[ CAS No. 76350-90-8 ] {[proInfo.proName]}

Name: 76350-90-8|(2-Methyl-[1,1'-biphenyl]-3-yl)methanol|97%
Brand: Ambeed
SKU: A113515
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2D 3D

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Quality Control of [ 76350-90-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 76350-90-8 ]

SDS Specification

Alternatived Products of [ 76350-90-8 ]

Product Details of [ 76350-90-8 ]

CAS No. :	76350-90-8	MDL No. :	MFCD00134200
Formula :	C₁₄H₁₄O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BGTLHJPGBIVQLJ-UHFFFAOYSA-N
M.W :	198.26	Pubchem ID :	596875
Synonyms :

Calculated chemistry of [ 76350-90-8 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	62.97
TPSA :	20.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.49
Log Po/w (XLOGP3) :	3.03
Log Po/w (WLOGP) :	3.0
Log Po/w (MLOGP) :	3.34
Log Po/w (SILICOS-IT) :	3.89
Consensus Log Po/w :	3.15

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.44
Solubility :	0.0723 mg/ml ; 0.000365 mol/l
Class :	Soluble
Log S (Ali) :	-3.12
Solubility :	0.15 mg/ml ; 0.000758 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.13
Solubility :	0.00145 mg/ml ; 0.00000733 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.8

Safety of [ 76350-90-8 ]

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

Application In Synthesis of [ 76350-90-8 ]

* 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 [ 76350-90-8 ]
Downstream synthetic route of [ 76350-90-8 ]

[ 76350-90-8 ] Synthesis Path-Upstream 1~8

1
[ 83647-43-2 ]
[ 98-80-6 ]
[ 76350-90-8 ]

Yield	Reaction Conditions	Operation in experiment
74.62%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium hydrogencarbonate In ethanol; toluene at 80℃; for 12 h; Inert atmosphere	To a solution of 20.00 g (99.47 mmol, 1.0 eq) of (3-bromo-2-methyl-phenyl)methanol 1A and 24.26 g (198.94 mmol, 2.0 eq) of phenylboronic acid in 156 mL of toluene and 52mL of EtOH, were added 812.3 mg (0.995 mmol, 0.01 eq) of Pd(dppf)Cl₂.CH₂Cl₂ and 25.07g (2 M, 149.21 mL, 3.0 eq) of NaHCC under nitrogen gas. The mixture was stirred at 80°C for 12 hours. The mixture was separated, and the aqueous phase was extracted with 2 x 400 mL of ethyl acetate (EtOAc). The combined organic phase was washed with 2 x 200 mL of brine, dried over Na₂SC>4, filtered and the solvent was concentrated. The residue was purified by column eluted with petroleum ether/ethyl acetate = 25/1-10/1 to give crude product (25 g) as a yellow solid. The solid was smashed in 100 mL of petroleum ether, and the suspension was filtered to give 15.00 g (74.62percent) of (2-methyl-[l,l'-biphenyl]-3-yl)methanol as a white solid. ^lH NMR (400 MHz, CDC1₃): δ 7.40-7.31 (m, 4H) 7.25-7.22 (m, 3H) 4.75-4.74 (m, 2H) 2.21 (m, 3H) 1.62~1.59(m, 1H).
2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium hydrogencarbonate In ethanol; toluene at 80℃; for 0.5 h; Inert atmosphere	A mixture of (3-bromo-2-methylphenyl)methanol (2.071 g, 10.3 mmol), phenylboronic acid (2.51 g, 20.60 mmol) and [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) dichloromethane complex (0.084 g, 0.103 mmol) in toluene (15.45 ml) and ethanol (5.15 ml) was placed under argon. To this solution was added sodium bicarbonate, 2M (15.45 ml, 30.9 mmol) and the mixture was heated at 80 °C for 30 min. The reaction mixture was diluted with 20 mL ethyl acetate and 5 mL water. The organic portion was concentrated by rotatory evaporation. The crude product was chromatographed on silica gel eluting with 0-40percent ethyl acetate in hexane to afford 2 g of an off-white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 7.47-7.29 (m, 7H), 7.23 (s, 1H), 4.80 (d, J=5.6 Hz, 2H), 2.27 (s, 3H), 1.63-1.59 (m, 1H).
2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium hydrogencarbonate In ethanol; toluene at 80℃; for 0.5 h; Inert atmosphere	A mixture of (3-bromo-2-methylphenyl)methanol (2.071 g, 10.3 mmol), phenylboronic acid (2.51 g, 20.60 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (0.084 g, 0.103 mmol) in toluene (15.45 mL) and ethanol (5.15 mL) was placed under argon. To this solution was added sodium bicarbonate, 2M (15.45 mL, 30.9 mmol) and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was diluted with 20 mL ethyl acetate and 5 mL water. The organic portion was concentrated by rotatory evaporation. The crude product was chromatographed on silica gel eluting with 0-40percent ethyl acetate in hexane to afford 2 g of an off-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.47-7.29 (m, 7H), 7.23 (s, 1H), 4.80 (d, J=5.6 Hz, 2H), 2.27 (s, 3H), 1.63-1.59 (m, 1H).

4.58 g

With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium hydrogencarbonate In ethanol; toluene at 80℃; for 0.5 h; Inert atmosphere

A mixture of compound 2 (4.6 g, 22.8 mmol), phenylboronic acid 3 (5.65 g, 46.3 mmol) and [ 1 , 1 ' -bis (diphenylphosphino) - ferrocene ] dichloropalladium ( I I ) dichloromethane complex (0.188 g, 0.103 mmol) in toluene (34.5 mL) and ethanol (11.3 mL) was placed under argon. To this solution sodium bicarbonate, 2M (34.5 mL, 69.0 mmol) was added and the mixture was heated at 80 °C for 30 min. Ethyl acetate (44 mL) and (11 mL) water were added to the reaction mixture. The organic extract was concentrated by rotatory evaporation. The crude product was chromatographed on silica gel eluting with 0-40percent ethyl acetate in hexane to afford 4.58 g of an off-white solid, mp: 58.0- 59.5 °C; 1H NMR (600 MHz, CDC13) δ [ppm] : 7.43-7.40 (m, 3H) , 7.35 (m, 1H) , 7.31-7.29 (m, 2H) , 1H) , 7.26 (t, J=7.6 Hz, 1H) , 7.20 (dd, Jl=7.6 Hz, J2=1.3 Hz, 1H) , 4.78 (s, 2H) , 2.25 (s, 3H) ; 13C NMR (151MHz, DMSO-d6) δ [ppm]: 143.0, 142.2, 140.0, 133.8, 129.7, 129.5, 128.2, 127.0, 126.9, 125.7, 64.2, 16.0; IR V (ATR cm-1) : 3365, 3054, 1601, 1469, 1047, 757.

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5857 - 5867
[2] Patent: WO2018/200571, 2018, A1, . Location in patent: Page/Page column 44-45
[3] Patent: WO2015/34820, 2015, A1, . Location in patent: Page/Page column 42
[4] Patent: US2015/291549, 2015, A1, . Location in patent: Paragraph 0210; 0211
[5] Patent: WO2017/118762, 2017, A1, . Location in patent: Page/Page column 39; 40

2
[ 84541-46-8 ]
[ 76350-90-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	at 100℃; for 15 h;	In four flask 65.0g2- methyl-3-chloromethyl-biphenyl (MCMBP), 2.9g tetra-n-butylammonium bromide, 73.8g50percent aqueous solution of sodium acetate, heated to reflux, 100 incubated for 15 hours. after the gas-phase testing of raw materials is less than 1percent, the reaction solution was slowly dropped 44.0g30percent aqueous NaOH, pH control between 12-13, 100 for 10 hours, 60 standing layered liquor recovered apply The organic layer was mixed with toluene and heptane recrystallized BFA wet product. The crude product was vacuum dried to obtain the final product BFA54.1g, purity greater than 99.5percent (GC), a yield of 91.0percent.

Reference： [1] Patent: CN103772151, 2016, B, . Location in patent: Paragraph 0078; 0079

3
[ 89951-60-0 ]
[ 76350-90-8 ]

Reference： [1] Patent: CN107011123, 2017, A, . Location in patent: Paragraph 0035; 0036

4
[ 502483-86-5 ]
[ 76350-90-8 ]

Reference： [1] Tetrahedron, 2008, vol. 64, # 19, p. 4275 - 4286
[2] Tetrahedron Letters, 2007, vol. 48, # 19, p. 3379 - 3383

5
[ 576-23-8 ]
[ 76350-90-8 ]

Reference： [1] Tetrahedron Letters, 2007, vol. 48, # 19, p. 3379 - 3383

6
[ 127168-82-5 ]
[ 76350-90-8 ]

Reference： [1] Tetrahedron Letters, 2007, vol. 48, # 19, p. 3379 - 3383

7
[ 76006-33-2 ]
[ 76350-90-8 ]

Reference： [1] Patent: US2015/291549, 2015, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5857 - 5867
[3] Patent: WO2017/118762, 2017, A1,

8
[ 76350-90-8 ]
[ 89951-60-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With Dess-Martin periodane In dichloromethane at 20℃; for 0.5 h;	To a solution of (2-methylbiphenyl-3-yl)methanol (TCI, CatNo.:H0777: 4.12 g, 20.8 mmol) in methylene chloride (60 mL) was slowly added Dess-Martin periodinane (9.25 g, 21.8 mmol). The resulting mixture was stirred at r.t. for 30 min, and then washed with saturated NaHCO₃, water and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0 to 30percent ethyl acetate in hexanes to give the desired product (3.30 g, 80percent). LC-MS calculated for C₁₄H₁₃O (M+H)⁺: m/z=197.2; found 197.2.
57.2%	With Dess-Martin periodane In dichloromethane for 0.5 h;	Dess-Martin periodinane (8.32 mmol) was added to a solution of (2-methyl-[1,1′-biphenyl]-3-yl)methanol (TCI, catH0777:1.5 g, 7.57 mmol) in methylene chloride (16.00 ml, 250 mmol). After 0.5 h, saturated aqueous NaHCO₃was added. After stirring for 0.5 h, the mixture was filtered. The organic layer was washed with saturated aqueous NaHCO₃, 10percent w/w aqueous Na₂CO₃, and then brine. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to provide the desired aldehyde as a pale orange paste. The crude material was purified by silica gel chromatography (eluting with 0-15percent ethyl acetate in hexanes) providing a colorless oil which was triturated w/ hexanes to give 0.85 g of the desired product as a white crystalline solid (57.2percent yield). LC-MS calculated for C₁₄H₁₃O (M+H)⁺: m/z=197.1; found 197.2. ¹H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 7.86 (dd, J=7.5, 1.3 Hz, 2H), 7.68-7.36 (m, 3H), 7.39-7.22 (m, 3H), 2.58 (s, 3H).

Reference： [1] Patent: US2017/320875, 2017, A1, . Location in patent: Paragraph 0298-0299
[2] Patent: US2018/177784, 2018, A1, . Location in patent: Paragraph 0522-0523
[3] Patent: WO2017/87777, 2017, A1, . Location in patent: Page/Page column 61-62

[ 76350-90-8 ] Synthesis Path-Downstream 1~88

1
[ 4489-12-7 ]
[ 76350-90-8 ]
[ 107686-57-7 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1987,vol. 60,p. 4385 - 4394

2
[ 76350-90-8 ]
5,7,7-Trichloro-8,8,8-trifluoro-4,4-dimethyl-2-oxo-octanenitrile [ No CAS ]
2-methyl-3-phenylbenzyl 3,3-dimethyl-4,6,6-trichloro-7,7,7-trifluoroheptanoate [ No CAS ]

Reference： [1]Chemistry Letters,1994,p. 703 - 706

3
[ 76350-90-8 ]
3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl-1-(cyanohydroxymethyl)cyclopropane [ No CAS ]
2-methyl-3-phenylbenzyl trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate [ No CAS ]
2-methyl-3-phenylbenzyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate [ No CAS ]

Reference： [1]Chemistry Letters,1994,p. 703 - 706

4
[ 75-77-4 ]
[ 76350-90-8 ]
[ 909792-54-7 ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 3802 - 3803

5
C₁₄H₁₂OLi^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 76350-90-8 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 3379 - 3383

6
4-bromo-1,3-dihydroisobenzofuran [ No CAS ]
[ 76350-90-8 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 3379 - 3383

7
[ 576-23-8 ]
[ 76350-90-8 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 3379 - 3383

8
[ 127168-82-5 ]
[ 76350-90-8 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 3379 - 3383

9
[ 502483-86-5 ]
[ 76350-90-8 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 4275 - 4286
[2]Tetrahedron Letters,2007,vol. 48,p. 3379 - 3383

10
[ 76350-90-8 ]
[ 935740-92-4 ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 3802 - 3803

11
[ 76350-90-8 ]
methyl 5-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxylate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 3802 - 3803

12
[ 76350-90-8 ]
trans-(2-methyl-3-phenylphenyl)methyl 3-formyl-2,2-dimethylcyclopropanecarboxylate [ No CAS ]

Reference： [1]Bulletin of the Chemical Society of Japan,1987,vol. 60,p. 4385 - 4394

13
[ 76350-90-8 ]
cis-(2-methyl-3-phenylphenyl)methyl 3-formyl-2,2-dimethylcyclopropanecarboxylate [ No CAS ]

Reference： [1]Bulletin of the Chemical Society of Japan,1987,vol. 60,p. 4385 - 4394

14
[ 76350-90-8 ]
bifenthrin [ No CAS ]

Reference： [1]Chemistry Letters,1994,p. 703 - 706

15
[ 76350-90-8 ]
[ 4445-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium permanganate; cetyltrimethylammonim bromide; In water; at 0 - 70℃; for 64h;	15 g of 2-methyl-3-biphenylmethanol and 75 mg cetyltrimethylammonium bromide were added to 150 ml of water, and the resultant mixture was cooled to 0 C. in an ice bath. 48 g of potassium permanganate was added to the cold mixture and reaction was stirred at 0 C. for 10 min., at room temperature for 16 h, then at 70 C. for 48 h. The clear solution containing black solid was filtered through a pad of celite, and washed with 100 ml of dichloromethane. The aqueous solution was then acidified to pH 3 with 6 N aqueous hydrochloric acid and extracted four times with 150 ml portions of ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, and concentrated to 12.9 g of product; 1H NMR (d6-DMSO): delta=7.28-7.46 (m, 5 H), 7.51-7.61 (m, 2 H), 7.84-7.89 (dd, 1H), 13.0 (s, 2H).

Reference： [1]Patent: US2004/254215,2004,A1 .Location in patent: Page 61-62

Yield	Reaction Conditions	Operation in experiment
		Examples of the substituted or unsubstituted aralkyl alcohol include; benzyl alcohol, 2-methyl-3 -phenylbenzyl alcohol, 2,3,4,5,6-pentafluorobenzyl alcohol, 2,3,5,6-tetrafluoro-4-(methoxyinthyl)benzyl alcohol, 2,3,5,6-tetrafluoro-4-methoxybenzyl alcohol, 2,3,5,6-tetrafluoro-4-chlorobenzyl alcohol, 2,3,5,6-tetrafluoro-4-bromobenzyl alcohol, 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl alcohol, 2,3,5,6-tetrafluoro-4-difluoromethylbenzyl alcohol, 2,3,5,6-tetrafluoro-4-methylbenzyl alcohol, ...
		Specific insecticidally useful compounds according to the invention include the esters derived from each of: ... 4-fluoro-3-phenoxybenzyl alcohol alpha-cyano-4-fluoro-3-phenoxybenzyl alcohol 5-benzyl-3-furylmethanol 2-allyl-3-methyl-4-hydroxycyclopent-2-enone 2-methyl-3-phenylbenzyl alcohol
		Method G 2-Methyl[1,1'-biphenyl]-3-methanol was prepared as follows: To 100 ml of stirred 50% aqueous ethanol was added 2-methyl-3-nitrobenzyl alcohol (41.8 g, 0.25 mole) and 85.0 grams of iron powder. The mixture was brought to reflux, and 5.2 ml of concentrated hydrochloric acid was slowly added. Upon complete addition, the reaction mixture was stirred under reflux for 2 hours. The reaction mixture was then made just basic with ethanolic 15% potassium hydroxide. The hot mixture was filtered through diactomaceous earth to remove the iron. The filter cake was washed with ethanol. The filtrate was acidified with hydrogen chloride, then allowed to stand at room temperature for 16 hours. The ethanol was removed by evaporation under reduced pressure. Hexane was added to the residue, and the water-hexane azeotrope was removed by distillation. The addition of hexane and the subsequent removal of the water-hexane azeotrope by distillation was repeated three times. The 3-hydroxymethyl-2-methylaniline hydrochloride residue thus obtained was used as follows. A stirred solution of 3-hydroxymethyl-2-methylaniline hydrochloride (43.4 g, 0.25 mole) and 17.2 ml of concentrated sulfuric acid in ice-water was cooled to 0, and a solution of sodium nitrite (17.3 g, 0.25 mole) in water was added dropwise. Upon complete addition, the reaction mixture was stirred for an additional 0.5 hour, then an additional 8 ml of concentrated sulfuric acid was added dropwise. With the temperature maintained at 0, a solution of potassium iodide (49.8 g, 0.30 mole) in water was added dropwise to the reaction mixture, followed by the addition of 0.1 gram of copper powder. The reaction mixture was slowly warmed to 70 where it stirred for 1 hour. The reaction mixture was then allowed to stand for 18 hours while cooling to room temperature. The reaction mixture was then taken up in water and extracted with chloroform. The chloroform extract was washed with an aqueous saturated solution of sodium bisulfite, then with water. The chloroform layer was dried and filtered. The filtrate was evaporated under reduced pressure to give 3-iodo-2-methylbenzyl alcohol (15.2 g) as a dark solid. In a photoreactor was placed 3-iodo-2-methylbenzyl alcohol (5.0 g, 0.02 mole) and 800 ml of benzene. To this was added sodium thiosulfate (5.0 g, 0.04 mole) in 15 ml of water. The mixture was purged with argon for 30 minutes, then irradiated with a 200 watt medium pressure ultraviolet lamp for 36.5 hours. The reaction mixture was then transferred to a separatory funnel. The photoreactor was washed with approximately 20 ml each of water, chloroform, and acetone. These washes were added to the separatory funnel. The organic layer was washed with aqueous 0.5 M sodium thiosulfate, then with an aqueous solution saturated with sodium chloride. The organic layer was then dried and filtered. The filtrate was evaporated under reduced pressure to an oily residue. The residue was purified by column chromatography on silica gel, elution with 1:1 hexane:chloroform, to give 2-methyl[1,1'-biphenyl]-3-methanol (2.4 g). The nmr and ir spectra were consistent with that expected for the named compound.

		Method G 2-Methyl[1,1'-biphenyl]-3-methanol was prepared as follows: To 100 ml of stirred 50% aqueous ethanol was added 2-methyl-3-nitrobenzyl alcohol (41.8 g, 0.25 mole) and 85.0 grams of iron powder. The mixture was brought to reflux, and 5.2 ml of concentrated hydrochloric acid was slowly added. Upon complete addition, the reaction mixture was stirred under reflux for 2 hours. The reaction mixture was then made just basic with ethanolic 15% potassium hydroxide. The hot mixture was filtered through diatomaceous earth to remove the iron. The filter cake was washed with ethanol. The filtrate was acidified with hydrogen chloride, then allowed to stand at room temperature for 16 hours. The ethanol was removed by evaporation under reduced pressure. Hexane was added to the residue, and the water-hexane azeotrope was removed by distillation. The addition of hexane and the subsequent removal of the water-hexane azeotrope by distillation was repeated three times. The 3-hydroxymethyl-2-methylaniline hydrochloride residue thus obtained was used as follows. A stirred solution of 3-hydroxymethyl-2-methylaniline hydrochloride (43.4 g, 0.25 mole) and 17.2 ml of concentrated sulfuric acid in ice-water was cooled to 0, and a solution of sodium nitrate (17.3 g, 0.25 mole) in water was added dropwise. Upon complete addition, the reaction mixture was stirred for an additional 0.5 hour, then an additional 8 ml of concentrated sulfuric acid was added dropwise. With the temperature maintained at 0, a solution of potassium iodide (49.8 g, 0.30 mole) in water was added dropwise to the reaction mixture, followed by the addition of 0.1 gram of copper powder. The reaction mixture was slowly warmed to 70 where it stirred for 1 hour. The reaction mixture was then allowed to stand for 18 hours while cooling to room temperature. The reaction mixture was then taken up in water and extracted with chloroform. The chloroform extract was washed with an aqueous saturated solution of sodium bisulfite, then with water. The chloroform layer was dried and filtered. The filtrate was evaporated under reduced pressure to give 3-iodo-2-methylbenzyl alcohol (15.2 g) as a dark solid. In a photoreactor was placed 3-iodo-2-methylbenzyl alcohol (5.0 g, 0.02 mole) and 800 ml of benzene. To this was added sodium thiosulfate (5.0 g, 0.04 mole) in 15 ml of water. The mixture was purged with argon for 30 minutes, then irradiated with a 200 watt medium pressure ultraviolet lamp for 36.5 hours. The reaction mixture was then transferred to a separatory funnel. The photoreactor was washed with approximately 20 ml each of water, chloroform, and acetone. These washes were added to the separatory funnel. The organic layer was washed with aqueous 0.5 M sodium thiosulfate, then with an aqueous solution saturated with sodium chloride. The organic layer was then dried and filtered. The filtrate was evaporated under reduced pressure to an oily residue. The residue was purified by column chromatography on silica gel, elution with 1:1 hexane:chloroform, to give 2-methyl[1,1'-biphenyl]-3-methanol (2.4 g). The nmr and ir spectra were consistent with that expected for the named compound.
		Method G 2-Methyl[1,1'-biphenyl]-3-methanol was prepared as follows: To 100 ml of stirred 50% aqueous ethanol was added 2-methyl-3-nitrobenzyl alcohol (41.8 g, 0.25 mole) and 85.0 grams of iron powder. The mixture was brought to reflux, and 5.2 ml of concentrated hydrochloric acid was slowly added. Upon complete addition, the reaction mixture was stirred under reflux for 2 hours. The reaction mixture was then made just basic with ethanolic 15% potassium hydroxide. The hot mixture was filtered through diatomaceous earth to remove the iron. The filter cake was washed with ethanol. The filtrate was acidified with hydrogen chloride, then allowed to stand at room temperature for 16 hours. The ethanol was removed by evaporation under reduced pressure. Hexane was added to the residue, and the water-hexane azeotrope was removed by distillation. The addition of hexane and the subsequent removal of the water-hexane azeotrope by distillation was repeated three times. The 3-hydroxymethyl-2-methylaniline hydrochloride residue thus obtained was used as follows. A stirred solution of 3-hydroxymethyl-2-methylaniline hydrochloride (43.4 g, 0.25 mole) and 17.2 ml of concentrated sulfuric acid in ice-water was cooled to 0, and a solution of sodium nitrite (17.3 g, 0.25 mole) in water was added dropwise. Upon complete addition, the reaction mixture was stirred for an additional 0.5 hour, then an additional 8 ml of concentrated sulfuric acid was added dropwise. With the temperature maintained at 0, a solution of potassium iodide (49.8 g, 0.30 mole) in water was added dropwise to the reaction mixture, followed by the addition of 0.1 gram of copper powder. The reaction mixture was slowly warmed to 70 where it stirred for 1 hour. The reaction mixture was then allowed to stand for 18 hours while cooling to room temperature. The reaction mixture was then taken up in water and extracted with chloroform. The chloroform extract was washed with an aqueous saturated solution of sodium bisulfite, then with water. The chloroform layer was dried and filtered. The filtrate was evaporated under reduced pressure to give 3iodo-2-methylbenzyl alcohol (15.2 g) as a dark solid. In a photoreactor was placed 3-iodo-2-methylbenzyl alcohol (5.0 g, 0.02 mole) and 800 ml of benzene. To this was added sodium thiosulfate (5.0 g, 0.04 mole) in 15 ml of water. The mixture was purged with argon for 30 minutes, then irradiated with a 200 watt medium pressure ultraviolet lamp for 36.5 hours. The reaction mixture was then transferred to a separatory funnel. The photoreactor was washed with approximately 20 ml each of water, chloroform, and acetone. These washes were added to the separatory funnel. The organic layer was washed with aqueous 0.5 M sodium thiosulfate, then with an aqueous solution saturated with sodium chloride. The organic layer was then dried and filtered. The filtrate was evaporated under reduced pressure to an oily residue. The residue was purified by column chromatography on silica gel, elution with 1:1 hexane:chloroform, to give 2-methyl[1,1'-biphenyl]-3-methanol (2.4 g).

17
[ 60310-81-8 ]
[ 76350-90-8 ]
(2-methyl[1,1'-biphenyl]-3-yl)methyl trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 3 By the method of Example 2, (2-methyl[1,1'-biphenyl]-3-yl)methyl trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylate (Compound 3) was prepared from trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride and 2-methyl-[1,1'-biphenyl]-3-methanol; yield 0.98 g as an oil. NMR (CDCl3, ppm): 1.15(s,3H); 1.27(s,3H); 1.53(d,J=5 Hz,1H); 1.93-2.18(m,1H); 2.22(s,3H); 4.02(ddd,J=3,8, 25 Hz,1H); 5.22(s,2H), 7.20-7.45(m,8H).

Reference： [1]Patent: US4552892,1985,A

18
(1R)-trans-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride [ No CAS ]
[ 76350-90-8 ]
(2-methyl-[1,1'-biphenyl]-3-yl)-methyl 1R-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; hydrogenchloride; In toluene;	(c) Synthesis of (2-methyl-[1,1'-biphenyl]-3-yl)methyl 1R-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate To a stirred mixture of 0.8 gram (0.004 mole) of (2-methyl-[1,1'-biphenyl]-3-methanol and 0.3 ml of pyridine was added 1.0 gram (0.004 mole) of 1R-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 25 ml of toluene. A solid precipitate formed immediately. The reaction mixture was stirred at ambient temperature for 16 hours, then poured into 50 ml of 2 N hydrochloric acid. The mixture was shaken and the organic layer separated. The organic layer was washed with one portion of 25 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was placed on a column of 100 grams of silica gel. Elution was accomplished with toluene. The appropriate fraction was concentrated under reduced pressure to give 1.11 grams of (2-methyl-[1,1'-biphenyl]-3-yl)methyl 1R-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. Gas chromatographic analysis indicated >98% purity. The ir spectrum was consistent with the proposed structure. nmr (CCl4): 1.32 (6H,2), 2.12 (2H,m), 2.21 (3H,s), 5.17 (2H,s), 6.95 (1H,d).

Reference： [1]Patent: US4395567,1983,A

19
[ 76350-90-8 ]
[ 115363-11-6 ]

Yield	Reaction Conditions	Operation in experiment
28 g	With Jones reagent; In acetone; at 25℃; for 6h;	Pour 40 g of CrO3 into a volumetric flask containing 120 mL of water, add 34.5 mL of concentrated H2SO4, shake well, and dilute to 150 mL with water to obtain Jones reagent.30 g of <strong>[76350-90-8]2-methyl-3-phenylbenzyl alcohol</strong> were added to the three-necked flask,32mL water, 200mL acetone, ice water bath, drop 90mL Jones reagent, control reaction temperature is 25 C, reaction 6 h,The reaction was followed by thin layer chromatography, and dichloromethane was used as a developing solvent. After the substrate point disappeared and the aldehyde point disappeared, the reaction was stopped, and the reaction took 6 h.The acetone was removed under reduced pressure, a large amount of precipitate was produced, suction filtration, and the filter cake was washed with water to whiteness, and dried to obtain a crude product of 30 g yield 99%.The crude product was dissolved in ethanol (the amount of ethanol was twice the mass of the product) and heated at 60 C.All were dissolved, filtered, and the filtrate was cooled to -10 C under electric stirring, and then the crystals were suction filtered, dried to obtain 28 g, and the melting point was measured at a melting point of 151-153 C.

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 12904 - 12905
[2]Patent: CN108947866,2018,A .Location in patent: Paragraph 0009

20
[ 999-97-3 ]
[ 76350-90-8 ]
[ 1316808-61-3 ]

Reference： [1]Applied Organometallic Chemistry,2011,vol. 25,p. 608 - 615

21
bifenthrin [ No CAS ]
[ 74609-46-4 ]
[ 76350-90-8 ]

Reference： [1]Journal of Molecular Catalysis B: Enzymatic,2013,vol. 97,p. 225 - 232

22
[ 83647-43-2 ]
[ 98-80-6 ]
[ 76350-90-8 ]

Yield	Reaction Conditions	Operation in experiment
74.62%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In ethanol; toluene; at 80℃; for 12h;Inert atmosphere;	To a solution of 20.00 g (99.47 mmol, 1.0 eq) of (3-bromo-2-methyl-phenyl)methanol 1A and 24.26 g (198.94 mmol, 2.0 eq) of phenylboronic acid in 156 mL of toluene and 52mL of EtOH, were added 812.3 mg (0.995 mmol, 0.01 eq) of Pd(dppf)Cl2.CH2Cl2 and 25.07g (2 M, 149.21 mL, 3.0 eq) of NaHCC under nitrogen gas. The mixture was stirred at 80C for 12 hours. The mixture was separated, and the aqueous phase was extracted with 2 x 400 mL of ethyl acetate (EtOAc). The combined organic phase was washed with 2 x 200 mL of brine, dried over Na2SC>4, filtered and the solvent was concentrated. The residue was purified by column eluted with petroleum ether/ethyl acetate = 25/1-10/1 to give crude product (25 g) as a yellow solid. The solid was smashed in 100 mL of petroleum ether, and the suspension was filtered to give 15.00 g (74.62%) of (2-methyl-[l,l'-biphenyl]-3-yl)methanol as a white solid. lH NMR (400 MHz, CDC13): delta 7.40-7.31 (m, 4H) 7.25-7.22 (m, 3H) 4.75-4.74 (m, 2H) 2.21 (m, 3H) 1.62~1.59(m, 1H).
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In ethanol; water; toluene; at 80℃; for 12h;Inert atmosphere; Sealed tube;	To a stirred solution of (3-bromo-2-methylphenyl)methanol (4, 1 g, 5 mmol), phenyl boronic acid (5, 1.4 g, 10 mmol) in toulene (12 mL) and EtOH (4 mL) were added PdCl2(dppf).DCM (0.04 g, 0.05 mmol) and 2M aqueous NaHC03 solution (4 mL), the reaction mixture was degasified with nitrogen gas for 10 min. The reaction mixture was then heated in a seal tube at 80 C for 12 h. The reaction mixture was filtered through celite; the filtrate was diluted with water and extracted with ethyl acetate (2 x 100 mL). The organic layer was then dried over sodium sulfate, evaporated and the crude was purified on combiflash MPLC using 20% ethyl acetate in hexanes as eluent to afford (2-methyl-[l, l'-biphenyl]-3-yl)methanol as off-white solid (6, Yield: 0.81 g, 73%). LCMS (ES) m/z = 199.1 [M+H]+
68.9%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;	The compound I-1C (2 g, 10 mmol) obtained in the previous step was dissolved in dioxane (30 ml).Add 2N aqueous potassium carbonate solution (10 ml),Then, phenylboric acid (1.46 g, 12 mmol) and tetrakistriphenylphosphine palladium (150 mg, 0.12 mmol) were added, and the obtained reaction solution was replaced with nitrogen three times.The reaction was carried out at 100 C for 3 hours under a nitrogen atmosphere, and TLC showed the reaction was completed.After the methanol was rotated under reduced pressure, a saturated ammonium chloride solution (250 ml) was added.The mixture was extracted with ethyl acetate (150 mL×3), and then evaporated. Ethyl acetate = 10/1 (volume ratio V / V)),Compound I-1D (1.36 g, pale yellow solid) was obtained.Yield: 68.9%.

2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In ethanol; toluene; at 80℃; for 0.5h;Inert atmosphere;	A mixture of (3-bromo-2-methylphenyl)methanol (2.071 g, 10.3 mmol), phenylboronic acid (2.51 g, 20.60 mmol) and [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) dichloromethane complex (0.084 g, 0.103 mmol) in toluene (15.45 ml) and ethanol (5.15 ml) was placed under argon. To this solution was added sodium bicarbonate, 2M (15.45 ml, 30.9 mmol) and the mixture was heated at 80 C for 30 min. The reaction mixture was diluted with 20 mL ethyl acetate and 5 mL water. The organic portion was concentrated by rotatory evaporation. The crude product was chromatographed on silica gel eluting with 0-40% ethyl acetate in hexane to afford 2 g of an off-white solid. 1H NMR (400MHz, CHLOROFORM-d) delta 7.47-7.29 (m, 7H), 7.23 (s, 1H), 4.80 (d, J=5.6 Hz, 2H), 2.27 (s, 3H), 1.63-1.59 (m, 1H).
2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In ethanol; toluene; at 80℃; for 0.5h;Inert atmosphere;	A mixture of (3-bromo-2-methylphenyl)methanol (2.071 g, 10.3 mmol), phenylboronic acid (2.51 g, 20.60 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (0.084 g, 0.103 mmol) in toluene (15.45 mL) and ethanol (5.15 mL) was placed under argon. To this solution was added sodium bicarbonate, 2M (15.45 mL, 30.9 mmol) and the mixture was heated at 80 C. for 30 minutes. The reaction mixture was diluted with 20 mL ethyl acetate and 5 mL water. The organic portion was concentrated by rotatory evaporation. The crude product was chromatographed on silica gel eluting with 0-40% ethyl acetate in hexane to afford 2 g of an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) delta 7.47-7.29 (m, 7H), 7.23 (s, 1H), 4.80 (d, J=5.6 Hz, 2H), 2.27 (s, 3H), 1.63-1.59 (m, 1H).
4.58 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In ethanol; toluene; at 80℃; for 0.5h;Inert atmosphere;	A mixture of compound 2 (4.6 g, 22.8 mmol), phenylboronic acid 3 (5.65 g, 46.3 mmol) and [ 1 , 1 ' -bis (diphenylphosphino) - ferrocene ] dichloropalladium ( I I ) dichloromethane complex (0.188 g, 0.103 mmol) in toluene (34.5 mL) and ethanol (11.3 mL) was placed under argon. To this solution sodium bicarbonate, 2M (34.5 mL, 69.0 mmol) was added and the mixture was heated at 80 C for 30 min. Ethyl acetate (44 mL) and (11 mL) water were added to the reaction mixture. The organic extract was concentrated by rotatory evaporation. The crude product was chromatographed on silica gel eluting with 0-40% ethyl acetate in hexane to afford 4.58 g of an off-white solid, mp: 58.0- 59.5 C; 1H NMR (600 MHz, CDC13) delta [ppm] : 7.43-7.40 (m, 3H) , 7.35 (m, 1H) , 7.31-7.29 (m, 2H) , 1H) , 7.26 (t, J=7.6 Hz, 1H) , 7.20 (dd, Jl=7.6 Hz, J2=1.3 Hz, 1H) , 4.78 (s, 2H) , 2.25 (s, 3H) ; 13C NMR (151MHz, DMSO-d6) delta [ppm]: 143.0, 142.2, 140.0, 133.8, 129.7, 129.5, 128.2, 127.0, 126.9, 125.7, 64.2, 16.0; IR V (ATR cm-1) : 3365, 3054, 1601, 1469, 1047, 757.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 5857 - 5867
[2]Patent: WO2018/200571,2018,A1 .Location in patent: Page/Page column 44-45
[3]Patent: WO2019/87214,2019,A1 .Location in patent: Paragraph 000121
[4]Patent: CN110092740,2019,A .Location in patent: Paragraph 0115; 0120-0121; 0128-0130
[5]Patent: WO2015/34820,2015,A1 .Location in patent: Page/Page column 42
[6]Patent: US2015/291549,2015,A1 .Location in patent: Paragraph 0210; 0211
[7]Patent: WO2017/118762,2017,A1 .Location in patent: Page/Page column 39; 40

23
[ 76350-90-8 ]
3-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}-1-phenylurea [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

24
[ 76350-90-8 ]
N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}-2-oxo-2H-chromene-6-sulfonamide [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

25
[ 76350-90-8 ]
N-{2-[({3-cyano-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

26
[ 76350-90-8 ]
(S)-1-(2,6-dimethoxy-4-((2-methylbiphenyl-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

27
[ 76350-90-8 ]
N-[2-[[[2-methoxy-6-[(2-methyl-[1,1'-biphenyl]-3-yl)methoxy]pyridin-3-yl]methyl]amino]ethyl]acetamide [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

28
[ 76350-90-8 ]
2-(6-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

29
[ 76350-90-8 ]
6-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline hydrochloride [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

30
[ 76350-90-8 ]
tert-butyl (2-((2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)(methyl)amino)ethyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

31
[ 76350-90-8 ]
(2-aminoethyl)({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)methylamine bistrifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

32
[ 76350-90-8 ]
6-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)nicotinaldehyde [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

33
[ 76350-90-8 ]
C₂₃H₂₄ClNO₂ [ No CAS ]

Reference： [1]Patent: WO2015/34820,2015,A1

34
[ 2420-16-8 ]
[ 76350-90-8 ]
3-chloro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxyl)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.97 g	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	Diisopropyl azodicarboxylate (1.01 g, 5 mmol) in THF (30 mL) was added dropwise to a cooled (0 C) solution of 4-hydroxy-3-chlorobenzaldehyde (0.782 g, 5 mmol), triphenylphosphine (1.3 g, 4.99 mmol) and intermediate 1A, 2 -methyl- [1,1 '- biphenyl]-3-yl)methanol (0.90 g, 4.54 mmol) in dry THF (30 mL). The resulting yello solution was allowed to slowly warm to room temperature with stirring overnight. Solvent was removed by rotary evaporator. The residue was purified on a 40 g silica gel column with 10: 1 Hexane:Ethyl acetate. Isolated 0.97 g of the desired product as white solid. 1H NMR (400MHz, CHLOROFORM-d) delta 9.90 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.81 (dd, J=8.6, 2.0 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.49 - 7.43 (m, 2H), 7.39 (d, J=7.1 Hz, 1H), 7.36 - 7.29 (m, 4H), 7.20 (d, J=8.3 Hz, 1H), 5.30 (s, 2H), 2.30 (s, 3H).

Reference： [1]Patent: WO2015/34820,2015,A1 .Location in patent: Page/Page column 46-47
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 286 - 304

35
[ 7283-96-7 ]
[ 76350-90-8 ]
C₁₉H₁₆O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.039 g	With bis(eta3-allyl-mu-chloropalladium(II)); di-tert-butyl (2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; caesium carbonate; In toluene;Inert atmosphere;	In a 8 mL clear vial, (2-methyl-[l,l'-biphenyl]-3-yl)methanol (50 mg, 0.252 mmol), cesium carbonate (123 mg, 0.378 mmol), 2-(Di-t-butylphosphino)-3-methoxy-6- methyl-2'-4'-6'-tri-i-propyl-l, -biphenyl (7.09 mg, 0.015 mmol), 4A molecular sieves(50mg) and toluene (0.4 mL) were combined. The reaction mixture was degassed with argon gas. 5-chlorothiophene-2-carbaldehyde (55.5 mg, 0.378 mmol, Cole, Andrew G.; Letourneau, Jeffrey John; Ho, Koc-Kan WO 2010059922 Al) and allylpalladium(ii) chloride dimer (2.77 mg, 7.57 muiotaetaomicron) were added. Then reaction mixture was heated at 90C for 24hrs. The reaction mixture was diluted with ethylacetate, filtered through celite and concentrated. The residue was purified using a gradient of 0 to 15% ethylacetate inpetroleum ether on a 4 gm silica gel column. The fractions containing the product were combined and concentration to give the desired aldehyde (0.039g). Example 118 was prepared from this aldehyde and 2-amino ethanol according to the reductive amination conditions as described for Example 1.

Reference： [1]Patent: WO2015/34820,2015,A1 .Location in patent: Page/Page column 56

36
[ 2973-78-6 ]
[ 76350-90-8 ]
3-bromo-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 20h;Cooling with ice;	To the ice-cooled solution of 3-bromo-4-hydroxybenzaldehyde 10 (0.71 g, 3.51 mmol) , triphenylphosphine (1.02 g, 3.89 mmol) and compound 4 (0.70 g, 0.52 mmol) in dry THF (21 mL) , diisopropyl azodicarboxylate (DIAD) (0.735 mL, 3.89 mmol) in THF (21 mL) was added dropwise. The resulting yellow solution was allowed to warm to room temperature and was stirred for additional 20 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 0-60% ethyl acetate in hexane . Recrystallization from MeOH yielded colourless solid (0.47 g, yield: 35%) .mp: 108.0-110.0 C; 1H NMR (600MHz, DMSO-d6) delta[ ppm]: 9.87 (s, 1H) , 8.14 (d, J=2.0 Hz, 1H) , 7.97 (dd, Jl= 6.5 Hz, J2=2.0 Hz, 1H) , 7.54 (m, 2H) , 7.46 (m, 2H) , 7.39 (m, 1H) , 7.33-7, 30 (m, 3H) , 7.22 (dd, Jl= 6.5 Hz, J2= 1 Hz, 1H) , 5.39 (s, 2H) , 2.23 (s, 3H) ; 13C NMR (151MHz, DMSO-d6) delta [ppm]: 190.6, 159.2, 142.2, 141.2, 134.6, 134.0, 133.9, 131.2, 130.8, 129.8, 129.2, 128.3, 127.5, 127.0, 125.6, 114.1, 111.9, 69.8, 15.9; IR V (ATR cm-1) 3063, 2852, 1689, 1594, 1278, 1254, 1189, 1048; HRMS (ESI-TOF) Calcd C21H17Br02 [M+Na]+: 403.0310; found [M+Na]+: 403.0302.
106.9 mg	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	To a cooled (0C) solution of 3-bromo-4-hydroxybenzaldehyde (101 mg, 0.5 mmol), triphenylphosphine (146 mg, 0.555 mmol) and (2-methyl-[l,l'-biphenyl]-3- yl)methanol (100 mg, 0.504 mmol) in dry THF (3 mL) was added dropwise of diisopropyl azodicarboxylate (0.108 mL, 0.555 mmol) in THF (3 mL). The resulting yellow solution was allowed to slowly warm to room temperature while stirring overnight. Excess solvent was evaporated by rotary evaporation. The crude residue was dissolved in methanol and purified via preparative LC/MS with the following conditions: Column: Waters XBridge CI 8, 19 x 200 mm, 5-muiotaeta particles; Guard Column: Waters XBridge CI 8, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 30-100% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 106.9 mg, and its estimated purity by LCMS analysis was 100%. LC/MS Method A: 3.1 minutes, M+1= 381.0, EM = 380.0.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 5857 - 5867
[2]Patent: WO2017/118762,2017,A1 .Location in patent: Page/Page column 43; 44
[3]Patent: WO2015/34820,2015,A1 .Location in patent: Page/Page column 67-68

37
[ 624-28-2 ]
[ 76350-90-8 ]
5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With 1,4,7,10,13,20-Hexaoxa<13.1>(1,2)benzenophan; potassium hydroxide; In toluene; for 1.5h;Reflux; Dean-Stark;	A mixture of 2,5-dibromopyridine (5 g, 21.11 mmol), (2-methyl-[l,l'-biphenyl]-3- yl)methanol (5.44 g, 27.4 mmol), dibenzo-18-crown-6 (0.380 g, 1.055 mmol), potassium hydroxide (2.84 g, 50.7 mmol) and toluene (50 mL) was stirred at reflux with a Dean- Stark trap ( pre-filled with toluene). After 1.5 hours, the heat was removed. TLC analysis showed that starting material was consumed. LC/MS consistent with crude desired product. The solvents were removed under reduced pressure by rotary evaporation. Water (50 mL) was added and the product extracted into dichloroethane (3x50 mL). The combined organic portion was dried over magnesium sulfate and filtered. The solvents were removed under reduced pressure by rotary evaporation to give 9.7 grams of a yellow oil. LC/MS was consistent with crude desired product. The yellow oil became an off- white solid on standing. Chromatographed on a 330g silica gel column with 0-20% ethyl acetate in hexanes to give the product (6.3g, 84%). 1H NMR (400MHz, DMSO-d6) delta 8.34 (dd, J=2.8, 0.5 Hz, 1H), 7.95 (dd, J=8.8, 2.5 Hz, 1H), 7.50 - 7.43 (m, 3H), 7.42 - 7.37 (m, 1H), 7.34 - 7.31 (m, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.23 - 7.18 (m, 1H), 6.95 (dd, J=8.8, 0.5 Hz, 1H), 5.41 (s, 2H), 2.20 (s, 3H).

Reference： [1]Patent: WO2015/34820,2015,A1 .Location in patent: Page/Page column 72-73

38
[ 76350-90-8 ]
[ 95-01-2 ]
2-hydroxy-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Cooling with ice;	Combined 2,4-dihydroxybenzaldehyde (3.14 g, 22.75 mmol),triphenylphosphine (5.97 g, 22.75 mmol) and (2-methyl-[1,1?-biphenyl]-3-yl)methanol (4.1 g, 20.68 mmol) in dry tetrahydrofuran (50 mL) and cooled on an ice/water bath. Added diisopropyl azodicarboxylate (4.33 mL, 22.25 mmol) in tetrahydrofuran (50 mL) dropwise. The resulting yellow solution was allowed to slowly warm to room temperature with stirring overnight. Excess solvent was removed by rotary evaporator. The reaction mixture was chromatoghraphed with 0-20% ethyl acetate in hexanes on silica gel to give the desired product (4.2 g, 64%). 1H NMR (400 MHz, CHLOROFORM-d) delta 11.53 (s, 1H), 9.76 (s, 1H), 7.51-7.29 (m, 11H), 6.67 (dd, J=8.6, 2.2 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.17 (s, 2H), 2.26 (s, 3H).

Reference： [1]Patent: US2015/291549,2015,A1 .Location in patent: Paragraph 0256; 0257

39
[ 76350-90-8 ]
3-[[2-formyl-5-[(2-methyl-3-phenylphenyl)methoxy]phenoxy]methyl]benzonitrile [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1
[2]Patent: WO2019/191624,2019,A1

40
[ 76350-90-8 ]
5-(2-formyl-5-((2-methylbiphenyl-3-yl)methoxy)phenoxy)pentanenitrile [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

41
[ 76350-90-8 ]
(R)-2-((2-(4-cyanobutoxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxypropanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

42
[ 76350-90-8 ]
(S)-4-((2-(4-cyanobutoxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

43
[ 76350-90-8 ]
3-((2-chloro-6-formyl-3-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzonitrile [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

44
[ 76350-90-8 ]
5-((2-formyl-5-((2-methylbiphenyl-3-yl)methoxy)phenoxy)methyl)-4-methylnicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

45
[ 76350-90-8 ]
(R)-2-(2-((5-cyano-4-methylpyridin-3-yl)methoxy)-4-((2-methylbiphenyl-3-yl)methoxy)benzylamino)-3-hydroxypropanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

46
[ 76350-90-8 ]
5-[[2-formyl-5-[(2-methyl-3-phenylphenyl)methoxy]phenoxy]methyl]pyridine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1
[2]Patent: WO2019/191624,2019,A1

47
[ 76350-90-8 ]
(R)-2-((2-((5-cyanopyridin-3-yl)methoxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxypropanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

48
[ 76350-90-8 ]
(S)-4-((2-((3-cyano-4-fluorobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

49
[ 131088-00-1 ]
[ 76350-90-8 ]
3-chloro-2-hydroxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
491 mg	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	Diisopropyl azodicarboxylate (0.758 mL, 3.82 mmol) in tetrahydrofuran (8.5 mL) was added dropwise to a cooled (0 C.) solution of 3-chloro-2,4-dihydroxybenzaldehyde (600 mg, 3.48 mmol), triphenylphosphine (1016 mg, 3.87 mmol) and 2-methyl-3-biphenylmethanol (758 mg, 3.82 mmol) in dry tetrahydrofuran (8.5 mL). The resulting reaction mixture was allowed to slowly warm to room temperature with stirring overnight. The crude product was purified by silica gel column chromatography employing 60% hexanes in dichloromethane (v/v) as eluent to yield 491 mg of the title compound as a colorless solid. 1H NMR (CHLOROFORM-d) delta: 11.80 (s, 1H), 9.77 (s, 1H), 7.47-7.50 (m, 2H), 7.42-7.46 (m, 2H), 7.35-7.40 (m, 1H), 7.31-7.34 (m, 2H), 7.28-7.31 (m, 2H), 6.78 (d, J=8.7 Hz, 1H), 5.30 (s, 2H), 2.28 (s, 3H).

Reference： [1]Patent: US2015/291549,2015,A1 .Location in patent: Paragraph 0590-0591

50
[ 116096-90-3 ]
[ 76350-90-8 ]
5-((4-bromo-2-formyl-5-((2-methylbiphenyl-3-yl)methoxy)phenoxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

51
[ 76006-33-2 ]
[ 76350-90-8 ]

Reference： [1]Patent: US2015/291549,2015,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 5857 - 5867
[3]Patent: WO2017/118762,2017,A1
[4]Patent: CN110092740,2019,A

52
[ 76350-90-8 ]
(S)-4-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

53
[ 76350-90-8 ]
N-{2-[({2-methoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

54
[ 76350-90-8 ]
(R)-2-((3-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxypropanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

55
[ 76350-90-8 ]
(S)-4-((3-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

56
[ 76350-90-8 ]
2-fluoro-5-((2-formyl-5-((2-methylbiphenyl-3-yl)methoxy)phenoxy)methyl)benzonitrile [ No CAS ]

Reference： [1]Patent: US2015/291549,2015,A1

57
[ 116096-90-3 ]
[ 76350-90-8 ]
5-bromo-2-hydroxy-4-((2-methylbiphenyl-3-yl)methoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.9%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	To a solution of (2-methyl-[1,1?-biphenyl]-3-yl)methanol (100 mg, 0.507 mmol) and 5-bromo-2,4-dihydroxybenzaldehyde (100 mg, 0.461 mmol) in tetrahydrofuran (5 mL), triphenylphosphine (145 mg, 0.553 mmol) was added. The reaction mixture was stirred at 0 C. for 15 minutes. Diisopropylazodicarboxylate (0.108 mL, 0.553 mmol) was added dropwise in tetrahydrofuran (5 mL). The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was concentrated and to the residue was added acetonitrile. A light yellow solid precipitated and was collected as the final product 5-bromo-2-hydroxy-4-((2-methyl-[1,1?-biphenyl]-3-yl)methoxy)benzaldehyde (62 mg, 0.156 mmol, 33.9% yield).

Reference： [1]Patent: US2015/291549,2015,A1 .Location in patent: Paragraph 0827; 0828

58
[ 84541-46-8 ]
[ 76350-90-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetrabutylammomium bromide; water; sodium acetate; at 100℃; for 15h;	In four flask 65.0g2- methyl-3-chloromethyl-biphenyl (MCMBP), 2.9g tetra-n-butylammonium bromide, 73.8g50% aqueous solution of sodium acetate, heated to reflux, 100 incubated for 15 hours. after the gas-phase testing of raw materials is less than 1%, the reaction solution was slowly dropped 44.0g30% aqueous NaOH, pH control between 12-13, 100 for 10 hours, 60 standing layered liquor recovered apply The organic layer was mixed with toluene and heptane recrystallized BFA wet product. The crude product was vacuum dried to obtain the final product BFA54.1g, purity greater than 99.5% (GC), a yield of 91.0%.

Reference： [1]Patent: CN103772151,2016,B .Location in patent: Paragraph 0078; 0079

59
[ 76350-90-8 ]
methyl 2-(2-methylbiphenyl-3-yl)furo[2,3-b]pyridine-6-carboxylate [ No CAS ]