[ CAS No. 83647-43-2 ] {[proInfo.proName]}

Name: 83647-43-2|(3-Bromo-2-methylphenyl)methanol|97%
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Quality Control of [ 83647-43-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 83647-43-2 ]

Product Details of [ 83647-43-2 ]

CAS No. :	83647-43-2	MDL No. :	MFCD11847531
Formula :	C₈H₉BrO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XYDXDWXAAQXHLK-UHFFFAOYSA-N
M.W :	201.06	Pubchem ID :	10035697
Synonyms :

Calculated chemistry of [ 83647-43-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.24
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) :	-6.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	2.09
Log Po/w (WLOGP) :	2.1
Log Po/w (MLOGP) :	2.61
Log Po/w (SILICOS-IT) :	2.81
Consensus Log Po/w :	2.36

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.78
Solubility :	0.333 mg/ml ; 0.00165 mol/l
Class :	Soluble
Log S (Ali) :	-2.14
Solubility :	1.44 mg/ml ; 0.00716 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.47
Solubility :	0.068 mg/ml ; 0.000338 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.28

Safety of [ 83647-43-2 ]

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

Application In Synthesis of [ 83647-43-2 ]

* 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 [ 83647-43-2 ]
Downstream synthetic route of [ 83647-43-2 ]

[ 83647-43-2 ] Synthesis Path-Upstream 1~10

1
[ 99548-54-6 ]
[ 83647-43-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran for 2 h; Inert atmosphere; Cooling with ice Stage #2: With Glauber's salt In tetrahydrofuran at 20℃; for 2 h;	Example 110 methyl { (3S) -6- [ (3-bromo-2-methylbenzyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate; [0990][0991]Methyl 3-bromo-2-methylbenzoate (2.29 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 mL) , under ice-cooling, lithium aluminum hydride (0.285 g, 7.50 mmol) was added by small portions, and the mixture was stirred under a nitrogen atmosphere for 2 hr. Sodium sulfate 10 hydrate (2.42 g, 7.50 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. Insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained solid was recrystallized from heptane-ethyl acetate to give 3-bromo-2-methylbenzyl alcohol (1.76 g, yield 88percent) as colorless crystals. This product (0.943 g, 4.69 mmol) was dissolved in acetonitrile (25 mL) , a Dess-Martin reagent (2.39 g, 5.63 mmol) was added by small portions under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was treated with saturated aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained colorless oil, methyl [ (3S) -6-amino-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.972 g, 4.69 mmol) and acetic acid(0.537 mL, 9.38 mmol) in acetonitrile (25 mL) was stirred under a nitrogen atmosphere at room temperature for 0.5 hr. Sodium triacetoxyborohydride (1.99 g, 9.38 mmol) was added to the reaction mixture, and the mixture was further stirred for 12 hr. The reaction mixture was treated with water and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 5:95-40:60) to give the title compound (1.59 g, yield 87percent, 2 steps) as a colorless oil.¹H NMR (300 MHz, CDCl₃) δ 2.42 (3H, s) , 2.48-2.59 (IH, m) , 2.68-2.78 (IH, m) , 3.68-3.83 (4H, m) , 3.89 (IH, br s) , 4.18- 4.30 (3H, m) , 4.71 (IH, t, J = 9.1 Hz), 6.07-6.16 (2H, m) , 6.93 (IH, d, J = 8.0 Hz), 7.01 (IH, t, J = 7.9 Hz), 7.23-7.30(IH, m) , 7.49 (IH, dd, J = 7.9, 1.1 Hz). MS m/z 390 (M + H)⁺.
84.3%	With sodium tetrahydroborate In ethanol at 0℃; Reflux	The methyl 2-methyl-3-bromobenzoate (10 g, 43.6 mmol) was dissolved in 100 mL of absolute ethanol in an ice-water bath,After stirring, sodium borohydride (4.1 g, 10.8 mmol) was added in portions,The reaction was stirred for 1h at 0 .Remove the ice bath, heat to reflux,The reaction was carried out overnight in the reflux state.TLC shows the reaction is complete, cooled, The solvent was removed by concentration under reduced pressure,To the residue was added 50 mL of acetone, concentrated under reduced pressure to remove acetone,To the residue was added 50 mL of saturated potassium carbonate solution,The mixture was stirred at 100 ° C for 1 hour,Extracted with 50 mL x 2 chloroform,The organic phase was dried over anhydrous magnesium sulfate, filtered,The organic phase was concentrated under reduced pressure, dried,2-methyl-3-bromobenzyl alcohol (7.39 g, yield: 84.3percent);

Reference： [1] Patent: WO2010/143733, 2010, A1, . Location in patent: Page/Page column 347-348
[2] Patent: CN106432214, 2017, A, . Location in patent: Paragraph 0023; 0024

2
[ 83647-40-9 ]
[ 83647-43-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium tetrahydroborate In methanol for 0.5 h;	To an ice cold solution of compound 3-Bromo-2-methylbenzaldehyde (5 g, 25 mmol) in MeOH (60 mL) was added NaBH₄ (2.8 g, 75 mmol) portion wise and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with ice water and volatiles were removed under reduced pressure. The mixture was diluted with water and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound (4.8 g, 95percent) as an off white solid.

Reference： [1] Patent: WO2017/158151, 2017, A1, . Location in patent: Page/Page column 148
[2] Patent: US2017/305909, 2017, A1, . Location in patent: Paragraph 0631; 0632
[3] Patent: WO2017/182495, 2017, A1, . Location in patent: Page/Page column 122

3
[ 76006-33-2 ]
[ 83647-43-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With borane-THF In tetrahydrofuran at 0 - 20℃; for 15 h; Inert atmosphere	Compound 1 (5.0 g, 23.2 mmol) was dissolved in anhydrous THF (25 mL) under argon and the reaction vessel was cooled to 0 °C in an ice bath. To this cooled solution BH3-THF complex (1M in THF, 35 mL) was added dropwise over a 3 h period. The reaction mixture was warmed to room temperature and stirred for an additional 12 h. The mixture was then poured into 1M hydrochloric acid (126 mL) and then extracted with Et20 (3 x 50 mL) . The organic extracts were combined, dried over anhydrous MgS04, filtered, and concentrated to afford the intermediate (4.6 g; 99 percent) as a colorless solid. The crude product was subjected to the subsequent reaction without further purification.
97%	Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; for 15 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water	3-Bromo-2-methyl-benzoic acid (20.0 g) was dissolved in anhydrous THF (200 mL) under nitrogen and the reaction vessel was cooled to 0° C. in an ice bath. To this cooled solution was added BH₃.THF complex (1M in THF, 140 mL) dropwise over a 3 h period. Once gas evolution had subsided, the reaction mixture was warmed to room temperature and stirred for an additional 12 h. The mixture was then poured into 1N hydrochloric acid (500 mL) cooled with ice and then extracted with Et₂O (3.x.150 mL). The organic extracts were combined, dried over anhydrous MgSO₄, filtered, and then concentrated to afford the intermediate (18.1 g; 97percent) as a colourless solid. ¹H-NMR (CDCl₃) δ=2.40 (s, 3 H), 4.70 (s, 2 H), 7.10 (t, 1 H), 7.30 (d, 1 H), 7.50 (d, 1 H).
97%	With borane-THF In tetrahydrofuran at 0 - 20℃; for 15 h;	Under a nitrogen atmosphere a IM solution of BH₃¹THF complex in THF (140 rnL) was added dropwise over a 3 h period to an ice cooled solution of commercially available 3-bromo-2-methyl-benzoic acid (20.0 g) in anhydrous THF (200 mL). Once gas evolution had subsided, the cooling bath was removed and mixture stirred at room temperature for 12 h. The mixture was then poured into a mixture of IN aqueous HCl (500 mL) and ice and then extracted with Et₂O (3 x 150 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (18.1 g, 97percent). ¹H-NMR (CDCl₃) D= 7.50 (d, 1 H), 7.30 (d, 1 H), 7.10 (t, 1 H), 4.70 (s, 2 H), 2.40 (s, 3 H).

97%	With borane-THF In tetrahydrofuran at 0 - 20℃; for 15 h;	Preparative Example 3; Step A; 3-Bromo-2-methyl-benzoic acid (20.0 g) was dissolved in anhydrous THF (200 mL) under nitrogen and the reaction vessel was cooled to 0° C. in an ice bath. To this cooled solution was added BH₃-THF complex (1M in THF, 140 mL) dropwise over a 3 h period. Once gas evolution had subsided, the reaction mixture was warmed to room temperature and stirred for an additional 12 h. The mixture was then poured into 1N hydrochloric acid (500 mL) cooled with ice and then extracted with Et₂O (3.x.150 mL). The organic extracts were combined, dried over anhydrous MgSO₄, filtered, and then concentrated to afford the intermediate (18.1 g; 97percent) as a colourless solid. ¹H-NMR (CDCl₃) δ=2.40 (s, 3H), 4.70 (s, 2H), 7.10 (t, 1H), 7.30 (d, 1H), 7.50 (d, 1H).
97%	With borane-THF In tetrahydrofuran at 0 - 20℃; for 15 h;	Step A. 3-Bromo-2-methyl-benzoic acid (20.0 g) was dissolved in anhydrous THF (200 mL) under nitrogen and the reaction vessel was cooled to 0°C in an ice bath. To this cooled solution was added BH₃THF complex (IM in THF, 14O mL) dropwise over a 3 h period. Once gas evolution had subsided, the reaction mixture was warmed to room temperature and stirred for an additional 12 h. The mixture was then poured into IN hydrochloric acid (500 mL) cooled with ice and then extracted with Et₂O (3 x 150 mL). The organic extracts were combined, dried over anhydrous MgSO₄, filtered, and then concentrated to afford the intermediate (18.1 g; 97 percent) as a colourless solid. ¹H-NMR (CDCl₃) δ = 2.40 (s, 3 H), 4.70 (s, 2 H), 7.10 (t, 1 H), 7.30 (d, 1 H), 7.50 (d, 1 H). Step A. Under a nitrogen atmosphere a IM solution of BH₃^THF complex in THF (140 mL) was added dropwise over a 3 h period to an ice cooled solution of commercially available 3-bromo-2-methyl-benzoic acid (20.0 g) in anhydrous THF (200 mL). Once gas evolution had subsided, the cooling bath was removed and mixture stirred at room temperature for 12 h. The mixture was then poured into a mixture of IN aqueous HCl (500 mL) and ice and then extracted with Et₂O (3 x 15O mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (18.1 g, 97percent). ¹H-NMR (CDCl₃) δ = 7.50 (d, 1 H), 7.30 (d, 1 H), 7.10 (t, 1 H), 4.70 (s, 2 H), 2.40 (s, 3 H).
934 mg	With sodium tetrahydroborate; iodine In tetrahydrofuran at 40℃; for 20 h; Cooling with ice	(1) Synthesis of (3-bromo-2-methylphenyl)methanol [99-1] (hereinafter referred to as a compound [99-1]) 3-Bromo-2-methylbenzoic acid (1.08 g) was dissolved in tetrahydrofuran (34 mL), and to the solution was added sodium borohydride (1.15 g) under ice cooling. A solution of iodine (3.81 g) in tetrahydrofuran (16 mL) was then added to the mixture in two portions, and the mixture was stirred at room temperature for 20 hours. 4N-hydrochloric acid was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The obtained organic layer was sequentially washed with an aqueous solution of 2N-sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (934 mg) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ: 7.52-7.50 (1H, m), 7.32 (1H, d, J = 7.6 Hz), 7.06 (1H, t, J = 7.8 Hz), 4.73 (2H, d, J = 5.9 Hz), 2.43 (3H, s), 1.58 (1H, t, J = 5.9 Hz).
7.8 g	With borane-THF In tetrahydrofuran at 20℃; Cooling with ice	Dissolved 3-bromo-2-methylbenzoic acid (8.4 g, 39.1 mmol) in tetrahydrofuran (100 mL) and cooled on ice/water. Added borane tetrahydrofuran complex (50.8 mL, 50.8 mmol) dropwise over 15-20 minutes. Stirred to room temperature over the weekend. Added 50 mL methanol dropwise to quench the excess borane. The solvent was removed by rotory evaporation. The solid was rotovaped from methanol to remove residual boron. 7.8 g of a pale yellow solid was isolated and used without further purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.53 (dd, J=7.9, 0.9 Hz, 1H), 7.34 (d, J=7.3 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 4.75 (s, 2H), 2.45 (s, 3H).
24 g	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 3 h;	3-Bromo-2-methylbenzoic acid (30 g, 139 mmol) was dissolved in tetrahydrofuran (THF) (180 mL) and cooled to 0 °C. Lithium aluminium hydride (9.5 g, 250 mmol) was added in small portions. After stirring for 3 h, no starting material was observed by TLC. The reaction mixture was carefully quenched with ethyl acetate (20 mL) and water (20 mL). Silica gel was added and the mixture was evaporated to dryness and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (1:1) resulting in the pure alcohol (3-bromo-2-methylphenyl)methanol (24 g) after evaporation. ¹H NMR (600 MHz, CDCl₃): 7.50 (d, 1H, J=8.1Hz), 7.29 (d, 1H, J=8.1Hz), 7.04 (t, 1H, J=8.1Hz), 4.68 (s, 2H), 2.40 (s, 3H), 1.90 (br s, 1H). ¹³C NMR (150 MHz, CDCl₃): 140.60, 135.84, 132.03, 127.12, 126.70, 126.05.
24 g	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 3 h;	[00157] 3-Bromo-2-methylbenzoic acid (30 g, 139 mmol) was dissolved in tetrahydrofuran (THF) (180 mL) and cooled to 0 °C. Lithium aluminium hydride (9.5 g, 250 mmol) was added in small portions. After stirring for 3 h, no starting material was observed by TLC. The reaction mixture was carefully quenched with ethyl acetate (20 mL) and water (20 mL). Silica gel was added and the mixture was evaporated to dryness and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (1:1) resulting in the pure alcohol (3-bromo-2- methylphenyl)methanol (24 g) after evaporation.1H NMR (600 MHz, CDCl3): 7.50 (d, 1H, J=8.1Hz), 7.29 (d, 1H, J=8.1Hz), 7.04 (t, 1H, J=8.1Hz), 4.68 (s, 2H), 2.40 (s, 3H), 1.90 (br s, 1H).13C NMR (150 MHz, CDCl3): 140.60, 135.84, 132.03, 127.12, 126.70, 126.05.
2.79 g	Stage #1: With sodium tetrahydroborate; iodine In tetrahydrofuran at 20℃; for 2 h; Stage #2: With hydrogenchloride In water	To a suspension of sodium borohydride (0.630 g, 16.7 mmol) in THF (82 mL), 3-bromo-2-methylbenzoic acid (3.00 g, 14.0 mmol) was added. The mixture was stirred until gas evolution ceased and iodine (1.77 g, 6.98 mmol) was added in small portions. The mixture was stirred at room temperature for 2 hours then the reaction was carefully quenched by the slow addition of aqueous HCl (2N). The resulting mixture was diluted with water and extracted with ether. The organic layer was washed three times with aqueous NaOH (2N), once with brine, dried over magnesium sulfate, filtered and concentrated to give (3-bromo-2-methylphenyl)methanol (27-1, 2.79 g) as a white solid.

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5857 - 5867
[2] Patent: WO2017/118762, 2017, A1, . Location in patent: Page/Page column 39
[3] Patent: US2006/173183, 2006, A1, . Location in patent: Page/Page column 119-120
[4] Patent: WO2006/128184, 2006, A2, . Location in patent: Page/Page column 144-145
[5] Patent: US2008/21024, 2008, A1, . Location in patent: Page/Page column 63
[6] Patent: WO2008/63671, 2008, A2, . Location in patent: Page/Page column 115, 121
[7] Journal of the American Chemical Society, 1961, vol. 83, p. 943 - 949
[8] Journal of the American Chemical Society, [9] Journal of the American Chemical Society, 2009, vol. 131, p. 1410 - 1412
[10] Journal of the American Chemical Society, 2010, vol. 132, # 1, p. 371 - 383
[11] Patent: WO2010/129379, 2010, A1, . Location in patent: Page/Page column 33
[12] Organic Letters, 2012, vol. 14, # 1, p. 338 - 341
[13] Patent: WO2013/66714, 2013, A1, . Location in patent: Page/Page column 36
[14] Patent: WO2013/66717, 2013, A1, . Location in patent: Page/Page column 21; 22
[15] Patent: WO2013/62892, 2013, A1, . Location in patent: Page/Page column 46
[16] Patent: WO2013/62900, 2013, A1, . Location in patent: Page/Page column 27; 28
[17] Patent: WO2013/90271, 2013, A1, . Location in patent: Page/Page column 29
[18] Patent: WO2013/39802, 2013, A1, . Location in patent: Page/Page column 39
[19] Patent: WO2013/66718, 2013, A2, . Location in patent: Page/Page column 20
[20] Patent: WO2013/28474, 2013, A1, . Location in patent: Page/Page column 27
[21] Patent: WO2014/15495, 2014, A1, . Location in patent: Page/Page column 24; 25
[22] Patent: WO2014/18764, 2014, A1, . Location in patent: Page/Page column 27
[23] Patent: WO2014/85210, 2014, A1, . Location in patent: Page/Page column 23; 24
[24] Patent: WO2014/99633, 2014, A2, . Location in patent: Page/Page column 30
[25] Patent: WO2014/126944, 2014, A2, . Location in patent: Page/Page column 29
[26] Patent: WO2015/17305, 2015, A1, . Location in patent: Page/Page column 39
[27] Patent: WO2015/65866, 2015, A1, . Location in patent: Page/Page column 26
[28] Patent: EP2878594, 2015, A1, . Location in patent: Paragraph 0829-0831
[29] Patent: WO2015/95097, 2015, A2, . Location in patent: Page/Page column 26
[30] Patent: WO2015/103756, 2015, A1, . Location in patent: Page/Page column 45
[31] Patent: WO2015/105736, 2015, A1, . Location in patent: Page/Page column 47
[32] Patent: WO2015/96035, 2015, A1, . Location in patent: Page/Page column 40
[33] Patent: WO2015/100147, 2015, A1, . Location in patent: Page/Page column 40
[34] Patent: US2015/291549, 2015, A1, . Location in patent: Paragraph 0208; 0209
[35] Patent: EP2632465, 2015, B1, . Location in patent: Paragraph 0082
[36] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 892 - 913
[37] Patent: WO2016/40330, 2016, A1, . Location in patent: Paragraph 00429
[38] Patent: WO2016/65582, 2016, A1, . Location in patent: Page/Page column 30
[39] Patent: WO2016/122994, 2016, A1, . Location in patent: Page/Page column 33
[40] Patent: EP2744499, 2016, B1, . Location in patent: Paragraph 0078
[41] Patent: WO2016/127358, 2016, A1, . Location in patent: Page/Page column 28; 29
[42] Patent: US9493474, 2016, B2, . Location in patent: Page/Page column 20
[43] Patent: US2017/37037, 2017, A1, . Location in patent: Paragraph 0181
[44] Patent: CN106432214, 2017, A,
[45] Organic Process Research and Development, 2018, vol. 22, # 1, p. 97 - 102
[46] Patent: EP2755656, 2016, B1, . Location in patent: Paragraph 0127
[47] Patent: WO2018/106818, 2018, A1, . Location in patent: Paragraph 00157
[48] Patent: US2018/312523, 2018, A1, . Location in patent: Paragraph 1856; 1857

4
[ 83647-42-1 ]
[ 83647-43-2 ]

Reference： [1] Patent: US5256666, 1993, A,
[2] Patent: US5151441, 1992, A,

5
[ 103038-43-3 ]
[ 83647-43-2 ]

Reference： [1] Chemistry - A European Journal, 2010, vol. 16, # 28, p. 8439 - 8445
[2] Journal of the American Chemical Society, 1961, vol. 83, p. 943 - 949

6
[ 52780-15-1 ]
[ 83647-43-2 ]

Reference： [1] Journal of the American Chemical Society, 1961, vol. 83, p. 943 - 949

7
[ 69321-60-4 ]
[ 83647-43-2 ]

Reference： [1] Patent: US2017/305909, 2017, A1,
[2] Patent: WO2017/182495, 2017, A1,

8
[ 529-20-4 ]
[ 83647-43-2 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 6, p. 1645 - 1652

9
[ 83647-43-2 ]
[ 83647-40-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With Dess-Martin periodane In tetrahydrofuran at 20℃; for 2 h;	Intermediate 22-1Preparation of 3-(3-bromo-2-methylbenzylidene)indolin-2-one Step 1 A mixture of (3-bromo-2-methylphenyl)methanol (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 500 mg, 2.49 mmol) in THF (20 mL) was stirred at rt and treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 1.58 g, 3.73 mmol). After 2 h, the mixture was diluted with ether (ca. 100 mL) and washed with 5percent aqueous sodium bisulfite, NaHCO3 (aq) and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 55:45 hexane-EtOAc) to provide 3-bromo-2-methylbenzaldehyde as a colorless oil (343 mg, 70percent). ¹H NMR (400 MHz, chloroform-d) δ 10.26 (1H, s), 7.78 (2H, ddd, J=9.7, 8.0, 1.2 Hz), 7.20-7.27 (1H, m), 2.75 (3H, s).
18.6 g	With manganese(IV) oxide In dichloromethane	(3-Bromo-2-methylphenyl)methanol (24 g, 119 mmol) was dissolved in dichloromethane (240 mL) and manganese (IV) oxide (103 g, 1.2 mol) was added. After stirring overnight, TLC showed no starting material. Reaction mixture was evaporated with silica gel and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (10:1) to afford the pure aldehyde 3-bromo-2-methylbenzaldehyde (18.6 g) after evaporation. ¹H NMR (600 MHz, CDCl₃): 10.25 (s, 1H), 7.78 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 2.75 (s, 3H). ¹³C NMR (150 MHz, CDCl₃): 191.84, 137.72, 130.93, 130.20, 127.61, 127.37, 126.82, 18.13.
18.6 g	With manganese(IV) oxide In dichloromethane	[00158] (3-Bromo-2-methylphenyl)methanol (24 g, 119 mmol) was dissolved in dichloromethane (240 mL) and manganese (IV) oxide (103 g, 1.2 mol) was added. After stirring overnight, TLC showed no starting materia re was evaporated with silica gel and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (10:1) to afford the pure aldehyde 3-bromo-2-methylbenzaldehyde (18.6 g) after evaporation.1H NMR (600 MHz, CDCl3): 10.25 (s, 1H), 7.78 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 2.75 (s, 3H).13C NMR (150 MHz, CDCl3): 191.84, 137.72, 130.93, 130.20, 127.61, 127.37, 126.82, 18.13.

2.76 g

Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1 h; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at -78 - 20℃; Inert atmosphere

To a solution of dimethylsulfoxide (2.99 mL, 41.8 mmol) in dichloromethane (55 mL) cooled to −78° C. under nitrogen, oxalyl chloride (2.0 M in dichloromethane, 10.4 mL, 20.8 mmol) was added slowly. The mixture was stirred at −78° C. for 30 minutes then a solution of 27-1 (2.79 g, 13.9 mmol) in dichloromethane (15 mL) was added dropwise by cannula. The mixture was stirred for 1 hour, triethylamine (5.8 mL, 41.8 mmol) was added slowly, and the reaction was allowed to warm to room temperature. The mixture was washed with saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 3-bromo-2-methylbenzaldehyde (27-2, 2.76 g).

Reference： [1] Patent: US2010/160303, 2010, A1, . Location in patent: Page/Page column 36
[2] Journal of the American Chemical Society, [3] Journal of the American Chemical Society, 2009, vol. 131, p. 1410 - 1412
[4] Journal of the American Chemical Society, 2010, vol. 132, # 1, p. 371 - 383
[5] Patent: WO2010/143733, 2010, A1, . Location in patent: Page/Page column 347-348
[6] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 892 - 913
[7] Patent: WO2016/40330, 2016, A1, . Location in patent: Paragraph 00430
[8] Organic Process Research and Development, 2018, vol. 22, # 1, p. 97 - 102
[9] Patent: WO2018/106818, 2018, A1, . Location in patent: Paragraph 00158
[10] Patent: US2018/312523, 2018, A1, . Location in patent: Paragraph 1856; 1858

10
[ 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

[ 83647-43-2 ] Synthesis Path-Downstream 1~22

1
[ 103038-43-3 ]
[ 83647-43-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With lithium aluminium tetrahydride In diethyl ether for 2h; Reflux;
	With lithium aluminium tetrahydride

Reference： [1]Bourne, Gregory T.; Kuster, Daniel J.; Marshall, Garland R. [Chemistry - A European Journal, 2010, vol. 16, # 28, p. 8439 - 8445]
[2]Lindsay,W.S. et al. [Journal of the American Chemical Society, 1961, vol. 83, p. 943 - 949]

2
[ 52780-15-1 ]
[ 83647-43-2 ]

Reference： [1]Journal of the American Chemical Society,1961,vol. 83,p. 943 - 949

3
[ 83647-42-1 ]
[ 83647-43-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrate; hydrogen bromide;copper(I) bromide; In water; toluene;	2. 3-Bromo-2-methylbenzyl alcohol A solution of 40.7 g of sodium nitrate in 300 ml of water is added dropwise to a mixture, cooled to 0 C., of 888 ml of water, 162 ml of 47% hydrobromic acid and 81.2 g of <strong>[83647-42-1]3-amino-2-methylbenzyl alcohol</strong>. Stirring is carried out for 30 minutes at 0 C., after which a suspension of 168.7 9 of copper(I) bromide in 750 ml of water is added a little at a time at this temperature. The reaction mixture is stirred in succession for 1 hour at 10 C., for 1 hour at room temperature and for 2 hours at 100 C. After cooling, the reaction mixture is extracted several times with ether. The combined organic phases are washed with water, dried and evaporated down. Purification by column chromatogrpahy over silica gel using toluene as the mobile phase gives 64.2 g of 3-bromo-2-methylbenzyl alcohol (mp. 97-100 C.).
	With sodium nitrate;copper(I) bromide; In water;	2. 3-Bromo-2-methylbenzyl alcohol A solution of 40.7 g of sodium nitrate in 300 ml of water is added dropwise to a mixture cooled to 0 C. and consisting of 888 ml of water, 162 ml of 47% strength hydrobromic acid and 81.2 g of <strong>[83647-42-1]3-amino-2-methylbenzyl alcohol</strong>. Stirring is carried out for 30 minutes at 0 C., after which a suspension of 168.7 g of copper(I) bromide in 750 ml of water is added a little at a time at this temperature. The reaction mixture is stirred in succession for 1 hour at 10 C, for 1 hour at room temperature and for 2 hours at 100 C. After cooling, the reaction mixture is extracted several times with ether. The combined organic phases are washed with water, dried and evaporated down. After purification by column chromatography over silica gel using toluene as the mobile phase, 64.2 g of 3-bromo-2-methylbenzyl alcohol of melting point 97-100 C. are obtained.

Reference： [1]Patent: US5256666,1993,A
[2]Patent: US5151441,1992,A

4
[ 83647-43-2 ]
[ 83647-40-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With Dess-Martin periodane; In tetrahydrofuran; at 20℃; for 2h;	Intermediate 22-1Preparation of 3-(3-bromo-2-methylbenzylidene)indolin-2-one Step 1 A mixture of (3-bromo-2-methylphenyl)methanol (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 500 mg, 2.49 mmol) in THF (20 mL) was stirred at rt and treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 1.58 g, 3.73 mmol). After 2 h, the mixture was diluted with ether (ca. 100 mL) and washed with 5% aqueous sodium bisulfite, NaHCO3 (aq) and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 55:45 hexane-EtOAc) to provide 3-bromo-2-methylbenzaldehyde as a colorless oil (343 mg, 70%). 1H NMR (400 MHz, chloroform-d) delta 10.26 (1H, s), 7.78 (2H, ddd, J=9.7, 8.0, 1.2 Hz), 7.20-7.27 (1H, m), 2.75 (3H, s).
	With Dess-Martin periodane; In acetonitrile; at 20℃; for 0.5h;	Example 110 methyl { (3S) -6- [ (3-bromo-2-methylbenzyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate; [0990][0991]Methyl 3-bromo-2-methylbenzoate (2.29 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 mL) , under ice-cooling, lithium aluminum hydride (0.285 g, 7.50 mmol) was added by small portions, and the mixture was stirred under a nitrogen atmosphere for 2 hr. Sodium sulfate 10 hydrate (2.42 g, 7.50 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. Insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained solid was recrystallized from heptane-ethyl acetate to give 3-bromo-2-methylbenzyl alcohol (1.76 g, yield 88%) as colorless crystals. This product (0.943 g, 4.69 mmol) was dissolved in acetonitrile (25 mL) , a Dess-Martin reagent (2.39 g, 5.63 mmol) was added by small portions under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was treated with saturated aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained colorless oil, methyl [ (3S) -6-amino-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.972 g, 4.69 mmol) and acetic acid(0.537 mL, 9.38 mmol) in acetonitrile (25 mL) was stirred under a nitrogen atmosphere at room temperature for 0.5 hr. Sodium triacetoxyborohydride (1.99 g, 9.38 mmol) was added to the reaction mixture, and the mixture was further stirred for 12 hr. The reaction mixture was treated with water and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 5:95-40:60) to give the title compound (1.59 g, yield 87%, 2 steps) as a colorless oil.1H NMR (300 MHz, CDCl3) delta 2.42 (3H, s) , 2.48-2.59 (IH, m) , 2.68-2.78 (IH, m) , 3.68-3.83 (4H, m) , 3.89 (IH, br s) , 4.18- 4.30 (3H, m) , 4.71 (IH, t, J = 9.1 Hz), 6.07-6.16 (2H, m) , 6.93 (IH, d, J = 8.0 Hz), 7.01 (IH, t, J = 7.9 Hz), 7.23-7.30(IH, m) , 7.49 (IH, dd, J = 7.9, 1.1 Hz). MS m/z 390 (M + H)+.
18.6 g	With manganese(IV) oxide; In dichloromethane;	(3-Bromo-2-methylphenyl)methanol (24 g, 119 mmol) was dissolved in dichloromethane (240 mL) and manganese (IV) oxide (103 g, 1.2 mol) was added. After stirring overnight, TLC showed no starting material. Reaction mixture was evaporated with silica gel and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (10:1) to afford the pure aldehyde 3-bromo-2-methylbenzaldehyde (18.6 g) after evaporation. 1H NMR (600 MHz, CDCl3): 10.25 (s, 1H), 7.78 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 2.75 (s, 3H). 13C NMR (150 MHz, CDCl3): 191.84, 137.72, 130.93, 130.20, 127.61, 127.37, 126.82, 18.13.

18.6 g	With manganese(IV) oxide; In dichloromethane;	[00158] (3-Bromo-2-methylphenyl)methanol (24 g, 119 mmol) was dissolved in dichloromethane (240 mL) and manganese (IV) oxide (103 g, 1.2 mol) was added. After stirring overnight, TLC showed no starting materia re was evaporated with silica gel and loaded on a small silica gel column. The product was eluted with hexane:ethyl acetate (10:1) to afford the pure aldehyde 3-bromo-2-methylbenzaldehyde (18.6 g) after evaporation.1H NMR (600 MHz, CDCl3): 10.25 (s, 1H), 7.78 (m, 2H), 7.23 (t, 1H, J=7.7Hz), 2.75 (s, 3H).13C NMR (150 MHz, CDCl3): 191.84, 137.72, 130.93, 130.20, 127.61, 127.37, 126.82, 18.13.
2.76 g		To a solution of dimethylsulfoxide (2.99 mL, 41.8 mmol) in dichloromethane (55 mL) cooled to -78 C. under nitrogen, oxalyl chloride (2.0 M in dichloromethane, 10.4 mL, 20.8 mmol) was added slowly. The mixture was stirred at -78 C. for 30 minutes then a solution of 27-1 (2.79 g, 13.9 mmol) in dichloromethane (15 mL) was added dropwise by cannula. The mixture was stirred for 1 hour, triethylamine (5.8 mL, 41.8 mmol) was added slowly, and the reaction was allowed to warm to room temperature. The mixture was washed with saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 3-bromo-2-methylbenzaldehyde (27-2, 2.76 g).

Reference： [1]Patent: US2010/160303,2010,A1 .Location in patent: Page/Page column 36
[2]Journal of the American Chemical Society,2009,vol. 131,p. 1410 - 1412
[3]Journal of the American Chemical Society,2010,vol. 132,p. 371 - 383
[4]Patent: WO2010/143733,2010,A1 .Location in patent: Page/Page column 347-348
[5]Journal of Medicinal Chemistry,2016,vol. 59,p. 892 - 913
[6]Patent: WO2016/40330,2016,A1 .Location in patent: Paragraph 00430
[7]Organic Process Research and Development,2018,vol. 22,p. 97 - 102
[8]Patent: WO2018/106818,2018,A1 .Location in patent: Paragraph 00158
[9]Patent: US2018/312523,2018,A1 .Location in patent: Paragraph 1856; 1858
[10]Patent: WO2020/15717,2020,A1 .Location in patent: Page/Page column 17-18

5
[ 201230-82-2 ]
[ 83647-43-2 ]
[ 1255206-67-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a IM TFA solution of Thallium Trifiuoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4- methyl-2-benzofuran-l (3H)-one. 1H-NMR (500 MHz, CDCl3) delta ppm 7.71 (d, J= 8.0 Hz, IH), 7.58 (d, J= 8.0 Hz, IH), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M trifluoroacetic acid solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 minutes to ensure complete removal of TFA. To the residue was then added palladium (II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and methanol (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a Celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran-l(3H)-one. ?-NMR (500 MHz, CDC13) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1 M trifluoroacetic acid solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 minutes to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and methanol (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a Celite diatomaceous earth pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2- benzofuran- 1 (3H)-one.1H-NMR (500 MHz, CDC13) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).

		Step B: 5-Bromo-4-methyl-2-benzofuran-U3H)-one: To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of ThalliumTrifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at RT. Analysis by LC showed a formation of product within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The solution was filtered through a celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to provide the title compound
		Step B: 5-Bromo-4-methyl-2-benzofuran-l(3H)-one: To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of ThalliumTrifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at RT. Analysis by LC showed a formation of product within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The solution was filtered through a celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to provide the title compound
		To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The solution was filtered through a Celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford the title compound: 1H-NMR (500 MHz, CDCI3) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		Step B: 5-Bromo-4-methyl-2-benzofuran-l(3H)-one To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M trifluoroacetic acid solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and methanol (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a diatomaceous earth pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran-l(3H)-one. 1H-NMR (500 MHz, CDC13) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M trifluoroacetic acid solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 minutes to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and methanol (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a Celite diatomaceous earth pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2- benzofuran-1 (3H)-one. -N R (500 MHz, CDC13) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2,37 (s, 3H).
		INTERMEDIATE 2 5-bromo-4-methyl-2-benzofuran-1 (3H)-one; Step B; To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution ofthalliumtrifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residuewas pumped under high vacuum for 30 min to ensure complete removal of TF A. To the residuewas then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushedwith CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. Thesolution was filtered through a Celite pad, washed with EtOAc, adsorbed onto silica and purifiedby silica gel chromatography to afford the title compound: 1H-NMR (500 MHz, CDCh) 8 ppm7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford title compound. 1H-NMR (500 MHz, CDC13) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford title compound. 1H-NMR (500 MHz, CDCI3) delta ppm 7.71 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4- methyl-2-benzofuran-l(3H)-one. -NMR (500 MHz, CDC13) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		Step B: 5-bromo-4-methyl-2-benzofuran-l(3H)-one: To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residuewas pumped under high vacuum for 30 mm to ensure complete removal of TEA. To the residue was then added Palladium(fl) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. Thesolution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford the title compound: ?H-NMR (500 MHz, CDC13) 6 ppm 7.71 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a fiask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a lM TFA solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT oyernight. Analysis by TLC showed no starting material remaining. The solyent was remoyed under yacuum, and the residuewas pumped under high yacuum for 30 min to ensure complete remoyal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The blaeksolution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford title compound. 1H-NMR (500 MHz, CDC13)ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		Step B: 5-bromo-4-methyl-2-benzofuran-1(3H)-one: To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of thalliumtrifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 mm to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran-1(3H)-one. ?H-NMR (500 MHz, CDC13) oe ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H),2.37 (s, 3H).
		: To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of ThalliumTrifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 mm to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g,59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5 -bromo-4-methyl-2-benzofuran- 1 (311)-one.1H-NMR (500 MHz, CDC13) oe ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J 8.0 Hz, 1H), 5.25 (s,2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2- metiiyiplienyijmethanol (6.0 g, 30 mmol) was added a 1 M TFA solutio of Thallium Trifiuoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT 16 h. Analysis by TLC showed no starting material remaining. The solve t was removed under vacuum, and the residue was pumped under high vacuum for 30 mm to ensure complete removal of TF A. To the residue was then added Palladiimi( ll) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at rt. Analysis by LC showed a big product spot within 2 h. To this solution was added ethyl acetate to precipitate the salts. The black solutio was filtered through a ('elite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography. 5-bromo~4-methyl-2~benzofuran~ 1 (3H)-one. ]H-NMR (500 MHz, CDCI3) delta ppm 7.71 (d, J = 8.0 Hz, i i l 7.58(d, J = 8.0 Hz, i i l 5.25 (s, 21 1 ). 2.37 (s, M l }.
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirredRT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 mm to ensurecomplete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was addeda 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred atRT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 mm to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), andMeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hr. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford the title compound. ?H-NMR (500 MHz, CDC13) oe ppm 7.71 (d, J 8.0 Hz, 1H), 7.58 (d, J 8.0 Hz,1H), 5.25 (s, 2H), 2.37 (s, 3H).
		Step B: 5-bromo-4-methyl-2-benzofuran-l(3H)-one: To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. After two hours, to this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford title compound.
		Step B: 5-bromo-4-methyl-2-benzofuran-l(3H)-one: To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. After two hours, to this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford title compound.
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3) delta ppm 7.71 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2-methylphenyl) methanol (6.0 g, 30 mmol) was added a 1M TFA solution of thallium trifluoroacetate (16.2 g, 29.8 mmol) . The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added palladium (II) chloride (529 mg, 2.98 mmol) , lithium chloride (2.53 g, 59.7 mmol) , magnesium oxide (2.41 g, 59.7 mmol) , and MeOH (150 mL) . The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through apad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran-1 (3H) -one. 1H NMR (500 MHz, CDCl3) delta ppm 7.71 (d, J 8.0 Hz, 1H) , 7.58 (d, J 8.0 Hz, 1H) , 5.25 (s, 2H) , 2.37 (s, 3H).
		To a flask charged with (3-bromo-2- methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at rt overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford title compound. 1H-NMR (500 MHz, CDCI3) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2-methylphenyl)methanol(6.0 g, 30 mmol) was added a 1M TFA solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture wasstirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed undervacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To theresidue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magne-sium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under COat room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethylacetate to precipitate the salts. The solution was filtered through a Celite pad, washed with EtOAc, adsorbed ontosilica and purified by silica gel chromatography to afford the title compound: 1H-NMR (500 MHz, CDCl3) delta ppm 7.71(d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		To a flask charged with (3-bromo-2-methylphenyl)metha- nol (6.0 g, 30 mmol) was added a 1M trifluoroacetic acidsolution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 minutes to ensure complete removal of TFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol), magnesium oxide (2.41 g, 59.7 mmol), and methanol (150 mE). The reaction was flushed with CO twice, and kept under CO at room temperature.Analysis by EC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a Celite diatomaceous earth pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran- 1 (3H)-one.?H-NMR (500 MHz, CDC13) oe ppm 7.71 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
		[0129] To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M trifluoroaceticacid solution of thallium trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. The solvent wasremoved under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal ofTFA. To the residue was then added palladium(II) chloride (529 mg, 2.98 mmol), lithium chloride (2.53 g, 59.7 mmol),magnesium oxide (2.41 g, 59.7 mmol), and methanol (150 mL). The reaction was flushed with CO twice, and kept underCO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethylacetate to precipitate the salts. The black solution was filtered through a diatomaceous earth pad, washed with EtOAc,adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran- I(3H)-one. 1HNMR(500 MHz, CDCl3) delta ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H)

Reference： [1]Patent: WO2010/129379,2010,A1 .Location in patent: Page/Page column 33
[2]Patent: WO2013/66714,2013,A1 .Location in patent: Page/Page column 36
[3]Patent: WO2013/66717,2013,A1 .Location in patent: Page/Page column 22
[4]Patent: WO2013/62892,2013,A1 .Location in patent: Page/Page column 46
[5]Patent: WO2013/62900,2013,A1 .Location in patent: Page/Page column 28
[6]Patent: WO2013/90271,2013,A1 .Location in patent: Page/Page column 29
[7]Patent: WO2013/39802,2013,A1 .Location in patent: Page/Page column 39; 40
[8]Patent: WO2013/66718,2013,A2 .Location in patent: Page/Page column 20-21
[9]Patent: WO2013/28474,2013,A1 .Location in patent: Page/Page column 27; 28
[10]Patent: WO2014/15495,2014,A1 .Location in patent: Page/Page column 24; 25
[11]Patent: WO2014/18764,2014,A1 .Location in patent: Page/Page column 27; 28
[12]Patent: WO2014/85210,2014,A1 .Location in patent: Page/Page column 24
[13]Patent: WO2014/99633,2014,A2 .Location in patent: Page/Page column 30
[14]Patent: WO2014/126944,2014,A2 .Location in patent: Page/Page column 29
[15]Patent: WO2015/17305,2015,A1 .Location in patent: Page/Page column 39; 40
[16]Patent: WO2015/65866,2015,A1 .Location in patent: Page/Page column 26; 27
[17]Patent: WO2015/95097,2015,A2 .Location in patent: Page/Page column 26
[18]Patent: WO2015/103756,2015,A1 .Location in patent: Page/Page column 45
[19]Patent: WO2015/105736,2015,A1 .Location in patent: Page/Page column 47
[20]Patent: WO2015/100147,2015,A1 .Location in patent: Page/Page column 40-41
[21]Patent: WO2015/96035,2015,A1 .Location in patent: Page/Page column 40
[22]Patent: EP2632465,2015,B1 .Location in patent: Paragraph 0083
[23]Patent: WO2016/65582,2016,A1 .Location in patent: Page/Page column 30
[24]Patent: WO2016/122994,2016,A1 .Location in patent: Page/Page column 33; 34
[25]Patent: EP2744499,2016,B1 .Location in patent: Paragraph 0078
[26]Patent: US9493474,2016,B2 .Location in patent: Page/Page column 20
[27]Patent: EP2755656,2016,B1 .Location in patent: Paragraph 0127; 0129

6
[ 83647-43-2 ]
[ 1255206-69-9 ]

Reference： [1]Patent: WO2013/66714,2013,A1
[2]Patent: WO2013/62900,2013,A1
[3]Patent: WO2013/90271,2013,A1
[4]Patent: WO2013/66718,2013,A2
[5]Patent: WO2013/28474,2013,A1
[6]Patent: WO2014/15495,2014,A1
[7]Patent: WO2014/18764,2014,A1
[8]Patent: WO2014/85210,2014,A1
[9]Patent: WO2014/99633,2014,A2
[10]Patent: WO2014/126944,2014,A2
[11]Patent: WO2015/17305,2015,A1
[12]Patent: WO2015/65866,2015,A1
[13]Patent: WO2015/95097,2015,A2
[14]Patent: WO2015/103756,2015,A1
[15]Patent: WO2015/105736,2015,A1
[16]Patent: WO2015/100147,2015,A1
[17]Patent: WO2015/96035,2015,A1
[18]Patent: WO2016/65582,2016,A1
[19]Patent: WO2016/122994,2016,A1
[20]Patent: EP2744499,2016,B1
[21]Patent: WO2016/127358,2016,A1
[22]Patent: US2017/37037,2017,A1
[23]Patent: EP2755656,2016,B1
[24]Patent: WO2013/39802,2013,A1
[25]Patent: WO2013/62892,2013,A1
[26]Patent: WO2013/66717,2013,A1

7
[ 865139-18-0 ]
[ 83647-43-2 ]
(4'-(benzyloxy)-2,2',6'-trimethylbiphenyl-3-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.2%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 1h;Microwave irradiation;	2-Methyl-3-bromo-phenylmethanol (201 mg, 1 mmol, prepared by a method disclosed in patent application ), (4-(benzyloxy)-2,6-dimethylphenyl) boronic acid 12b (300 mg, 1.20 mmol), 1 mL 2 M aqueous sodium carbonate solution, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (33 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) were dissolved in 1 mL of N,N-dimethylformamide. The reaction mixture was reacted at 120 C under microwave condition for 1 hour. The resulting mixture was added with 10 mL of water and extracted with ethyl acetate (20 mL*2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (4'-(benzyloxy)-2,2',6'-trimethylbiphenyl-3-yl)methanol 12c (190 mg, yield 57.2%) as a red slime. MS m/z (ESI): 333.3 [M+1]
57.2%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;	2-Methyl-3-bromo-phenylmethanol (201 mg, 1 mmol, prepared by a method disclosed in PCT patent application WO2010143733), (4-(benzyloxy)-2,6-dimethylphenyl) boronic acid 12b (300 mg, 1.20 mmol), 1 mL of 2M aqueous sodium carbonate solution, 2-dicyclohexylphosphino-2?,6?-dimethoxy-1,1?-biphenyl (33 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) were dissolved in 1 mL of N,N-dimethylformamide. The reaction mixture was reacted at 120 C. under microwave conditions for 1 hour. The resulting mixture was mixed with 10 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (4?-(benzyloxy)-2,2?,6?-trimethylbiphenyl-3-yl)methanol 12c (190 mg, yield 57.2%) as a red slime. MS m/z (ESI): 333.3 [M+1]

Reference： [1]Patent: EP2803664,2014,A1 .Location in patent: Paragraph 0158; 0160
[2]Patent: US2015/5282,2015,A1 .Location in patent: Paragraph 0232; 0235; 0236

8
[ 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

9
[ 83647-43-2 ]
[ 1675203-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium hydrogencarbonate / toluene; ethanol / 0.5 h / 80 °C / Inert atmosphere 2: caesium carbonate; palladium diacetate; tert-butyl XPhos / toluene / 80 °C / Inert atmosphere 3: sodium cyanoborohydride / N,N-dimethyl-formamide; acetic acid / 20 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/34820, 2015, A1

10
[ 83647-43-2 ]
[ 22080-96-2 ]
4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Cooling with ice;	A solution of <strong>[22080-96-2]4-hydroxy-2,6-dimethoxybenzaldehyde</strong> (3.99 g, 21.88 mmol), triphenylphosphine (6 g, 22.88 mmol) and (3-bromo-2-methylphenyl)methanol (4 g, 19.89 mmol) in dry THF (50 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate (4.25 mL, 21.88 mmol) in THF (50 mL) was added dropwise. The resulting yellow solution was allowed to slowly warm to room temperature with stirring overnight. Excess solvent was removed by rotary evaporator. The crude product was purified by chromatography on a 360 g silica gel cartridge eluting with ethyl acetate in hexanes. Fractions containing the desired product were combined and the solvent removed under vacuum to give the title compound (4.0 g, 55%). 1H NMR (400MHz, CHLOROFORM-d) delta 10.39 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.18 (s, 2H), 5.13 (s, 2H), 3.91 (s, 6H), 2.49 (s, 3H).

Reference： [1]Patent: WO2015/34820,2015,A1 .Location in patent: Page/Page column 76

11
[ 83647-43-2 ]
[ 164014-95-3 ]
[ 1675205-18-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; caesium acetate In tetrahydrofuran Reflux;
98%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; caesium acetate In tetrahydrofuran for 24h; Inert atmosphere; Reflux;	34.1 (1) Synthesis of Intermediate 34-1 3-Bromo-2-methylbenzyl alcohol (3.25 g, 16.16 mmol), benzo-1,4-dioxane-6-boronic acid (3.64 g, 20.23 mmol), Cesium acetate (7.75 g, 40.38 mmol) and PdCl 2 (dppf) (1.19 g, 1.62 mmol) were suspended in 50 mL of THF, under argon protection, refluxed for 24 h, After cooling and concentration, the residue was added with water, extracted with DCM, the organic phase was washed with water, concentrated and purified by column chromatography to obtain 4.05 g of a colorless oil with a yield of 98%.
98%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; caesium acetate In tetrahydrofuran for 24h; Inert atmosphere; Reflux;	34.1 (1) Synthesis of Intermediate 34-1 3-Bromo-2-methylbenzyl alcohol (3.25 g, 16.16 mmol), benzo-1,4-dioxane-6-boronic acid (3.64 g, 20.23 mmol), Cesium acetate (7.75 g, 40.38 mmol) and PdCl 2 (dppf) (1.19 g, 1.62 mmol) were suspended in 50 mL of THF, under argon protection, refluxed for 24 h, After cooling and concentration, the residue was added with water, extracted with DCM, the organic phase was washed with water, concentrated and purified by column chromatography to obtain 4.05 g of a colorless oil with a yield of 98%.

95%	With tripotassium phosphate tribasic; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) In tetrahydrofuran at 20℃; for 48h; Inert atmosphere;	Intermediate: (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use. In a 1 L rb flask charge (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (5.201 g, 28.9 mmol), (3-bromo-2-methylphenyl)methanol (5.00 g, 24.87 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (also known as second generation XPhos precatalyst, CAS number 1310584-14-5, See Kinzel, Tom; Zhang, Yong; Buchwald, Stephen L. J. Am. Chem. Soc. 2010, 132(40), 14073-14075.) (0.588 g, 0.747 mmol), add previously deoxygenated tetrahydrofuran (124 mL) and 0.5 M aq Pottasium phosphate, tribasic solution (124 mL, 62.2 mmol), place under nitrogen and sparge with additional nitrogen for 10 minutes. The reaction was stirred under nitrogen at room temperature for 2 days. Ethyl acetate (300 mL) was added to the reaction followed by 200 mL of brine then the reaction was partitioned in a sepratory funnel. The organic extract was washed again (1×) with brine and dried over magnesium sulfate, filtered and solvent removed in vacuo using a rotary evaporator. The crude reaction product (7.84 g dark oil) was purified by silica gel chromatography eluting with a step gradient of 25% ethyl acetate in hexanes and 30% ethyl acetate in hexanes. The purified product (6.19 g, 95% yield) was obtained as a brown oil. 1H NMR (CHLOROFORM-d) δ: 7.37 (dd, J=7.4, 1.1 Hz, 1H), 7.21-7.26 (m, 1H), 7.17-7.21 (m, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.77 (dd, J=8.3, 2.1 Hz, 1H), 4.77 (s, 2H), 4.31 (s, 4H), 2.27 (s, 3H).
93.2%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Sodium hydrogenocarbonate In ethanol; toluene at 20℃; for 3h; Inert atmosphere;	1.3 (3) Preparation of Compound I-2-7 Compound I-2-5 (3.5 g, 19.45 mmol),Compound I-2-6 (2.61 g, 12.97 mmol),Pd(dppf)Cl2·CH2Cl2 (120 mg, 1.30 mmol) was added to a 250 mL three-neck bottle.Add toluene (19 mL) and ethanol (6.35 mL).Replace N2 three times, add NaHCO3 (19mL, 2M, 38.92mmol) for 3h at room temperature,The reaction was completely detected by TLC, the reaction system was spun dry, dissolved with ethyl acetate, washed with water, and the organic phase was dried.Column chromatography gave Compound I-2-7 in an amount of 3.1 g, yield 93.2%.
90%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; Sodium hydrogenocarbonate In ethanol; toluene at 85℃; for 12h; Inert atmosphere;
76%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Sodium hydrogenocarbonate In ethanol; toluene at 80℃; for 0.5h; Inert atmosphere;
66.4%	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 100℃; for 24h; Inert atmosphere;	Synthesis of Compound L1 Compound L1 was synthesized in line with the procedure. First, 200 mL bulk of 1,4-Dioxane and pure water (v:v = 4:1) was prepared under ventilating nitrogen (N2). 1,4-Benzodioxane-6-boronic acid (1.8 g, 0.01 mol), (3-bromo-2-methylphenyl)methanol (2.0 g, 0.01 mol), Potassium carbonate (13.0 g, 0.09 mol) mixed with Tetrakis(triphenylphosphine)palladium (1.0 g, 0.8 mmol) were dissolved in 200 mL Diox-H2O solution. Next, the mixture was stirred under N2 and heated at 100 through condensation reflux for 24 h. After removing 1,4-Dioxane by vacuum distillation and removal of salt via extraction, then the product was concentrated by rotary evaporation and purified by silica gel column chromatography (Hexane/Ethyl acetate = 3/1) to obtain 1.7 g (66.4%) as yellow oil.
66.4%	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 100℃; for 24h; Inert atmosphere;	1.1 (1) Synthesis of compound L1 First, the solvent (1,4-dioxane: pure water=4:1, v/v) totals 200 ml, and the oxygen in the mixed solvent is exhausted by nitrogen. Take benzo-1,4-dioxane-6-boronic acid (1.8g, 0.01mol), 3-bromo-2-methylbenzyl alcohol (2.0g, 0.01mol), anhydrous potassium carbonate (13.0g, 0.09mol) into the reaction flask, put in a magnetic stir bar, and then add tetrakis(triphenylphosphine)palladium (1.0g, 0.80mmol). A drying condenser was inserted into the mouth of the reaction flask, a solvent was injected, and heated at 100 °C under nitrogen protection, the condensed water was refluxed and reacted for 24 hours. After the reaction, the reaction solution was cooled, and the solvent 1,4-dioxane was removed using a rotary evaporator. Add appropriate amount of water to the reaction flask to dissolve potassium carbonate. Add dichloromethane to extract 5 times, each adding volume of about 50 ml. After drying with anhydrous sodium sulfate, spin to dry, separate and purify by column chromatography (n-hexane: ethyl acetate=1: 3, v/v), and vacuum dry to obtain 1.7 g of yellow oil (yield: 66.4%), namely compound L1.
0.59 g	With tripotassium phosphate tribasic; 2nd Generation XPhos precatalyst In tetrahydrofuran; lithium hydroxide monohydrate Inert atmosphere; Sealed tube;	Intermediate 112A: (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)boronic acid (0.537 g, 2.98 mmol),(3- bromo-2-methylphenyl)methanol (0.5 g, 2.487 mmol) and 2nd Generation XPhos precatalyst (0.059 g, 0.075 mmol) was covered with THF (24 ml) and degassed. Potassium phosphate, tribasic (12.43 ml, 6.22 mmol) added as an 0.5 M aqueous solution. The reaction was stirred at room temperature sealed under argon overnight. The solvent was removed by rotary evaporation. The residue was purified using 3: 1 hexanes: ethyl acetate on a 24 g silica gel column. The fractions containing the desired product provided 0.59g of the title compound as a colorless oil. 1H NMR (400MHz, CHLOROFORM-d) δ 7.39 (d, J=7.3 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.22 - 7.18 (m, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.83 (d, J=1.7 Hz, 1H), 6.78 (dd, J=8.2, 1.8 Hz, 1H), 4.79 (d, J=5.9 Hz, 2H), 4.33 (s, 4H), 2.28 (s, 3H).
	With tripotassium phosphate tribasic; [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloro palladium(II) In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 1h; Inert atmosphere;	15.1 Step 1: [3-(2, 3-dihydro-l, 4- ol Step 1: [3-(2, 3-dihydro-l, 4- ol (0524) A mixture of (3-bromo-2-methylphenyl)methanol (139 mg, 0.69 mmol), potassium phosphate (360 mg, 1.7 mmol), 2,3-dihydro-l,4-benzodioxin-6-ylboronic acid (0.130 g, 0.724 mmol) and dichloro[l,l'-bis(dicyclohexylphosphino)ferrocene]palladium(II) (0.03 g, 0.03 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was purged with N2 then stirred at 90 °C for 1 h. The reaction mixture was cooled to room temperature then quenched water and extracted with ethyl acetate. The combined organic phase was dried over MgS04 and concentrated. The residue was used directly in the next step without further purification. LC-MS calculated for C16H15O2 (M+H-H20)+: m/z = 239.1; found 239.1.
	With tripotassium phosphate tribasic; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) In tetrahydrofuran
	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 100℃; for 24h; Inert atmosphere;	1.1.1 (1) Synthesis of compound L1: First, the solvent (1,4-dioxane: pure water=4:1, v/v) in total is 200 mL, and the oxygen in the mixed solvent is exhausted by nitrogen gas. Take benzo-1,4-dioxane-6-boronic acid (1.8g, 0.01mol), 3-bromo-2-methylbenzyl alcohol (2.0g, 0.01mol), anhydrous potassium carbonate (13.0g, 0.09 mol) into the reaction flask, put in a magnetic stir bar, and then add tetrakis (triphenylphosphine) palladium (1.0 g, 0.80 mmol). A drying condenser was inserted into the mouth of the reaction flask, a solvent was injected, and heated at 100°C under nitrogen protection, the condensed water was refluxed, and the reaction was carried out for 24 hours. After the reaction, the reaction solution was cooled, and the solvent 1,4-dioxane was removed using a rotary evaporator. Add appropriate amount of water to the reaction flask to dissolve potassium carbonate. Add dichloromethane to extract 5 times, each adding volume of about 50mL. After drying with anhydrous sodium sulfate, spin to dry, separate and purify by column chromatography (n-hexane: ethyl acetate=1: 3, v/v), and dry in vacuum to obtain a yellow oil, namely compound L1;
	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; Sodium hydrogenocarbonate In ethanol; toluene at 80℃; for 3h; Inert atmosphere;	4.1.3. (2-Methyl-[1,10-biphenyl]-3-yl)methanol (4) General procedure: To a solution of intermediate 3 (2.00 g, 10.00 mmol) in toluene(16 mL) and ethanol (5 mL) were added phenylboronic acid (2.45 g,20.10 mmol), NaHCO3 (2.50 g, 3.10 mmol) and PdCl2(dppf)(75.00 mg, 0.10 mmol) with the protection of nitrogen. The reactionmixture was stirred at 80 C for 3 h. Monitored by TLC analysis, thesolvent was concentrated in vacuo. Then EtOAC and water wereused to extract the residues. Washing and drying of combinedorganic phases were carried out with brine and Na2SO4, accordinglyand in vacuo concentration procedure was used to obtain intermediate4 (crude gray solid) without any further purification 1.90 g,yield 95.0%.
	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; Sodium hydrogenocarbonate In ethanol; toluene at 80℃; for 3h; Inert atmosphere;	4.1.3. (2-Methyl-[1,10-biphenyl]-3-yl)methanol (4) General procedure: To a solution of intermediate 3 (2.00 g, 10.00 mmol) in toluene(16 mL) and ethanol (5 mL) were added phenylboronic acid (2.45 g,20.10 mmol), NaHCO3 (2.50 g, 3.10 mmol) and PdCl2(dppf)(75.00 mg, 0.10 mmol) with the protection of nitrogen. The reactionmixture was stirred at 80 C for 3 h. Monitored by TLC analysis, thesolvent was concentrated in vacuo. Then EtOAC and water wereused to extract the residues. Washing and drying of combinedorganic phases were carried out with brine and Na2SO4, accordinglyand in vacuo concentration procedure was used to obtain intermediate4 (crude gray solid) without any further purification 1.90 g,yield 95.0%.
95 g	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; tripotassium phosphate tribasic In tetrahydrofuran at 25℃; for 2h; Inert atmosphere;	1;2; 5 Then, to a solution of compound 2 (79.6 g, 442 mmol, 1.00 eq) and K3PO4 (1.82 M, 851 mL, 3.50 eq) in THF (500 mL) was added Pd(dppf)Cl2 (9.72 g, 13.2 mmol, 0.03 eq) under N2. The mixture was stirred at 25° C. for two (2) hrs. The results were verified by TLC which showed that all compound 2 (Rf=0.6) was consumed and a new spot (Rf=0.4) was detected. The mixture was poured into H2O (500 mL) and extracted with ethyl acetate (400 mL*3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude compound 4 was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=30/1 to 5/1) (Rf=0.4). The compound 4 (95.0 g, 365 mmol, 82.5% yield, 98.5% purity) was obtained as a light-yellow. The resulting compound is set forth in FIG. 11.
95 g	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; tripotassium phosphate tribasic In tetrahydrofuran at 25℃; for 2h; Inert atmosphere;	1;2; 5 Then, to a solution of compound 2 (79.6 g, 442 mmol, 1.00 eq) and K3PO4 (1.82 M, 851 mL, 3.50 eq) in THF (500 mL) was added Pd(dppf)Cl2 (9.72 g, 13.2 mmol, 0.03 eq) under N2. The mixture was stirred at 25° C. for two (2) hrs. The results were verified by TLC which showed that all compound 2 (Rf=0.6) was consumed and a new spot (Rf=0.4) was detected. The mixture was poured into H2O (500 mL) and extracted with ethyl acetate (400 mL*3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude compound 4 was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=30/1 to 5/1) (Rf=0.4). The compound 4 (95.0 g, 365 mmol, 82.5% yield, 98.5% purity) was obtained as a light-yellow. The resulting compound is set forth in FIG. 11.

Reference： [1]Guo, Jialin; Luo, Longlong; Wang, Zhihong; Hu, Naijing; Wang, Wei; Xie, Fei; Liang, Erguang; Yan, Xinlin; Xiao, Junhai; Li, Song [Journal of Medicinal Chemistry, 2020, vol. 63, # 22, p. 13825 - 13850]
[2]Current Patent Assignee: ACADEMY OF MILITARY MEDICAL SCIENCES - WO2022/33303, 2022, A1 Location in patent: Page/Page column 49-50
[3]Current Patent Assignee: ACADEMY OF MILITARY MEDICAL SCIENCES - WO2022/33303, 2022, A1 Location in patent: Page/Page column 49-50
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2015/291549, 2015, A1 Location in patent: Paragraph 0212; 0213
[5]Current Patent Assignee: GUANGZHOU DANKANG MEDICINE BIOLOGICAL - CN110092779, 2019, A Location in patent: Paragraph 0122; 0131-0134
[6]Butera, Roberto; Ważyńska, Marta; Magiera-Mularz, Katarzyna; Plewka, Jacek; Musielak, Bogdan; Surmiak, Ewa; Sala, Dominik; Kitel, Radoslaw; De Bruyn, Marco; Nijman, Hans W.; Elsinga, Philip H.; Holak, Tad A.; Dömling, Alexander [ACS Medicinal Chemistry Letters, 2021, vol. 12, # 5, p. 768 - 773]
[7]Guzik, Katarzyna; Zak, Krzysztof M.; Grudnik, Przemyslaw; Magiera, Katarzyna; Musielak, Bogdan; Törner, Ricarda; Skalniak, Lukasz; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A. [Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5857 - 5867]
[8]Miao, Yinxing; Lv, Gaochao; Chen, Yinfei; Qiu, Ling; Xie, Minhao; Lin, Jianguo [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 24]
[9]Current Patent Assignee: JIANGSU INSTITUTE OF NUCLEAR MEDICINE - CN112028916, 2020, A Location in patent: Paragraph 0066-0073
[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/34820, 2015, A1 Location in patent: Page/Page column 54-55
[11]Current Patent Assignee: INCYTE CORP - WO2017/87777, 2017, A1 Location in patent: Page/Page column 76
[12]Liu, Mei; Zhang, Yu; Guo, Yu; Gao, Jian; Huang, Wenhai; Dong, Xiaowu [Medicinal Chemistry Research, 2021, vol. 30, # 6, p. 1230 - 1239]
[13]Current Patent Assignee: JIANGSU INSTITUTE OF NUCLEAR MEDICINE - CN113264967, 2021, A Location in patent: Paragraph 0079-0084
[14]Bian, Jinlei; Du, Qianming; Kou, Junping; Li, Yu; Li, Zhiyu; Wang, Min; Xu, Xi; Zhang, Di; Zhao, Tengteng [European Journal of Medicinal Chemistry, 2022, vol. 233]
[15]Bian, Jinlei; Du, Qianming; Kou, Junping; Li, Yu; Li, Zhiyu; Wang, Min; Xu, Xi; Zhang, Di; Zhao, Tengteng [European Journal of Medicinal Chemistry, 2022, vol. 233]
[16]Current Patent Assignee: NAMMI THERAPEUTICS - US2022/80051, 2022, A1 Location in patent: Paragraph 0022; 0032; 0599-0600; 0603-0604
[17]Current Patent Assignee: NAMMI THERAPEUTICS - US2022/80051, 2022, A1 Location in patent: Paragraph 0022; 0032; 0599-0600; 0603-0604

12
[ 83647-43-2 ]
[ 76574-42-0 ]

Reference： [1]Patent: WO2015/105779,2015,A1
[2]Patent: WO2017/158151,2017,A1
[3]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 74 - 79

13
[ 83647-43-2 ]
[ 1628317-18-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: dichloromethane 2.1: sodium methylate / methanol / -10 - 4 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 0.17 h / Reflux 4.1: potassium hydroxide / methanol / Reflux 5.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 6.1: ammonium hydroxide / dichloromethane / 20 °C 7.1: trichlorophosphate / chloroform / Reflux 8.1: potassium hydride / mineral oil; tetrahydrofuran / 0.08 h / Inert atmosphere 8.2: 1 h / -95 - 90 °C / Inert atmosphere 8.3: 0.5 h / -95 - -70 °C / Inert atmosphere 9.1: triethylamine; sodium tris(acetoxy)borohydride / dichloromethane / 20 °C

Reference： [1]Borkin, Dmitry; Pollock, Jonathan; Kempinska, Katarzyna; Purohit, Trupta; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Miao, Hongzhi; Shukla, Shirish; He, Miao; Sun, Duxin; Cierpicki, Tomasz; Grembecka, Jolanta [Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 892 - 913]

14
[ 83647-43-2 ]
[ 1857417-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1.1: dichloromethane 2.1: sodium methylate / methanol / -10 - 4 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 0.17 h / Reflux 4.1: potassium hydroxide / methanol / Reflux 5.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 6.1: ammonium hydroxide / dichloromethane / 20 °C 7.1: trichlorophosphate / chloroform / Reflux 8.1: potassium hydride / mineral oil; tetrahydrofuran / 0.08 h / Inert atmosphere 8.2: 1 h / -95 - 90 °C / Inert atmosphere 8.3: 0.5 h / -95 - -70 °C / Inert atmosphere 9.1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 10.1: triethylamine; sodium tris(acetoxy)borohydride / dichloromethane / 15 h / 20 °C 11.1: hydrogenchloride / methanol; water / 1 h / 20 °C

15
[ 83647-43-2 ]
[ 1255206-67-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of ThalliumTrifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLCshowed no starting material remaining. The solvent was removed under vacuum, and the residuewas pumped under high vacuum for 30 mm to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big productspot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford title compound. ?H-NMR (500 MHz, CDC13) oe ppm 7.71 (d, J= 8.0 Hz, 1H), 7.58 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).

Reference： [1]Patent: WO2016/127358,2016,A1 .Location in patent: Page/Page column 28; 29

16
[ 83647-43-2 ]
thallium(III) trifluoroacetate [ No CAS ]
[ 1255206-67-7 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; at 20℃;	To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hr. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a CELITE pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford the title compound. 1H-NMR (500 MHz, CDCl3) delta ppm 7.71 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).

Reference： [1]Patent: US2017/37037,2017,A1 .Location in patent: Paragraph 0182

17
[ 83647-40-9 ]
[ 83647-43-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium tetrahydroborate; In methanol; for 0.5h;	To an ice cold solution of compound 3-Bromo-2-methylbenzaldehyde (5 g, 25 mmol) in MeOH (60 mL) was added NaBH4 (2.8 g, 75 mmol) portion wise and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with ice water and volatiles were removed under reduced pressure. The mixture was diluted with water and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound (4.8 g, 95%) as an off white solid.
	With sodium tetrahydroborate; In tetrahydrofuran; at 17 - 25℃; for 2h;Inert atmosphere;	Sodium borohydride (1.78 g, 47.1 mmol) was added to a solution of <strong>[83647-40-9]3-bromo-2-methylbenzaldehyde</strong> (7.50 g, 37.7 mmol) in THF (151 mL) and the reaction was stirred at room temperature for 2 hours. The reaction was cooled in an ice-bath and quenched by addition of 2N HCl solution, then extracted with EtOAc (*2). The combined organics were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated to dryness to afford (3-bromo-2-methylphenyl)methanol (7.73 g,>100%) as a pale yellow solid. 1H NMR (500 MHz, CDCl3, 27 C.) 1.99 (1H, br s), 2.41 (3H, s), 4.70 (2H, s), 7.05 (1H, t), 7.30 (1H, d), 7.49-7.53 (1H, m).
	With sodium tetrahydroborate; In tetrahydrofuran; at 20℃; for 2h;	Preparation of (3-bromo-2-methylphenyl)methanol Sodium borohydride (1.78 g, 47.1 mmol) was added to a solution of 3-bromo-2- methylbenzaldehyde (7.50 g, 37.7 mmol) in THF (151 mL) and the reaction was stirred at room temperature for 2 hours. The reaction was cooled in an ice-bath and quenched by addition of aqueous HC1 (2N), then extracted with EtOAc (x2). The combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness to afford (3-bromo-2-methylphenyl)methanol (7.73 g; 100%) as a pale yellow solid. XH NMR (500 MHz, CDC13, 27 C) 1.99 (1H, br s), 2.41 (3H, s), 4.70 (2H, s), 7.05 (1H, t), 7.30 (1H, d), 7.49 - 7.53 (1H, m).

Reference： [1]Patent: WO2017/158151,2017,A1 .Location in patent: Page/Page column 148
[2]Patent: US2017/305909,2017,A1 .Location in patent: Paragraph 0631; 0632
[3]Patent: WO2017/182495,2017,A1 .Location in patent: Page/Page column 122

18
[ 41438-18-0 ]
[ 83647-43-2 ]
4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde [ No CAS ]
4-((3-bromo-2-methylbenzyl)oxy)-3-chloro-2-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A B A solution of diisopropyl azodicarboxylate (2.67 ml, 12.90 mmol) in THF (24.42 ml) was added dropwise to the solution of (3-bromo-2-methylphenyl)methanol (2.357 g, 11.72 mmol), a mixture of regio-isomers 5-chloro-<strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> and 3-chloro-<strong>[41438-18-0]4-hydroxy-2-methylbenzaldehyde</strong> (2 g, 11.72 mmol), and triphenylphosphine (3.38 g, 12.90 mmol) in THF (48.8 ml) at 0C. The resulting yellow solution was allowed to warm to rt and stirred overnight. The solvent was removed under vacuum. The crude material was purified by silica gel chromatography using 5-50% EtOAc/Hex. The product fractions were collected and the solvent removed under vacuum to give : 4-((3- bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde (A) and 4-((3-bromo-2- methylbenzyl)oxy)-3-chloro-2-methylbenzaldehyde (B) (1.1g, 27% yield). The regio isomers were then separated by SFC chromatography. Experimental Details for SFC chromatography: (0936) Column: ChiralCel OD-H, 5 x 25cm, 5mum (0937) Mobile Phase: 38% MeOH / 62% CO2 (0938) Pressure: 100 bar (0939) Temperature: 35C (0940) Flow Rate: 300 mL/min (0941) UV: 220 nm (0942) Injection: 3.5 mL (~13.6 mg/mL in MeOH:CHCl3, 1:1) Peak 1 and Peak 2 were concentrated under vacuum. Peak 1 corresponds to the acetal of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde (A) by NMR formed under SFC conditions. The aldehyde was reformed by dissolving Peak 1 in 2 mL DCM and adding 1 mL water and 1 mL TFA. The mixture was stirred for 30 min. The organic layer was collected and washed with bicarbonate and brine, dried over sodium sulfate and concentrated to give 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-methylbenzaldehyde (140 mg).1H NMR (400 MHz, CHLOROFORM-d) delta 10.12 (s, 1H), 7.86 (s, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.85 (s, 1H), 5.20 (s, 2H), 2.67 (s, 3H), 2.47 (s, 3H). .

Reference： [1]Patent: WO2018/44963,2018,A1 .Location in patent: Page/Page column 235-236

19
[ 18278-34-7 ]
[ 83647-43-2 ]
4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 23h;	4-((3-Bromo-2-methylbenzyl)oxy)-2-methoxybenzaldehyde (20) (3-Bromo-2-methylphenyl)methanol (19, 450 mg, 2.238 mmol), 4-hydroxy-2-methoxybenzaldehyde (18, 409 mg, 2.69 mmol), and triphenylphosphine (881 mg, 3.36 mmol) were added to THF (6.0 mL). DIAD (0.653 mL, 3.36 mmol) was added dropwise to the reaction mixture, and stirred at room temperature for 23 h. Sat. NH4Cl (aq.) was added to the reaction mixture, and extracted with AcOEt. The organic phase was washed with water and concentrated under reduced pressure. Chromatographic purification on silica-gel (n-hexane / AcOEt = 85:15 to 65:35) followed by crystallization from n-hexane-AcOEt (2:1, 9 mL) gave the titled compound (270 mg, 0.805 mmol, 36% yield). 1H NMR (CDCl3) δ: 10.31 (d, 1H, J = 0.5 Hz), 7.83 (d, 1H, J = 8.6 Hz), 7.59 (d, 1H, J = 7.8 Hz), 7.34 (d, 1H, J = 7.8 Hz), 7.09 (t, 1H, J = 7.8 Hz), 6.62 (dd, 1H, J = 8.6, 2.4 Hz), 6.53 (d, 1H, J = 2.4 Hz), 5.12 (s, 2H), 3.90 (s, 3H), 2.46 (s, 3H). UPLC-MS Retention time = 1.990 min; ESI-MS (positive) m/z: 335, 337(M+H).
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	6.1 Step-1: 4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzaldehyde (_-4) Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (1.5 mL) is added dropwise to a cooled (0 C) solution of 4-hydroxy-2-methoxybenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and (3-bromo-2-methylphenyl)methanol II-3 (1.0 mmol) in dry tetrahydrofuran (3 mL). The resulting reaction mixture is allowed to slowly warm to room temperature with stirring overnight. The product is filtered from the reaction mixture using a Buchner filter funnel and rinsed with tetrahydrofuran (approx. 3 mL) then dried in vacuo at room temperature to yield the title compound II-4. The crude is used for next step without further purification.
	With di-isopropyl azodicarboxylate; triphenylphosphine In 2-methyltetrahydrofuran at 0 - 20℃; for 4h;	27.1 Step 1: To a solution of 4-hydroxy-2-methoxybenzaldehyde (341 mg, 2.24 mmol), (3-bromo-2- methylphenyl)methanol (410 mg, 2.04 mmol), PPh3 (801 mg, 3.06 mmol) in 2-MeTHF (7.0 mL) at 0 °C280 was added Diisopropyl azodicarboxylate (0.6 mL, 3.06 mmol). The ice bath was removed and the reaction mixture was then stirred at rt. After 4h, the reaction mixture was directly purified by column chromatography (Si02, 1% EtOAc/hexanes to 50% EtOAc/hexanes) to give 4-((3-bromo-2- methylbenzyl)oxy)-2-methoxybenzaldehyde

Reference： [1]Kawashita, Seiji; Aoyagi, Koichi; Yamanaka, Hiroshi; Hantani, Rie; Naruoka, Shiori; Tanimoto, Atsuo; Hori, Yuji; Toyonaga, Yukiyo; Fukushima, Kyoko; Miyazaki, Susumu; Hantani, Yoshiji [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 17, p. 2464 - 2467]
[2]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD; ARISING INTERNATIONAL INC - WO2018/26971, 2018, A1 Location in patent: Page/Page column 30
[3]Current Patent Assignee: GILEAD SCIENCES INC - WO2018/195321, 2018, A1 Location in patent: Page/Page column 280; 281

20
[ 83647-43-2 ]
[ 95652-81-6 ]
6-((3-bromo-2-methylbenzyl)oxy)-2-methoxynicotinaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(3-Bromo-2-methylphenyl) methanol (300 mg, 1.49 mmol) was dissolved in DMF (6 ml).Sodium hydride (60 % dispersion in mineral oil, 72 mg, and 1.79 mmol) was added. The suspension wasstirred at room temperature for 5 mm before <strong>[95652-81-6]6-chloro-2-methoxynicotinaldehyde</strong> (256 mg, 1.49 mmol)was added in one portion. Complete conversion was detected after stirring at room temperature for 30 mi EtOAc and water were added to the mixture. The organic layer was evaporated under reduced pressure. The residue was purified by silica gel chromatography using Hexanes I EtOAc as the eluent to afford 6-((3 -bromo-2-methylbenzyl) oxy)-2-methoxynicotinaldehyde.

Reference： [1]Patent: WO2018/195321,2018,A1 .Location in patent: Page/Page column 218; 219

21
[ 83647-43-2 ]
[ 1061650-37-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; caesium acetate / tetrahydrofuran / Reflux 2.1: hydrazine hydrate monohydrate / ethanol / 3 h / Reflux 2.2: 0.5 h / Reflux
	Multi-step reaction with 3 steps 1.1: caesium acetate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / tetrahydrofuran / 23 h / Inert atmosphere; Reflux 2.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 24 h / 0 - 20 °C / Inert atmosphere 3.1: ethanol; hydrazine hydrate monohydrate / 3 h / Reflux 3.2: 0.5 h / Reflux
	Multi-step reaction with 3 steps 1: caesium acetate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / tetrahydrofuran / 23 h / Inert atmosphere; Reflux 2: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 24 h / 0 - 20 °C / Inert atmosphere 3: hydrazine hydrate monohydrate / ethanol / 3 h / Reflux

Reference： [1]Guo, Jialin; Luo, Longlong; Wang, Zhihong; Hu, Naijing; Wang, Wei; Xie, Fei; Liang, Erguang; Yan, Xinlin; Xiao, Junhai; Li, Song [Journal of Medicinal Chemistry, 2020, vol. 63, # 22, p. 13825 - 13850]
[2]Current Patent Assignee: INST MILITARY MEDICINE ACADEMY MILITARY SCIENCES PLA; ACADEMY OF MILITARY MEDICAL SCIENCES - WO2022/33303, 2022, A1
[3]Current Patent Assignee: INST MILITARY MEDICINE ACADEMY MILITARY SCIENCES PLA; ACADEMY OF MILITARY MEDICAL SCIENCES - WO2022/33303, 2022, A1

22
[ 83647-43-2 ]
[ 517874-21-4 ]
[ 1675205-18-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; Sodium hydrogenocarbonate In ethanol; lithium hydroxide monohydrate; toluene at 80℃; for 3h; Inert atmosphere;	4 Compound 20 (2.0 g, 9.9 mmol), compound 21 (1.1 g, 11.9 mmol) and Pd(dppf)Cl (55 mg, 0.01 mmol) were dissolved in toluene (16 mL) and ethanol (8 mL) under nitrogen protection, and then added Aqueous sodium bicarbonate solution (14.9 mL, 2 M, 29.7 mmol) was heated to 80 degrees and reacted for 3 hours. TLC showed (PE:EA=4:1) that the reaction of the raw materials was complete. Ethyl acetate (30 mL) and water (10 mL) were added, and the aqueous layer was extracted three times with EA. The organic layers were combined, dried over anhydrous sodium sulfate, spin-dried, and purified by column (PE:EA=10:1), and the result was light. 1.89 g of yellow solid, yield 74%.

Reference： [1]Current Patent Assignee: WEST CHINA HOSPITAL OF SICHUAN UNIV - CN114573558, 2022, A Location in patent: Paragraph 0071-0074

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P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 83647-43-2 ] {[proInfo.proName]}

Quality Control of [ 83647-43-2 ]

Related Doc. of [ 83647-43-2 ]

Product Details of [ 83647-43-2 ]

Calculated chemistry of [ 83647-43-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 83647-43-2 ]

Application In Synthesis of [ 83647-43-2 ]

[ 83647-43-2 ] Synthesis Path-Upstream 1~10

[ 83647-43-2 ] Synthesis Path-Downstream 1~22

Related Functional Groups of [ 83647-43-2 ]

Aryls

Bromides

Alcohols

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 83647-43-2 ]