[ CAS No. 156001-49-9 ]

Name: 156001-49-9|4-Bromo-1-(bromomethyl)-2-methylbenzene|97%
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Quality Control of [ 156001-49-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 156001-49-9 ]

SDS Specification

Alternatived Products of [ 156001-49-9 ]

Product Details of [ 156001-49-9 ]

CAS No. :	156001-49-9	MDL No. :	MFCD12025011
Formula :	C₈H₈Br₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RRBOULIORCZELO-UHFFFAOYSA-N
M.W :	263.96	Pubchem ID :	22569018
Synonyms :

Calculated chemistry of [ 156001-49-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	1
Num. H-bond acceptors :	0.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.94
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.62
Log Po/w (XLOGP3) :	3.54
Log Po/w (WLOGP) :	3.5
Log Po/w (MLOGP) :	4.12
Log Po/w (SILICOS-IT) :	3.97
Consensus Log Po/w :	3.55

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.08
Solubility :	0.0217 mg/ml ; 0.0000823 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.22
Solubility :	0.157 mg/ml ; 0.000596 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.89
Solubility :	0.00336 mg/ml ; 0.0000127 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.89

Safety of [ 156001-49-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P260-P270-P271-P264-P280-P362+P364-P303+P361+P353-P301+P330+P331-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405	UN#:	3261
Hazard Statements:	H302+H312+H332-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 156001-49-9 ]

* 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 [ 156001-49-9 ]
Downstream synthetic route of [ 156001-49-9 ]

[ 156001-49-9 ] Synthesis Path-Upstream 1~7

1
[ 17100-58-2 ]
[ 156001-49-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 5℃;	Step b intermediate 51 <n="63"/>1 -Bromo-4-(bromomethyl)-3 -methylbenzene(4-Bromo-2-methylphenyl) methanol (10.4 g, 51.6 mmol) is dissolved in anhydrous CH₂Cl₂ (150 mL) and CBr₄ (18.8 g, 56.8 mmol) added. The reaction mixture is cooled to 0-5⁰C and PPh₃ (14.9 g, 56.8 mmol) is added. The reaction mixture is stirred overnight then hexane / EtOAc (9:1) (250 mL) is added with vigorous stirring. The triphenylphosphine oxide that forms during the reaction is filtered off and the filtrates are concentrated in vacuo. The resulting oil is purified on a silica gel pad with hexane / EtOAc (8:2). The solvent are removed on a rotary evaporator and the bromoform is removed by vacuum distillation (15 mm Hg, bp: 40-50⁰C) to provide the expected product l-Bromo-4-(bromomethyl)-3-methylbenzene (13.23 g, 97 percent) as a yellow oil. IH NMR (300 MHz, CHLOROFORM-D): δ 7.37-7.27 (2H, m), 7.17 (IH, d, /= 8.1 Hz), 4.45 (2H, s), 2.39 (3H,s).
97%	With phosphorus tribromide In dichloromethane at 0 - 20℃;	Intermediate 13: 4-bromo-1-(bromomethvl)-2-methylbenzene; To a solution of (4-bromo-2-methylphenyl) methanol, intermediate 12, (100 g, 0. 5mol) in dicholoromethane (1 L) was added dropwise phosphorus tribromine (54.2 g, 0.2 mol) at 0 ⁰C. After addition, the reaction mixture was stirred for 2 hours at RT. The mixture was adjusted to pH=7 with a saturated solution of NaHCO₃. The separated organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to give the title product (4-bromo-2- methylphenyl)methanol, (128 g, 97percent yield). ¹H NMR: (400 MHZ, CDCI₃) δ 7.43 (t, 1 H), 7.32- 7.37 (m, 2H), 4.67 (s, 2H), 2.33 (s, 3H).
95%	With phosphorus tribromide In chloroform at 0 - 20℃; for 3 h; Inert atmosphere	PBr3 (14.54 g, 53.7mmol, 1.2 eq) was added to the solution of (4-bromo-2-methylphenyl)methanol (9.0 g, 44.76mmol, 1.0 eq) in CHC13 (100 mL) at 0 °C under nitrogen atmosphere and the solution wasallowed to warm up to ambient temperature. The solution was, then, stirred at ambienttemperature for 3 h. After complete consumption of starting material, the reaction mixture was diluted with chloroform and washed with saturated aq NaHCO3 and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvents evaporated from the filtrate under reduced pressure to afford 4-bromo-1-(bromomethyl)-2-methylbenzene (11.2 g, 95percent) asyellow solid.

89%	With phosphorus tribromide In dichloromethane at 0 - 20℃; for 1 h;	[0653j To a solution of (4-bromo-2-methylphenyl)methanol (1.3 g, 6.7 mmol) in CH2C12 (50 mL) was added PBr3 (0.95 mL, 10 mmol) at 0 °C. The mixture was stirred at rt for 1 h, quenched with ice-water (50 mL) and the pH value was adjusted to 7.0 with 50percent aqueous NaOH solution. The mixture was extracted with EtOAc (100 mL x 2) and the combined organic layers were washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo to give 4-bromo-1- (bromomethyl)-2-methylbenzene (1.56 g, yield: 89percent) as a white solid which was used in next step without further purification.
81%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 5 h;	Triphenylphosphine (11.35 g, 43.27 mmol) followed by carbon tetrabromide (14.35 g, 43.27 mmol) were added to a solution of (4-bromo-2-methyl-phenyl)-methanol (7.25 g, 36 mmol) in CH₂CI₂ (200 mL). The mixture was stirred at room temperature for 5 hours. The solution was concentrated to 15 ml. The residue was purified by flash column chromotography (1percent to 10percent EtOAc in Hexane) gave the product as brown oil (9.25 g, 81percent yield). ¹H NMR (400 MHz, CDCI₃) 5: 2.39 (3 H, s) 4.45 (2 H, s) 7.17 (1 H, d, J=8.08 Hz) 7.29 (2 H, m) 7.30 (1 H, dd, J=8.08, 2.02 Hz) 7.34 (1 H, s)

Reference： [1] Patent: WO2008/18827, 2008, A1, . Location in patent: Page/Page column 61-62
[2] Patent: WO2010/15652, 2010, A2, . Location in patent: Page/Page column 36
[3] Patent: WO2017/34990, 2017, A1, . Location in patent: Page/Page column 41
[4] Patent: WO2015/89337, 2015, A1, . Location in patent: Paragraph 0653
[5] Patent: US6359135, 2002, B1, . Location in patent: Page column 122
[6] Patent: US6369261, 2002, B1, . Location in patent: Page column 120
[7] Patent: US6369225, 2002, B1, . Location in patent: Page column 44, 121
[8] Patent: WO2006/18725, 2006, A1, . Location in patent: Page/Page column 164
[9] Patent: US6313107, 2001, B1,
[10] Patent: US6252090, 2001, B1,
[11] Patent: WO2008/148867, 2008, A2, . Location in patent: Page/Page column 39
[12] Patent: WO2009/23964, 2009, A1, . Location in patent: Page/Page column 23-24
[13] Patent: WO2006/46593, 2006, A1, . Location in patent: Page/Page column 194
[14] Patent: WO2013/43232, 2013, A2, . Location in patent: Paragraph 00619
[15] Organic Letters, 2013, vol. 15, # 22, p. 5818 - 5821
[16] Patent: WO2006/109633, 2006, A1, . Location in patent: Page/Page column 168-169

2
[ 68837-59-2 ]
[ 156001-49-9 ]

Reference： [1] Patent: WO2013/43232, 2013, A2,
[2] Organic Letters, 2013, vol. 15, # 22, p. 5818 - 5821

3
[ 99548-55-7 ]
[ 156001-49-9 ]

Reference： [1] Patent: WO2013/43232, 2013, A2,

4
[ 143-33-9 ]
[ 156001-49-9 ]
[ 215800-05-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	at 0 - 20℃;	Step c intermediate 522-(4-bromo-2-methylphenyl)acetonitrilel-Bromo-4-(bromomethyl)-3-methylbenzene (13.2 g, 50.1 mmol) is dissolved in DMF (65 mL). The reaction mixture is cooled to 0-5⁰C and NaCN (3.66 g, 74.6 mmol) is added follow by water (8 mL). The reaction is stirred overnight at room temperature and water (170 mL) is added followed by NaHCO₃ sat. (130 mL) and hexane/Et₂O (2:1) (150 mL). The organic phase is separated and the aqueous phase extracted with hexane / Et₂O (2:1) (3 x 150 mL). The combined organic phases are washed with water (170 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-methylphenyl)acetonitrile (9.76 g, 93 percent) as an orange oil. IH NMR (300 MHz, CHLOROFORM-D): δ 7.40-7.32 (2H, m), 7.23 (2H, d, /= 8.2 Hz), 3.61 (2H, s), 2.32 (3H, s).
92.7%	at 20℃;	To a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (3.96 g, 15 mmol) dissolved in DMF (16. mL)₍ were, a'dd^jspdjum cyanide (0.85 g, '17.25 mmol) and waler (1.8 ml). The reaction was sti'rred for oye'rriigh't at room temperature. To the reaction was added 1 00 ml water; 80 mL saturated NaHCO₃, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3 x 100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na₂SO₄. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7percent yield). ¹H NMR (400 MHz, CDCI₃): 6 2.32 (2 H, s), 3.62 (1 H, s), 7.20-7.27 (1 H, m), 7.32-7.41 (1 H, m).

Reference： [1] Patent: WO2008/18827, 2008, A1, . Location in patent: Page/Page column 61-62
[2] Patent: WO2006/18725, 2006, A1, . Location in patent: Page/Page column 164

5
[ 773837-37-9 ]
[ 156001-49-9 ]
[ 215800-05-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 20℃; for 5 h; Inert atmosphere	NaCN (2.78 g, 56.80mmol, 1.5 eq) was added to the solution of 4-bromo-1-(bromomethyl)-2-methylbenzene (10.00 g, 37.80 mmol, 1.0 eq) in DMF and H20 (10:1, 110 mL) under nitrogen atmosphere and thesolution was stirred at ambient temperature for 5 h. After complete consumption of starting material, the reaction mixture was diluted with ice cold water and extracted with diethyl ether. The organic extract was then washed with water, dried over anhydrous sodium sulfate, filtered, and solvent evaporated from the filtrated under reduced pressure to afford 2-(4-bromo-2- methylphenyl)acetonitrile as off white solid (7.5 g, 95percent).

Reference： [1] Patent: WO2017/34990, 2017, A1, . Location in patent: Page/Page column 41

6
[ 156001-49-9 ]
[ 215800-05-8 ]

Reference： [1] Patent: WO2013/43232, 2013, A2, . Location in patent: Paragraph 00620

7
[ 151-50-8 ]
[ 156001-49-9 ]
[ 215800-05-8 ]

Reference： [1] Patent: WO2009/23964, 2009, A1, . Location in patent: Page/Page column 24
[2] Patent: WO2006/46593, 2006, A1, . Location in patent: Page/Page column 194
[3] Patent: WO2006/109633, 2006, A1, . Location in patent: Page/Page column 168-169

[ 156001-49-9 ] Synthesis Path-Downstream 1~69

1
[ 128-44-9 ]
[ 156001-49-9 ]
[ 1026505-61-2 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

2
[ 156001-49-9 ]
C₁₈H₁₅BrN₂O₄S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

3
[ 156001-49-9 ]
[2-(4-Bromo-2-methyl-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-(3Z)-ylidene]-cyano-acetic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

4
[ 156001-49-9 ]
[ 1027172-78-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

5
[ 156001-49-9 ]
[ 1026251-38-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

6
[ 156001-49-9 ]
[ 1026508-74-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

7
[ 288-32-4 ]
[ 156001-49-9 ]
[ 345965-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In N,N-dimethyl-formamide;	1-(4-Bromo-2-methyl-benzyl)-1H-imidazole (Intermediate 139) A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was treated with NaH (20.0 mg, 0.86 mmol) and heated to 90 C. After 1 h a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 190.0 mg, 0.72 mmol) in 3 mL DMF was added and stirring at 90 C. continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 160.0 mg (88%) was isolated by column chromatography (5% MeOH-EtOAc) as a colorless solid. 1H NMR (CDCl3) delta: 7.46 (1H, s), 7.34 (1H, dd, J=1.8 Hz), 7.30 (1H, dd, J=1.8, 8.2 Hz), 7.08 (1H, t, J=1.2 Hz), 6.83 (1H, t, J=1.2 Hz), 6.80 (1H, d, J=8.2 Hz), 5.03 (2H, s), 2.23 (3H, s).
	With NaH; In N,N-dimethyl-formamide;	1-(4-Bromo-2-methyl-benzyl)-1H-imidazole (Intermediate 139) A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was treated with NaH (20.0 mg, 0.86 mmol) and heated to 90 C. After Ih a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 190.0 mg, 0.72 mmol) in 3 mL DM1F was added and stirring at 90 C. continued for Ihour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 160.0 mg (88%) was isolated by column chromatography (5% MeOH-EtOAc) as a colorless solid. 1H NMR (CDCl3) delta: 7.46 (1H, s), 7.34 (1H, dd, J=1.8 Hz), 7.30 (1H, dd, J=1.8, 8.2 Hz), 7.08 (1H, t, J=1.2 Hz), 6.83 (1H, t, J=1.2 Hz), 6.80 (1H, d, J =8.2 Hz), 5.03 (2H, s), 2.23 (3H, s).

Reference： [1]Patent: US6359135,2002,B1 .Location in patent: Page column 122
[2]Patent: US6369261,2002,B1 .Location in patent: Page column 120
[3]Patent: US6369225,2002,B1 .Location in patent: Page column 44, 121
[4]Patent: US6313107,2001,B1
[5]Patent: US6252090,2001,B1

8
[ 2615-15-8 ]
[ 156001-49-9 ]
[ 121392-48-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil;	Example 32 1,21-Bis[4-(alpha-hydroperoxyisopropyl)-2-methylphenyl]-2,5,8,11,14,17,20-heptaoxaheneicosane To a solution of 354 mg (3.85 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (20 ml) was added 1.00 g (3.54 mmol) of hexaethylene glycol, and the mixture was reacted at 40 - 50C for 30 min. Then, 2.06 g (7.79 mmol) of <strong>[156001-49-9]4-bromo-2-methylbenzyl bromide</strong> was added, and the mixture was allowed to react at room temperature for 17 hours. To the reaction solution at 0C was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with ethyl acetate-hexane (1:4) yielded 2.02 g (3.12 mmol) of 1,21-bis(4-bromo-2-methylphenyl)-2,5,8,11,14,17,20-heptaoxaheneicosane.

Reference： [1]Patent: EP328643,1994,B1

9
[ 17100-58-2 ]
[ 156001-49-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 5℃;	Step b intermediate 51 <n="63"/>1 -Bromo-4-(bromomethyl)-3 -methylbenzene(4-Bromo-2-methylphenyl) methanol (10.4 g, 51.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (18.8 g, 56.8 mmol) added. The reaction mixture is cooled to 0-50C and PPh3 (14.9 g, 56.8 mmol) is added. The reaction mixture is stirred overnight then hexane / EtOAc (9:1) (250 mL) is added with vigorous stirring. The triphenylphosphine oxide that forms during the reaction is filtered off and the filtrates are concentrated in vacuo. The resulting oil is purified on a silica gel pad with hexane / EtOAc (8:2). The solvent are removed on a rotary evaporator and the bromoform is removed by vacuum distillation (15 mm Hg, bp: 40-500C) to provide the expected product l-Bromo-4-(bromomethyl)-3-methylbenzene (13.23 g, 97 %) as a yellow oil. IH NMR (300 MHz, CHLOROFORM-D): delta 7.37-7.27 (2H, m), 7.17 (IH, d, /= 8.1 Hz), 4.45 (2H, s), 2.39 (3H,s).
97%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃;	Intermediate 13: 4-bromo-1-(bromomethvl)-2-methylbenzene; To a solution of (4-bromo-2-methylphenyl) methanol, intermediate 12, (100 g, 0. 5mol) in dicholoromethane (1 L) was added dropwise phosphorus tribromine (54.2 g, 0.2 mol) at 0 0C. After addition, the reaction mixture was stirred for 2 hours at RT. The mixture was adjusted to pH=7 with a saturated solution of NaHCO3. The separated organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to give the title product (4-bromo-2- methylphenyl)methanol, (128 g, 97% yield). 1H NMR: (400 MHZ, CDCI3) delta 7.43 (t, 1 H), 7.32- 7.37 (m, 2H), 4.67 (s, 2H), 2.33 (s, 3H).
95%	With phosphorus tribromide; In chloroform; at 0 - 20℃; for 3h;Inert atmosphere;	PBr3 (14.54 g, 53.7mmol, 1.2 eq) was added to the solution of (4-bromo-2-methylphenyl)methanol (9.0 g, 44.76mmol, 1.0 eq) in CHC13 (100 mL) at 0 C under nitrogen atmosphere and the solution wasallowed to warm up to ambient temperature. The solution was, then, stirred at ambienttemperature for 3 h. After complete consumption of starting material, the reaction mixture was diluted with chloroform and washed with saturated aq NaHCO3 and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvents evaporated from the filtrate under reduced pressure to afford 4-bromo-1-(bromomethyl)-2-methylbenzene (11.2 g, 95%) asyellow solid.

89%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 1h;	[0653j To a solution of (4-bromo-2-methylphenyl)methanol (1.3 g, 6.7 mmol) in CH2C12 (50 mL) was added PBr3 (0.95 mL, 10 mmol) at 0 C. The mixture was stirred at rt for 1 h, quenched with ice-water (50 mL) and the pH value was adjusted to 7.0 with 50% aqueous NaOH solution. The mixture was extracted with EtOAc (100 mL x 2) and the combined organic layers were washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo to give 4-bromo-1- (bromomethyl)-2-methylbenzene (1.56 g, yield: 89%) as a white solid which was used in next step without further purification.
81%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 5h;	Triphenylphosphine (11.35 g, 43.27 mmol) followed by carbon tetrabromide (14.35 g, 43.27 mmol) were added to a solution of (4-bromo-2-methyl-phenyl)-methanol (7.25 g, 36 mmol) in CH2CI2 (200 mL). The mixture was stirred at room temperature for 5 hours. The solution was concentrated to 15 ml. The residue was purified by flash column chromotography (1% to 10% EtOAc in Hexane) gave the product as brown oil (9.25 g, 81% yield). 1H NMR (400 MHz, CDCI3) 5: 2.39 (3 H, s) 4.45 (2 H, s) 7.17 (1 H, d, J=8.08 Hz) 7.29 (2 H, m) 7.30 (1 H, dd, J=8.08, 2.02 Hz) 7.34 (1 H, s)
	With N-Bromosuccinimide; triphenylphosphine; In dichloromethane;	4-Bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138) A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in 5 mL CH2Cl2 was cooled to 0 C. and N-bromosuccinimide (309.0 mg, 1.74 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25 C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil. 1H NMR (CDCl3) delta: 7.32 (1H, d, J=2.0 Hz), 7.29 (1H, dd, J=2.0, 7.9 Hz), 7.15 (1H, d, J=7.9 Hz), 4.43 (2H, s), 2.37 (3H, s).
	With triphenylphosphine; In N-Bromosuccinimide;	4-Bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138) A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in 5 mL CH2C12 was cooled to 0 C. and N-bromosuccinimide (309.0 mg, 1.74 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25 C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil. 1H NMR (CDCl3) delta: 7.32 (1H, d, J=2.0 Hz), 7.29 (1H, dd, J=2.0, 7.9 Hz), 7.15 (1H, d, J=7.9 Hz), 4.43 (2H, s), 2.37 (3H, s).
	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃;	To a stirred solution of (4-Bromo-2-methyl-phenyl)-methanol (as obtained in preparation 25) (4.58 g, 22.8 mmol) in CH2CI2 (50 ml) is added , under Argon and at RT, carbon tetrabromide (9.27 g, 27.4 mmol) followed by thphenylphosphine (7.25 g, 27.4 mmol). The mixture is stirred overnight and then concentrated in vacuo. The crude residue is then purified by chromatography (silicagel, hexane: EtOAc 25:1) to afford the title compound as a clear oil.
	With hydrogen bromide; acetic acid; In water; at 50℃; for 12h;	Step 2: 4-bromo-l-(bromomethyl)-2-methylbenzene; Hydrobromic acid (cone, 2 eq.) was added to a stirred solution of the alcohol from step 1 (1 eq.) in acetic acid (0.22M). The mixture was stirred at 50 C for 12 h, cooled down to room temperature, poured in water and extracted with Et2O. The organic extract was washed with <n="25"/>water, aqueous sodium hydrogen carbonate (3x), brine, dried over MgSO4, filtered and concentrated to afford the desired benzyl bromide as a light yellow solid.
	With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 3h;	To a solution of (4-bromo-2-methylphenyl)methanol 132 (4 g) in DCM was added PBr3 (5.42 g) at 0 C. The mixture was stirred for 3 h at room temperature. DCM was added and washed with water and aq NaHC03 until pH ~ 7. The organic layer was separated, dried over Na2S04, and concentrated under reduced pressure to give 4-bromo- l -(bromomethyl)-2- methylbenzene 133 as a brown oil (3.8 g). The compound was used in the next reaction without further purification. ? NMR (400 MHz, CDC13) ppm: 7.37 (s, 1 H), 7.34 (d, J= 8 Hz, 1 H), 7.20 (d, J= 8 Hz, 1 H), 4.48 (s, 2H), 2.41 (s, 3H).

Reference： [1]Patent: WO2008/18827,2008,A1 .Location in patent: Page/Page column 61-62
[2]Patent: WO2010/15652,2010,A2 .Location in patent: Page/Page column 36
[3]Patent: WO2017/34990,2017,A1 .Location in patent: Page/Page column 41
[4]Patent: WO2015/89337,2015,A1 .Location in patent: Paragraph 0653
[5]Patent: US6359135,2002,B1 .Location in patent: Page column 122
[6]Patent: US6369261,2002,B1 .Location in patent: Page column 120
[7]Patent: US6369225,2002,B1 .Location in patent: Page column 44, 121
[8]Patent: WO2006/18725,2006,A1 .Location in patent: Page/Page column 164
[9]Patent: US6313107,2001,B1
[10]Patent: US6252090,2001,B1
[11]Patent: WO2008/148867,2008,A2 .Location in patent: Page/Page column 39
[12]Patent: WO2009/23964,2009,A1 .Location in patent: Page/Page column 23-24
[13]Patent: WO2006/46593,2006,A1 .Location in patent: Page/Page column 194
[14]Patent: WO2013/43232,2013,A2 .Location in patent: Paragraph 00619
[15]Organic Letters,2013,vol. 15,p. 5818 - 5821
[16]Patent: WO2006/109633,2006,A1 .Location in patent: Page/Page column 168-169

10
[ 151-50-8 ]
[ 156001-49-9 ]
[ 215800-05-8 ]

Yield	Reaction Conditions	Operation in experiment
	In water; N,N-dimethyl-formamide; at 80℃; for 72h;	Step 3: (4-bromo-2-methylphenvD acetonitrile; KCN (1.4 eq.) was added to a stirred solution of the benzyl bromide in DMF (0.22M) and a small amount of water (1%). The suspension was stirred 72h at 80 C. The reaction was monitored by NMR of small aliquots. The final mixture was cooled down to room temperature, poured in water and extracted with Et2theta. The organic extract was washed with water (2x), brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with Hexane/EtOAc (5 then 10%) to give the title compound III.l as a yellow solid.

Reference： [1]Patent: WO2009/23964,2009,A1 .Location in patent: Page/Page column 24
[2]Patent: WO2006/46593,2006,A1 .Location in patent: Page/Page column 194
[3]Patent: WO2006/109633,2006,A1 .Location in patent: Page/Page column 168-169

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE XIV 4-Bromo-2-methylbenzyl bromide STR24 The title compound is obtained from 10 g (49.7 mmol) of the compound from Example XII analogously to the instructions of Example XLIX. Yield: 10.9 g (83% of theory) Rf: 0.8 (petroleum ether/ethyl acetate=10:1)

12
[ 143-33-9 ]
[ 156001-49-9 ]
[ 215800-05-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	In water; N,N-dimethyl-formamide; at 0 - 20℃;	Step c intermediate 522-(4-bromo-2-methylphenyl)acetonitrilel-Bromo-4-(bromomethyl)-3-methylbenzene (13.2 g, 50.1 mmol) is dissolved in DMF (65 mL). The reaction mixture is cooled to 0-50C and NaCN (3.66 g, 74.6 mmol) is added follow by water (8 mL). The reaction is stirred overnight at room temperature and water (170 mL) is added followed by NaHCO3 sat. (130 mL) and hexane/Et2O (2:1) (150 mL). The organic phase is separated and the aqueous phase extracted with hexane / Et2O (2:1) (3 x 150 mL). The combined organic phases are washed with water (170 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-methylphenyl)acetonitrile (9.76 g, 93 %) as an orange oil. IH NMR (300 MHz, CHLOROFORM-D): delta 7.40-7.32 (2H, m), 7.23 (2H, d, /= 8.2 Hz), 3.61 (2H, s), 2.32 (3H, s).
92.7%	In water; N,N-dimethyl-formamide; at 20℃;	To a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (3.96 g, 15 mmol) dissolved in DMF (16. mL)( were, a'dd^jspdjum cyanide (0.85 g, '17.25 mmol) and waler (1.8 ml). The reaction was sti'rred for oye'rriigh't at room temperature. To the reaction was added 1 00 ml water; 80 mL saturated NaHCO3, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3 x 100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7% yield). 1H NMR (400 MHz, CDCI3): 6 2.32 (2 H, s), 3.62 (1 H, s), 7.20-7.27 (1 H, m), 7.32-7.41 (1 H, m).

Reference： [1]Patent: WO2008/18827,2008,A1 .Location in patent: Page/Page column 61-62
[2]Patent: WO2006/18725,2006,A1 .Location in patent: Page/Page column 164

13
[ 1160431-28-6 ]
[ 156001-49-9 ]
[ 1160433-99-7 ]

Yield	Reaction Conditions	Operation in experiment
		Description 241 : 1-[6-( 2-(2-methyl-4-bromobenzyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid (D241); To a solution of Ethyl 1-[6-( 2-hydroxy-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3-carboxylate (D56g, 0.6g, 2 mmol) in CH3CN (20 ml), <strong>[156001-49-9]4-bromo-2-methylbenzyl bromide</strong> D44c (0. 647g, 2.45 mmol) and Cs2CO3 (0.79g, 2.45 mmol, 1.2 eq) were added. The mixture was refluxed for I Ohours and then poured into water, extracted with CH2CI2 and dried over Na2SO4. The organic phase was concentrated under reduced pressure to leave a yellow oil which was dissolved in EtOH (70ml )and a few drops of THF. 1 N NaOH solution was added (6ml_, 5.85 mmol) and the mixture was heated at 700C for 48hours. After evaporation of the organic solvents in vacuo, the reaction mixture was acidified to pH= 5 with 1 N HCI solution. The resulting precipitate was filtered, washed with water and dried to give the title compound as a cream powder (0.56g, 62.9%). LC/MS: 479 (M+H) Rt = 3.54 min.

Reference： [1]Patent: WO2009/71504,2009,A1 .Location in patent: Page/Page column 142

14
[ 1207618-04-9 ]
[ 156001-49-9 ]
[ 1207618-13-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With caesium carbonate; In acetonitrile; at 70℃; for 4h;	Intermediate 27: ethyl 1 -[4-(2-[(4-bromo-2-methylphenyl)methyl]oxy}-5-methylphenyl)- 1,3-thiazol-2-yl]-4-piperidinecarboxylate; To a solution of ethyl 1-[4-(2-hydroxy-5-methylphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, intermediate 9, (400 mg, 1.155 mmol), in acetonitrile (20 ml.) were added cesium carbonate (1129 mg, 3.46 mmol) and <strong>[156001-49-9]4-bromo-1-(bromomethyl)-2-methylbenzene</strong>, intermediate 13, (320 mg, 1.212 mmol). The reaction mixture was stirred at 700C for 4 hours before being cooled and filtrated. The filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography (dichloromethane/cHex 30/70 and dichloromethane) to give the title compound ethyl 1-[4-(2-[(4-bromo-2-methylphenyl)methyl]oxy}-5-methylphenyl)-1 ,3- thiazol-2-yl]-4-piperidinecarboxylate (570 mg, 1.077 mmol, 93 %) as a white solid. LCMS : (M+H)+= 530, Rt= 4.68 min. 1H NMR (CDCI3) £7.95 (d, 1 H), 7.35-7.2 (m, 3H), 7 (s, 1 H), 6.95 (dd, 1 H), 6.8 (d, 1 H), 4.9 (s, 2H), 4.1 (q, 2H), 3.95 (m, 2H), 3.05 (m, 2H), 2.45 (m, 1 H), 2.3 (s, 3H), 2.25 (s, 3H), 1.95 (m, 2H), 1.85-1.7 (m, 2H), 1.2 (t, 3H).

Reference： [1]Patent: WO2010/15652,2010,A2 .Location in patent: Page/Page column 42

15
[ 1207536-87-5 ]
[ 156001-49-9 ]
[ 1207536-94-4 ]

Yield	Reaction Conditions	Operation in experiment
66%		Description 19: Ethyl 1-(4-( 5-chloro-2-(4-bromo-2-methylbenzyloxy)-phenyl)pyrimidin- 2-yl)-5-trifluoromethyl-pyrazole-4-carboxylate (D19); To a solution of ethyl 1-(4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl)-5-trifluoromethyl- pyrazole-4-carboxylate (D14a, 1g, 2.42mmol) in acetone (80ml), was added Cs2CO3 (1.18g, 3.63mmol) and the mixture was stirred at room temperature for 15 minutes. Intermediate x (0.64g, 2.42mmol) was then added and the mixture was heated under reflux overnight, then cooled and the salts were filtered off. The filtrate was concentrated under reduced pressure and the residue was triturated with iPr2O. The resulting precipitate was filtered and dried. The title compound was obtained as a white powder (0.95g, yield= 66%). LC/MS: 597.2 (M+H), Rt= 4.48min. 1H NMR (CDCI3, ppm) : 8.8 (d, 1 H), 8.21 (bs, 2H), 8.08 (d, 1 H), 7.47 to 7.36 (m, 3H), 7.22 (d, 1 H), 7.06 (d, 1 H), 5.12 (s, 2H), 4.42 (q, 2H), 2.31 (s, 3H), 1.43 (t, 3H).

Reference： [1]Patent: WO2010/15653,2010,A1 .Location in patent: Page/Page column 49

16
[ 1207536-88-6 ]
[ 156001-49-9 ]
[ 1207536-95-5 ]

Yield	Reaction Conditions	Operation in experiment
97.7%		Description 20: Ethyl 1-(4-( 2-(4-bromo-2-methylbenzyloxy)-phenyl)pyrimidin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D20); To a solution of 2-chloro-4-(2-hydroxyphenyl)pyrimidine (D9, 2g, 5.29mmol) in acetone (80ml), was added Cs2CO3 (2.59g, 7.94mmol) and the mixture was stirred at room temperature for 15 minutes. <strong>[156001-49-9]4-bromo-2-methyl-benzyl bromide</strong> (D6n, 1.54g, 5.82mmol) was then added and the mixture was heated under reflux overnight and poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH2CI2 then CH2CI2/Me0H, 99/1 ). The title compound was obtained as a yellow oil (2.9g, yield= 97.7%). LC/MS: 562.8 (M+H), Rt= 4.26min. 1H NMR (CDCI3, ppm) : 8.8 (d, 1 H), 8.25 (s+d, 2H), 8.1 (d, 1 H), 7.55 (t, 1 H), 7.4 (m, 2H), 7.25 (d, 1 H), 7.2 (t, 1 H), 7.15 (d, 1 H), 5.15 (s, 2H), 4.4 (q, 2H), 2.35 (s, 3H), 1.4 (t, 3H).

Reference： [1]Patent: WO2010/15653,2010,A1 .Location in patent: Page/Page column 49

17
[ 1423070-80-7 ]
[ 156001-49-9 ]
[ 1423071-45-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetone; at 20℃; for 16h;	A mixture of 1-59 (1.3 mmol, 0.44 -g), R-58 (1.6 mmol, 0.42 g), and Cs2C03 (2.6 mmol, 0.86 g) is dissolved in acetone (10 mL) and stirred at ambient temperature for 16 h. The mixture is filtered and then concentrated under reduced pressure to give title intermediate which is used without further purification.

Reference： [1]Patent: WO2013/25425,2013,A1 .Location in patent: Page/Page column 104

18
potassium cyanide [ No CAS ]
[ 156001-49-9 ]
[ 215800-05-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; In dichloromethane; water; at 0 - 20℃; for 16h;	To a solution of 4-bromo- l -(bromomethyl)-2-methylbenzene 133 (3.8) in a mixture of DCM and water was added TBAB and KCN (2.94 g) at 0 C. The mixture was stirred for 16 h at room temperature. DCM was added and the mixture was washed with water and saturated aq NaHCCh. The organic layer was separated, dried over Na2S04, and concentrated under reduced pressure to afford 2-(4-bromo-2-methylphenyl)acetonitrile 134 as a brown solid (2.9 g). The compound was used in the next reaction without further purification. LCMS: m/z 210 (M+l )+.

Reference： [1]Patent: WO2013/43232,2013,A2 .Location in patent: Paragraph 00620

19
[ 68837-59-2 ]
[ 156001-49-9 ]

Reference： [1]Patent: WO2013/43232,2013,A2
[2]Organic Letters,2013,vol. 15,p. 5818 - 5821

20
[ 99548-55-7 ]
[ 156001-49-9 ]

Reference： [1]Patent: WO2013/43232,2013,A2

21
[ 156001-49-9 ]
[ 958646-47-4 ]

Reference： [1]Patent: WO2013/43232,2013,A2
[2]Patent: WO2006/109633,2006,A1

22
[ 156001-49-9 ]
[ 1261653-82-0 ]

Reference： [1]Patent: WO2013/43232,2013,A2

23
[ 156001-49-9 ]
[ 1428761-11-8 ]

Reference： [1]Patent: WO2013/43232,2013,A2

24
[ 156001-49-9 ]
[ 1428761-12-9 ]

Reference： [1]Patent: WO2013/43232,2013,A2

25
[ 156001-49-9 ]
[ 57260-71-6 ]
[ 1446819-44-8 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 1986 - 2014

26
[ 156001-49-9 ]
2-(3,5-dimethoxyphenyl)-N-(3-(4-((3-methylbiphenyl-4-yl)methyl)piperazine-1-carbonyl)phenyl)acetamide [ No CAS ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 1986 - 2014

27
[ 156001-49-9 ]
1-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine [ No CAS ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 1986 - 2014

28
[ 156001-49-9 ]
t-butyl 4-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 1986 - 2014

29
[ 156001-49-9 ]
C₂₀H₂₇BrO₅ [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5818 - 5821

30
[ 156001-49-9 ]
C₂₁H₂₉BrO₆ [ No CAS ]
C₂₁H₂₉BrO₆ [ No CAS ]
C₂₁H₂₉BrO₆ [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5818 - 5821

31
[ 156001-49-9 ]
[ 603-35-0 ]
((4-bromo-2-methylphenyl)methyl)triphenylphosphonium bromide [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5818 - 5821

32
[ 1375107-47-3 ]
[ 156001-49-9 ]
[ 1534374-11-2 ]

Yield	Reaction Conditions	Operation in experiment
463 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 4-cyclopropyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.398 g) in DMF (5 mL) was added 4-bromo-l-(bromomethyl)-2-methylbenzene (0.5 g) and anhydrous potassium carbonate (0.524 g). The reaction flask was capped with needle septa ventilation and stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure to afford the crude title product (463 mg), which was used without further purification. MS(ES)+ m/e 394.7 [M+H]+.

Reference： [1]Patent: WO2014/8223,2014,A2 .Location in patent: Page/Page column 158

33
[ 156001-49-9 ]
1-(4-[(2S)-2-amino-3-hydroxy-2-methylpropoxy]methyl}-3-methylphenyl)-4-(4-methylphenyl)butan-1-one hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

34
[ 156001-49-9 ]
C₃₃H₄₄NO₈P [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

35
[ 156001-49-9 ]
C₂₃H₃₁NO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

36
[ 156001-49-9 ]
C₂₈H₃₉NO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

37
[ 156001-49-9 ]
C₃₁H₄₃NO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

38
[ 156001-49-9 ]
C₂₇H₃₅NO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

39
[ 156001-49-9 ]
(2R)-2-amino-2-methyl-3-({2-methyl-4-[4-(4-methylphenyl)butanoyl]benzyl}oxy)propyl dihydrogen phosphate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

40
[ 156001-49-9 ]
[ 219567-09-6 ]
C₂₀H₃₀BrNO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Sodium hydride (60%, 0.6 g, 13 mmol) was added to a solution of methyl (2R,4R)-2-tert-butyl-4-(hydroxymethyl)-4-methyl-1,3-oxazolidine-3-carboxylate (13) (3.0 g, 13 mmol) in DMF (30 mL) at 0 C. The reaction mixture was stirred for 10 min, at which time 4-bromo-3-chlorobenzylbromide (5.5 g, 20 mmol) was added. The resulting mixture was warmed to ambient temperature and then stirred for 2 h. The reaction mixture was added to saturated aq NH4Cl (50 mL). The resulting biphasic mixture was poured into water and extracted with AcOEt (50 mL × 2). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography (hexane/AcOEt = 1:0 to 4:1)

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4246 - 4256

41
[ 1361941-18-5 ]
[ 156001-49-9 ]
5-(4-bromo-2-methylbenzyl)-2-cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		[01 69j To a mixture of 2-cyclopropyl-4H-thieno [2,3 -c]pyrrol-6(5H)-one (150 mg, 0.8 mmol) in dry DMF (6 ml) was added 60% NaH (50 mg, 1.3 mmol) at 0 C. The mixture was stirred at rt for 10 mm after which 4-bromo- 1 -(bromomethyl)-2-methylbenzene (264 mg, 1.0 mmol) was added. The mixture was stirred at rt for 1 h. Then the reaction was quenched by water (5 mL) and diluted EtOAc (100 mL), washed by brine (40 mL). The organic phase was dried and concentrated to give a crude residue which was purified by silica gel column chromatography (petroleum ether/EtOAc, 8:1 to 5:1) to give the compound 5 -(4-bromo-2-methylbenzyl)-2- cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one (35 mg, yield: 12%) as a light yellow solid. ESIMS (M+H): 362.1.

Reference： [1]Patent: WO2015/89337,2015,A1 .Location in patent: Paragraph 0169

42
[ 1361941-18-5 ]
[ 156001-49-9 ]
2-cyclopropyl-5-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one [ No CAS ]

Reference： [1]Patent: WO2015/89337,2015,A1

43
[ 156001-49-9 ]
1-(4-bromo-2-methylbenzyl)-4-isobutylpiperazin-2-one [ No CAS ]

Reference： [1]Patent: WO2015/89337,2015,A1

44
[ 76003-29-7 ]
[ 156001-49-9 ]
tert-butyl 4-(4-bromo-2-methylbenzyl)-3-oxopiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		[0654j To a solution of tert-butyl 3 -oxopiperazine- 1 -carboxylate (1.2 g, 6.0 mmol) in THF (200 mL) was added NaH (320 mg, 8.1 mmol) with ice-bath cooling. After stirring at 0 C for 1 h, a solution of <strong>[156001-49-9]4-bromo-1-(bromomethyl)-2-methylbenzene</strong> (1.42 g, 5.4 mmol) in THF (5 mL) was added dropwise over a period of 10 mm, the ice-bath was removed and the mixture was stirred at rt for 2 h. The mixture was diluted with ice-water (50 mL) and extracted with EtOAc (100 mL x 2) and the combined organic phases were washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford a residue which was purified by silica gel column (petroleum ether/EtOAc = 5:1) to give tert-butyl 4-(4-bromo-2-methylbenzyl)-3-oxopiperazine- 1- carboxylate (1.6 g, yield: 77%) as white solid. ESI-MS (M+H-56) : 327.0. ?H NMR (400 MHz, CDC13) 5: 7.34 (s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 4.61 (s, 2H), 4.16 (s, 2H), 3.60 (t,J= 5.2 Hz, 2H), 3.24 (t,J= 5.2 Hz, 2H), 2.27 (s, 3H), 1.47 (s, 9H).

Reference： [1]Patent: WO2015/89337,2015,A1 .Location in patent: Paragraph 0654

45
8-cyclopropyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one [ No CAS ]
[ 156001-49-9 ]
4-[(4-bromo-2-methylphenyl)methyl]-8-cyclopropyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		4-[(4-bromo-2-methylphenyl)methyl]-8-cyclopropyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one In a 100-mL round bottom flask with magnetic stir bar, 8-cyclopropyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one (540 mg, 2.44 mmol, 1.00 equiv) was dissolved in N,N-dimethylformamide (10 mL), to which was added sodium hydride (216 mg, 5.40 mmol, 2.21 equiv, 60%) in portions at 0 C. The mixture was stirred at 0 C. for 10 min and was added by <strong>[156001-49-9]4-bromo-1-(bromomethyl)-2-methylbenzene</strong> (853.6 mg, 3.23 mmol, 1.32 equiv) slowly at 0 C. The reaction mixture was warmed up to room temperature and stirred for 1 h at room temperature. When the reaction was done, it was quenched by the addition of 20 mL sat. NH4Cl solution and the mixture was extracted with ethyl acetate (3*50 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (1% to 20% gradient) to afford 4-[(4-bromo-2-methylphenyl)methyl]-8-cyclopropyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one (900 mg, 90%) as white solid. MS: m/z=404.0 [M+H]+

Reference： [1]Patent: US2016/96834,2016,A1 .Location in patent: Paragraph 0769

46
[ 1160431-42-4 ]
[ 156001-49-9 ]
[ 1160431-71-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With caesium carbonate; In acetone; at 70℃; for 16h;	To a solution of ethyl 1 -(6-(3, 5-difluoro-2-hydroxyphenyl)pyridi n-2-yl)piperidine-4-carboxylate (5 g, 13.80 mmol) in acetone (lOOmL) were added cesium carbonate (8.99g, 27.6mmol) and <strong>[156001-49-9]4-bromo-1-(bromomethyl)-2-methylbenzene</strong> (5.46 g, 20.70 mmol). The reaction mixture was stirred at 70 C for l6hrs, then cooled and diluted with water (100 mL). After extraction with EtOAc (3xlOOmL), the organic phase was washed with brine solution (100 mL), dried over anhydrous Na2504 and concentrated under reduced pressure to afford the title compound (6 g, 68.0 % yield).LCMS (a): Rt: 3.48 mi MIz = 545.24 (M+H)

Reference： [1]Patent: WO2016/42536,2016,A1 .Location in patent: Page/Page column 26

47
[ 156001-49-9 ]
ethyl 1-(6-(2-((4-(1-(2-(1H-1,2,4-triazol-1-yl)acetyl)piperidin-4-yl)-2-methylbenzyl)oxy)-3,5-difluorophenyl)pyridin-2-yl)piperidine-4-carboxylate [ No CAS ]