[ CAS No. 1378388-20-5 ] {[proInfo.proName]}

Name: 1378388-20-5|3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one|97%
Brand: Ambeed
SKU: A445680
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Quality Control of [ 1378388-20-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1378388-20-5 ]

Product Details of [ 1378388-20-5 ]

CAS No. :	1378388-20-5	MDL No. :	MFCD29917576
Formula :	C₁₇H₁₃ClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BBBRYVDJZUVJPB-UHFFFAOYSA-N
M.W :	284.74	Pubchem ID :	69673366
Synonyms :

Calculated chemistry of [ 1378388-20-5 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.24
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	79.28
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.32 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.86
Log Po/w (XLOGP3) :	3.82
Log Po/w (WLOGP) :	4.27
Log Po/w (MLOGP) :	3.46
Log Po/w (SILICOS-IT) :	5.23
Consensus Log Po/w :	3.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.46
Solubility :	0.00996 mg/ml ; 0.000035 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.07
Solubility :	0.0244 mg/ml ; 0.0000856 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.54
Solubility :	0.0000829 mg/ml ; 0.000000291 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.77

Safety of [ 1378388-20-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1378388-20-5 ]

* 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 [ 1378388-20-5 ]
Downstream synthetic route of [ 1378388-20-5 ]

[ 1378388-20-5 ] Synthesis Path-Upstream 1~8

1
[ 1378388-20-5 ]
[ 1378390-29-4 ]

Reference： [1] Patent: WO2013/75029, 2013, A1,
[2] Patent: US2013/309196, 2013, A1,
[3] Patent: US2014/178336, 2014, A1,
[4] Patent: US2015/361073, 2015, A1,

2
[ 1378388-20-5 ]
[ 1378391-38-8 ]

Reference： [1] Patent: US2014/178336, 2014, A1,
[2] Patent: US2015/361073, 2015, A1,

3
[ 1378388-19-2 ]
[ 1378388-20-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	With palladium(II) pentavalerate; potassium carbonate; P(p-C₆H₄F)3; Trimethylacetic acid In N,N-dimethyl acetamide at 60℃; for 24 h; Inert atmosphere	3-chloro-10,ll-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol), tri(4- fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen- l(2H)-one (27.8 g, 76.2 mmol) in dimethyacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60 °C for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography(Hexanes/DCM) to yield 3-chloro-10,l l -dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67percent yield) as an off-white solid.
67%	With palladium(II) pentavalerate; potassium carbonate; P(p-C₆H₄F)3; Trimethylacetic acid In N,N-dimethyl acetamide at 60℃; for 24 h; Inert atmosphere	To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol), tri(4-fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 76.2 mmol) in dimethyacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60° C. for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography (Hexanes/DCM) to yield 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67percent yield) as an off-white solid.
67%	With palladium(II) pentavalerate; potassium carbonate; P(p-C₆H₄F)3; Trimethylacetic acid In N,N-dimethyl acetamide at 60℃; for 24 h; Inert atmosphere	3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol), tri(4-fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 76.2 mmol) in dimethyacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60° C. for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography (Hexanes/DCM) to yield 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67percent yield) as an off-white solid.

14.9 g	With palladium(II) pentavalerate; potassium carbonate; P(p-C₆H₄F)3; Trimethylacetic acid In N,N-dimethyl acetamide at 60℃; for 24 h; Inert atmosphere	27.8 g (76.2 mmol) of iv-3 was added to 380 ml of dimethylacetamide and stirred to dissolve;1.18 g (3.8 mmol) of palladium (II) pivalate, 1.20 g (3.8 mmol) of tris(4-fluorophenyl)phosphine, 2.33 g (22.8 mmol) of pivalic acid and31.8 g (228 mmol) of potassium carbonate was evacuated and refilled with argon five times;Under argon, stir at 60°C for 24 hours. The reaction was cooled to room temperature and t-butyl methyl ether and water were added.Stir for 3 hours and filter through celite and rinse with t-butyl methyl ether. The organic layer was separated, washed twice with water and once with brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, and the filtrate was evaporated to dryness under reduced pressure.Separation by silica gel column chromatography eluting with a mixed solvent of dichloromethane:petroleum ether (5:5) to collect the desired components,Evaporation under reduced pressure gave 14.9 g of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromene-8(9H)-one (iv-4).
14.9 g	With palladium(II) pentavalerate; potassium carbonate; P(p-C₆H₄F)3; Trimethylacetic acid In N,N-dimethyl acetamide at 60℃; for 24 h; Inert atmosphere	The second step: add 27.8 g (76.2 mmol) iv-3380ml dimethylacetamide, stir to dissolve; add in order1.18 g (3.8 mmol) of palladium (II) pivalate,1.20g (3.8mmol)Tris(4-fluorophenyl)phosphine, 2.33 g (22.8 mmol)Pivalic acid and 31.8 g (228 mmol) of potassium carbonate were evacuated.Argon gas was backfilled 5 times; under argon, it was stirred at 60°C for 24 hours.Cool the reaction to room temperature and add t-butyl methyl ether and water.Stir for 3 hours and filter through diatomaceous earthRinse with tert-butyl methyl ether. Separate the organic layer,Wash twice with water and once with brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography and eluted with a mixed solvent of dichloromethane:petroleum ether (5:5) to collect the desired fraction. After evaporation under reduced pressure, 14.9 g of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromene-8(9H)-one (iv-4) was obtained.

Reference： [1] Patent: WO2013/75029, 2013, A1, . Location in patent: Page/Page column 53-55
[2] Patent: US2013/309196, 2013, A1, . Location in patent: Paragraph 0206
[3] Patent: US2014/178336, 2014, A1, . Location in patent: Paragraph 0235
[4] Patent: US2015/361073, 2015, A1, . Location in patent: Paragraph 0438
[5] Patent: CN106916134, 2017, A, . Location in patent: Paragraph 0013; 0023
[6] Patent: CN107540679, 2018, A, . Location in patent: Paragraph 0031; 0033
[7] Patent: CN107556324, 2018, A, . Location in patent: Paragraph 0030; 0031; 0033

4
[ 22009-38-7 ]
[ 1378388-20-5 ]

Reference： [1] Patent: WO2013/75029, 2013, A1,
[2] Patent: US2013/309196, 2013, A1,
[3] Patent: US2014/178336, 2014, A1,
[4] Patent: US2015/361073, 2015, A1,
[5] Patent: CN107540679, 2018, A,
[6] Patent: CN107556324, 2018, A,

5
[ 66192-24-3 ]
[ 1378388-20-5 ]

6
[ 1380084-58-1 ]
[ 1378388-20-5 ]

Reference： [1] Patent: CN105801553, 2016, A,

7
[ 1072-85-1 ]
[ 1378388-20-5 ]

Reference： [1] Patent: CN105801553, 2016, A,

8
[ 1993-03-9 ]
[ 1378388-20-5 ]

Reference： [1] Patent: CN105801553, 2016, A,

[ 1378388-20-5 ] Synthesis Path-Downstream 1~45

1
[ 1378388-20-5 ]
potassium vinyltrifluoroborate [ No CAS ]
[ 1378391-36-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In propan-1-ol; for 5.5h;Inert atmosphere; Reflux;	3-Vinyl-10,ll-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A 3-neck oven-dried 500 mL round-bottom flask was cooled under Ar, then charged with 3- Chloro-10,l l-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (12.0 g, 42.1 mmol), potassium vinyltrifluoroborate (8.47 g, 6.32 mmol), Pd(OAc)2 (473 mg, 2.11 mmol), SPhos (1.74 g, 4.25 mmol), K2CO3 (17.5 g, 126 mmol) and anhydrous propanol (120 mL). The reaction mixture was sparged with Ar for 16 min, then heated to reflux for 5.5 h. Upon completion, the reaction mixture was cooled to RT and concentrated under reduced pressure. The crude residue was suspended in DCM, then washed with H20 and brine. The organic solution was dried over MgSO i, filtered and concentrated under reduced pressure. The resulting residue was further purified via silica plug, eluting with DCM to afford 3-vinyl-10,l l-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (10.2 g, 87%).
87%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In propan-1-ol; for 5.5h;Inert atmosphere; Reflux;	A 3-neck oven-dried 500 mL round-bottom flask was cooled under Ar, then charged with 3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (12.0 g, 42.1 mmol), potassium vinyltrifluoroborate (8.47 g, 6.32 mmol), Pd(OAc)2 (473 mg, 2.11 mmol), SPhos (1.74 g, 4.25 mmol), K2CO3 (17.5 g, 126 mmol) and anhydrous propanol (120 mL). The reaction mixture was sparged with Ar for 16 min, then heated to reflux for 5.5 h. Upon completion, the reaction mixture was cooled to RT and concentrated under reduced pressure. The crude residue was suspended in DCM, then washed with H2O and brine. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was further purified via silica plug, eluting with DCM to afford 3-vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (10.2 g, 87%).
87%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In propan-1-ol; for 5.5h;Inert atmosphere; Reflux;	3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A 3-neck oven-dried 500 mL round-bottom flask was cooled under Ar, then charged with 3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (12.0 g, 42.1 mmol), potassium vinyltrifluoroborate (8.47 g, 6.32 mmol), Pd(OAc)2 (473 mg, 2.11 mmol), SPhos (1.74 g, 4.25 mmol), K2CO3 (17.5 g, 126 mmol) and anhydrous propanol (120 mL). The reaction mixture was sparged with Ar for 16 min, then heated to reflux for 5.5 h. Upon completion, the reaction mixture was cooled to RT and concentrated under reduced pressure. The crude residue was suspended in DCM, then washed with H2O and brine. The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was further purified via silica plug, eluting with DCM to afford 3-vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (10.2 g, 87%).

With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium hydroxide; In 2-methyltetrahydrofuran; water; at 0.7℃;

3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (5.00 g) (Compound (5-3)) was combined with palladium (II) acetate (0.20 g), 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl (0.72 g) 2-methyltetrahydrofuran (50 mL). A solution of potassium hydroxide (3.94 g) and water (29 mL) was added followed by potassium vinyltrifluoroborate (3.53 g). The mixture was heated to about 70 C. After complete conversion, the temperature was adjusted to about 50 C. and N-acetyl cysteine (0.72 g) was added followed by celite (2.5 g). After 3 h, the mixture was filtered and the organic phase was washed with a 5% aqueous potassium hydroxide solution (15 mL) and 1M aqueous hydrochloric acid (1×75 mL and 1×50 mL). The organic phase was concentrated under reduced pressure and the temperature adjusted to about 50 C. Heptane (10 mL) was added, the temperature adjusted to about 23 C. and the mixture was filtered. The filter cake was washed with heptane (5 mL) and dried under reduced pressure at about 40 C. to provide 3-vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (Compound (O)). HRMS (ESI+ MS/MS) Calculated for C19H17O2 m/z (M+H): 277.1229. Found: 277.1238; 1H NMR (400 MHz, CDCl3) delta 7.69 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 6.72 (dd, J=17.5, 10.9 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 5.32 (d, J=10.8 Hz, 1H), 5.11 (s, 2H), 3.03-2.89 (m, 2H), 2.70-2.58 (m, 2H), 2.21-2.06 (m, 2H).

Reference： [1]Patent: WO2013/75029,2013,A1 .Location in patent: Page/Page column 140; 141
[2]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0365
[3]Patent: US2014/178336,2014,A1 .Location in patent: Paragraph 0236
[4]Patent: US2015/361073,2015,A1 .Location in patent: Paragraph 0446

2
[ 1378388-20-5 ]
[ 1066-54-2 ]
[ 1438383-91-5 ]

Yield	Reaction Conditions	Operation in experiment
33.4%	With dichloro bis(acetonitrile) palladium(II); potassium phosphate; XPhos; In acetonitrile; at 65℃; for 6h;Inert atmosphere;	A 300 mL flask equipped with an overhead stirrer and a reflux condenser under an atmosphere of nitrogen was charged with 3-chloro-10,l l-dihydro-5H-dibenzo[c,g]chromen-8(9H)- one (10. Og, 35.12 mmol), powdered anhydrous tripotassium phosphate (22.4 g, 105.4 mmol), XPhos (1.34 g, 2.81 mmol), and PdCl2(MeCN)2 (364 mg, 1.40 mmol). Acetonitrile (140 mL) was added followed by TMSacetylene (18 mL, 141 mmol). The mixture was heated to 65 C. After 6h, the reaction was judged complete, and the mixture was cooled to 20 C. The mixture was filtered through a fritted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 150 mL under reduced pressure and extracted with heptane (50 mL, 3 x 100 mL). N-Acetyl cysteine (15 g) was added to the acetonitrile phase, and the mixture was agitated for 5 h at 45 C. The mixture was cooled to ambient temperature, filtered through a fritted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 120 mL under reduced pressure. Water (120 mL) was added and the mixture was agitated for 40 minutes at 45 C and then cooled to ambient temperature. After 30 minutes the mixture was filtered through a fritted funnel to provide 3- ((trimethylsilyl)ethynyl)-10,l l -dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (4.07 g, 33.4% yield ) as a yellow solid: 400 MHz lH NMR (CDC13) delta 7.65 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (dd, J = 8.1 , 1.4 Hz, 1H), 7.27 (s, 1H), 5.06 (s, 2H), 2.95 (t, J = 6.1 Hz, 2H), 2.67 - 2.59 (m, 2H), 2.18 - 2.08 (m, 2H), 0.26 (s, 9H).
33.4%	With dichloro bis(acetonitrile) palladium(II); potassium phosphate; XPhos; In acetonitrile; at 65℃; for 6h;Inert atmosphere;	3-((Trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A 300 mL flask equipped with an overhead stirrer and a reflux condenser under an atmosphere of nitrogen was charged with <strong>[1378388-20-5]3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one</strong> (10.0 g, 35.12 mmol), powdered anhydrous tripotassium phosphate (22.4 g, 105.4 mmol), XPhos (1.34 g, 2.81 mmol), and PdCl2(MeCN)2 (364 mg, 1.40 mmol). Acetonitrile (140 mL) was added followed by TMSacetylene (18 mL, 141 mmol). The mixture was heated to 65 C. After 6 h, the reaction was judged complete, and the mixture was cooled to 20 C. The mixture was filtered through a fitted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 150 mL under reduced pressure and extracted with heptane (50 mL, 3*100 mL). N-Acetyl cysteine (15 g) was added to the acetonitrile phase, and the mixture was agitated for 5 h at 45 C. The mixture was cooled to ambient temperature, filtered through a fitted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 120 mL under reduced pressure. Water (120 mL) was added and the mixture was agitated for 40 minutes at 45 C. and then cooled to ambient temperature. After 30 minutes the mixture was filtered through a fitted funnel to provide 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (4.07 g, 33.4% yield) as a yellow solid: 400 MHz 1H NMR (CDCl3) delta 7.65 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (dd, J=8.1, 1.4 Hz, 1H), 7.27 (s, 1H), 5.06 (s, 2H), 2.95 (t, J=6.1 Hz, 2H), 2.67-2.59 (m, 2H), 2.18-2.08 (m, 2H), 0.26 (s, 9H).
	With dichloro bis(acetonitrile) palladium(II); potassium phosphate; XPhos; In acetonitrile; at 65℃; for 6h;	A 300 mL flask equipped with an overhead stirrer and a reflux condenser under an atmosphere of nitrogen was charged with <strong>[1378388-20-5]3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one</strong> (10.0 g, 35.12 mmol), powdered anhydrous tripotassium phosphate (22.4 g, 105.4 mmol), XPhos (1.34 g, 2.81 mmol), and PdCl2(MeCN)2 (364 mg, 1.40 mmol). Acetonitrile (140 mL) was added followed by TMSacetylene (18 mL, 141 mmol). The mixture was heated to 65 C. After 6 h, the reaction was judged complete, and the mixture was cooled to 20 C. The mixture was filtered through a fritted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 150 mL under reduced pressure and extracted with heptane (50 mL, 3×100 mL). N-Acetyl cysteine (15 g) was added to the acetonitrile phase, and the mixture was agitated for 5 h at 45 C. The mixture was cooled to ambient temperature, filtered through a fitted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 120 mL under reduced pressure. Water (120 mL) was added and the mixture was agitated for 40 minutes at 45 C. and then cooled to ambient temperature. After 30 minutes the mixture was filtered through a fritted funnel to provide 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (4.07 g, 33.4% yield) as a yellow solid: 400 MHz 1H NMR (CDCl3) delta 7.65 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (dd, J=8.1, 1.4 Hz, 1H), 7.27 (s, 1H), 5.06 (s, 2H), 2.95 (t, J=6.1 Hz, 2H), 2.67-2.59 (m, 2H), 2.18-2.08 (m, 2H), 0.26 (s, 9H)

With dichloro bis(acetonitrile) palladium(II); potassium phosphate; XPhos; In water; acetonitrile; at 0.65℃; for 0.6h;

A reaction flask at ambient temperature was charged with <strong>[1378388-20-5]3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one</strong> (10.0 g,) (Compound (5-3)), powdered anhydrous tripotassium phosphate (22.4 g), 2-dicyclohexylphosphino-2?,4?,6?-triisopropylbiphenyl (?XPhos?) (1.34 g), and PdCl2(MeCN)2 (364 mg). Acetonitrile (140 mL) was added followed by trimethylsilylacetylene (18 mL). The mixture was heated to about 65 C. After about 6 h, the reaction was judged complete, and the mixture was cooled to about 20 C. The mixture was drained and filtered through a fitted funnel, and the filter cake was washed with MeCN. The filtrate was concentrated to about 150 mL under reduced pressure and extracted with heptane (50 mL, then 3×100 mL). N-Acetyl cysteine (15 g) was added to the MeCN phase, and the mixture was agitated for about 5 h at about 45 C. The mixture was cooled to about 23 C., filtered through a fritted funnel, and the filter cake was washed with MeCN. The filtrate was concentrated to about 120 mL under reduced pressure. Water (120 mL) was added and the mixture was agitated for about 40 minutes at about 45 C. and then cooled to ambient temperature. After about 30 minutes the mixture was filtered through a fitted funnel to provide 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (Compound (7)). MS (ESI+ MS/MS) Calculated for Chemical Formula: C22H23O2Si m/z (M+H): 347.1467. Found: 347.1486. 1H NMR (400 MHz, CDCl3) delta 7.65 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (dd, J=8.1, 1.4 Hz, 1H), 7.27 (s, 1H), 5.06 (s, 2H), 2.95 (t, J=6.1 Hz, 2H), 2.67-2.59 (m, 2H), 2.18-2.08 (m, 2H), 0.26 (s, 9H)

Reference： [1]Patent: WO2013/75029,2013,A1 .Location in patent: Page/Page column 209; 210
[2]Patent: US2014/178336,2014,A1 .Location in patent: Paragraph 0244
[3]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0525
[4]Patent: US2015/361073,2015,A1 .Location in patent: Paragraph 0486

3
[ 1378388-19-2 ]
[ 1378388-20-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	With palladium(II) trimethylacetate; potassium carbonate; P(p-C6H4F)3; Trimethylacetic acid; In N,N-dimethyl acetamide; at 60℃; for 24h;Inert atmosphere;	3-chloro-10,ll-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol), tri(4- fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen- l(2H)-one (27.8 g, 76.2 mmol) in dimethyacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60 C for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography(Hexanes/DCM) to yield 3-chloro-10,l l -dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67% yield) as an off-white solid.
67%	With palladium(II) trimethylacetate; potassium carbonate; P(p-C6H4F)3; Trimethylacetic acid; In N,N-dimethyl acetamide; at 60℃; for 24h;Inert atmosphere;	To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol), tri(4-fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 76.2 mmol) in dimethyacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60 C. for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography (Hexanes/DCM) to yield 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67% yield) as an off-white solid.
67%	With palladium(II) trimethylacetate; potassium carbonate; P(p-C6H4F)3; Trimethylacetic acid; In N,N-dimethyl acetamide; at 60℃; for 24h;Inert atmosphere;	3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol), tri(4-fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g, 76.2 mmol) in dimethyacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60 C. for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography (Hexanes/DCM) to yield 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67% yield) as an off-white solid.

	With palladium diacetate; potassium carbonate; triphenylphosphine; Trimethylacetic acid; In N,N-dimethyl acetamide; at 0.6℃;	A mixture of 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (1.00 g) (Compound (5-2)), potassium carbonate (1.19 g), triphenylphosphine (38.3 mg), palladium (II) acetate (32.4 mg), pivalic acid (86.4 mg) and N,N-dimethylacetamide (5 mL) was heated to about 60 C. After complete consumption of the starting material, water (20 mL) was added. The mixture was filtered, and the filter cake washed with water (2×20 mL) and then with hexane (2×5 mL). The filter cake was dried under reduced pressure at ambient temperature to provide 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (Compound (5-3)). 1H NMR (400 MHz, CDCl3) delta 77.65 (d, J=8.3 Hz, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 5.06 (s, 2H), 3.02-2.86 (m, 2H), 2.73-2.53 (m, 2H), 2.26-2.00 (m, 2H).
	With 2.9-dimethyl-1,10-phenanthroline; potassium tert-butylate; In benzene; at 100℃;Sealed tube;	91.4 mg of 7 - ((2-bromo-5-chlorophenyl) oxo) -3,4-dihydronaphthalol-1 (2H) -one was dissolved in 4 mL of benzene,Followed by the addition of ligand copper reagent 21mg and potassium tert-butanol 70mg, sealing 100 reaction,TLC was monitored until the reaction was complete, cooled to room temperature and purified to give intermediate I.
14.9 g	With palladium(II) trimethylacetate; potassium carbonate; P(p-C6H4F)3; Trimethylacetic acid; In N,N-dimethyl acetamide; at 60℃; for 24h;Inert atmosphere;	27.8 g (76.2 mmol) of iv-3 was added to 380 ml of dimethylacetamide and stirred to dissolve;1.18 g (3.8 mmol) of palladium (II) pivalate, 1.20 g (3.8 mmol) of tris(4-fluorophenyl)phosphine, 2.33 g (22.8 mmol) of pivalic acid and31.8 g (228 mmol) of potassium carbonate was evacuated and refilled with argon five times;Under argon, stir at 60C for 24 hours. The reaction was cooled to room temperature and t-butyl methyl ether and water were added.Stir for 3 hours and filter through celite and rinse with t-butyl methyl ether. The organic layer was separated, washed twice with water and once with brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, and the filtrate was evaporated to dryness under reduced pressure.Separation by silica gel column chromatography eluting with a mixed solvent of dichloromethane:petroleum ether (5:5) to collect the desired components,Evaporation under reduced pressure gave 14.9 g of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromene-8(9H)-one (iv-4).
14.9 g	With palladium(II) trimethylacetate; potassium carbonate; P(p-C6H4F)3; Trimethylacetic acid; In N,N-dimethyl acetamide; at 60℃; for 24h;Inert atmosphere;	The second step: add 27.8 g (76.2 mmol) iv-3380ml dimethylacetamide, stir to dissolve; add in order1.18 g (3.8 mmol) of palladium (II) pivalate,1.20g (3.8mmol)Tris(4-fluorophenyl)phosphine, 2.33 g (22.8 mmol)Pivalic acid and 31.8 g (228 mmol) of potassium carbonate were evacuated.Argon gas was backfilled 5 times; under argon, it was stirred at 60C for 24 hours.Cool the reaction to room temperature and add t-butyl methyl ether and water.Stir for 3 hours and filter through diatomaceous earthRinse with tert-butyl methyl ether. Separate the organic layer,Wash twice with water and once with brine. The organic layer was dried over magnesium sulfate overnight, the solid was filtered off, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography and eluted with a mixed solvent of dichloromethane:petroleum ether (5:5) to collect the desired fraction. After evaporation under reduced pressure, 14.9 g of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromene-8(9H)-one (iv-4) was obtained.

Reference： [1]Patent: WO2013/75029,2013,A1 .Location in patent: Page/Page column 53-55
[2]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0206
[3]Patent: US2014/178336,2014,A1 .Location in patent: Paragraph 0235
[4]Patent: US2015/361073,2015,A1 .Location in patent: Paragraph 0438
[5]Patent: CN106916134,2017,A .Location in patent: Paragraph 0013; 0023
[6]Patent: CN107540679,2018,A .Location in patent: Paragraph 0031; 0033
[7]Patent: CN107556324,2018,A .Location in patent: Paragraph 0030; 0031; 0033

4
[ 22009-38-7 ]
[ 1378388-20-5 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: US2014/178336,2014,A1
[4]Patent: US2015/361073,2015,A1
[5]Patent: CN107540679,2018,A
[6]Patent: CN107556324,2018,A

5
[ 66192-24-3 ]
[ 1378388-20-5 ]

6
[ 1378388-20-5 ]
[ 1378388-22-7 ]

Yield	Reaction Conditions	Operation in experiment
>95%	With copper(ll) bromide; In chloroform-d1; ethyl acetate; at 80℃; for 2h;	9-bromo-3-chloro-10,ll-dihydro-5H-dibenzo[c,g]chromen-8(9H)-oneTo a mixture of 3-chloro-10,l l-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.8 g, 52 mmol) in chloroform (50 mL) and ethyl acetate (50 mL) was added copper(II) bromide (24.3 g, 104 mmol). The reaction was heated to 80 C for 2 hours and then cooled to room temperature. The mixture was diluted with dichloromethane and washed twice with a 5: 1 solution of saturated aqueous ammonium chloride and aqueous ammonium hydroxide (~38%), and washed once with water. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield 9-bromo-3-chloro- 10,1 l-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (18.5 g, >95% yield) with >95% purity.
> 95%	With copper(ll) bromide; In chloroform; ethyl acetate; at 80℃; for 2h;	To a mixture of <strong>[1378388-20-5]3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one</strong> (14.8 g, 52 mmol) in chloroform (50 mL) and ethyl acetate (50 mL) was added copper(II) bromide (24.3 g, 104 mmol). The reaction was heated to 80 C. for 2 hours and then cooled to room temperature. The mixture was diluted with dichloromethane and washed twice with a 5:1 solution of saturated aqueous ammonium chloride and aqueous ammonium hydroxide (38%), and washed once with water. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield 9-bromo-<strong>[1378388-20-5]3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one</strong> (18.5 g, >95% yield) with >95% purity. Note: This reaction is not always this clean. Sometimes there is over-bromination and sometimes there is significant starting material. These impurities can be removed by flash column chromatography.
18.2 g	With copper(ll) bromide; In chloroform; ethyl acetate; at 80℃; for 2h;	14.8 g (52 mmol) of iv-4 was added to 50 ml of chloroform and 50 ml of ethyl acetate and stirred to dissolve;24.3 g (104 mmol) of copper (II) bromide was stirred and heated to 80[deg.] C., stirring was continued for 2 hours and then cooled to room temperature.Dichloromethane was added and washed sequentially with saturated ammonium chloride, 38% ammonium hydroxide solution and water. The organic layer was dried over magnesium sulfate overnight and the solid was filtered offThe filtrate was evaporated to dryness under reduced pressure, and the residue was separated by silica gel column chromatography and eluted with a mixed solvent of dichloromethane:petroleum ether (5:5).The components are required and evaporated to dryness under reduced pressure to give 9-bromo-<strong>[1378388-20-5]3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromene-8(9H)-one</strong>(IV).18.2g.

18.2 g

With copper(ll) bromide; In chloroform; ethyl acetate; at 80℃; for 2h;

The third step: 14.8 g (52 mmol) of iv-4 was added to 50 ml of chloroform and 50 ml of ethyl acetate and stirred to dissolve;24.3 g (104 mmol) of copper(II) bromide, stir and heat to 80C,Continue stirring for 2 hours,Then cool to room temperature. Add dichloromethane,Sequentially wash with saturated ammonium chloride, 38% ammonium hydroxide solution and water. The organic layer was dried over magnesium sulfate overnightThe solid was filtered off and the filtrate was evaporated to dryness under reduced pressure.Separation with silica gel column chromatography using dichloromethane:Elution with petroleum ether (5:5) mixed solvent to collect the required components,Evaporation under reduced pressure gave IV 18.2 g

Reference： [1]Patent: WO2013/75029,2013,A1 .Location in patent: Page/Page column 53-55
[2]Patent: US2013/309196,2013,A1 .Location in patent: Paragraph 0207
[3]Patent: CN107540679,2018,A .Location in patent: Paragraph 0031; 0034
[4]Patent: CN107556324,2018,A .Location in patent: Paragraph 0030; 0031; 0034

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[ 1378388-20-5 ]
[ 1378389-64-0 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1404296-86-1 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

9
[ 1378388-20-5 ]
[ 1378390-29-4 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: US2014/178336,2014,A1
[4]Patent: US2015/361073,2015,A1

10
[ 1378388-20-5 ]
[ 1378390-26-1 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

11
[ 1378388-20-5 ]
[ 1378390-35-2 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: US2013/309196,2013,A1
[4]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378390-38-5 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: US2013/309196,2013,A1
[4]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378390-61-4 ]

Reference： [1]Patent: WO2013/75029,2013,A1

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[ 1378388-20-5 ]
[ 1378390-66-9 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378390-69-2 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378390-71-6 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378390-79-4 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1377604-61-9 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378391-39-9 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378391-42-4 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: US2015/361073,2015,A1
[4]Patent: US2015/361073,2015,A1
[5]Patent: US2015/361073,2015,A1

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[ 1378388-20-5 ]
[ 1378391-43-5 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378391-62-8 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1438383-89-1 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: WO2013/75029,2013,A1
[3]Patent: US2013/309196,2013,A1
[4]Patent: US2013/309196,2013,A1
[5]Patent: US2014/178336,2014,A1
[6]Patent: US2014/178336,2014,A1
[7]Patent: US2014/178336,2014,A1
[8]Patent: US2015/361073,2015,A1
[9]Patent: US2015/361073,2015,A1
[10]Patent: US2015/361073,2015,A1
[11]Patent: CN106518832,2017,A

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[ 1438383-92-6 ]

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[ 1378388-20-5 ]
(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate [ No CAS ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: WO2013/75029,2013,A1

26
[ 1378388-20-5 ]
[ 1378392-91-6 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: CN107540679,2018,A
[4]Patent: CN107556324,2018,A

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[ 1378388-20-5 ]
[ 1404296-87-2 ]

Reference： [1]Patent: WO2013/75029,2013,A1
[2]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
(2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate [ No CAS ]

Reference： [1]Patent: US2013/309196,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
[ 1378390-75-0 ]

Reference： [1]Patent: US2013/309196,2013,A1

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[ 1378388-20-5 ]
(2S,5S)-1-tert-butyl 2-(2-(9-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 5-methylpyrrolidine-1,2-dicarboxylate [ No CAS ]

Reference： [1]Patent: US2013/309196,2013,A1
[2]Patent: US2013/309196,2013,A1
[3]Patent: US2013/309196,2013,A1

31
[ 1378388-20-5 ]
[ 1378391-38-8 ]

Reference： [1]Patent: US2014/178336,2014,A1
[2]Patent: US2015/361073,2015,A1

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[ 1378388-20-5 ]
[ 1438383-90-4 ]

Reference： [1]Patent: US2014/178336,2014,A1
[2]Patent: US2015/361073,2015,A1

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[ 1378388-20-5 ]
[ 1615709-30-2 ]

Reference： [1]Patent: US2014/178336,2014,A1
[2]Patent: US2014/178336,2014,A1
[3]Patent: US2014/178336,2014,A1

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[ 1378388-20-5 ]
[ 1615709-31-3 ]

Reference： [1]Patent: US2014/178336,2014,A1
[2]Patent: US2014/178336,2014,A1
[3]Patent: US2014/178336,2014,A1

35
[ 1378388-20-5 ]
9-bromo-3-(2-chloroacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one [ No CAS ]

Reference： [1]Patent: US2015/361073,2015,A1
[2]Patent: US2015/361073,2015,A1
[3]Patent: US2015/361073,2015,A1

36
[ 1378388-20-5 ]
C₄₄H₅₅N₃O₁₃ [ No CAS ]

Reference： [1]Patent: US2015/361073,2015,A1
[2]Patent: US2015/361073,2015,A1
[3]Patent: US2015/361073,2015,A1

37
(4-chloro-2'-fluorobiphenyl-2-yl)methanol [ No CAS ]
[ 1378388-20-5 ]

Reference： [1]Patent: CN105801553,2016,A

38
[ 1380084-58-1 ]
[ 1378388-20-5 ]

Reference： [1]Patent: CN105801553,2016,A

39
4-(8-chloro-6H-benzo[c]chromen-2-yl)butanoic acid [ No CAS ]
[ 1378388-20-5 ]

Yield	Reaction Conditions	Operation in experiment
		Under a nitrogen atmosphere, 7185 g of the compound was added to a 10 L four-necked flask in that order,Dichloromethane 4 L,DMF. Temperature below 20 , dropwise add 109g of thionyl chloride, dropping after warming to reflux reaction 1 hour.Cooling, temperature control 10 toThe lower part of the addition of aluminum trichloride 122g, add finished after the removal of ice bath, about 10 reaction 0.5 hours. TLC monitoring of raw materials consumptionLost. Poured into ice water 3L, the separation, aqueous phase with DCM1.5Lx2 extraction. The organic phases were combined and washed with 1N sodium hydroxideAqueous solution 2L wash once, saturated salt water 2L wash once, anhydrous sodium sulfate drying, filtration, concentration was Velpatasvir155 g of intermediate (Ia), 95% yield, 94% purity (HPLC).

Reference： [1]Patent: CN105801553,2016,A .Location in patent: Paragraph 0129; 0130; 0131; 0132

40
[ 1072-85-1 ]
[ 1378388-20-5 ]

Reference： [1]Patent: CN105801553,2016,A

41
[ 1993-03-9 ]
[ 1378388-20-5 ]

Reference： [1]Patent: CN105801553,2016,A

42
[ 764-48-7 ]
[ 1378388-20-5 ]
C₂₁H₂₀O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; potassium carbonate; In water; at 95℃; for 1.5h;Inert atmosphere;	Taking compound I (20.03g, 70mmol), 2-ethylene oxy ethanol (9.36g, 108mmol), palladium acetate (0.80g, 3 . 6mmol), 1,3-double-(diphenylphosphine) propane (2.96g, 7.2mmol), potassium carbonate (14.56g, 104mmol) in 200 ml of water and stir the, 95 C reflux reaction 1.5h, the reaction is complete, cooling to room temperature, is added to the reaction solution in the 100 ml ethyl acetate, stirring 5min, slowly dropping 37% concentrated hydrochloric acid 16 ml, then completing, stirring reaction 1h, after the reaction is complete by adding ethyl acetate 200 ml, liquid, the organic layer for 10% potassium carbonate aqueous solution to wash once, the organic layer dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain compound III (19.62g, 96%), adding 67 ml of methanol in 65 C reflow 10min, slow cooling to room temperature 1h, filtering to obtain compound III (18.62g, 91%).

Reference： [1]Patent: CN106518832,2017,A .Location in patent: Paragraph 0032; 0033

43
[ 1378388-20-5 ]
C₁₈H₁₄O₄ [ No CAS ]

Reference： [1]Patent: CN106916134,2017,A

44
[ 773837-37-9 ]
[ 1378388-20-5 ]
3-cyano-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		3.36 g of intermediate I obtained in step (1) and 2.1 g of sodium cyanide were dissolved in 15 mL of N-methylpyrrolidone,And the mixture was heated under reflux for 14 hours to obtain a black reaction solution. After the reaction solution was cooled to 85 C, 2.5 mL of hydrochloric acid was added,The ferric chloride solution (7.5 mL (0.53 g / mL) was added and the mixture was stirred at 75-80 C for 1.5 hours.Cooled to room temperature and extracted with toluene. The organic phase was washed with 5M hydrochloric acid and dried to give intermediate II.

Reference： [1]Patent: CN106916134,2017,A .Location in patent: Paragraph 0013; 0025

45
[ 928-56-3 ]
[ 1378388-20-5 ]
C₂₁H₁₉ClO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; potassium carbonate; In tetrahydrofuran; water; for 2.5h;Reflux;	Take compound I (28.5 g, 100 mmol),1-Cl-2-ethoxyethylene (16.0 g, 150 mmol),Palladium acetate (1.00 g, 4.5 mmol),1,3-bis(diphenylphosphino)propane (4.23 g, 10.2 mmol),Potassium carbonate (20.7 g, 150 mmol) was stirred well in 200 ml of 60% aqueous THF.The reaction was refluxed for 2.5 h, the reaction was completed, and cooled to room temperature.Slowly add 24 ml of 37% concentrated hydrochloric acid, drip, and stir for 3 h.After the reaction was completed, ethyl acetate was added and extracted twice with 100 ml each time.The organic layers were combined and washed once with 10% aqueous potassium carbonate solution.The organic layer was dried over anhydrous sodium sulfate and filtered.Concentration under reduced pressure gave Compound III (31.2 g, 95.4%).Add 90 ml of methanol and reflux at 65 C for 10 min, slowly cool to room temperature for 1 h,Compound III (30.1 g, 91.3%) was obtained by filtration.

Reference： [1]Patent: CN108276421,2018,A .Location in patent: Paragraph 0041; 0042

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[ 1378388-20-5 ]

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 1378388-20-5 ] {[proInfo.proName]}

Quality Control of [ 1378388-20-5 ]

Related Doc. of [ 1378388-20-5 ]

Product Details of [ 1378388-20-5 ]

Calculated chemistry of [ 1378388-20-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1378388-20-5 ]

Application In Synthesis of [ 1378388-20-5 ]

[ 1378388-20-5 ] Synthesis Path-Upstream 1~8

[ 1378388-20-5 ] Synthesis Path-Downstream 1~45

Related Functional Groups of [ 1378388-20-5 ]

Chlorides

Ketones

Related Parent Nucleus of [ 1378388-20-5 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1378388-20-5 ]

Related Parent Nucleus of
[ 1378388-20-5 ]