[ CAS No. 78471-43-9 ] {[proInfo.proName]}

Name: 78471-43-9|Methyl 4-bromo-2-bromomethylbenzoate|97%
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3d Animation Molecule Structure of 78471-43-9

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Quality Control of [ 78471-43-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 78471-43-9 ]

SDS Specification

Alternatived Products of [ 78471-43-9 ]

Product Details of [ 78471-43-9 ]

CAS No. :	78471-43-9	MDL No. :	MFCD04114319
Formula :	C₉H₈Br₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SGFACFBLUAWICV-UHFFFAOYSA-N
M.W :	307.97	Pubchem ID :	22031079
Synonyms :

Calculated chemistry of [ 78471-43-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	58.26
TPSA :	26.3 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) :	-6.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.7
Log Po/w (XLOGP3) :	3.02
Log Po/w (WLOGP) :	2.98
Log Po/w (MLOGP) :	3.39
Log Po/w (SILICOS-IT) :	3.39
Consensus Log Po/w :	3.1

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.8
Solubility :	0.0493 mg/ml ; 0.00016 mol/l
Class :	Soluble
Log S (Ali) :	-3.24
Solubility :	0.178 mg/ml ; 0.000579 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.57
Solubility :	0.00833 mg/ml ; 0.000027 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.09

Safety of [ 78471-43-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P260-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P406-P405	UN#:	3261
Hazard Statements:	H314-H290	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 78471-43-9 ]

* 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 [ 78471-43-9 ]
Downstream synthetic route of [ 78471-43-9 ]

[ 78471-43-9 ] Synthesis Path-Upstream 1~8

1
[ 99548-55-7 ]
[ 78471-43-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 2 h;	A mixture of methyl 4-bromo-2-methylbenzoate (1 g, 4.4 mmol), NBS (0.80 g, 4.4 mmol), BPO (56 mg, 0.23 mmol), and CCl₄ (20 mL) was stirred at 85 °C for 2 hours. The mixture was filtered with a pad of silica gel and concentrated to afford the desired product (1.3 g, 97percent yield).
92%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h; 250 W lamp irradiation	REFERENCE EXAMPLE 2; Methyl 4-bromo-2-(bromomethyl)benzoate; To a solution of methyl 4-bromo-2-methylbenzoate (9.60 g, 0.42 mol, obtained in reference example 1) in CCI₄ (150 mL), Λ/-bromosuccinimide (7.46g, 0.42mol) and benzoyl peroxide (0.19g, 0.79mmol) were added. The reaction mixture was stirred EPO <DP n="37"/>4h at room temperature while irradiated with a 250 Watt lamp and it was then filtered to remove the precipitated solids. The filtrate was washed with 1 N NaOH and water and it was dried over Na₂SO₄. The solvent was evaporated to afford11.87 g of the desired compound as an oil that solidified on standing (yield: 92percent, uncorrected).¹H NMR (300 MHz, CDCI₃) δ (TMS): 3.94 (s, 3 H), 4.90 (s, 2 H)₁ 7.51 (dd, J = 8.4Hz₁ J¹ = 2.1 Hz, 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H).
92%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h; Light irradiation	Reference Example 2; Methyl 4-bromo-2-(bromomethyl)benzoateTo a solution of methyl 4-bromo-2-methylbenzoate (9.60 g, 0.42 mol, obtained in reference example 1) in CCl₄(150 mL), N-bromosuccinimide (7.46 g, 0.42 mol) and benzoyl peroxide (0.19 g, 0.79 mmol) were added. The reaction mixture was stirred 4 h at room temperature while irradiated with a 250 Watt lamp and it was then filtered to remove the precipitated solids. The filtrate was washed with 1N NaOH and water and it was dried over Na₂SO₄. The solvent was evaporated to afford 11.87 g of the desired compound as an oil that solidified on standing (yield: 92percent, uncorrected).¹H NMR (300 MHz, CDCl₃) 8 (TMS): 3.94 (s, 3H), 4.90 (s, 2H), 7.51 (dd, J=8.4 Hz, J'=2.1 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H).

92%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h; Irradiation	REFERENCE EXAMPLE 2; Methyl 4-bromo-2-(bromomethyl)benzoate; To a solution of methyl 4-bromo-2-methylbenzoate (9.60 g, 0.42 mol, obtained in reference example 1) in CCI₄ (150 mL), Λ/-bromosuccinimide (7.46g, 0.42mol) and benzoyl peroxide (0.19g, 0.79mmol) were added. The reaction mixture was stirred 4h at room temperature while irradiated with a 250 Watt lamp and it was then filtered to remove the precipitated solids. The filtrate was washed with 1 N NaOH and water and it was dried over Na₂SO₄. The solvent was evaporated to afford 11.87 g of the desired compound as an oil that solidified on standing (yield: 92percent, uncorrected).¹H NMR (300 MHz, CDCI₃) δ (TMS): 3.94 (s, 3 H), 4.90 (s, 2 H), 7.51 (dd, J = 8.4 Hz, J' = 2.1 Hz, 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H).
90%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 2 h; Inert atmosphere; Reflux	Example 1295-{2-[2-Amino-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl]-3-methy1-l^^,4-tetrahydroisoquinolin-7- yll-Σ-cyclopropylisoindolin-l-oneStep I methyl 4-bromo-2-(bromomethyl)benzoate; A mixture of methyl 4-bromo-2-methylbenzoate (0.7 g, 0.003 mol), N-bromosuccinimide (0.65 g, 0 0037 mol) and benzoyl peroxide (0 038 g, 0.00016 mol) in carbon tetrachloride (30 niL) was refluxed under an atmosphere of nitrogen for 2 h. The mixture was cooled to RT, and filtered through silica gel eluting with dichloromethane followed by diethyl ether. The mixture was concentrated and the residue was purified by chromatography on silica gel with 30percent EtOAc in hexanes to afford the desired product (0.86 g, 90percent).
79%	With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane	Example 33B Methyl 4-bromo-2-(bromomethyl)benzoate A solution of Example 33A (1.02 g, 4.47 mmol) in CCl₄ (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na₂SO₄), filtered, and concentrated to provide the desired product (1.1 g, 79percent).
79%	With azobisisobutyronitrile In tetrachloromethane	Example 263B 4-Bromo-2-bromomethyl-benzoic acid methyl Ester A solution of Example 263A (1.02 g; 4.5 mmol) in CCl₄ (22 mL) was treated with AIBN (65 mg; 0.4 mmol), heated at reflux for 4 hrs., washed with water, dried (Na₂SO₄) and concentrated to provide the desired product (1.1 g; 79percent).
79%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4 h; Heating / reflux	Example 33B methyl 4-bromo-2-(bromomethyl)benzoate A solution of Example 33A (1.02 g, 4.47 mmol) in CCl₄ (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na₂SO₄), filtered, and concentrated to provide the desired product (1.1 g, 79percent).
74%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 5 h;	Step 2: Methyl 4-Bromo-2-(bromomethyl)benzoate A solution of methyl 4-bromo-2-methylbenzoate (1.0 g, 4.3 mmol) in CCl₄ was treated with N-bromosuccinimide (0.93 g, 5.2 mmol) and benzoyl peroxide (0.53 g, 2.2 mmol), heated at 85° C. for 5 h, cooled to room temperature and filtered The filtercake was washed with CCl₄ and the filtrates were combined and concentrated in vacuo to provide an oil residue. The residue was purified by ISCO CombiFlash.(R). chromatography (silica, 0-5percent ethyl acetate in hexanes) to afford the title compound, 1.59 g (74percent), MS (EI) m/z 308 [M]⁺.
74%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 5 h;	Step 2: Methyl 4-bromo-2-(bromomethyl)benzoate A solution of methyl 4-bromo-2-methylbenzoate (1.0 g, 4.3 mmol) in carbon tetrachloride was treated with N-bromosuccinimide (0.93 g, 5.2 mmol) and benzoyl peroxide (0.53 g, 2.2 mmol), heated at 85° C. for 5 h, cooled to room temperature and filtered. The filtercake was washed with methylene chloride. The combined filtrates were concentrated in vacuo. The residue was purified by ISCO CombiFlash.(R). chromatography (silica, 0-5percent ethyl acetate in hexanes) to afford 1.59 g (74percent) of methyl 4-bromo-2-(bromomethyl)benzoate as a light yellow oil. MS (EI) m/z 308 [M]⁺.
72%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 80℃;	[00528] Intermediate 51 a: methyl 4-bromo-2-(bromomethyl)benzoate [00529] A mixture of methyl 4-bromo-2-methylbenzoate (2.5g, 10.91 mmol) and NBS (1 .94g, 10.91 mmol) in acetonitrile (22mL) was degassed and AIBN (72mg, 0.44mmol) added. The mixture was stirred and heated at 80 °C overnight and then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-25percent EtOAc inheptane to give methyl 4-bromo-2-(bromomethyl)benzoate (2.44g, 7.91 mmol, 72percent) as a colourlessoil that solidified upon standing.1H NMR (CDCI3, 400MHz) O/ppm: 7.87 (1H, d, J= 8.4Hz), 7.65 (1H, d, J= 2.0Hz), 7.53 (1H, dd, J=8.4Hz, 2.0Hz), 4.92 (2H, 5), 3.96 (3H, 5).MS Method 2: RT: 1 .90 mi mlz 226.8/228.8 [M-Br]
72%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethaneInert atmosphere; Reflux	To 2-methyl-4-bromobenzoic acid methyl ester (2.995g, 12,584 mm, 1 . 0equiv) of carbon tetrachloride (40 ml) is added to solution N-bromo succinimide (2.338g, 13.2 mm, 1 . 05equiv), benzoyl peroxide (152 mg, 0 . 629 mm, 0 . 05equiv), and heated to reflux in a nitrogen atmosphere. The TLC monitoring the reaction is complete, cooling to room temperature, filtered, concentrated under reduced pressure the solvent. Column chromatography (petroleum ether: ethyl acetate = 10:1) treatment to obtain pale brown solid (2.78g, yield 72percent).
72.9%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 85℃; for 18 h;	Methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol), NBS (79.2 g, 445.27 mmol), Azo-isobutyronitrile (2.58 g, 16 mmol) in acetonitrile (600 mL) were combined and refluxed at 85 °C for 18 h. The mixture was concentrated, and to the residue was added dichloromethane (150 mL). The resultant solid was removed by filtration. The filtrate was concentrated and purified by flash column chromatography (0-4percent EtOAc in Hexanes). Fractions containing product was concentrated under reduced pressure and further dried under high vacuum to give Methyl-4-bromo-2- (bromomethyl) benzoate (100 g, 324.70 mmol, 72.9 percent yield) as an off-white solid. 1H NIVIR (300 MHz, Dimethylsulfoxide-d6) 7.88 (d, J 2.2 Hz, 1H), 7.82 (dd, J 8.4, 2.1 Hz, 1H), 7.72— 7.64 (m, 1H), 5.00 (s, 2H), 3.88 (s, 3H).
72.9%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 85℃; for 18 h;	Methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol), NBS (79.2 g, 445.27 mmol), Azo-isobutyronitrile(2.58 g, 16 mmol) in acetonitrile (600 mL) were combined and refluxed at 85°C for 18hours. The mixture was concentrated, and to the residue was added dichloromethane (150 mL). The resultant solid was removed by filtration. The filtrate was concentrated and purified by flash column chromatography (0-4percent EtOAc in Hexanes). Fractions containing product was concentrated under reduced pressure and further dried under highvacuum to give Methyl-4-bromo-2-(bromomethyl) benzoate (100 g, 324.70 mmol, 72.9percent yield) as an off-white solid. 1HNMR (300 IVIHz, Dimethylsulfoxide-d6) 7.88 (d, J2.2 Hz, 1H), 7.82 (dd, J= 8.4, 2.1 Hz, 1H), 7.72—7.64 (m, 1H), 5.00 (s, 2H), 3.88 (s,3H).
68%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 16 h;	To a solution of methyl 4-bromo-2-methylbenzoate (5.0 g, 21.83 mmol) in carbon tetrachloride (100 mL) was added BS (4.3 g, 24.01 mmol), the suspension was heated at 80 °C for 5 min, then AIBN (1.07 g, 6.55 mmol) was added. The suspension continued to stir at 80 °C for 16 h, then cooled to RT and filtered. The filtrate was concentrated to give the crude product, which was purified by silica-gel column to give methyl 4-bromo-2-methylbenzoate (4.6 g, 68percent) as a white solid.
66%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21.75 h; Heating / reflux	Step 2: A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (1 15 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1 :1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl- benzoic acid methyl ester, in 66percent yield; ¹H NMR (DMSCMs) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
66%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21 h; Reflux	A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1:1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66percent yield; ¹H NMR (DMSO-d₆) 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
66%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21.75 h; Reflux	[00408j Step 2: A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1:1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66percent yield; 1H NMR (DMSO-d6) ö 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
66%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21.75 h; Reflux	A mechanically stirred mixture of 4-bromo-2-methyl -benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1 : 1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4: 1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66percent yield; 1H MR (DMSO-i) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
62.5%	With N-Bromosuccinimide; dibenzoyl peroxide In chloroform at 100℃; for 2 h; Inert atmosphere	Methyl 4-bromo-2-(bromomethyl)benzoate To a solution of methyl 4-bromo-2-methylbenzoate (5.0 g, 21.83 mmol) in chloroform (20 mL), under nitrogen, was added NBS (3.88 g, 21.83 mmol) and benzoyl peroxide (0.264 g, 1.091 mmol). The mixture was refluxed at 100 °C for 2 h., filtered and concentrated to afford methyl 4-bromo-2-(bromomethyl)benzoate (5.0 g, 13.64 mmol, 62.5 percent yield). LC-MS: m/z 307 (M+H)⁺1.28 min (ret. time).
60%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4.08333 h; Inert atmosphere; Reflux	This intermediate (18.51 mmol) is dissolved in carbon tetrachloride (100 mL) and N-bromosuccinimide (5.57 g, 24.06 mmol) is added. AIBN (122 mg, 740 μmol) is then added and the mixture purged with nitrogen for 5 minutes. The reaction mixture is then refluxed for four hours. After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated. The residue is purified by flash chromatography (silica gel, 2:1 petroleum ether/ethyl acetate) to give the title compound (3.42 g, 60percent).
60%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4.08333 h; Heating / reflux	Step 1 4-Bromo-2-bromomethyl-benzoιc acid methyl ester <n="93"/>[00354] 4-Bromo-2-methyl-benzoic acid (4 6 g, 21 39 mmol) is dissolved in 2M HCl in MeOH and refluxed for 3 hours The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4 24 g, 86 percent) This intermediate (18 51 mmol) is dissolved m carbon tetrachloride (100 mL) and N-bromosuccinimide (NBS) (5 57 g, 24 06 mmol) is added AIBN (122 mg, 740 mol) is then added and the mixture purged with nitrogen for 5 mm The reaction mixture is then refluxed for 4 hours After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated The residue is puπfied by flash chromatography (silica gel, 2 1 petroleum ether/ethyl acetate) to give the title compound (3 42g, 60 percent)
60%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4.08333 h; Heating / reflux	4-Bromo-2-methyl-benzoic acid (4.6 g, 21.39 mmol) is dissolved in 2M HCl inMeOH and refluxed for 3 hours. The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4.24 g, 86 percent). This intermediate (18.51 mmol) is dissolved in carbon tetrachloride (100 mL) and N-bromosuccinimide (NBS) (5.57 g, 24.06 mmol) is added. AIBN (122 mg, 740 μmol) is then added and the mixture purged with nitrogen for 5 min. The reaction mixture is then refluxed for 4 hours. After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated. The residue is purified by flash chromatography (silica gel, 2:1 petroleum ether/ethyl acetate) to give the title compound (3.42g, 60 percent).
60%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18 h; Reflux	Part B:A solution of compound 2 (3S8 mg, 1.69 mmol), W-bromosuccinimide ( NBS, 302 mg,1 ,69 mmol) and benzoyl peroxide (12.3 mg, 0.05 mmol) in carbon tetrachloride (6 mL) was heated to reflux for 18 hours. LC-MS analysis indicated the reaction was complete. The reaction mixture was diluted with diethyl ether (10 mL) and passed through a plug of ceSite to remove precipitates. The filtrate was washed with saturated NaHCO₃, dried over magnesium sulfate, concentrated and purified by flash column chromatography, gradient elution (0 to 100 percent) hexane / ethyl acetate, to afford compound 3 as a colorless oil (310 mg, 60 percent yield). HPLC-MS t_R = 2.00 min (UV₂₅₄ n_m); mass calculated for formula C₉H₈Br₂O₂ SOS-Q, observed LCMS m/z 306.9 (M+H).
41%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 5 h;	Step 2. To a solution of 28 (1.0 g, 4.37 mmol) and NBS (0.93 g, 5.24 mmol) in CC14 (10 mL) was added BPO (106 mg, 0.44.00 mmol). The reaction mixture was stirred at 80°C for 5 h. Upon completion, the reaction was quenched with H20 (10 mL) and extracted with ethyl acetate (3 x 20 mL). The the organic layer was washed with H20 (3 x 10 mL), concentrated, and purified by prep-TLC (petroleum : ethyl acetate = 20: 1) to afford 29 (610 mg, 41percent).
37.5%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h;	To a stirring solution of methyl 4-bromo-2-methylbenzoate (600 mg, 2.62 mmol) in carbon tetrachloride (70 mL) was added /V-bromo succinimide (466 mg, 2.62 mmol) and benzoyl peroxide (12 mg) and the resultant reaction mixture was stirred in presence of sodium lamp at RT for 4 h. The reaction mixture was filtered through celite and washed with 2N sodium hydroxide solution, dried over sodium sulphate and concentrated under reduced pressure to afford Methyl 4-bromo-2-(bromomethyl)benzoate as a solid (300 mg, 37.5percent).
1.8 g	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethaneInert atmosphere; Reflux	Synthesis of methyl 4-bromo-2-(bromomethyl)benzoate (46): A solution of methyl 4-bromo-2-methylbenzoate 45 (2000 mg, 8.77 mmol), N-bromosuccinimide (NBS) (3035 mg, 17.54 mmol), benzoyl peroxide (BPO) (1061 mg, 4.39 mmol) in CC1₄ (20 mL) was refluxed overnight under nitrogen atmosphere. After cooling to room temperature, the mixture was washed with brine (20 mL X 2) and dried over anhydrous Na₂S0₄. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (2-5percent EtO Ac/petroleum ether) to give methyl 4-bromo-2- (bromomethyl)benzoate 46 as a white solid (yield: 1.8 g, 67percent). LCMS: m/z 308.7 [M+H]⁺; t_R = 1.88 min.
75 g	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20 - 60℃; for 4 h; Irradiation	To a solution of 6D (50 g, 0.22 mol) in CC14 (750 mL) was added N-bromosuccinimide(38.9 g, 0.22 mol) and benzoyl peroxide(1.1 g, 4.4 mmol) at room temperature. The reaction mixture was stirred 4 hr at 60 °C while irradiatedwith a 250 watt lamp. The mixturewas cooled to room temperature, washedwith 1 M aq. NaOH, water, and dried over Na2S04.The solvent wasevaporated to afford the crude 6E (75g) as oil ' which wastaken to next step directly.
33.1 g	at 80℃; for 18 h; Inert atmosphere	To a mixture of methyl 4-bromo-2-methylbenzoate (25.0 g) and (trifluoromethyl)benzene (400 mL) were slowly added N-bromosuccinimide (19.4 g) and 2,2′-azobis(isobutyronitrile) (1.79 g) at room temperature. The mixture was heated under reflux under nitrogen atmosphere at 80° C. for 18 hr, and cooled to room temperature. The insoluble substance was filtered off, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.1 g). (1065) ¹H NMR (300 MHz, DMSO-d₆) δ 3.87 (3H, s), 4.99 (2H, s), 7.65-7.73 (1H, m), 7.78-7.84 (1H, m), 7.89 (1H, d, J=2.3 Hz)

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1324 - 1328
[2] Patent: WO2018/68017, 2018, A1, . Location in patent: Page/Page column 126
[3] Patent: WO2007/339, 2007, A1, . Location in patent: Page/Page column 35-36
[4] Patent: US2010/222363, 2010, A1, . Location in patent: Page/Page column 13
[5] Patent: WO2007/337, 2007, A1, . Location in patent: Page/Page column 30
[6] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 184
[7] Patent: US2003/187026, 2003, A1,
[8] Patent: US2003/187026, 2003, A1,
[9] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 26; 77
[10] Patent: US2009/69300, 2009, A1, . Location in patent: Page/Page column 33
[11] Patent: US2009/69370, 2009, A1, . Location in patent: Page/Page column 18
[12] Patent: WO2016/51193, 2016, A1, . Location in patent: Paragraph 00527; 00528; 00529
[13] Patent: CN105315283, 2016, A, . Location in patent: Paragraph 0094; 0097; 0098
[14] Patent: WO2017/120446, 2017, A1, . Location in patent: Paragraph 00465
[15] Patent: WO2017/120422, 2017, A1, . Location in patent: Paragraph 00376; 00388
[16] Patent: WO2018/169777, 2018, A1, . Location in patent: Paragraph 0267
[17] Patent: WO2008/27542, 2008, A2, . Location in patent: Page/Page column 90
[18] Patent: WO2015/200795, 2015, A1, . Location in patent: Paragraph 00389
[19] Patent: WO2016/57503, 2016, A1, . Location in patent: Paragraph 00408
[20] Patent: WO2017/117118, 2017, A1, . Location in patent: Paragraph 00472
[21] Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 492 - 503
[22] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 571
[23] Patent: US2009/286798, 2009, A1, . Location in patent: Page/Page column 28-29
[24] Patent: WO2007/131991, 2007, A1, . Location in patent: Page/Page column 90-91
[25] Patent: WO2007/138072, 2007, A2, . Location in patent: Page/Page column 82
[26] Patent: WO2009/158369, 2009, A1, . Location in patent: Page/Page column 39
[27] Patent: WO2018/49328, 2018, A1, . Location in patent: Page/Page column 35; 36
[28] Patent: WO2011/134468, 2011, A1, . Location in patent: Page/Page column 132
[29] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 999 - 1004
[30] Patent: WO2006/63167, 2006, A1, . Location in patent: Page/Page column 32-33
[31] Patent: US2003/114448, 2003, A1,
[32] Patent: US6162808, 2000, A,
[33] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1628 - 1631
[34] Patent: EP1382603, 2004, A1, . Location in patent: Page 217
[35] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 18, p. 5310 - 5313
[36] Patent: US2007/49603, 2007, A1, . Location in patent: Page/Page column 91
[37] Patent: WO2006/48727, 2006, A1, . Location in patent: Page/Page column 80
[38] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9434 - 9445
[39] Patent: WO2014/28968, 2014, A1, . Location in patent: Page/Page column 63
[40] Patent: WO2014/152738, 2014, A1, . Location in patent: Page/Page column 113; 114
[41] Patent: WO2014/146491, 2014, A1, . Location in patent: Page/Page column 100
[42] Journal of Organic Chemistry, 2014, vol. 79, # 23, p. 11592 - 11608
[43] Patent: WO2015/3166, 2015, A1, . Location in patent: Paragraph 00413
[44] Patent: WO2015/81891, 2015, A1, . Location in patent: Page/Page column 136
[45] Patent: WO2016/61751, 2016, A1, . Location in patent: Page/Page column 61
[46] Patent: US2017/15655, 2017, A1, . Location in patent: Paragraph 1064-1065
[47] Patent: WO2018/2437, 2018, A1, . Location in patent: Page/Page column 81
[48] Patent: WO2018/140809, 2018, A1, . Location in patent: Paragraph 00391

2
[ 99548-55-7 ]
[ 7440-33-7 ]
[ 78471-43-9 ]

Reference： [1] Patent: US5721193, 1998, A,

3
[ 68837-59-2 ]
[ 78471-43-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 999 - 1004
[2] Patent: WO2011/134468, 2011, A1,
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9434 - 9445
[4] Patent: WO2014/28968, 2014, A1,
[5] Journal of Organic Chemistry, 2014, vol. 79, # 23, p. 11592 - 11608
[6] Patent: WO2015/3166, 2015, A1,
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1324 - 1328
[8] Patent: WO2015/92713, 2015, A1,
[9] Patent: WO2015/200795, 2015, A1,
[10] Patent: CN105315283, 2016, A,
[11] Patent: US2017/15655, 2017, A1,
[12] Patent: WO2016/57503, 2016, A1,
[13] Patent: WO2017/120446, 2017, A1,
[14] Patent: WO2017/117118, 2017, A1,
[15] Patent: WO2017/120422, 2017, A1,
[16] Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 492 - 503
[17] Patent: WO2018/49328, 2018, A1,
[18] Patent: WO2007/138072, 2007, A2,
[19] Patent: WO2009/158369, 2009, A1,

4
[ 74-89-5 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	at 50℃; Sealed tube	[00530] Intermediate 51 b: 5-bromo-2-methyl-isoindolin-1 -one[00531] To a reaction tube containing methyl 4-bromo-2-(bromomethyl)benzoate (1 .2g, 3.gmmol) was added methylamine (2.OM in THF, lOmL, 2Ommol). The tube was sealed and the mixture was stirred and heated at 50 °C overnight. The mixture was then cooled to room temperature, filtered and the precipitate washed with THF. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography using an eluent of 0-100percent EtOAc in heptane to give 5-bromo-2- methyl-isoindolin-1-one (623mg, 2.7Smmol, 71percent yield) as a white solid.1H NMR (CDCI3, 400MHz) O/ppm: 7.73-7.68 (1H, m), 7.64-7.56 (2H, m), 4.36 (2H, 5), 3.19 (3H, 5). MS Method 3: RT: 3.18 mi m/z226.0/228.0 [M+H]
68%	With triethylamine In tetrahydrofuran at 100℃; for 12 h; Sealed tube	Synthesis of 5-bromo-2-methylisoindolin-1-one (2) A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (1, 1 g, 3.26 mmol), 2 M methylamine in tetrahydrofuran (1.95 mL, 3.9 mmol) and triethylamine (0.9 mL, 6.52 mmol) was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with water. The organic was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane to afford 5-bromo-2-methylisoindolin-1-one (2). Yield: 0.5 g, 68percent; MS (ESI) m/z 226, 228 [M+1]⁺.
0.112 g	at 90℃; for 24 h;	Step A: 5-bromo-2-methylisoindolin-l-one [0234] Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90°C) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). ^lU NMR (500 MHz, CDC1₃) δ ppm 3.19 (s, 3 H), 4.36 (s, 2 H), 7.57 - 7.62 (m, 2 H), 7.70 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]⁺ 226.3.

Reference： [1] Patent: WO2016/51193, 2016, A1, . Location in patent: Paragraph 00527; 00530; 00531
[2] Patent: US10112955, 2018, B2, . Location in patent: Page/Page column 29
[3] Patent: WO2013/148603, 2013, A1, . Location in patent: Paragraph 0233-0234
[4] Patent: EP3406612, 2018, A1, . Location in patent: Paragraph 0086; 0087

5
[ 124-40-3 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Reference： [1] Patent: WO2010/128324, 2010, A1, . Location in patent: Page/Page column 119

6
[ 78471-43-9 ]
[ 868066-91-5 ]

Reference： [1] Patent: WO2014/28968, 2014, A1,
[2] Patent: WO2015/92713, 2015, A1,

7
[ 78471-43-9 ]
[ 552330-86-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With ammonia In methanol; water for 18 h;	[0189] 4-Bromo-2-bromomethyl-benzoic acid methyl ester (3.70g) was suspended in 2M NH3 in MeOH (36mL) and concentrated ammonium hydroxide (12mL) for eighteen hours. The solid product was filtered to provide the title compound as a colourless solid (2.3 Og, 90percent). ^.H NMR (300MHz, CDCI3): 6 7.68 (m, 3H), 4.44 (s, 2H).
87%	With ammonium hydroxide In 1,4-dioxane at 20℃; for 3 h;	A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (3 g, 9.74 mmol, 1.0 equiv) and ammonium hydroxide (30 mL, 30percent) in 1 ,4-dioxane (250 mL) was stirred for 3 h at 20°C. The resulting mixture was concentrated under vacuum. The crude product was purified by recrystallization from ethyl acetate to afford the title compound (1.8, 87percent) as a white solid.
81%	With ammonia In tetrahydrofuran; methanol at 20℃; for 4 h;	4-Bromo-2-bromomethyl-benzoic acid methyl ester was prepared according to literature. A solution of 4-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 4 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in water, filtered, then sonicated in diethylether and filtered to give the desired product as a white solid.5-Bromo-2,3-dihydro-isoindol-l-one: (81 percent yield, 100 percent purity) m/z (LC-MS, ESP): 212.3/214.3 [M+H]⁺ R/T = 3.06 min

72%	With ammonia In methanol at 40℃; for 18 h;	Combine 4-bromo-2-bromomethyl-benzoic acid methyl ester (3.0 g, 9.7 mmol) and 7M NH3 in methanol (100 mL, 700 mmol) in a sealed tube and heat in a 40°C oil bath for 18 hours. Cool the resulting suspension to room temperature and filter to obtain 1.5 g of 5-bromo-2, 3-dihydro-isoindol-1-one (72 percent). Combine 5-bromo-2, 3-dihydro-isoindol-1-one (1. 1 g, 5.0 mmol), bis- pinocalatodiboron (1.4 g, 5.5 mmol), [1, l'-Bis (diphenylphosphino) - ferocene] dichloropaladium (II) complex with dichloromethane (408 mg, 0.5 mmol) and potassium acetate (1.5 g, 15.0 mmol) in a 200 mL flask with a septum. Add dimethyl sulfoxide (27 mL) and heat in a 90°C oil bath for 18 hours. Cool the resulting slurry to room temperature and dilute with water (100 mL). Extract the resulting slurry with dichloromethane (3 x 75 mL). Wash the combined organic layers with brine (40 mL), dry (Na2S04), filter and concentrate in vacuo to obtain 1.6 g of a mixture of the title product and bis-pinocalatodiboron (1: 0.05), which is used without further purification.
72%	at 85℃; for 36 h;	Step B: 5-bromoisoindolin-1-one: Methyl 4-bromo-2-(bromomethyl)benzoate (5.00 g, 16.2 mmol) in NH₃(34.8 mL, 244 mmol) was heated in a bomb-reactor at 85° C. for 36 hours, then cooled and concentrated to a solid. The solid was triturated with ethyl acetate, filtered and concentrated to a light brown solid. The mother liquor was concentrated and purified by silica gel chromatography using 1-5percent MeOH/dichloromethane to provide additional product (2.5 g, 72percent).
72%	Stage #1: With ammonia In methanol at 0℃; for 0.166667 h; Stage #2: With ammonium hydroxide In methanol at 20℃; for 16 h;	Ammonia gas was purged to a stirring solution of methyl 4-bromo-2- (bromomethyl)benzoate (200 mg, 0.649 mmol) in methanol at 0 °C for 10 min. To the resulting reaction mixture ammonium hydroxide (0.5 mL) was added and the reaction mixture was stirred at RT for 16 h. The obtained solid was separated by filtration and dried to afford 5-Bromoisoindolin-l-one as a solid (100 mg, 72percent).
72%	With ammonia In methanol at 20℃;	General procedure: Methyl 4-bromo-2-methylbenzoate (19.90 g, 86.9 mmol) was dissolved in benzene (200 mL), to which was added N-bromosuccinimide (18.56 g, 100 mmol) and 2,2’-azobis(2-methylpropionitrile) (1.43 g, 8.69 mmol). This mixture was heated at 80°C overnight then upon cooling, filtered and the filtrate diluted with Et20 (300 mL). This solution was washed with sat.sodium metabisuiphite solution (which was also back-extracted with 2x50 mL Et20), then all Et20 fractions combined and washed with brine (150 mL), dried (Na2SO4) and filtered. The solvent was removed under reduced pressure to yield an oil which was purified by filtration through a plug of silica (5percent EtOAc/hexanes as eluant), giving an oil which solidified to a white solid under vacuum. ‘H NMR shows this material to be 93percent thedesired bromide, along with 7percent unreacted starting material and a trace of dibromide (total of 26.7 g). This solid was dissolved in MeOH (500 mL) and NH3 (g) bubbled through the solution until saturated. This mixture was stirred overnight at room temperature then all solvent removed under reduced pressure. The resulting solid was suspended and stirred in Et20 (200 mL), then collected by filtration. This procedure was repeated, but using waterand the solid again collected by filtration and dried under vacuum. The title compound was isolated as a crystalline cream solid (13.30 g, 72percent). ‘H NMR [400 MHz, (CD3)2S01 6 8.59 (br s, 1 H), 7.83 (dd, J = 1.5, 0.6 Hz, 1 H), 7.66 (dd, J = 8.0, 1.7 Hz, 1 H), 7.59 (d, J 8.1 Hz, I H), 4.37 (s, 2 H). LRMS (APCI) calcd for C8H6BrNO 212, 214 (MH), found 212,214.
72.6%	Inert atmosphere; Sealed tube	5-Bromoisoindolin-1 -one A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (5.0 g, 16.24 mmol) and NH4OH (21.07 mL, 162 mmol) under nitrogen was sealed and stirred overnight. The reaction was then filtered to afford 5-bromoisoindolin-1-one (2.5 g, 1 1.79 mmol, 72.6 percent yield). LC-MS: m/z 212 (M+H)⁺0.98 min (ret. time).
65%	With ammonia In methanol at 90℃; for 0.0833333 h;	Step 2: 5-Bromo-2,3-dihydro-isoindol-1-one 4-Bromo-2-bromomethyl-benzoic acid methyl ester (0.5 g, 16.2 mmol) is treated with methanolic ammonia (10 mL, 7 N NH₃ in MeOH) for 5 minutes at 90° C. After cooling to room temperature the precipitate formed is filtered off and washed with a small amount of methanol affording the title compound (224 mg, 65percent) as a colourless solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm) 4.41 (s, 2H, CH₂), 7.64 (d, 1H, H_ar), 7.70 (d, 1H, H_ar), 7.87 (s, 1H, H_ar), 8.67 (bs, 1H, NH). LCMS 99.6percent, Rt=2.49 min, m/z 212 (M+H, AP⁺ formic acid).
65%	With ammonia In methanol at 90℃; for 0.0833333 h;	4-Bromo-2-bromomethyl-benzoic acid methyl ester (0.5g, 16.2mmol) is treated with methanolic ammonia (1OmL, 7 N NH₃ in MeOH) for 5 minutes at 9O⁰C. After cooling to room temperature a precipitate is formed, collected by filtration and washed with a small amount of methanol to afford the title compound as a colourless solid (224mg, 65percent). ¹H-NMR (400MHz, dζ- DMSO) δ(ppm) 4.41 (2H, s), 7.64 (IH, d), 7.70 (IH, d), 7.87 (IH, s), 8.67 (IH, br s). LCMS: Rt 2.49min, (99.6percent), m/z (APCI) 212 (M+H)⁺.
61%	With ammonium hydroxide; ammonia In methanol at 20℃;	Step A: 5-bromoisoindolin-l-one [0229] Methyl 4-bromo-2-(bromomethyl)benzoate (0.157 g, 0.510 mmol) was suspended in ammonia (2M solution in MeOH, 0.255 mL, 1.784 mmol). Ammonium hydroxide (0.517 mL, 7.65 mmol) was added and the mixture was stirred at RT overnight. A resulting white solid was collected by vacuum filtration, washed with water, and dried under high vacuum overnight to give the title compound as a white solid (0.066 g, 61percent). 1H NMR (500 MHz, CDC1₃) δ ppm 4.45 (s, 2 H), 6.35 (br s, 1 H), 7.60 - 7.68 (m, 2 H), 7.74 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]⁺ 212.3.
52%	With ammonia In tetrahydrofuran; methanol at 20℃; for 24 h;	Example 33C 5-bromoisoindolin-1-one A solution of Example 33B (1.1 g, 3.57 mmol) in THF (20 mL) at room temperature was treated with 1N NH₃ in methanol (7.14 mL, 7.14 mmol), stirred for 24 hours, and filtered. The filter cake was washed with diethyl ether (100 mL) to provide the desired product (0.4 g, 52percent).
35 g	With ammonium hydroxide; ammonia In methanol at 20℃;	The crude 6E (75 g) wassuspended in NH3/MeOH(2M,750mL)andconcentrated ammonium hydroxide (250 mL) at room temperature for overnight. The mixture was filtered and the filter cake was dried in vacuo to give 6F (35 g, 75percent for two steps)as white solid. 1H-NMR (400MHz,DMSO_d6): 8.64-8.66(s, IH), 7.83(s,IH),7.66-7.68(d, IH), 7.59-7.6l(s,IH), 4.37(s, 2H

Reference： [1] Patent: WO2006/20879, 2006, A1, . Location in patent: Page/Page column 66-67
[2] Patent: WO2015/52264, 2015, A1, . Location in patent: Paragraph 0637; 0638
[3] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 121
[4] Patent: WO2005/73205, 2005, A1, . Location in patent: Page/Page column 25
[5] Patent: US2007/49603, 2007, A1, . Location in patent: Page/Page column 91-92
[6] Patent: WO2011/134468, 2011, A1, . Location in patent: Page/Page column 132
[7] Patent: WO2014/28968, 2014, A1, . Location in patent: Page/Page column 63
[8] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 571
[9] Patent: US2009/286798, 2009, A1, . Location in patent: Page/Page column 28-29
[10] Patent: WO2007/138072, 2007, A2, . Location in patent: Page/Page column 82
[11] Patent: WO2013/148603, 2013, A1, . Location in patent: Paragraph 0228-0229
[12] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 26
[13] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 140
[14] Patent: WO2015/81891, 2015, A1, . Location in patent: Page/Page column 136; 137
[15] Patent: WO2008/65199, 2008, A1, . Location in patent: Page/Page column 75

8
[ 78471-43-9 ]
[ 376584-62-2 ]

Reference： [1] Patent: WO2011/134468, 2011, A1,
[2] Patent: WO2013/148603, 2013, A1,
[3] Patent: WO2007/138072, 2007, A2,
[4] Patent: WO2008/65199, 2008, A1,

[ 78471-43-9 ] Synthesis Path-Downstream 1~30

1
[ 24666-56-6 ]
[ 78471-43-9 ]
[ 1010100-26-1 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;	1 To a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1a, 15 g, 48.7 mmol) in DMF (150 mL) was added 3-aminopiperidine-2,6-dione-HCl (Ib, 6.9 g, 53.6 mmol) and K2CO3 (20.2 g, 146.1 mmol). The resulting mixture was heated at 70° C. for 16 h after which time the reaction mixture was cooled to rt and then concentrated to dryness. To the resulting residue, water was added and the mixture stirred at rt for 30 min. The resultant solid was filtered and washed with ether and ethyl acetate. The solid was dried under vacuum filtration to afford 1c (10.6 g, 32.9 mmol, 67% yield). MS [M+H]+=323.0. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.91-7.88 (m, 1H), 7.72 (dd, J=8.1, 1.6 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=17.7 Hz, 1H), 4.34 (d, J=17.7 Hz, 1H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.29 (m, 1H), 2.01 (dtd, J 12.7, 5.3, 2.3 Hz, 1H).
67%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;	1.1 Step 1.3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1c) To a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1a, 15 g, 48.7 mmol) in DMF (150 mL) was added 3-aminopiperidine-2,6-dioneHCl salt (1b, 6.9 g, 53.6 mmol) and K2CO3 (20.2 g, 146.1 mmol). The resulting mixture was stirred at 70 °C for 16 h after which time the reaction mixture was cooled to rt and then concentrated to dryness. To the resulting residue, water was added and the mixture stirred at rt for 30 min. The resultant solid was filtered and washed with ether and ethyl acetate. The solid was dried under vacuum filtration to afford 1c (10.6 g, 32.9 mmol, 67% yield). MS [M+H]+ = 323.0. 1H NMR (400 MHz, DMSO-d6) ^ 10.99 (s, 1H), 7.91-7.88 (m, 1H), 7.72 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 4.34 (d, J = 17.7 Hz, 1H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.29 (m, 1H), 2.01 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H).
67%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;	1 Example 1: 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (INT-1) Intermediate 1a was prepared as described in U.S. Patent Application US 2009/0142297. To a stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1a, 15 g, 48.7 mmol) in DMF (150 mL) was added 3-aminopiperidine-2,6-dione HCl salt (1b, 6.9 g, 53.6 mmol) and K2CO3 (20.2 g, 146.1 mmol) and the obtained reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to r.t. and concentrated to dryness. Water was added and the mixture was stirred at r.t. for 30 min. The obtained solid was filtered, washed with ethyl acetate, and dried under vacuum filtration to afford 3- (5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione INT-1 (10.6 g, 32.9 mmol, 67% yield). MS [M+H]+ = 323.0.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.91-7.88 (m, 1H), 7.72 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 4.34 (d, J = 17.7 Hz, 1H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.29 (m, 1H), 2.01 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H).

65%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 20h;	Intermediate 5: 3-(6-bromo-3-oxo-LH-isoindol-2-yI)piperidine-2, 6-dione (Int-5) To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (3.08 g, 10 mmol) in DMF (30 mL) was added 3-aminopiperidine-2, 6-dione, HC1 (Accela, catalog : SY030429, 1.81 g, 11 mmol) and potassium carbonate (4.15 g, 30 mmol). The reaction mixture was heated at 70 °C for 20 h. The reaction was cooled to RT and concentrated to dryness under reduced pressure. Water (50 mL) was added to the residue and the mixture was stirred at RT for 30 min then filtered. The resulting solid was washed with EtOAc to give 3-(6-bromo-3-oxo-1H-isoindol-2-yl)piperidine-2, 6-dione (2.1 g, 65% yield) as a pale-grey solid. LCMS m/z calcd for C13H12BrN2O3 [M+H]+: 323.0; found: 323.1.
65%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 20h;	Intermediate 5: 3-(6-bromo-3-oxo-LH-isoindol-2-yI)piperidine-2, 6-dione (Int-5) To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (3.08 g, 10 mmol) in DMF (30 mL) was added 3-aminopiperidine-2, 6-dione, HC1 (Accela, catalog : SY030429, 1.81 g, 11 mmol) and potassium carbonate (4.15 g, 30 mmol). The reaction mixture was heated at 70 °C for 20 h. The reaction was cooled to RT and concentrated to dryness under reduced pressure. Water (50 mL) was added to the residue and the mixture was stirred at RT for 30 min then filtered. The resulting solid was washed with EtOAc to give 3-(6-bromo-3-oxo-1H-isoindol-2-yl)piperidine-2, 6-dione (2.1 g, 65% yield) as a pale-grey solid. LCMS m/z calcd for C13H12BrN2O3 [M+H]+: 323.0; found: 323.1.
57%	With triethylamine	Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C192-1) Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C192-1) Methyl 4-bromo-2-(bromomethyl)benzoate (300mg, 0.974mmol), 3-aminopiperidine-2,6-dione hydrochloride (208mg, 1.266mmol), and triethylamine (128mg, 1.266mmol) were dissolved in 5mL of acetonitrile, and the mixture was stirred at 80°C under nitrogen protection overnight. The mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the crude product was purified by Flash to afford white solid compound C192-1(180mg, yield 57.0%). LCMS: [M + H]+ = 323, 325.
57%	With triethylamine In acetonitrile at 80℃; Inert atmosphere;	Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C192-1) Methyl 4-bromo-2-(bromomethyl)benzoate (300 mg, 0.974mmol), 3-aminopiperidine-2,6-dione hydrochloride (208 mg, 1.266mmol), and triethylamine (128 mg, 1.266mmol) were dissolved in 5mL of acetonitrile, and the mixture was stirred at 80°C under nitrogen protection overnight. The mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the crude product was purified by Flash to afford white solid compound C192-1(180 mg, yield 57.0%). LCMS: [M + H]+ = 323, 325.
44%	With triethylamine at 20℃; for 25h; Inert atmosphere;
44%	With triethylamine at 20℃; for 25h;
43.8%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	1.C; 2.C C. 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Methyl-4-bromo-2-(bromomethyl) benzoate (100 g, 324.70 mmol), 3-Aminopiperidine-2,6-dione.hydrochloride (53.2 g, 324.70 mmol), triethylamine (113.29 mL, 811.75 mmol), and dry dimethylformamide (400 mL) were combined and stirred at room temperature under inert atmosphere for 18 hours. The reaction was cooled to 5°C and diluted with water (400 mL), acetic acid (115 mL), diethylether (300 mL) with continued stirring at room temperature for 2 hours. The resultant solid was filtered, washed with ether (100 mL) and further dried under high vacuum to give 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (46 g, 142.35 mmol, 43.8 % yield) as a light blue solid. MS(ESI) m/z 325.0 [M+1].
43%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;
42%	With triethylamine In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere;	2.1 To a stirred mixture of methyl 4-bromo-2-(bromomethyl)benzoate (Compound 10, 20.0 g, 64.8 mmol, 1.00 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (10.64 g, 83.0 mmol, 1.28 equiv) in DMF (80 ml) was added TEA (22.4mL, 162.2 mmol, 2.50 equiv) dropwise at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 16 h. This was followed by addition of H20 (60 mL), AcOH (23 mL) and Et20 (60 mL) in sequence at 25 °C. The mixture was stirred at 25 °C for 2 h. The precipitated solids were collected by filtration and washed with Et20 (60 mL). This resulted in 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (9.0 g, 42%) as a light blue solid. LCMS (ESI): 323.32 (M+H)+
39%	With triethylamine In N,N-dimethyl-formamide at 75℃; for 12h;	2 Step 2-3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.1 mmol, HCl) and methyl 4-bromo-2-(bromomethyl)benzoate (5.10 g, 16.5 mmol) in DMF (50.0 mL) was added TEA (4.92 g, 48.6 mmol). The reaction mixture was stirred at 75° C. for 12 hrs. On completion, the reaction mixture was diluted with water (200 mL) and filtered. The filtered cake was collected. The reaction mixture was concentrated in vacuo. The residue was triturated with EA:H2O=1:1 (50 mL) to give the title compound (1.70 g, 39% yield) as blue solid. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.90 (s, 1H), 7.74-7.66 (m, 2H), 5.14-5.09 (m, 1H), 4.50-4.33 (m, 2H), 2.95-2.86 (m, 1H), 2.70-2.61 (m, 1H), 2.42-2.36 (m, 1H), 2.04-2.01 (m, 1H).
20%	With triethylamine In N,N-dimethyl-formamide at 20℃;	5.5.76.3 Step 3: A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (5OmL), water (250OmL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refiuxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-l- oxo-l,3-dihydro-isoindol~2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSCM;) δ 1.97-2.04 (m, I H), 2.32-2.46 (m, IH), 2.56-2.63 (m, IH), 2.85-2.97 (m, IH), 4.34 (d, J = 17.7 Hz, IH), 4.47 (d, J = 17.7 Hz, IH), 5.1 1 (dd, J = 13.2 Hz, J = 5.1 Hz, IH), 7.67 (d, J = 8.1 Hz, IH), 7.72 (dd, J = 8.1 Hz, J = 1.5 Hz, IH), 7.89 (d, J = 0.9 Hz, IH), 11.00 (s, I H).
20%	Stage #1: 3-amino-piperidine-2,6-dione hydrochloride; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide for 1.25h; Stage #2: With glacial acetic acid for 2h; Reflux;	6.6.3 A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50mL), water (2500mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 11.00 (s, 1H).
20%	Stage #1: 3-amino-piperidine-2,6-dione hydrochloride; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With glacial acetic acid for 2h; Reflux;	3 [00409j Step 3: A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water, and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes, and air dried overnight to give 25.4 g of 3 -(5-bromo- 1 -oxo- 1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6- dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) ö 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H),5.11 (dd,J= 13.2Hz,J5.1 Hz, 1H),7.67(d,J8.1 Hz, 1H),7.72(dd,J=8.1 Hz,J= 1.5Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 11.00 (s, 1H).
20%	Stage #1: 3-amino-piperidine-2,6-dione hydrochloride; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With glacial acetic acid for 2h; Reflux;	6.6.3 A mechanically stirred mixture of 4-bromo-2-bromomethyl -benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50mL), water (2500mL) and a 1 : 1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-l-oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6- dione as a grey solid, in 20% yield; 1H MR (DMSO-i) δ 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J = 17.7 Hz, 1H), 4.47 (d, J = 17.7 Hz, 1H), 5.11 (dd, J = 13.2 Hz, J = 5.1 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 11.00 (s, 1H).
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 16h;
	In acetonitrile at 80℃; Alkaline conditions;

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2019/62309, 2019, A1 Location in patent: Paragraph 0732; 0734
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2020/165833, 2020, A1 Location in patent: Page/Page column 296-297
[3]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2022/29573, 2022, A1 Location in patent: Page/Page column 311
[4]Current Patent Assignee: PRELUDE THERAPEUTICS INCORPORATED - WO2022/99117, 2022, A1 Location in patent: Paragraph 393
[5]Current Patent Assignee: PRELUDE THERAPEUTICS INCORPORATED - WO2022/99117, 2022, A1 Location in patent: Paragraph 393
[6]Current Patent Assignee: BEIJING TIDE PHARMACEUTICAL CO LTD; SINO BIOPHARMACEUTICAL LIMITED; BEIJING TEDE PHARMACEUTICAL - EP4019021, 2022, A1
[7]Current Patent Assignee: BEIJING TIDE PHARMACEUTICAL CO LTD; SINO BIOPHARMACEUTICAL LIMITED; BEIJING TEDE PHARMACEUTICAL - EP4019021, 2022, A1 Location in patent: Paragraph 0176-0177
[8]Hansen, Joshua D.; Condroski, Kevin; Correa, Matthew; Muller, George; Man, Hon-Wah; Ruchelman, Alexander; Zhang, Weihong; Vocanson, Fan; Crea, Tim; Liu, Wei; Lu, Gang; Baculi, Frans; Lebrun, Laurie; Mahmoudi, Afshin; Carmel, Gilles; Hickman, Matt; Lu, Chin-Chun [Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 492 - 503]
[9]Hansen, Joshua D.; Correa, Matthew; Alexander, Matt; Nagy, Mark; Huang, Dehua; Sapienza, John; Lu, Gang; Lebrun, Laurie A.; Cathers, Brian E.; Zhang, Weihong; Tang, Yang; Ammirante, Massimo; Narla, Rama K.; Piccotti, Joseph R.; Pourdehnad, Michael; Lopez-Girona, Antonia [Journal of Medicinal Chemistry, 2021, vol. 64, # 4, p. 1835 - 1843]
[10]Current Patent Assignee: SIEMENS ENERGY AG; BRISTOL-MYERS SQUIBB CO - WO2017/120422, 2017, A1 Location in patent: Paragraph 00377; 00389
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2021/171493, 2021, A1 Location in patent: Paragraph 0191
[12]Current Patent Assignee: ORUM THERAPEUTICS INC. - WO2021/198965, 2021, A1 Location in patent: Paragraph 0508
[13]Current Patent Assignee: KYMERA THERAPEUTICS INC - US2019/192668, 2019, A1 Location in patent: Paragraph 3097; 3099
[14]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2008/27542, 2008, A2 Location in patent: Page/Page column 90
[15]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/200795, 2015, A1 Location in patent: Paragraph 00390
[16]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/57503, 2016, A1 Location in patent: Paragraph 00409
[17]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/117118, 2017, A1 Location in patent: Paragraph 00473
[18]Current Patent Assignee: ARVINAS - WO2018/140809, 2018, A1 Location in patent: Paragraph 00391
[19]Zhang, Jingyu; Che, Jinxin; Luo, Xiaomin; Wu, Mingfei; Kan, Weijuan; Jin, Yuheng; Wang, Hanlin; Pang, Ao; Li, Cong; Huang, Wenhai; Zeng, Shenxin; Zhuang, Weihao; Wu, Yizhe; Xu, Yongjin; Zhou, Yubo; Li, Jia; Dong, Xiaowu [Journal of Medicinal Chemistry, 2022]

2
[ 99548-55-7 ]
[ 7440-33-7 ]
[ 78471-43-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide In dichloromethane	6 Reference Example 6 Reference Example 6 A mixture of methyl 4-bromo-2-methylbenzoate (45 g), N-bromosuccinimide (38.4 g) and dichloromethane was heated at reflux under irradiation from two 120 Watt tungsten lamps for five hours. The mixture was then cooled to -15° C. and filtered and the filtrate was evaporated. The residue was recrystallized from cyclohexane to give methyl 4-bromo-2-(bromomethyl)benzoate as pale yellow crystals (39.9 g), m.p. 79.2° C.

Reference： [1]Current Patent Assignee: BAYER AG - US5721193, 1998, A

3
[ 6291-01-6 ]
[ 78471-43-9 ]
5-bromo-2-cyclobutyl-1-oxo-isoindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In toluene; for 2h;Heating / reflux;	Under nitrogen atmosphere, 200 mg of 4-bromo-2-bromomethyl methyl benzoate was dissolved in toluene. Then, 418 mg of cyclobutylamine hydrochloride and 0.4 ml of triethylamine were added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled down to room temperature, and after distilling out the solvents under reduced pressure, the residues were separated and purified by thin-layer silicagel column chromatography (ethyl acetate/hexane=1/2) to obtain 60 mg of the above compound as a white solid. 1HNMR(400MHz,CDCl3.)delta.:1.74-1.80(2H,m), 2.23-2.30(4H,m), 4.43(2H,s), 4.89-4.93(1H,m), 7.58(1H,d,J=8.0Hz), 7.62(1H,s), 7.68(1H,d,J=8.0Hz) ESI-MS Found:m/z 266.2[M+H]+

Reference： [1]Patent: EP1726585,2006,A1 .Location in patent: Page/Page column 87

4
[ 75-31-0 ]
[ 78471-43-9 ]
[ 864866-47-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In toluene Reflux;
	With triethylamine In toluene Reflux;
	With triethylamine In methanol at 100℃; Heating / reflux;	36.1 Under nitrogen atmosphere, 500 mg of 4-bromo-2-bromomethyl methyl benzoate was dissolved in 10 ml of methanol, 0.42 ml of isopropylamine and 0.67 ml of triethylamine were added, and the mixture was stirred all night by heating at 100°C under reflux. The reaction solution was cooled down to room temperature, and after distilling out the solvents under reduced pressure, residues were separated and purified by silicagel column chromatography (ethyl acetate/hexane=1/2), to obtain 222 mg of the above compound as a white solid. 1HNMR(400MHz,CDCl3.)δ.:1.39(6H,d,J=6.8Hz), 4.31(2H,s), 4.62-4.69(1H,m), 7.59(1H,d,J=8.0Hz), 7.61(1H,s), 7.70(1H,d,J=8.0Hz) ESI-MS Found:m/z 254.1[M+H]+

Reference： [1]Cho, Gyeong Hi; Kim, Taehun; Son, Woo Seung; Seo, Seon Hee; Min, Sun-Joon; Cho, Yong Seo; Keum, Gyochang; Jeong, Kyu-Sung; Koh, Hun Yeong; Lee, Jiyoun; Pae, Ae Nim [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 6, p. 1324 - 1328]
[2]Location in patent: scheme or table Ito, Satoru; Hirata, Yukari; Nagatomi, Yasushi; Satoh, Atsushi; Suzuki, Gentaroh; Kimura, Toshifumi; Satow, Akio; Maehara, Shunsuke; Hikichi, Hirohiko; Hata, Mikiko; Ohta, Hisashi; Kawamoto, Hiroshi [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 18, p. 5310 - 5313]
[3]Current Patent Assignee: MERCK & CO INC - EP1726585, 2006, A1 Location in patent: Page/Page column 41

5
[ 124-40-3 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; for 18h;Heating; Reflux;	A solution of methyl 4-bromo-2-(bromomethyl)benzoate (410 mmol) in MeNH2ZMeOH (1500 niL) was heated to reflux and stirred for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica eluting with petroleum ether / ethyl acetate (6:1 to 3:1) to afford the sub-titled compound (48.5 g).1H NMR (400 MHz, CDCl3): delta 7.63-7.61 (m, IH), 7.53-7.54 (m, 2H), 4.29 (s, 2H), 3.12 (s, 3H).

Reference： [1]Patent: WO2010/128324,2010,A1 .Location in patent: Page/Page column 119

6
[ 28466-26-4 ]
[ 78471-43-9 ]
[ 1315544-56-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 1.5h;	As shown in step 5-i of Scheme 5, methyl 4-bromo-2-(bromomethyl)benzoate (Compound 2018, 2.08 g, 6.75 mmol; prepared by reacting l-(4-bromo-2- methylphenyl)ethanone with NBS),lH-pyrazol-4-amine (561 mg, 6.75 mmol), and DIEA (873 mg, 1.18 mL, 6.75 mmol) were combined in DMF (7.78 mL) and heated at 110 C for 90 min. The reaction mixture was diluted with MeOH (60 mL) and the resulting white crystaline solid was collected by filtration and dried under vacuum to give 5-bromo-2-(lH- pyrazol-4-yl)isoindolin-l-one (Compound 2019, 1.21 g, 4.35 mmol, 64% yield): ESMS (Mu+Eta) 279.99

Reference： [1]Patent: WO2011/87776,2011,A1 .Location in patent: Page/Page column 56-57; 58

7
[ 78471-43-9 ]
[ 376584-62-2 ]

Reference： [1]Patent: WO2011/134468,2011,A1
[2]Patent: WO2013/148603,2013,A1
[3]Patent: WO2007/138072,2007,A2
[4]Patent: WO2008/65199,2008,A1

8
[ 1003-03-8 ]
[ 78471-43-9 ]
[ 864867-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile for 12h; Inert atmosphere; Reflux;
	With triethylamine In toluene at 110℃; for 16h; Inert atmosphere;	34-1.2 5-bromo-2-cvclopentyl-2,3-dihvdro-lH-isoindol-l-one (1-34-1) To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (6.00 g, 19.5 mmol), in toluene (100 mL), was added cyclopentylamine (1.83 g, 21.49 mmol) and toluene (100 mL). Triethylamine (3.96 g, 39.1 mmol) was added and the resulting solution was stirred for 16 hours at 110°C. The resulting mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by silica chromatography, eluting with 0.5-1% methanol in dichloromethane to afford 1-34-1 as a solid: LCMS (ESI) calc'd for Ci3Hi5BrNO [M + H]+: 280, 282, found 280, 282; 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.70-7.65 (m, 2H), 4.71-4.64 (m, 1H), 4.53 (s, 2H), 2.07-1.91 (m, 2H), 1.89-1.81 (m, 2H), 1.79-1.74 (m, 4H).

Reference： [1]Sidique, Shyama; Dhanya, Raveendra-Panickar; Sheffler, Douglas J.; Nickols, Hilary Highfield; Yang, Li; Dahl, Russell; Mangravita-Novo, Arianna; Smith, Layton H.; D'Souza, Manoranjan S.; Semenova, Svetlana; Conn, P. Jeffrey; Markou, Athina; Cosford, Nicholas D.P. [Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9434 - 9445]
[2]Current Patent Assignee: PHARMARON INC - WO2014/146491, 2014, A1 Location in patent: Page/Page column 100

9
[ 3182-95-4 ]
[ 78471-43-9 ]
2-[(1S)-1-benzyl-2-hydroxyethyl]-5-bromoisoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 140℃; for 2h; Microwave irradiation;	55.A.A 2-[(1S)-2-amino-1-benzyl-ethyl]-5-bromo-isoindolin-1-one Step A 2-[(1S)-2-amino-1-benzyl-ethyl]-5-bromo-isoindolin-1-one A solution of methyl 4-bromo-2-(bromomethyl)benzoate (1.0 g, 3.24 mmol), (2S)-2-amino-3-phenyl-1-propanol (0.49 g, 3.24 mmol) and N,N-diisopropylethylamine (2.06 mL, 11.8 mmol) in 1-butanol (8 mL) was stirred at 140° C. for 2 h under microwave. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (20 mL) and EtOAc (20 mL). The organic phase was separated and the aqueous layer was extracted with EtOAc (2*30 mL). The combined organic phases were washed with water, brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with MeOH/EtOAc (0-5%) to give 0.8 g (71% yield) of the final product as off-white solid. LC/MS found: 346.0 (M+H)+.

Reference： [1]Current Patent Assignee: INCYTE CORP - US2013/96144, 2013, A1 Location in patent: Paragraph 0344; 0345

10
[ 74-89-5 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	In tetrahydrofuran; at 50℃;Sealed tube;	[00530] Intermediate 51 b: 5-bromo-2-methyl-isoindolin-1 -one[00531] To a reaction tube containing methyl 4-bromo-2-(bromomethyl)benzoate (1 .2g, 3.gmmol) was added methylamine (2.OM in THF, lOmL, 2Ommol). The tube was sealed and the mixture was stirred and heated at 50 C overnight. The mixture was then cooled to room temperature, filtered and the precipitate washed with THF. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography using an eluent of 0-100% EtOAc in heptane to give 5-bromo-2- methyl-isoindolin-1-one (623mg, 2.7Smmol, 71% yield) as a white solid.1H NMR (CDCI3, 400MHz) O/ppm: 7.73-7.68 (1H, m), 7.64-7.56 (2H, m), 4.36 (2H, 5), 3.19 (3H, 5). MS Method 3: RT: 3.18 mi m/z226.0/228.0 [M+H]
68%	With triethylamine; In tetrahydrofuran; at 100℃; for 12h;Sealed tube;	Synthesis of 5-bromo-2-methylisoindolin-1-one (2) A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (1, 1 g, 3.26 mmol), 2 M methylamine in tetrahydrofuran (1.95 mL, 3.9 mmol) and triethylamine (0.9 mL, 6.52 mmol) was heated at 100 C. for 12 h in a sealed tube. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with water. The organic was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane to afford 5-bromo-2-methylisoindolin-1-one (2). Yield: 0.5 g, 68%; MS (ESI) m/z 226, 228 [M+1]+.
0.112 g	In methanol; at 90℃; for 24h;	Step A: 5-bromo-2-methylisoindolin-l-one [0234] Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90C) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). lU NMR (500 MHz, CDC13) delta ppm 3.19 (s, 3 H), 4.36 (s, 2 H), 7.57 - 7.62 (m, 2 H), 7.70 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]+ 226.3.

	In methanol; ethanol;Reflux;	To a solution of compound 1a (15 g, 50 mmol) in methanol (150 ml) was added methylamine (25 ml, 33% inethanol), and the reaction was refluxed overnight. After the organic solvent was drained off, the mixture was separatedby silica gel column chromatography (PE/EA= 3:1) to provide a yellow oily compound 1b.HNMR(CDCl3),7.5-7.7(m,3H),4.3(s,2H),3.1(s,3H).MS(ESI)m/z:225.9(M+H)+.
	for 18h;Reflux;	Methyl 4-bromo-2- (bromomethyl) benzoate (Formula 5-1, 2.5 g, 8.12 mmol) was dissolved in 2M methanamine (122 ml, 244 mmol, 30 eq) and then stirred at reflux for 18 hours. After completion of the reaction, Extracted with dichloromethane. The organic layer was washed with H 2 O, dried over anhydrous MgSO 4, and the solvent was removed under reduced pressure.Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a target compound (Formula 5-2).

Reference： [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00527; 00530; 00531
[2]Patent: US10112955,2018,B2 .Location in patent: Page/Page column 29
[3]Patent: WO2013/148603,2013,A1 .Location in patent: Paragraph 0233-0234
[4]Patent: EP3406612,2018,A1 .Location in patent: Paragraph 0086; 0087
[5]Patent: KR2019/109007,2019,A .Location in patent: Paragraph 0219-0222

11
[ 26734-08-7 ]
[ 78471-43-9 ]
[ 1463053-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / methanol / 24 h / 85 °C 2: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / N,N-dimethyl acetamide / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2013/148603, 2013, A1

12
[ 26734-08-7 ]
[ 78471-43-9 ]
[ 864867-55-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In methanol at 85℃; for 24h;	22.A Step A: 5-bromo-2-(3-hydroxy-3-methylbutyl)isoindolin-l-one Step A: 5-bromo-2-(3-hydroxy-3-methylbutyl)isoindolin-l-one [0239] To methyl 4-bromo-2-(bromomethyl)benzoate (0.220 g, 0.714 mmol) suspended in MeOH (6.0 mL) were added 4-amino-2-methylbutan-2-ol (0.077 g, 0.750 mmol) and Et3N (0.156 mL, 1.107 mmol). The mixture was heated to reflux (85°C) for 24 hours, then cooled to RT, and concentrated in vacuo to give the title compound, which was used without further purification.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2013/148603, 2013, A1 Location in patent: Paragraph 0238-0239

13
[ 78471-43-9 ]
[ 868066-91-5 ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Patent: WO2015/92713,2015,A1

14
[ 50910-54-8 ]
[ 78471-43-9 ]
[ 918331-66-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In ethanol at 50℃; for 4h; Sealed tube;	15.1 5-bromo-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.500 g, 1.62 mmol), trans-4-aminocyclohexanol hydrochloride (0.295 g, 1.95 mmol), and potassium carbonate (0.44 g, 3.2 mmol) in ethanol (5.0 mL) was stirred in a sealed vial at 50° C. for 4 h. After cooling, the mixture was diluted with ethyl acetate (10 mL), and was filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with ethyl ether (3 mL). The precipitates were collected by filtration and washed with ethyl ether to afford the desired product. LCMS (M+H)+=309.9/312.0.

Reference： [1]Current Patent Assignee: INCYTE CORP - US2014/171405, 2014, A1 Location in patent: Paragraph 0268; 0269

15
[ 1311315-20-4 ]
[ 78471-43-9 ]
methyl 4-bromo-2-(((1-(trifluoromethyl)cyclohexyl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 90℃; for 96h;	I-92.4 methyl 4-bromo-2-(((l -(trifluoromethyl)cyclohexyl) amino)methyl)benzoate A mixture of potassium carbonate (2.04 g, 14.73 mmol), methyl 4-bromo-2- (bromomethyl)benzoate (1.82 g, 5.89 mmol) and l-(trifluoromethyl)cyclohexanamine hydrochloride (0.60 g, 2.95 mmol) in acetonitrile (50 mL) was heated at 90°C for 96 hours. The solid was removed byfiltration after the reaction was cooled to ambient temperature. The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography eluting with EtO Ac/petroleum ether (1/50) to afford the title compound. LCMS (ESI) calc'd for Ci6H2oBrF3N02 [M + H]+: 394, 396 (1 : 1) found 394, 396 (1 : 1).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/146493, 2014, A1 Location in patent: Page/Page column 82; 83

16
[ 25932-11-0 ]
[ 78471-43-9 ]
methyl 4-bromo-2-(phenylsulfonylmethyl)benzoate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 11592 - 11608

17
[ 78471-43-9 ]
[ 926307-72-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ammonium hydroxide; ammonia / methanol / 20 °C 2: triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 140 °C / 22502.3 Torr

Reference： [1]Current Patent Assignee: HAN - WO2015/81891, 2015, A1

18
3-aminopiperidine-2,6-dione hydrochloric acid salt [ No CAS ]
[ 78471-43-9 ]
[ 1010100-26-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 48h; Inert atmosphere;
78%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 80℃; for 16h;	Intermediate 6f: 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione DIPEA (8.0 mL, 45.00 mmol) was added in one portion to a stirred solution of methyl 4-bromo-2- (bromomethyl)benzoate (4.62 g, 15 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (3.70 g, 22.50 mmol) in acetonitrile (67 mL) at 20°C under air. The resulting solution was stirred at 80 °C for 16 hours. The reaction mixture was cooled to 20 °C and filtered.The solid was washed with MeCN (20 mL) and diethyl ether (2 x 20 mL) to afford the title compound (3.80 g, 78 %) as a blue solid; 1H NMR (400 MHz, DMSO, 30°C) 1.95- 2.08 (1H, m), 2.34- 2.46 (1H, m), 2.57- 2.65 (1H, m), 2.91 (1H, ddd), 4.35 (1H, d), 4.48 (1H, d), 5.11 (1H, dd), 7.67 (1H, d), 7.72 (1H, dd), 7.83- 7.96 (1H, m), 10.98 (1H, s); m/z: ES+ [M+H]+ 324.9.
66%	Stage #1: 3-aminopiperidine-2,6-dione hydrochloric acid salt; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; Stage #2: With acetic acid In N,N-dimethyl-formamide at 120℃; for 2h;	Step 1: Synthesis of 3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6- dione To a mixture of methyl 4-bromo-2-(bromomethyl)benzoate (10.0 g, 32.47 mmol, 1 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (1.2 g, 39.21mmol, 1.20 equiv) in DMF (40 mL) was added Et3N (11.3 mL, 81.30 mmol, 2.50 equiv) dropwise. The reaction mixture was stirred for 16 hr at room temperature. 50 mL HOAc was added and stirring continued at 120oC for 2 h. The reaction was cooled and diluted with water (500 mL). The resulting solid was filtered, washed with water (100 mL) and further dried under high vacuum. This resulted in 6.95 g (66%) of 3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione as a light pale solid. MS (ES+): m/z 323 [M+H+].

43.8%

Stage #1: 3-aminopiperidine-2,6-dione hydrochloric acid salt; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; Stage #2: With acetic acid In diethyl ether; water; N,N-dimethyl-formamide at 5 - 20℃; for 2h;

6.1.C C. 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione: Methyl-4-bromo-2- (bromomethyl) benzoate (100 g, 324.70 mmol), 3-Aminopiperidine-2,6-dione.hydrochloride (53.2 g, 324.70 mmol), triethylamine (113.29 mL, 811.75 mmol), and dry dimethylformamide(400 mL) were combined and stirred at room temperature under inert atmosphere for 18 h. The reaction was cooled to 5 °C and diluted with water (400 mL), acetic acid (115 mL), diethylether (300 mL) with continued stirring at room temperature for 2 hrs. The resultant solid was filtered, washed with ether (100 mL) and further dried under high vacuum to give 3-(5-Bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione (46 g, 142.35 mmol, 43.8 % yield) as a light blue solid. MS (ESI) m/z 325.0 [M+1].

Reference： [1]Borrows, Rachel E. A.; Diène, Coura R.; Fairley, Gary; Fallan, Charlene; Fillery, Shaun M.; Hayhow, Thomas G.; Scott, James S.; Watson, David W. [Chemistry - A European Journal, 2020, vol. 26, # 70, p. 16818 - 16823]
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2020/201080, 2020, A1 Location in patent: Page/Page column 73
[3]Current Patent Assignee: ARVINAS - WO2021/77010, 2021, A1 Location in patent: Paragraph 00639; 00640
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/120446, 2017, A1 Location in patent: Paragraph 00466

19
[ 78471-43-9 ]
[ 1010100-28-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere 1.2: 2 h / 5 - 20 °C 2.1: 1,1'-bis-(diphenylphosphino)ferrocene; zinc diacetate; bis(dibenzylideneacetone)-palladium⁽⁰⁾ / N,N-dimethyl-formamide / 20 h / 120 °C / Inert atmosphere 3.1: methanesulfonic acid; palladium 10% on activated carbon; hydrogen / N,N-dimethyl acetamide / 20 h / 40 °C / 2585.81 Torr
	Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere 2: zinc diacetate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 20 h / 120 °C / Inert atmosphere 3: methanesulfonic acid; palladium 10% on activated carbon; hydrogen / N,N-dimethyl acetamide / 20 h / 40 °C / 2585.81 Torr
	Multi-step reaction with 3 steps 1: triethylamine / 25 h / 20 °C / Inert atmosphere 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 1,1'-bis-(diphenylphosphino)ferrocene / 20 h / 120 °C / Inert atmosphere 3: methanesulfonic acid; palladium on activated charcoal / N,N-dimethyl acetamide / 20 h / 40 °C / 2585.81 Torr / Inert atmosphere

	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 80 °C 2: zinc diacetate; 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 16 h / 120 °C 3: palladium on activated charcoal; hydrogen; methanesulfonic acid / N,N-dimethyl acetamide / 16 h / 70 °C
	Multi-step reaction with 4 steps 1: triethylamine / 25 h / 20 °C 2: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 20 h / 120 °C 3: nickel dichloride; sodium tetrahydroborate / 1-methyl-pyrrolidin-2-one / 15 h / 20 °C 4: hydrogenchloride / water; 1,4-dioxane / 2 h / 20 °C
	Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl-formamide / 16 h / 25 °C / Inert atmosphere 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 1,1'-bis-(diphenylphosphino)ferrocene; zinc diacetate / N,N-dimethyl-formamide / 2 h / 120 °C / Microwave irradiation; Inert atmosphere 3: hydrogenchloride; hydrogen; platinum(IV) oxide / methanol / 16 h / 20 - 25 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/120446, 2017, A1
[2]Current Patent Assignee: SIEMENS ENERGY AG; BRISTOL-MYERS SQUIBB CO - WO2017/120422, 2017, A1
[3]Hansen, Joshua D.; Condroski, Kevin; Correa, Matthew; Muller, George; Man, Hon-Wah; Ruchelman, Alexander; Zhang, Weihong; Vocanson, Fan; Crea, Tim; Liu, Wei; Lu, Gang; Baculi, Frans; Lebrun, Laurie; Mahmoudi, Afshin; Carmel, Gilles; Hickman, Matt; Lu, Chin-Chun [Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 492 - 503]
[4]Current Patent Assignee: ARVINAS - WO2018/140809, 2018, A1
[5]Hansen, Joshua D.; Correa, Matthew; Alexander, Matt; Nagy, Mark; Huang, Dehua; Sapienza, John; Lu, Gang; Lebrun, Laurie A.; Cathers, Brian E.; Zhang, Weihong; Tang, Yang; Ammirante, Massimo; Narla, Rama K.; Piccotti, Joseph R.; Pourdehnad, Michael; Lopez-Girona, Antonia [Journal of Medicinal Chemistry, 2021, vol. 64, # 4, p. 1835 - 1843]
[6]Current Patent Assignee: ORUM THERAPEUTICS INC. - WO2021/198965, 2021, A1

20
[ 78471-43-9 ]
[ 1860875-51-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere 1.2: 2 h / 5 - 20 °C 2.1: 1,1'-bis-(diphenylphosphino)ferrocene; zinc diacetate; bis(dibenzylideneacetone)-palladium⁽⁰⁾ / N,N-dimethyl-formamide / 20 h / 120 °C / Inert atmosphere 3.1: methanesulfonic acid; 10% Pd/C; hydrogen / N,N-dimethyl acetamide / 20 h / 40 °C / 2585.81 Torr 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 25 °C
	Multi-step reaction with 4 steps 1: triethylamine / 25 h / 20 °C 2: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 20 h / 120 °C 3: 10% Pd/C; hydrogen / N,N-dimethyl acetamide / 20 h / 40 °C / 2585.81 Torr 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 25 °C
	Multi-step reaction with 4 steps 1: triethylamine / N,N-dimethyl-formamide / 18 h / 20 °C 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 1,1'-bis-(diphenylphosphino)ferrocene; zinc diacetate / N,N-dimethyl-formamide / 18 h / 120 °C 3: hydrogen; 10% Pd/C / water; propan-1-ol / 5 h / 35 - 45 °C / 1810.07 - 2327.23 Torr 4: 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide / 12 h / 35 - 40 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/120446, 2017, A1
[2]Hansen, Joshua D.; Correa, Matthew; Alexander, Matt; Nagy, Mark; Huang, Dehua; Sapienza, John; Lu, Gang; Lebrun, Laurie A.; Cathers, Brian E.; Zhang, Weihong; Tang, Yang; Ammirante, Massimo; Narla, Rama K.; Piccotti, Joseph R.; Pourdehnad, Michael; Lopez-Girona, Antonia [Journal of Medicinal Chemistry, 2021, vol. 64, # 4, p. 1835 - 1843]
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2021/171493, 2021, A1

21
[ 20035-08-9 ]
[ 78471-43-9 ]
methyl 4-bromo-2-[(ethanesulfonyl)methyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 60℃; for 6h;	4-Bromo-2-ethanesulfonylmethyl-benzoic acid methyl ester (L-71) Sodium ethanesulfinate (5.279 g; 45 mmol) is added to a solution of 4-bromo-2-bromomethyl-benzoic acid methyl ester L-71' (20.0 g; 23.0 mmmol) in DMF (200 mL). The mixture is heated to 60 C. for 6 h. Ethyl acetate and water are added to the reaction mixture. The reaction mixture is extracted 3 times with ethyl acetate. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified on silica gel column chromatography. HPLC-MS: (M+H)+=321

Reference： [1]Patent: US2018/44335,2018,A1 .Location in patent: Paragraph 0909-0910

22
[ 4623-24-9 ]
[ 78471-43-9 ]
C₁₆H₁₁BrN₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 5245 - 5256

23
[ 95-23-8 ]
[ 78471-43-9 ]
5-(5-bromo-1-oxo-isoindolin-2-yl)-1,3-dihydrobenzimidazol-2-one [ No CAS ]

Reference： [1]Patent: WO2019/43217,2019,A1

24
[ 95-23-8 ]
[ 78471-43-9 ]
methyl 4-bromo-2-[[(2-oxo-1,3-dihydrobenzimidazol-5-yl)amino]methyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; at 25℃; for 12h;	To a solution of methyl 4-bromo-2-(bromomethyl)benzoate160 (1.0 g) in methanol (10 ml) was added triethylamine (0.56 ml) and 5-amino-l,3-dihydro-2H-benzimidazol-2-one (0.4 g).The reaction mixture was stirred at 25 C for 12 hours. The yellow suspension obtained was filtered and the solid dried in vacuo to afford crude methyl 4-bromo-2-[[(2-oxo-l,3- dihydrobenzimidazol-5-yl)amino]methyl]benzoate (1 g, 98.7%) which was used in the next step without further purification.

Reference： [1]Patent: WO2019/43217,2019,A1 .Location in patent: Page/Page column 134

25
[ 2353-44-8 ]
[ 78471-43-9 ]
[ 1010100-26-1 ]

Yield	Reaction Conditions	Operation in experiment
53%	With triethylamine In N,N-dimethyl-formamide at 80℃; for 12h; Inert atmosphere;	1 Step 1: Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 4-bromo-2-(bromomethyl)benzoate (10.0 g, 32.47 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), 3-aminopiperidine-2,6-dione (4.2 g, 32.78 mmol, 1.00 equiv), triethylamine (8.2 g, 81.04 mmol, 2.50 equiv). The resulting solution was stirred for 12 h at 80. The reaction was then quenched by the addition of water. The solid was collected, and the resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). The collected fractions were combined and concentrated under vacuum. This resulted in 5.6 g (53%) of 3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione as a purple solid. LC/MS (ESI) m/z: 323.00/325.00 [M+1] +.

Reference： [1]Current Patent Assignee: YALE UNIVERSITY; ARVINAS - WO2020/51564, 2020, A1 Location in patent: Paragraph 1863; 1864

26
[ 1306603-98-4 ]
[ 78471-43-9 ]
C₂HF₃O₂*C₂₀H₁₈F₃N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / toluene / 110 °C 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate / tetrahydrofuran; water / 1 h / 90 °C / Sealed tube

Reference： [1]Current Patent Assignee: INCYTE CORP - WO2020/102198, 2020, A1

27
[ 1306603-98-4 ]
[ 78471-43-9 ]
5-bromo-2-(1-cyclopropyl-2-hydroxyethyl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In toluene at 110℃;	46.1 Step 1.5-Bromo-2-(1-cyclopropyl-2-hydroxyethyl)isoindolin-1-one (racemic mixture prepared) To a mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.020 g, 0.065 mmol, Ark Pharm AK-26333) and 2-amino-2-cyclopropylethan-1-ol, HCl salt (13 mg, 0.097 mmol, Enamine EN300-77885) in toluene (2.0 mL) was added triethylamine (0.018 mL, 0.13 mmol). The mixture was heated at 110 °C overnight. Solvent was removed in vacuo and the product was used in Step 2 without further purification. LCMS for C13H15BrNO2 (M+H)+: calculated monoisotopic m/z = 296.0; found 296.0.

Reference： [1]Current Patent Assignee: INCYTE CORP - WO2020/102198, 2020, A1 Location in patent: Page/Page column 246

28
[ 78471-43-9 ]
[ 1261869-76-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ammonium hydroxide / methanol; ethanol / 17 h / Reflux 2: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C / Inert atmosphere

Reference： [1]Bagal, Sharan K.; Barton, Peter; Bloecher, Andrew; Borodovsky, Alexandra; Code, Erin; Fillery, Shaun M.; Gregson, Clare; Hsu, Jessie Hao-Ru; Kawatkar, Sameer P.; Li, Chengzhi; Longmire, David; Nai, Youfeng; Nash, Samuel C.; O' Donovan, Daniel H.; Pike, Andrew; Pike, Kurt G.; Rawlins, Phillip B.; Read, Jon A.; Robinson, James; Shen, Minhui; Tang, Jia; Wang, Peng; Williamson, Beth; Woods, Haley [Journal of Medicinal Chemistry, 2021, vol. 64, # 23, p. 17146 - 17183]

29
[ 1818885-54-9 ]
[ 78471-43-9 ]
[ 2505498-66-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile; methyl 4-bromo-2-(bromomethyl)benzoate With triethylamine In acetonitrile at 100℃; for 10h; Stage #2: With caesium carbonate In methanol; acetonitrile at 100℃; for 10h;	3.1 Step 1: Synthesis of 4-((1r,3r)-3-(5-bromo-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile. Triethylamine (3 eq.) was added to a mixture of 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile and methyl 4-bromo-2-(bromomethyl)benzoate in CH3CN. After the mixture was stirred at 100 °C for 10 h, MeOH and Cs2CO3 were added. After the mixture was stirred at 100 °C for another 10 h, the solvents were evaporated under reduced pressure to afford the corresponding crude 4-((1r,3r)-3-(5-bromo-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile that was purified by flash column chromatography (DCM:MeOH = 20:1) with 70% yield. ESI-MS: 472.06.

Reference： [1]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2022/11204, 2022, A1 Location in patent: Paragraph 0389-0390

30
[ 1818885-54-9 ]
[ 78471-43-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
52.9%	Stage #1: 2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile; methyl 4-bromo-2-(bromomethyl)benzoate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With triethylamine In toluene for 16h; Reflux;	Synthesis of 4-((1r,3r)-3-(5-bromo-1-isoindolin-2-yl)-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile Compound 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile (1.0 g, 3.59 mmol) and K2CO3(743.0 mg, 5.38 mmol) were added to 20 mL DMF, and methyl 4-bromo-2-(bromomethyl)benzoate (1.10 g, 3.59 mmol) was added to the reaction solution in portions. The reaction solution was stirred at room temperature for 1 h. The reaction was completed by TLC detection, and a new spot was formed, to which were added ethyl acetate and saturated brine for extraction. The organic layer was washed twice with saturated brine, dried with anhydrous sodium sulfate, rotatory evaporated to dry, and purify by silica gel column chromatography, to provide 1.2 g of oily liquid, to which were added 10 mL of toluene and 1 mL of triethylamine. The resultant solution was heated and stirred for 16 h under reflux. The solvent was rotatory evaporated, and then a small amount of petroleum ether and ethyl acetate (4:1) were added. The solid was filtered and dried, to provide 4-((1r,3r)-3-(5-bromo-1-isoindolin-2-yl))-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile as a white solid (900.0 mg, 1.9 mmol), with a yield of 52.9%.
52.9%	Stage #1: 2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile; methyl 4-bromo-2-(bromomethyl)benzoate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With triethylamine In toluene for 16h; Reflux;	Synthesis of 4-((1r,3r)-3-(5-bromo-1-isoindolin-2-yl)-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile Compound 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile (1.0 g, 3.59 mmol) and K2CO3(743.0 mg, 5.38 mmol) were added to 20 mL DMF, and methyl 4-bromo-2-(bromomethyl)benzoate (1.10 g, 3.59 mmol) was added to the reaction solution in portions. The reaction solution was stirred at room temperature for 1 h. The reaction was completed by TLC detection, and a new spot was formed, to which were added ethyl acetate and saturated brine for extraction. The organic layer was washed twice with saturated brine, dried with anhydrous sodium sulfate, rotatory evaporated to dry, and purify by silica gel column chromatography, to provide 1.2 g of oily liquid, to which were added 10 mL of toluene and 1 mL of triethylamine. The resultant solution was heated and stirred for 16 h under reflux. The solvent was rotatory evaporated, and then a small amount of petroleum ether and ethyl acetate (4:1) were added. The solid was filtered and dried, to provide 4-((1r,3r)-3-(5-bromo-1-isoindolin-2-yl))-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile as a white solid (900.0 mg, 1.9 mmol), with a yield of 52.9%.

Reference： [1]Current Patent Assignee: HINOVA PHARMACEUTICALS - EP3957633, 2022, A1 Location in patent: Paragraph 0084; 0085
[2]Current Patent Assignee: HINOVA PHARMACEUTICALS - EP3957633, 2022, A1 Location in patent: Paragraph 0084; 0085

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[ 78471-43-9 ] Synthesis Path-Upstream 1~8

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Aryls

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