[ CAS No. 676134-68-2 ]

Name: 676134-68-2|6-Bromoisochroman-4-one|97%
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Quality Control of [ 676134-68-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 676134-68-2 ]

SDS Specification

Alternatived Products of [ 676134-68-2 ]

Product Details of [ 676134-68-2 ]

CAS No. :	676134-68-2	MDL No. :	MFCD09744079
Formula :	C₉H₇BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KOROTCDTJPLXMA-UHFFFAOYSA-N
M.W :	227.05	Pubchem ID :	45489802
Synonyms :

Calculated chemistry of [ 676134-68-2 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	48.27
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) :	-6.38 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.02
Log Po/w (XLOGP3) :	1.84
Log Po/w (WLOGP) :	2.01
Log Po/w (MLOGP) :	1.5
Log Po/w (SILICOS-IT) :	3.08
Consensus Log Po/w :	2.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.78
Solubility :	0.379 mg/ml ; 0.00167 mol/l
Class :	Soluble
Log S (Ali) :	-2.01
Solubility :	2.2 mg/ml ; 0.00971 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.72
Solubility :	0.0437 mg/ml ; 0.000192 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.13

Safety of [ 676134-68-2 ]

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

Application In Synthesis of [ 676134-68-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 676134-68-2 ]
Downstream synthetic route of [ 676134-68-2 ]

[ 676134-68-2 ] Synthesis Path-Upstream 1~1

1
[ 676134-67-1 ]
[ 676134-68-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	at 20℃;	Step Two; 6-Bromo-isochroman-4-one; 0 Bt\\ . COoH i AD) i . Br C02H 1. Ac2O 0 i OC02H 2. Basic Resin i O A solution of Bromo-2-carboxymethoxymethyl-benzoic acid in acetic anhydride (350 mL) containing potassium acetate (170 g) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined ethyl acetate phase was then washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield a red semi-solid. Purification by flash column chromatography over silica (85 : 15 hexanes/ethyl acetate) gave the enol acetate (7.59 g, 29percent for three steps) as a golden syrup : 1H NMR (300 MHz, CDC13) 8 7.37 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.04 (s, 2H), 2.29 (s, 3H). Unactivated Dowex 500A OH anion exchange resin (1 g) added in one portion to a solution of the acetate enol acetate (5.95 g, 22.11 mmol) in methanol (50 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was gravity filtered and the resin washed with fresh methanol. The combined filtrate was then concentrated under reduced pressure to yield 6-Bromo- isochroman-4-one (4.32 g, 86percent) as a yellow oil, which solidified on standing

Reference： [1] Patent: WO2005/95326, 2005, A2, . Location in patent: Page/Page column 162-163

[ 676134-68-2 ] Synthesis Path-Downstream 1~69

1
[ 676134-67-1 ]
[ 676134-68-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With methanol; at 20℃;	Step Two; 6-Bromo-isochroman-4-one; 0 Bt . COoH i AD) i . Br C02H 1. Ac2O 0 i OC02H 2. Basic Resin i O A solution of Bromo-2-carboxymethoxymethyl-benzoic acid in acetic anhydride (350 mL) containing potassium acetate (170 g) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined ethyl acetate phase was then washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield a red semi-solid. Purification by flash column chromatography over silica (85 : 15 hexanes/ethyl acetate) gave the enol acetate (7.59 g, 29% for three steps) as a golden syrup : 1H NMR (300 MHz, CDC13) 8 7.37 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.04 (s, 2H), 2.29 (s, 3H). Unactivated Dowex 500A OH anion exchange resin (1 g) added in one portion to a solution of the acetate enol acetate (5.95 g, 22.11 mmol) in methanol (50 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was gravity filtered and the resin washed with fresh methanol. The combined filtrate was then concentrated under reduced pressure to yield 6-Bromo- isochroman-4-one (4.32 g, 86%) as a yellow oil, which solidified on standing

Reference： [1]Patent: WO2005/95326,2005,A2 .Location in patent: Page/Page column 162-163

2
[ 676134-68-2 ]
[ 676134-70-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium tetrahydroborate; In ethanol; water; at 0 - 20℃; for 2.0h;	Step Three; 6-Bromo-isochroman-4-ol; A solution of sodium borohydride (300 mg, 7.93 mmol) dissolved in a minimum amount of ice cold water was added dropwise at 0 C to a solution of 6-Bromo-isochroman-4-one (1.49 g, 6.56 mmol) in absolute ethanol (27.0 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The phases were separated and the organic phase washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield 6-Bromo-isochroman-4-ol (1.44 g, 95%) as a white solid
95%	With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 2.0h;	A solution of sodium borohydride (300 mg, 7.93 mmol) in a minimum amount of ice cold water was added dropwise at 0 C to a solution of 6- bromo-isochromen-4-one (1.49 g, 6.56 mmol) in absolute ethanol (27.0 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The phases were separated and the organic phase was washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield 6-Bromo- isochromen-4-ol (1.44 g, 95%) as a white solid :'H NMR (300 MHz, CDCl3) No. 7.40 (dd, J= 8.3, 1.8 Hz, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.15 (d, J= 1.8 Hz, 1H), 4.63 (ABq, J= 15.3 Hz, 2H), 4.49 (d, J= 8.6 Hz, 1H), 4.07 (dd, J= 12.0, 2.8 Hz, 1 H), 3.83 (dd, J = 12.0, 2.8 Hz, 1 H) 2. 60 (d, J = 9.2 Hz, 1 H).

Reference： [1]Patent: WO2005/95326,2005,A2 .Location in patent: Page/Page column 163
[2]Patent: WO2005/87714,2005,A2 .Location in patent: Page/Page column 268

3
C₁₀H₇BrO₄ [ No CAS ]
[ 676134-68-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With Dowex 500A; In methanol; at 20℃;	A solution of bromo-2-carboxymethoxymethyl-benzoic acid in acetic anhydride (350 mL) containing potassium acetate (170 g) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phase was then washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield a red semi-solid. Purification by flash column chromatography over silica (85: 15 hexanes/ethyl acetate) yielded the enol acetate (7.59 g, 29% for three steps) as a golden syrup :'H NMR (300 MHz, Ceci3) 8 7.37 (dd, J= 8.2, 1.9 Hz, 1H), 7.19 (d, J= 1.9 Hz, 1H), 6.82 (d, J= 8.2 Hz, 1H), 5.04 (s, 2H), 2.29 (s, 3H). Unactivated Dowex 500A OH anion exchange resin (1 g) added in one portion to a solution of the acetate enol acetate (5.95 g, 22.11 mmol) in methanol (50 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was gravity filtered and the resin washed with fresh methanol. The combined filtrate was then concentrated under reduced pressure to yield 6-bromo-isochromen-4- one (4.32 g, 86%) as a yellow oil, which solidified on standing :'H NMR (300 MHz, Ceci3) 8 7.90 (d, J = 8.3 Hz, 1 H), 7.56 (dd, J = 8.3, 1.7 Hz, 1 H), 7.41 (d, J = 1.7 Hz, 1 H), 4.86 (s, 2H), 4.36 (s, 2H).

Reference： [1]Patent: WO2005/87714,2005,A2 .Location in patent: Page/Page column 267

4
[ 676134-68-2 ]
[ 593-56-6 ]
(Z)-6-bromo-N-methoxyisochroman-4-imine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol at 20℃; for 18h;	6.1 Step 1 : Preparation of (Z)-6-bromo-N-methoxy-isochroman-4-imine To a solution of 6-bromoisochroman-4-one (500 mg, 2.14 mmol, 1 .00 equiv.) in methanol (4.27 ml_) was added O-methylhydroxylamine hydrochloride (357 mg, 4.27 mmol, 2.00 equiv.). After the orange solution was stirred at RT for 18 hours the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (cyclohexane:EtOAc) to give (Z)-6-bromo-N-methoxy-isochroman-4- imine as a white solid. LC-MS (Method A), Rt = 1 .10 min, MS: (M+H) = 256, 258. 1H NMR (400 MHz, CDCl3) d ppm: 8.13 (d, 1 H), 7.45 (dd, 1 H), 7.00 (d, 1 H), 4.72 (s, 2H), 4.63 (s, 2H), 4.01 (s, 3H).

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1 Location in patent: Page/Page column 59

5
[ 676134-68-2 ]
[ 3332-29-4 ]
(Z)-6-bromo-N-ethoxyisochroman-4-imine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol at 20℃; for 1h;	7.1 Step 1 : Preparation of (Z)-6-bromo-N-ethoxy-isochroman-4-imine To a solution of 6-bromoisochroman-4-one (1 .00 g, 4.27 mmol, 1 .00 equiv.) in methanol (8.5 ml_) was added O-ethylhydroxylamine hydrochloride (0.83 g, 8.54 mmol, 2.00 equiv.). After the orange solution was stirred at RT for 1 hour the reaction mixture was concentrated in vacuo. Then the residue was purified by flash chromatography (cyclohexane:EtOAc) to give (Z)-6-bromo-N-ethoxy-isochroman-4- imine as a beige gum. LC-MS (Method A), Rt = 1 .19 min, MS: (M+H) = 270, 272. 1H NMR (400 MHz, CDCl3) d ppm: 8.13 (d, 1 H), 7.44 (dd, 1 H), 7.00 (d, 1 H), 4.73 (s, 2H), 4.63 (s, 2H), 4.25 (q, 2H), 1 .34 (t, 3H)

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1 Location in patent: Page/Page column 60-61

6
[ 676134-68-2 ]
methyl (E)-2-[(4Z)-4-(cyclopropylmethoxyimino)isochroman-6-yl]-3-methoxyprop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: methanol / 18 h / 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 3: triethylamine; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 18 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

7
[ 676134-68-2 ]
(Z)-N-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-4-imine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: methanol / 18 h / 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

8
[ 676134-68-2 ]
methyl (E)-3-methoxy-2-[(4Z)-4-methoxyiminoisochroman-6-yl]prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: methanol / 18 h / 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 3: catacxium A; potassium phosphate; palladium diacetate / 1,4-dioxane; water / 18 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

9
[ 676134-68-2 ]
(Z)-N-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-4-imine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: methanol / 1 h / 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

10
[ 676134-68-2 ]
methyl (E)-2-[(4Z)-4-ethoxyiminoisochroman-6-yl]-3-methoxyprop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: methanol / 1 h / 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 3: catacxium A; potassium phosphate; palladium diacetate / 1,4-dioxane; water / 18 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

11
[ 676134-68-2 ]
methyl (E)-3-methoxy-2-(4-oxoisochroman-6-yl)prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 2: catacxium A; potassium phosphate; palladium diacetate / 1,4-dioxane; water / 2 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

12
[ 676134-68-2 ]
methyl (E)-2-[(4Z)-4-benzyloxyiminoisochroman-6-yl]-3-methoxyprop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 2: catacxium A; potassium phosphate; palladium diacetate / 1,4-dioxane; water / 2 h / 90 °C / Inert atmosphere 3: methanol / 3 h / 20 °C

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

13
[ 676134-68-2 ]
methyl (E)-3-methoxy-2-[(4Z)-4-prop-2-ynoxyiminoisochroman-6-yl]prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere 2: catacxium A; potassium phosphate; palladium diacetate / 1,4-dioxane; water / 2 h / 90 °C / Inert atmosphere 3: methanol / 3 h / 20 °C

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1

14
[ 676134-68-2 ]
O-(cyclopropylmethyl)hydroxylamine hydrochloride [ No CAS ]
(Z)-6-bromo-N-(cyclopropylmethoxy)isochroman-4-imine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol at 20℃; for 18h;	5.1 Step 1 : Preparation of (Z)-6-bromo-N-(cvclopropylmethoxy)isochroman-4-imine To a solution of 6-bromoisochroman-4-one (500 mg, 2.14 mmol, 1 .00 equiv.) in methanol (4.27 ml_) was added 0-(cyclopropyimethyl)hydroxylamine hydrochloride (528 mg, 4.27 mmol, 2.00 equiv.). After the orange solution was stirred at RT for 18 hours the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (cyclohexane:EtOAc) to give (Z)-6-bromo-N- (cyclopropylmethoxy)isochroman-4-imine as a beige gum. LC-MS (Method A), Rt = 1 .25 min, MS: (M+H) = 296, 298. 1H NMR (400 MHz, CDCl3) d ppm: 8.1 1 (d, 1 H), 7.44 (dd, 1 H), 6.99 (d, 1 H), 4.77 (s, 2H), 4.63 (s, 2H), 4.02 (d, 2H), 1 .17-1 .28 (m, 1 H), 0.56-0.63 (m, 2H), 0.31-0.37 (m, 2H).

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1 Location in patent: Page/Page column 57-58

15
[ 676134-68-2 ]
[ 73183-34-3 ]
6-(4,4,5,5-tetramethyl-1,3.2-dioxaborolan-2-yl)isochroman-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 1h; Inert atmosphere;	8.1 Step 1 : Preparation of 6-(4,4,5.5-tetramethyl-1 ,3.2-dioxaborolan-2-yl)isochroman-4-one To a solution of 6-bromoisochroman-4-one (0.50 g, 2.20 mmol, 1 .00 equiv.) in dioxane (1 1 .0 ml_) was added potassium acetate (0.44 g, 4.40 mmol, 2.00 equiv.) and bis(pinacolato)diboron (0.62 g, 2.42 mmol, 1 .10 equiv.). The solution was degassed with argon for 5 min and PdCl2(dppf) (0.08 g, 0.1 1 mmol, 0.05 equiv.) was introduced. Then the reddish suspension was stirred at 100°C for 1 hour. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc.and the total combined organic layer was washed with water and brine, dried with Na2SO 4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (cyclohexane:EtOAc) to give 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)isochroman-4-one as a white solid. LC-MS (Method A), Rt = 1 .05 min, MS: (M+H) = 275. 1H NMR (400 MHz, CDCl3) d ppm: 8.53 (s, 1 H), 8.00 (dd, 1 H), 7.25 (dd, 1 H), 4.93 (s, 2H), 4.40 (s, 2H), 1 .37 (s, 12H).

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/9026, 2021, A1 Location in patent: Page/Page column 62-63

16
methyl 6-bromo-4-oxo-isochromane-3-carboxylate [ No CAS ]
[ 676134-68-2 ]

Yield	Reaction Conditions	Operation in experiment
50 g	With hydrogenchloride In ethanol; water for 1h;	1.4 Step 4. 6-Bromoisochroman-4-one A mixture of methyl 6-bromo-4-oxo-isochromane-3-carboxylate (140 g, 487 mmol) in EtOH (500 ml_) and HCI (12 M, I L) was stirred at 120°C for 1 hr. The reaction mixture was cooled to 25 °C and filtered. The filter cake was saved. The filtrate was diluted with water (2 L) and extracted with MTBE (1 .5 L x 2). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give brown oil. The brown oil was combined with the filter cake and then triturated with EtOH (200 ml_) at 0°C for 0.5 hrs. The solid was collected by filtration, washed with EtOH (50 ml_ x 2) and dried in vacuo affording the title compound (50 g, 242 mmol) as a yellow solid. 1H NMR (400MHz, CDCI3) d = 8.17 (d, J = 20 Hz, 1 H), 7.69-7.67 (m, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 4.85 (s, 2H), 4.37 (s, 2H) ppm.
50 g	With hydrogenchloride In ethanol at 120℃; for 1h;	4 A mixture of methyl 6-bromo-4-oxo-isochromane-3-carboxylate (140 g, 487 mmol) in EtOH (500 mL) and HCI (12 M, I L) was stirred at 120°C for 1 hr. The reaction mixture was cooled to 25 °C and filtered. The filter cake was saved. The filtrate was diluted with water (2 L) and extracted with MTBE (1 .5 L x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give brown oil. The brown oil was combined with the filter cake and then triturated with EtOH (200 mL) at 0°C for 0.5 hrs. The solid was collected by filtration, washed with EtOH (50 mL_ x 2) and dried in vacuo affording the title compound (50 g, 242 mmol) as a yellow solid. (1114) 1H NMR (400MHz, CDCI3) δ = 8.17 (d, J = 20 Hz, 1 H), 7.69-7.67 (m, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 4.85 (s, 2H), 4.37 (s, 2H) ppm.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1 Location in patent: Page/Page column 71-72
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1 Location in patent: Page/Page column 346-347

17
[ 676134-68-2 ]
(R)-4-cyano-N-((2-(3-(dimethylamino)-2-oxopyridin-1(2H)-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide formic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 5.1: palladium [2'-(amino-κN)[1,1'-biphenyl]-2-yl-κC][[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κO); caesium carbonate / 1,4-dioxane / 12 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

18
[ 676134-68-2 ]
(R)-4-cyano-4-methyl-N-((2-(6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridin-2(1H)-yl)-1,6-naphthyridin-7-yl)methyl)isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 16 h / 120 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

19
[ 676134-68-2 ]
(R)-N-((2-(6-(azetidin-1-yl)pyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 30 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

20
[ 676134-68-2 ]
(R)-4-cyano-N-((6-(2-methoxyphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

21
[ 676134-68-2 ]
(R)-4-cyano-4-methyl-N-((6-phenylthiazolo[5,4-c]pyridazin-3-yl)methyl)isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 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 / 1 h / 20 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

22
[ 676134-68-2 ]
(S)-N-((2-(6-cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl)-4-fluoro-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: diethylamino-sulfur trifluoride / dichloromethane / 0.33 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK IG / Resolution of racemate 4.1: 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 / 2 h / 20 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

23
[ 676134-68-2 ]
(R)-N-((2-(3-bromo-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 2 h / 120 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

24
[ 676134-68-2 ]
(R)-4-cyano-N-((2-(4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide formic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 2 h / 120 °C 6.1: dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium phosphate / water; 1,4-dioxane / 2 h / 60 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

25
[ 676134-68-2 ]
methyl 1-(7-(((R)-4-cyano-4-methylisochromane-6-carboxamido)methyl)-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

26
[ 676134-68-2 ]
6-bromo-4-methylisochromane-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3: potassium hydroxide; ethanol; water / 5 h / 90 °C
	Multi-step reaction with 3 steps 1: cerium(III) chloride / tetrahydrofuran / 3 h / -50 - 30 °C 2: indium tribromide / dichloromethane / 1 h / 0 - 25 °C 3: potassium hydroxide / water; ethanol / 5 h / 90 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1

27
[ 676134-68-2 ]
(6-bromo-4-methylisochroman-4-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3: potassium hydroxide; ethanol; water / 5 h / 90 °C 4: borane-THF / tetrahydrofuran / 2 h / 25 °C
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 3 h / -50 - 30 °C 2.1: indium tribromide / dichloromethane / 1 h / 0 - 25 °C 3.1: potassium hydroxide / water; ethanol / 5 h / 90 °C 4.1: borane-THF / 2 h / 0 - 25 °C 4.2: 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1

28
[ 676134-68-2 ]
(4S)-4-(hydroxymethyl)-4-methylisochromane-6-carboxylic acid [ No CAS ]
(4R)-4-(hydroxymethyl)-4-methylisochromane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3: potassium hydroxide; ethanol; water / 5 h / 90 °C 4: borane-THF / tetrahydrofuran / 2 h / 25 °C 5: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 16 h / 100 °C / 775.74 Torr 6: ammonium hydroxide / isopropyl alcohol / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

29
[ 676134-68-2 ]
6-bromo-4-methylisochromane-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C
	Multi-step reaction with 2 steps 1: cerium(III) chloride / tetrahydrofuran / 3 h / -50 - 30 °C 2: indium tribromide / dichloromethane / 1 h / 0 - 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1

30
[ 676134-68-2 ]
4-(hydroxymethyl)-4-methyl-isochromane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3: potassium hydroxide; ethanol; water / 5 h / 90 °C 4: borane-THF / tetrahydrofuran / 2 h / 25 °C 5: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 16 h / 100 °C / 775.74 Torr

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

31
[ 676134-68-2 ]
(4S)-4-cyano-4-methylisochromane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

32
[ 676134-68-2 ]
(4R)-4-cyano-4-methylisochromane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

33
[ 676134-68-2 ]
(4R)-4-hydroxy-4-methylisochromane-6-carboxylic acid [ No CAS ]
(4S)-4-hydroxy-4-methylisochromane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: palladium diacetate; potassium carbonate; dicyclohexyl(3-dicyclohexylphosphaniumylpropyl)phosphonium ditetrafluoroborate; water / dimethyl sulfoxide / 14 h / 100 °C 2.2: DAICEL CHIRALPAK AD / Resolution of racemate
	Multi-step reaction with 2 steps 1.1: cerium(III) chloride / tetrahydrofuran / 3 h / -50 - 30 °C 2.1: water; potassium carbonate; palladium diacetate; dicyclohexyl(3-dicyclohexylphosphaniumylpropyl)phosphonium ditetrafluoroborate / dimethyl sulfoxide / 14 h / 100 °C 2.2: DAICEL CHIRALPAK AD

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1

34
[ 676134-68-2 ]
6-bromo-4-fluoro-4-methylisochromane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2: diethylamino-sulfur trifluoride / dichloromethane / 0.33 h / 0 - 25 °C
	Multi-step reaction with 2 steps 1: cerium(III) chloride / tetrahydrofuran / 3 h / -50 - 30 °C 2: diethylamino-sulfur trifluoride / dichloromethane / 0.33 h / 0 - 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1

35
[ 676134-68-2 ]
(4R)-4-fluoro-4-methylisochromane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: diethylamino-sulfur trifluoride / dichloromethane / 0.33 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK IG / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

36
[ 676134-68-2 ]
(4S)-4-fluoro-4-methylisochromane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: diethylamino-sulfur trifluoride / dichloromethane / 0.33 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK IG / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

37
[ 676134-68-2 ]
(4R)-N-[(4-bromo-2-pyridyl)methyl]-4-cyano-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

38
[ 676134-68-2 ]
tert-butyl 7-[2-[[[(4R)-4-cyano-4-methylisochromane-6-carbonyl]amino]methyl]-4-pyridyl]-2,7-diazaspiro[3.4]octane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 5.1: sodium t-butanolate; [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate / 1,4-dioxane / 2 h / 70 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

39
[ 676134-68-2 ]
(4R)-4-cyano-N-[[4-(2,6-diazaspiro[3.4]octan-6-yl)-2-pyridyl]methyl]-4-methylisochromane-6-carboxamide trifluoroacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 5.1: sodium t-butanolate; [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate / 1,4-dioxane / 2 h / 70 °C 6.1: dichloromethane / 1 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

40
[ 676134-68-2 ]
(4R)-4-cyano-4-methyl-N-[[4-(2-phenyl-2,7-diazaspiro[3.4]octan-7-yl)-2-pyridyl]methyl]isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 5.1: sodium t-butanolate; [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate / 1,4-dioxane / 2 h / 70 °C 6.1: dichloromethane / 1 h / 25 °C 7.1: sodium t-butanolate; [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate / 1,4-dioxane / 3 h / 70 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

41
[ 676134-68-2 ]
(4R)-4-cyano-4-methyl-N-[[4-(1-phenylazetidin-3-yl)-2-pyridyl]methyl]isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

42
[ 676134-68-2 ]
(4R)-N-[(4-benzyloxy-2-pyridyl)methyl]-4-cyano-4-methylisochromane-6-carboxamide formic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

43
[ 676134-68-2 ]
(4R)-4-cyano-4-methyl-N-[[4-[(1S,2S)-2-phenylcyclopropyl]-2-pyridyl]methyl]isochromane-6-carboxamide [ No CAS ]
(4R)-4-cyano-4-methyl-N-[[4-[(1R,2R)-2-phenylcyclopropyl]-2-pyridyl]methyl]isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 5.1: dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium phosphate / water; 1,4-dioxane / 12 h / 80 °C 5.2: DAICEL CHIRALCEL OJ-H / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

44
[ 676134-68-2 ]
(4R)-4-cyano-4-methyl-N-[[4-(2-phenylethyl)-2-pyridyl]methyl]isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 30 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

45
[ 676134-68-2 ]
methyl 3-[(E)-2-[2-[[[(4R)-4-cyano-4-methylisochromane-6-carbonyl]amino]methyl]-4-pyridyl]vinyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

46
[ 676134-68-2 ]
(4R)-4-cyano-4-methyl-N-[[4-(phenoxymethyl)-2-pyridyl]methyl]isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 30 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

47
[ 676134-68-2 ]
(R)-4-cyano-4-methyl-N-((4-((1s,3S)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide [ No CAS ]
(R)-4-cyano-4-methyl-N-((4-((1r,3R)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 4.2: DAICEL CHIRALPAK AD

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

48
[ 676134-68-2 ]
C₂₉H₃₁N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 4.2: DAICEL CHIRALPAK AD

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

49
[ 676134-68-2 ]
(R)-4-cyano-N-((4-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]
(R)-4-cyano-N-((4-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 25 °C 4.2: DAICEL CHIRALCEL OD / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

50
[ 676134-68-2 ]
(R)-4-cyano-4-methyl-N-((4-(6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridin-2(1H)-yl)pyridin-2-yl)methyl)isochromane-6-carboxamide formic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 5.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 40 h / 30 - 120 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

51
[ 676134-68-2 ]
(R)-4-cyano-N-((4-((3-cyanobenzyl)oxy)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 5.1: caesium carbonate / dimethyl sulfoxide / 16 h / 100 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

52
[ 676134-68-2 ]
(R)-N-((4-(benzylthio)pyridin-2-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 5.2: 2 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

53
[ 676134-68-2 ]
(4R)-4-cyano-N-((4-(1-(6-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

54
[ 676134-68-2 ]
6-bromo-4-(difluoromethyl)isochroman-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -78 °C 2: magnesium; sodium acetate; acetic acid / N,N-dimethyl-formamide; water / 2 h / 25 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

55
[ 676134-68-2 ]
(4R)-4-cyano-4-methyl-N-[[2-(1-piperidyl)-1,6-naphthyridin-7-yl]methyl]isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

56
[ 676134-68-2 ]
6-bromo-4-(difluoromethyl)-4-fluoroisochroman [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -78 °C 2: magnesium; sodium acetate; acetic acid / N,N-dimethyl-formamide; water / 2 h / 25 °C 3: diethylamino-sulfur trifluoride / dichloromethane / 2 h / 0 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

57
[ 676134-68-2 ]
(R)-4-cyano-4-methyl-N-((6-phenylisoquinolin-3-yl)methyl)isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

58
[ 676134-68-2 ]
(S)-4-(difluoromethyl)-4-fluoroisochroman-6-carboxylic acid [ No CAS ]
(R)-4-(difluoromethyl)-4-fluoroisochroman-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -78 °C 2.1: magnesium; sodium acetate; acetic acid / N,N-dimethyl-formamide; water / 2 h / 25 °C 3.1: diethylamino-sulfur trifluoride / dichloromethane / 2 h / 0 °C 4.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 16 h / 100 °C / 775.74 Torr 4.2: DAICEL CHIRALPAK IG / Resolution of racemate

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

59
[ 676134-68-2 ]
(4R)-4-cyano-4-methyl-N-[(2-phenylthiazolo[5,4-c]pyridin-6-yl)methyl]isochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 15 h / 20 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

60
[ 676134-68-2 ]
(R)-4-cyano-N-((2-(4-cyclobutyl-2-methoxyphenyl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 25 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

61
[ 676134-68-2 ]
(R)-N-((2-chloro-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

62
[ 676134-68-2 ]
(R)-4-cyano-N-((2-(7-fluoro-1,2-dimethyl-1H-indol-4-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 5.1: dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium phosphate / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

63
[ 676134-68-2 ]
(R)-4-cyano-N-((2-(imidazo[1,2-b]pyridazin-3-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: cerium(III) chloride / tetrahydrofuran / 1 h / -50 - 20 °C 2.1: indium(III) bromide / dichloromethane / 1 h / 0 - 25 °C 3.1: palladium diacetate; potassium carbonate; 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) salt; water / dimethyl sulfoxide / 4 h / 100 °C / 775.74 Torr 3.2: DAICEL CHIRALPAK AD-H / Resolution of racemate 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1

64
[ 676134-68-2 ]
[ 75-16-1 ]
6-bromo-4-methylisochroman-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
105 g	With cerium(III) chloride In tetrahydrofuran at -50 - 20℃; for 1h;	1.5 Step 5. 6-Bromo-4-methyl-isochroman-4-ol Methylmagnesium bromide (3 M in THF, 440 ml_) was added dropwise to a mixture of 6- bromoisochroman-4-one (100 g, 440 mmol) and CeC (54.3 g, 220 mmol, dried in a muffle furnace at 300°C for 3 hrs.) in THF (2 L) at -50 °C. The mixture was warmed to 20°C and stirred for 1 hr. The reaction mixture was poured into water (2 L) and then filtered through diatomite. The diatomite was then washed with EA (2L). The filtrate was separated and the aqueous layer was extracted with EA (1 L x 2). The combined organic layers were washed with brine (2 L), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by FCC (Eluent: PE:EA = 50:1 to 3:1) affording the title compound (105 g, 432 mmol) as light yellow oil. 1H NMR (400MHz, DMSO-d6) d = 7.67 (d, J = 2.0 Hz, 1 H), 7.38-7.35 (m, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 5.35 (s, 1 H), 4.71 - 4.58 (m, 2H), 3.68 - 3.59 (m, 1 H), 3.58 - 3.50 (m, 1 H), 1 .38 (s, 3H) ppm.
	With cerium(III) chloride In tetrahydrofuran at -50 - 30℃; for 3h;	5 Methylmagnesium bromide (3 M in THF, 440 mL) was added dropwise to a mixture of 6- bromoisochroman-4-one (100 g, 440 mmol) and CeCL (54.3 g, 220 mmol, dried in a muffle furnace at 300°C for 3 hrs.) in THF (2 L) at -50 °C. The mixture was warmed to 20°C and stirred for 1 hr. The reaction mixture was poured into water (2 L) and then filtered through diatomite. The diatomite was then washed with EA (2L). The filtrate was separated and the aqueous layer was extracted with EA (1 L x 2). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by FCC (Eluent: PE:EA = 50:1 to 3:1) affording the title compound (105 g, 432 mmol) as light yellow oil. (1117) 1H NMR (400MHz, DMSO-d6) δ = 7.67 (d, J = 2.0 Hz, 1 H), 7.38-7.35 (m, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 5.35 (s, 1 H), 4.71 - 4.58 (m, 2H), 3.68 - 3.59 (m, 1 H), 3.58 - 3.50 (m, 1 H), 1 .38 (s, 3H) ppm.

65
[ 676134-68-2 ]
[ 1535-65-5 ]
6-bromo-4-(difluoro(phenylsulfonyl)methyl)isochroman-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3 g	With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 2h;	1.1 Step 1. 6-Bromo-4-(difluoro(phenylsulfonyl)methyl)isochroman-4-ol LiHMDS (1 M, 26.4 mL) was added to a solution of 6-bromoisochroman-4-one (3 g, 13.2 mmol), difluoromethylsulfonylbenzene (2.8 mL, 19.8 mmol) in THF (30 mL) at -78 °C. The mixture was stirred at -78 °C for 2 hr. The reaction mixture was poured into saturated aq. NH4CI (50 mL) and extracted with EA (50 mL x 2). The organic layer was washed with brine (50 mL) and dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA = 10:1 to 3:1) affording the title compound (3 g, 6.70 mmol) as yellow solid . LCMS (ESI) m/z: [M+H20J+ = 435.8, 437.8. 1H NMR (400MHz, CDCb) d = 8.04 (d, J = 7.6 Hz, 2H), 7.90 - 7.89 (m, 1 H), 7.85 - 7.76 (m, 1 H), 7.71 - 7.62 (m,2H), 7.49 - 7.47 (m, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 5.00 (d, J = 12.4 Hz, 1 H), 4.93 - 4.73 (m, 2H), 3.93 - 3.88 (m, 1 H), 3.83 (s,1 H).

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1 Location in patent: Page/Page column 71; 80

66
[ 79669-50-4 ]
[ 676134-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 8 h 1.2: 8 h / 0 - 25 °C / Alkaline conditions 2.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 - 25 °C 3.1: hydrogenchloride / ethanol; water / 1 h
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 8 h 2: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 - 25 °C 3: hydrogenchloride / ethanol; water / 1 h
	Multi-step reaction with 2 steps 1.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / 8 h / 80 °C 1.2: 8 h / 0 - 25 °C 2.1: hydrogenchloride / ethanol / 1 h / 120 °C

	Multi-step reaction with 3 steps 1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / tetrachloromethane / 2 h / 85 °C 2: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 25 °C / Inert atmosphere 3: hydrogenchloride / ethanol / 1 h / 120 °C
	Multi-step reaction with 3 steps 1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / tetrachloromethane / 8 h / 80 °C 2: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 25 °C / Inert atmosphere 3: hydrogenchloride / ethanol / 1 h / 120 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[3]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1
[4]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1
[5]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1

67
[ 79670-17-0 ]
[ 676134-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 - 25 °C 2: hydrogenchloride / ethanol; water / 1 h
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 25 °C / Inert atmosphere 2: hydrogenchloride / ethanol / 1 h / 120 °C

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155320, 2021, A1
[2]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1

68
[ 676134-68-2 ]
[ 1779-49-3 ]
6-bromo-4-methyleneisochromane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
350 mg	Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at -30℃; for 1h; Inert atmosphere; Stage #2: 6-bromoisochroman-4-one In tetrahydrofuran at -30 - 20℃; for 16h; Inert atmosphere;	1 To a solution of methyl(triphenyl)phosphonium;bromide (943.98 mg, 2.64 mmol) in THF (5 mL) was added n-BuLi (2.5 M, 1 .15 mL) dropwise at -30 °C under N2. The mixture was stirred at -30 °C for 1 hr. A solution of 6-bromoisochroman-4-one (Prepared according to the method in Intermediate 10B) (0.5 g, (1322) 2.20 mmol) in THF (1 mL) was added dropwise at -30 °C under N2. The mixture was stirred at 20 °C for 16 hrs. The reaction was quenched with Sat.NH4CI (20 mL) and the mixture was extracted with EtOAc (10 mL *3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, concentrated in vacuum to give a residue, which was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=5/1) to give Intermediate A (350 mg, 1 .54 mmol) as yellow oil. (1323) LCMS (ESI) m/z: [81BrM+H]+ = 227.1. (1324) 1H NMR (400 MHz, CDCI3) δ = 7.73 (d, J= 2.0 Hz, 1 H), 7.28 (m, 1 H), 6.84 (d, J=8.0 Hz, 1 H), 5.53 (s, 1 H), 4.99 (s, 1 H), 4.67 (s, 2H), 4.35 (s, 2H) ppm.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1 Location in patent: Page/Page column 370-371

69
[ 676134-68-2 ]
[ 141-78-6 ]
ethyl 2-(6-bromo-4-hydroxyisochroman-4-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 g	Stage #1: ethyl acetate With lithium hexamethyldisilazane In tetrahydrofuran at -65℃; for 0.25h; Inert atmosphere; Stage #2: 6-bromoisochroman-4-one In tetrahydrofuran at -65℃; for 2h;	1 To a solution of ethyl acetate (620.86 mg, 7.05 mmol, 689.84 uL) in THF(l mL) was added LiHMDS (1 M, 6.61 mL) at -65 °C under N2 atmosphere. The mixture was stirred at -65 °C for 15mins. A solution of 6- bromoisochroman-4-one (Prepared according to the method in Intermediate 10B) (1 g, 4.40 mmol) in THF (2 mL) was added at -65 °C. The mixture was stirred at -65 °C for 2 hrs. The reaction mixture was quenched by saturated aq. NH4CI (50 mL) and extracted by EA (50 mL_*2). The combined organic layer was washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated to give residue. The residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~30% Ethylacetate/Petroleum ethergradient 50 mL/min). The eluent was concentrated to afford Intermediate A (1 g, 3.17 mmol) as colorless oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.67 (d, J = 2.0 Hz, 1 H), 7.41 - 7.39 (m, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 5.64 (s, 1 H), 4.73 - 4.56 (m, 2H), 4.06 (d, J = 11.2 Hz, 1 H), 4.02 - 3.93 (m, 2H), 3.52 (d, J = 11 .2 Hz, 1 H), 2.83 - 2.74 (m, 1 H), 2.69 - 2.59 (m, 1 H), 1 .11 - 1 .07 (m, 3H) ppm.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2021/155316, 2021, A1 Location in patent: Page/Page column 395-396

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P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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H250	Catches fire spontaneously if exposed to air
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H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
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H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
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H361d	Suspected of damaging the unborn child
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H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 676134-68-2 ]

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[ 676134-68-2 ] Synthesis Path-Upstream 1~1

[ 676134-68-2 ] Synthesis Path-Downstream 1~69

Related Functional Groups of [ 676134-68-2 ]

Bromides

Ketones

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Other Aromatic Heterocycles

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[ 676134-68-2 ]

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[ 676134-68-2 ]