 8.8 mmol). Heat at 60 C. 18 h, add K2CO3 (1.40 g), KI (1.21 g), and additional bromo-ether (1.22 g). Heat at 100 C. 18 h, allow to cool, and partition between ether and water. Dry (MgSO4) and concentrate to obtain the crude product as a yellow oil.

Reference： [1]Patent: US2005/239795,2005,A1 .Location in patent: Page/Page column 23

5
[ 77771-03-0 ]
[ 77771-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; hydrogenchloride; In dichloromethane;	EXAMPLE 1 STR14 Variant (a) A solution of 45.9 g (0.225 mol) of <strong>[77771-03-0]3-bromo-4-fluoro-benzyl alcohol</strong> in 45 ml of methylene chloride was added dropwise to a suspension of 78 g of pyridine/CrO3 /HCl in 450 ml of methylene chloride. During this addition, the temperature of the mixture rose to about 40 C. The mixture was then subsequently stirred for 1 hour, the organic phase was decanted from the chromium salts and the solvent was distilled off in vacuo. The residue was distilled. 39 g (86% of theory) of 3-bromo-4-fluoro-benzaldehyde with a boiling point of 63-65 C./0.3 mm Hg were thus obtained.
	With potassium dichromate; sulfuric acid; In dichloromethane; water;	Variant (c) A mixture of 29.4 g (0.3 mol) of sulphuric acid, 50 ml of water and 2 ml of Aliquat 336 (tricapryl-methyl-ammonium chloride) was added to a solution of 20.5 g (0.1 mol) of <strong>[77771-03-0]3-bromo-4-fluoro-benzyl alcohol</strong> in 250 ml of methylene chloride at room temperature. Thereafter, 9.7 g (0.033 mol) of potassium dichromate were added to the reaction mixture and the temperature was kept at about 25 C. for 2 hours by cooling slightly. After adding 100 ml of water, the organic phase was separated off and the aqueous phase was extracted once more with 100 ml of methylene chloride. The organic phases were washed twice with 100 ml of water each time, then once with 100 ml of saturated sodium bicarbonate solution and once more with 100 ml of water, dried over sodium sulphate and evaporated in vacuo. The residue was distilled. 16.3 g (81% of theory) of 3-bromo-4-fluoro-benzaldehyde were obtained in this manner as a colorless oil with a boiling point of 65 C./0.3 mm Hg.
	With sodium hydroxide; nitric acid; In water; toluene;	Variant (b) 10.2 g (0.05 mol) of <strong>[77771-03-0]3-bromo-4-fluoro-benzyl alcohol</strong> were added to a mixture of 10 g of nitric acid (density: 1.4) and 5 ml of water at 30-35 C. and the mixture was then stirred at room temperature for 5 hours. After adding 30 g of ice, sodium hydroxide solution was added to the mixture until the pH value reached 13, and the mixture was then extracted by shaking with 200 ml of toluene. The organic phase was washed three times with 50 ml of water each time, dried over sodium sulphate and then evaporated. The residue was distilled. 6.1 g (60% of theory) of 3-bromo-4-fluoro-benzaldehyde were thus obtained in the form of an oil which slowly solidified and had a melting point of 29-31 C.

Reference： [1]Synthetic Communications,2009,vol. 39,p. 366 - 370
[2]Patent: US4626601,1986,A
[3]Patent: US4626601,1986,A
[4]Patent: US4626601,1986,A

6
[ 77771-03-0 ]
[ 78239-71-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; phosphorus tribromide; sodium hydrogencarbonate; In toluene;	Stage 3: 3-Bromo-4-fluorobenzyl bromide Pyridine (0.7 cm3) and a solution of 3-bromo-4-fluorobenzyl alcohol (5 g) in dry toluene (50 cm3) were added to a stirred solution of phosphorus tribromide (2.64 g) in dry toluene (50 cm3) under an atmosphere of nitrogen, the temperature of the reaction mixture being maintained at -10 C. during the addition. The mixture was allowed to warm to the ambient temperature (ca. 20 C.) and was stirred for one hour. The mixture was poured into ice and the products extracted into diethyl ether. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulphate to give an orange-red oil, shown by thin layer chromatography to contain two components. NMR spectroscopy of the mixture suggested the presence of a phosphite intermediate and the required product. The oil was redissolved in dry toluene (50 cm3) and further phosphorus tribromide (0.2 g) and pyridine (0.7 cm3) added. The mixture was stirred at 50 C. for 4 hours and then stood at the ambient temperature for 17 hours. The mixture was poured into ice and sodium bicarbonate solution added to neutralise the resulting acid mixture. The products were extracted into diethyl ether, and the combined organic extracts washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent gave a white solid which was purified by flash column chromatography on a silica gel support, eluding with petroleum ether containing 5% by volume diethyl ether, to give the title compound (4.6 g) as a colourless crystalline solid. 90 MHz 1 H NMR (CDCl3): 4.42 (2H,s); 7.0-7.7 (3H,m)
	With phosphorus tribromide; In water; toluene;	EXAMPLE 2 STR16 20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol were dissolved in 100 ml of anhydrous toluene, and 10 g of phosphorus tribromide were added dropwise at 0 to 10 C., while stirring. The mixture was then stirred at room temperature for 2 hours. The reaction batch was subsequently poured into 500 ml of water, the organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. The residue was distilled in vacuo. 24 g (89.6% of theory) of 3-bromo-4-fluoro-benzyl bromide with a boiling point of 99-100 C./3 mbars were obtained.
	With boron tribromide; In dichloromethane; at 0 - 20℃; for 1h;	(3-Bromo-4-fluorophenyI)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3 mL). The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml, 0.863 <n="179"/>mmol) was added. The mixture was stirred at O deg for 1 h, then it for 1 h. The reaction was quenched with water, and the mixture was transfered to a separatory funnel with half- saturated NaHCO3 (15 mL), and the aqueous phase was extracted with DCM (3 x 20 mL). The organics were combined, washed with half-saturated brine (5 mL), dried over sodium sulfate and concentrated. Purification of the residue through silica gel (40 mL) using 5% EtOAc-hexane afforded the title compound.

	With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 65h;Inert atmosphere;	Tetrabromomethane (7.28 g) was added to a solution of 3-bromo-4-fluorophenyl)methanol (3.0 g, CAS: 7777 1-03-0) in THF (50 mL) at 0C under an argon atmosphere. Then, a solution of triphenylphosphine (5.76 g) in THF (30 mL) was added dropwise over a period of 40 minutes. The mixture was warmed up to rt and kept at this temperature for 65 hours. The reaction mixturewas poured then into ice/water and was extracted two times with ethyl acetate. The organic layers were washed once with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (0% to 10% ethyl acetate in heptane) to give the title compound as a light yellow liquid (5.10 g, 95%, purity 70%). MS (El): mlz = 267.9 [Mf?.
19.7 g	With phosphorus tribromide; In dichloromethane; for 1h;Cooling with ice;	The compound M-29-1 (15.1 g, 7.4 mmol) was dissolved in 50 mL of dichloromethane, and phosphorus tribromide (19.9 g, 7.4 mmol) was added dropwise thereto under ice-cooling, and the mixture was reacted for 1 hour, water was added, and dichloromethane was extracted.The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate.The solvent was removed in vacuo to give compound M-29-2 (19.7 g).

Reference： [1]Patent: US4792563,1988,A
[2]Patent: US4326087,1982,A
[3]Patent: WO2007/61670,2007,A1 .Location in patent: Page/Page column 176-177
[4]Patent: WO2017/37146,2017,A1 .Location in patent: Page/Page column 219; 220
[5]Patent: CN110041333,2019,A .Location in patent: Paragraph 0817-0818; 0821-0822

7
[ 103-83-3 ]
[ 1007-16-5 ]
[ 5197-95-5 ]
[ 541-41-3 ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium borohydrid; In diethyl ether; water;	EXAMPLE 2 STR10 10.8 g of chloroformic acid ethyl ester were added dropwise to a solution of 20.8 g of 95% pure 4-fluoro-3-bromo-benzoic acid and 13.5 g of dimethylbenzylamine in 200 ml of diethyl ether at 0 C. Stirring was continued at 0 to 20 C. for 1 hour and the hydrochloride which had precipitated was then filtered off. After adding 0.1 g of triethylbenzylammonium bromide, a solution of 7.6 g of sodium borohydride in 50 ml of water was added dropwise to the filtrate at 20 C. The reaction mixture was subsequently stirred at 20 C. for 3 hours and was then acidified with dilute hydrochloric acid. The ether phase was separated off and washed once with 30 ml of saturated sodium bicarbonate solution. The ether phase was then concentrated. 17.3 g (93.4% of theory) of 4-fluoro-3-bromobenzyl alcohol were thus obtained in the form of a colorless oil. The sodium bicarbonate solution was acidified. The unreacted 4-fluoro-3-bromobenzoic acid precipitated and was filtered off and dried in air.

Reference： [1]Patent: US4386035,1983,A

8
[ 77771-03-0 ]
[ 865-47-4 ]
[ 100-44-7 ]
3-bromo-4-fluorobenzyl ether [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In tetrahydrofuran; water;	EXAMPLE 7 STR21 20.5 g (0.1 mol) of <strong>[77771-03-0]3-bromo-4-fluoro-benzyl alcohol</strong> were added to a solution of 12.3 g (0.11 mol) of potassium tert.-butylate in 200 ml of tetrahydrofuran at 20 C. During this addition, the temperature increased to about 40 C. The mixture was subsequently stirred at 20 C. for about 1 hour and 12.6 g (0.1 mol) of benzyl chloride were then added dropwise to the reaction mixture. Thereafter, the mixture was heated under reflux for one hour. It was then cooled. About 200 ml of water and 50 ml of concentrated hydrochloric acid were added to the reaction mixture and the mixture was extracted twice with 200 ml of diethyl ether each time. The combined extracts were concentrated, dried over sodium sulphate and then subjected to fractional distillation. 14.2 g (48.2% of theory) of 3-bromo-4-fluoro-benzyl ether were obtained in the form of a light yellow oil of boiling point 165 C./7 mbars.

Reference： [1]Patent: US4326087,1982,A

9
[ 1634-04-4 ]
[ 1007-16-5 ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium borohydrid;aluminium trichloride; In diethylene glycol dimethyl ether; water;	STR9 Reduction of 4-fluoro-3-bromobenzoic acid: 6.7 g of aluminum chloride were added to a solution of 10.9 g of 95% pure 3-bromo-4-fluorobenzoic acid in 150 ml of diglyme at 20 C. The reaction mixture was subsequently stirred at 20 C. for 10 minutes and 5.7 g of sodium borohydride were then added in portions at 20 to 25 C. After 12 hours, about 100 ml of water (vigorous foaming) and then about 1 ml of 10% strength hydrochloric acid were added dropwise. About 100 ml of tert.-butyl methyl ether were added and the organic phase was separated off. It was washed once with about 30 ml of saturated sodium bicarbonate solution. The ether phase was then concentrated. 6.7 g (76% of theory) of 4-fluoro-3-bromo-benzyl alcohol were obtained. The sodium bicarbonate solution was acidified. 1 g of unreacted 4-fluoro-3-bromobenzoic acid precipitated and was filtered off and dried in air. According to the 1 H-nuclear magnetic resonance spectrum, the acid recovered was of the same quality as the acid employed.

Reference： [1]Patent: US4386035,1983,A

10
[ 1007-16-5 ]
[ 79-22-1 ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium borohydrid; triethylamine; In tetrahydrofuran; dichloromethane; water;	2 g of triethylamine, dissolved in 5 ml of tetrahydrofuran, were added dropwise to a solution of 4.2 g of 3-bromo-4-fluoro-benzoic acid and 1.95 g of chloroformic acid methyl ester in 30 ml of tetrahydrofuran at 20 C., while stirring. Stirring was continued for a further 40 minutes at 20-25 C. and the hydrochloride which had precipitated was then filtered off. 5.5 g of sodium borohydride, dissolved in 20 ml of water, were added dropwise to the filtrate at 10 to 20 C., while stirring. Stirring was then continued for a further 4 hours at 20 C. The reaction batch was subsequently poured into 100 ml of water and extracted by shaking with 80 ml of methylene chloride. The methylene chloride phase was separated off and dried over magnesium sulphate and the solvent was then distilled off in vacuo. 1.95 g (95% of theory) of 3-bromo-4-fluoro-benzyl alcohol were obtained as a colorless oil.

Reference： [1]Patent: US4386035,1983,A

11
[ 16940-66-2 ]
3-bromo-4-fluoro-benzoic acid fluoride [ No CAS ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ice-water; isopropyl alcohol;	STR15 221 g (1 mol) of 3-bromo-4-fluoro-benzoyl fluoride were added dropwise to a mixture of 30.4 g (0.8 mol) of sodium tetrahydridoborate and 840 ml of isopropanol at 20-25 C. in the course of 3 hours. The reaction mixture was stirred for about a further 30 minutes and then poured into 2 liters of ice-water. The pH was adjusted to 1 by adding concentrated hydrochloric acid, and the organic layer was then separated off. The aqueous phase was subsequently extracted with 200 ml of methylene chloride. The combined organic phases were dried and filtered and the filtrate was distilled. 163 g (79.5% of theory) of 3-bromo-4-fluoro-benzyl alcohol of boiling point 137 C./16 mbars and of refractive index nD20 =1.5623 were obtained.

Reference： [1]Patent: US4326087,1982,A

12
[ 206551-41-9 ]
[ 82702-31-6 ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium borohydrid;aluminium trichloride; In diethylene glycol dimethyl ether;	EXAMPLE 3 STR11 4-Fluoro-3-bromo-benzyl alcohol from fluorobromobenzoic acid methyl ester: First 3.8 g (0.1 mole) of sodium borohydride and then 4.5 g (0.033 mole) of aluminum chloride were added in portions to a solution of 23.3 g (0.1 mole) of 4-fluoro-3-bromobenzoic acid methyl ester in 50 ml of diglyme at 5° C. The mixture was subsequently stirred, without cooling, until the exothermic reaction had ended (a rise in temperature up to about 50° C.) and the reaction was then allowed to go to completion in the course of 1 hour at 100° C. The reaction solution was then poured onto a mixture of 125 ml of icewater and 12 ml of concentrated hydrochloric acid and the benzyl alcohol which had separated out was separated off and distilled in vacuo. 18.7 g (91percent of theory) of 4-fluoro-3-bromobenzyl alcohol were obtained in this manner as a colorless oil with a boiling point of 65° to 70° C. (0.1 mbar).

Reference： [1]Patent: US4386035,1983,A

13
[ 77771-03-0 ]
[ 78239-72-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In tetrachloromethane;	EXAMPLE 6 STR20 41 g (0.2 mol) of <strong>[77771-03-0]3-bromo-4-fluoro-benzyl alcohol</strong> were dissolved in 250 ml of carbon tetrachloride, and 26 g of thionyl chloride were added dropwise at 20 C., while stirring. The mixture was then stirred at 25-30 C. for 4 hours and the solvent and excess thionyl chloride were subsequently stripped off at 20 C. under a waterpump vacuum. The residue was distilled in vacuo. 29 g (64.9% of theory) of 3-bromo-4-fluoro-benzyl chloride with a boiling point of 85-87 C./3 mbars were obtained.

Reference： [1]Patent: US4326087,1982,A

14
[ 77771-03-0 ]
[ 124-63-0 ]
[ 866862-23-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃; for 2h;	Step 2: To the product of Step 1 (3.609, 17.6 mmol), in CH2Cl2 (40 ml) at 0 C. add CH3SO2Cl (1.56 ml, 20 mmol) and Et3N (2.93 ml, 21 mmol). Stir 2 h and add satd. NaHCO3. Extract with CH2Cl2, dry (MgSO4), and concentrate to obtain the crude mesylate as a yellow oil.
	With triethylamine; In dichloromethane; at -20 - 20℃;	A cooled (-20 0C) solution of <strong>[77771-03-0]3-bromo-4-fluorobenzyl alcohol</strong> (Oakwood; 500 mg; 2.44 mmol) and methanesulfonyl chloride (123 muL; 1.59 mmol) in DCM (5 mL) was treated with a solution of triethylamine (255 muL; 1.83 mmol) in DCM (2.5 mL). The reaction mixture was allowed to warm to RT and stirred for 30 minutes before being quenched with water. The phases were separated and the organic phase was washed with HCI (0.1 N in water) and brine, dried over MgSO4, filtered and concentrated to dryness affording a residue, which was purified by flash column chromatography), eluting with cyclohexane containing increasing amounts of EtOAc, to give the title compound as a colorless liquid.1H NMR (300MHz, DMSOd6) delta [ppm] 7.84 (1 H, dd, J= 6.7, J= 2.1 Hz), 7.54 (1 H, ddd, J= 8.7, J= 4.9, J= 2.1 Hz), 7.45 (1 H, d, J= 8.7 Hz), 5.25 (2H, s), 3.27 (3H, s).
	With triethylamine; In dichloromethane; at 0℃; for 0.5h;	To a solution of <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (53 g, 0.258 mol) in DCM (500 mL) at 0 C was added Et3N (108 mL, 775 mmol, 3 eq) and methanesulfonyl chloride (24 mL, 310 mmol, 1.2 eq) successively. After stirring 30 min, the reaction mixture was partitioned in DCM and water. The organic layer was dried over MgS04 and evaporated in vacuo to give 3-bromo-4-fluorobenzyl methanesulfonate (60 g), which used to the next step without further purification. 1H NMR (400 MHz, CDC13) delta 7.65-7.62 (m, 1H), 7.37-7.33 (m, 1H), 7.16 (t, J=4.4 Hz, 1H), 5.17 (s, 2H), 2.99 (s, 3H).

With triethylamine; In dichloromethane; at 0℃; for 0.5h;

To a solution of <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (53 g, 0.258 mol) in DCM (500 mL) at 0 0C was added Et3N (108 mL, 775 mmol, 3 eq) and methanesulfonyl chloride (24 mL, 310 mmol, 1.2 eq) successively. After stirring 30 min, the reaction mixture was partitioned in DCM and water. The organic layer was dried over MgSO4 and evaporated in vacuo to give 3-bromo-4-fluorobenzyl methanesulfonate (60 g), which used to the next step without further purification. 1U NMR (400 MHz, CDCl3) delta 7.65-7.62 (m, IH), 7.37-7.33 (m, IH), 7.16 (t, J=4.4 Hz, IH), 5.17 (s, 2H), 2.99 (s, 3H).

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7299 - 7317
[2]Patent: US2007/66620,2007,A1 .Location in patent: Page/Page column 26
[3]Patent: WO2010/92043,2010,A1 .Location in patent: Page/Page column 64-65
[4]Patent: WO2011/71565,2011,A1 .Location in patent: Page/Page column 159
[5]Patent: WO2010/93845,2010,A1 .Location in patent: Page/Page column 148
[6]ChemistryOpen,2019,vol. 8,p. 114 - 125

15
[ 77771-03-0 ]
[ 503-17-3 ]
C₁₁H₁₀BrFO [ No CAS ]
[ 1120371-01-8 ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 2066 - 2067

16
[ 110-87-2 ]
[ 77771-03-0 ]
[ 1159894-71-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 2.25h;	2-(3-bromo-4-fluoro-benzyloxy)-tetrahydropyrane; A solution of 5 g (24.39 mmol) <strong>[77771-03-0](3-bromo-4-fluoro-phenyl)-methanol</strong> and 5.6 ml (60.98 mmol) 3,4-dihydro-2H-pyrane in 50 ml absolute dichloromethane is mixed at 0 C. with a small amount covering the tip of a spatula of toluene sulfonic acid monohydrate and stirred for 15 minutes. After 2 hours of stirring at room temperature, it is mixed with diethyl ether. The organic phase is separated off, washed with a sodium chloride and sodium carbonate solution and water, and then again with a sodium chloride solution, dried over sodium sulfate, and the solvent is removed under vacuum. The resulting raw product is purified by way of column chromatography on silica gel using diethyl ether/n-hexane (1:3).Form: colorless oilYield: 6.42 g (22.19 mmol; 91%)Rf: 0.78 (diethyl ether/n-hexane=1:1)

Reference： [1]Patent: US2010/256389,2010,A1 .Location in patent: Page/Page column 4

17
[ 77771-03-0 ]
[ 1297551-06-4 ]

Reference： [1]Patent: US2011/130445,2011,A1

18
[ 77771-03-0 ]
rac-ethyl 2-(3-bromo-4-fluorophenyl)-trans-cyclopropanecarboxylate [ No CAS ]

Reference： [1]Patent: US2011/130445,2011,A1

19
[ 77771-03-0 ]
rac-ethyl 2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclopropanecarboxylate [ No CAS ]

Reference： [1]Patent: US2011/130445,2011,A1

20
[ 77771-03-0 ]
rac-ethyl 2-[3-amino-4-fluorophenyl]-trans-cyclopropanecarboxylate [ No CAS ]

Reference： [1]Patent: US2011/130445,2011,A1

21
[ 77771-03-0 ]
ethoxycarbonylmethylenephosphorane [ No CAS ]
[ 1147334-61-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With manganese(IV) oxide; In toluene;Reflux;	Example 40AEthyl 3-(3-bromo-4-fluorophenyl)acrylate; 9.65 g (111 mmol) of manganese dioxide were added to a solution of 6.5 g (31.7 mmol) of <strong>[77771-03-0]3-bromo-4-fluorobenzyl alcohol</strong> and 13.25 g (38 mmol) of ethoxycarbonylmethylenephosphorane in 390 ml of toluene. The reaction mixture was heated at reflux, a further 9.65 g of manganese dioxide were added after 1 h and heating under reflux was continued overnight. After cooling, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (mobile phase cylclohexane/ethyl acetate 5:1). This gave 7.05 g (81% of theory) of the target product in the form of an E/Z isomer mixture.LC-MS (Method 4): Rt=1.33 min and 1.35 min; m/z=273/275 (M+H)+.

Reference： [1]Patent: US2011/130445,2011,A1 .Location in patent: Page/Page column 30

22
[ 77771-03-0 ]
[ 501420-63-9 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

23
[ 77771-03-0 ]
[ 887268-22-6 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7299 - 7317

24
[ 77771-03-0 ]
[ 1609540-78-4 ]

Reference： [1]Synlett,2014,vol. 25,p. 123 - 127

25
[ 77771-03-0 ]
[ 1609540-85-3 ]

Reference： [1]Synlett,2014,vol. 25,p. 123 - 127

26
[ 77771-03-0 ]
[ 1609540-89-7 ]

Reference： [1]Synlett,2014,vol. 25,p. 123 - 127

27
[ 1007-16-5 ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With borane-THF; In tetrahydrofuran; at 20℃;	General procedure: 3-bromo-4-fluorobenzoic acid (25 g, 114.15 mmol) was dissolved in THF (250 ml)and cooled to 0 C, to this was added borane-tetrahydrofuran complex (1.0 M inTHF) (228 ml, 228.30 mmol) and the reaction was warmed to room temperature andstirred for 2 hours. The reaction was quenched with saturated Na2CO3 (100 mL),extracted with EtOAc (3 x 100 mL), the organic layer was dried over MgSO4, filteredand evaporated to afford a colourless liquid. The crude product was purified bydistillation at 0.25 mBar, collecting fractions that distilled at 90 C to afford (3-bromo-4-fluorophenyl)methanol (21.50 g, 92 %) as a colourless liquid.

Reference： [1]Synlett,2014,vol. 25,p. 123 - 127

28
[ 77771-03-0 ]
[ 13294-41-2 ]

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 4458 - 4462

29
[ 77771-03-0 ]
[ 71-43-2 ]
[ 317334-84-2 ]

Yield	Reaction Conditions	Operation in experiment
	With boron trifluoride diethyl etherate; at 80℃; for 2h;	General procedure: In a round-bottom flask, phenylmethanol (0.54 g, 5.0 mmol) and BF3-OEt2(755 muL, 6.0 mmol) were dissolved in benzene (5.0 mL). After stirring for 2 hat 80 oC, the mixture was cooled to room temperature and then directly purified by column chromatography on silica gel using petroleum ether as eluent to give diphenylmethane(colorless oil, 0.67 g, 80% yield). The same procedure was utilizedfor all the synthesis of benzylic alcohols and diarylmethanes (2a-d, 2j-w).

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 4458 - 4462

30
[ 77771-03-0 ]
[ 21020-27-9 ]
(Z)-1-(3-bromo-4-fluorophenyl)-5-methylhex-3-en-1-ol [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 11902 - 11905

31
[ 77771-03-0 ]
(3-ethynyl-4-fluorophenyl)methanol [ No CAS ]

Reference： [1]Patent: WO2015/2994,2015,A2

32
[ 77771-03-0 ]
3-ethynyl-4-fluorobenzyl methanesulfonate [ No CAS ]

Reference： [1]Patent: WO2015/2994,2015,A2

33
[ 77771-03-0 ]
3-cyclopropyl-4-fluorobenzyl methanesulfonate [ No CAS ]

Reference： [1]Patent: WO2015/2994,2015,A2

34
[ 77771-03-0 ]
[ 1066-54-2 ]
{4-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 100℃; for 48h;Inert atmosphere; Sealed tube;	Step 1: {4-Fluoro-3-[(trimethylsilyl)ethynyl]phenyI}methanol A reaction vial was charged with <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (1.0 g, 4.9 mmol), (PPh3)2PdCl2 (68 mg, 0.10 mmol), Cul (37 mg, 0.20 mmol), and TEA (5.0 mL, 36 mmol). The vial was purged with argon and then sealed with a cap. After sonication, (trimethylsilyl)acetylene (1.0 mL, 7.3 mmol) was added to the mixture, and the resulting mixture was heated at 100 C for 48 h. The reaction was diluted with EtOAc (lOOmL) and the EtOAc layer was washed with 1 M HCl (60 mLx2), water (60 mL) and brine (60 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified on silica gel to give {4-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol (287 mg, 26%).

Reference： [1]Patent: WO2015/2994,2015,A2 .Location in patent: Paragraph 00200

35
[ 77771-03-0 ]
[ 1065010-87-8 ]
(3-cyclopropyl-4-fluorophenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; water; at 100℃; for 4h;Microwave irradiation; Inert atmosphere;	Step 1: (3-Cyclopropyl-4-fluorophenyl)methanol A microwave reaction vial was charged with <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (530 mg, 2.6 mmol), potassium cyclopropyltrifluoroborate (0.77 g, 5.2 mmol), Cs2C03 (2.5 g, 7.8 mmol), Iota,Gamma- bis(diphenylphosphino)ferrocenedichloropalladium(II) (95 mg, 0.13 mmol), THF (10.6 mL) and water (1.1 mL). After sealing with cap under an atmosphere of argon, the mixture was heated at 100 C for 4 h. The reaction was diluted with EtOAc and the mixture was filtered through a celite pad. The residual solid was rinsed with EtOAc and water. The two layers were transferred into a separatory funnel and then separated. The water layer was extracted with EtOAc (x2). The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified on silica gel to give (3-cyclopropyl-4- fluorophenyl)methanol (309 mg, 72%) as a light yellow oil. ,

Reference： [1]Patent: WO2015/2994,2015,A2 .Location in patent: Paragraph 00206

36
[ 557-21-1 ]
[ 77771-03-0 ]
[ 227609-85-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl acetamide; at 150℃; for 0.666667h;	2-Fluoro-5-(hydroxymethyl)benzonitrile. To a sol. of <strong>[77771-03-0]3-bromo-4-fluorobenzyl alcohol</strong> (0.609 mL, 5.00 mmol) in DMA (10 mL) is added Zn(CN)2(323 mg, 2.75 mmol,), Pd2(dba)3(100 mg, 0.109 mmol), DPPF (77.3 mg, 0.135 mmol) and poly(methylhydrosiloxane) (0.11 mL). The resulting mixture is stirred at 150 C in a microwave for 40 min. The reaction is repeated twice using the same conditions and quantities. The combined 3 reaction mixtures are filtered over Celite, the cake is rinced with EtOAc, and the filtrate is concentrated in vacuo. Purification of the crude by FC (Combiflash, column 40 g, flow 40 mL/min, EtOAc / heptane 5:95? 60:40) yields the title product. LC-MS: tR= 0.59 min., conditions 3.

Reference： [1]Patent: WO2016/41892,2016,A1 .Location in patent: Page/Page column 41

37
[ 77771-03-0 ]
3-cyano-4-fluorobenzyl methanesulfonate [ No CAS ]

Reference： [1]Patent: WO2016/41892,2016,A1

38
[ 77771-03-0 ]
[ 22446-37-3 ]
methyl 2-(2-((3-bromo-4-fluorobenzyl)oxy)phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	Intermediate 37. Methyl 2-(2-((3-bromo-4-fluorobenzyl)oxy)phenyl)acetate To a solution of <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (205 mg, 1 .0 mmol) and methyl-2-(2- hydroxyphenyl)acetate (216 mg, 1 .3 mmol) in THF (10.0 ml_) at 0 C was added triphenylphosphine (341 mg, 1 .3 mmol) and diisopropylazodicarboxylate (0.253 ml_, 1 .3 mmol). The mixture was stirred at 0 C, then gradually warmed to room termperature and stirred overnight. The reaction mixture was partitioned between EtOAc and H20. The layers were separated and the organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc = 100:0 to 50:50) to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.63 (dd, J=6.57, 2.15 Hz, 1 H) 7.29 - 7.35 (m, 1 H) 7.20 - 7.28 (m, 2 H) 7.13 (t, J=8.40 Hz, 1 H) 6.96 (td, J=7.45, 1 .01 Hz, 1 H) 6.86 - 6.90 (m, 1 H) 5.02 (s, 2 H) 3.69 (s, 2 H), 3.67 (s, 3 H).

Reference： [1]Patent: WO2016/88082,2016,A1 .Location in patent: Page/Page column 69

39
[ 77771-03-0 ]
[ 22446-37-3 ]
2-(2-((3'-(2-amino-2-oxoethyl)-6-fluoro[1,1'-biphenyl]-3-yl)methoxy)phenyl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2016/88082,2016,A1

40
[ 77771-03-0 ]
1-[(3-bromo-4-fluorophenyl)methyl]-4-methylpiperazine-2,5-dione [ No CAS ]

Reference： [1]Patent: WO2017/37146,2017,A1

41
[ 77771-03-0 ]
(S)-2,6-difluoro-4-((1-(2-fluoro-5-(methoxymethyl)phenyl)ethyl)amino)-N-(thiazol-4-yl)benzenesulfonamide [ No CAS ]