[ CAS No. 1002727-88-9 ] {[proInfo.proName]}

Name: 1002727-88-9|2-(Chroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane|97%
Brand: Ambeed
SKU: A165636
Price: 17.0 USD
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Quality Control of [ 1002727-88-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1002727-88-9 ]

SDS Specification

Alternatived Products of [ 1002727-88-9 ]

Product Details of [ 1002727-88-9 ]

CAS No. :	1002727-88-9	MDL No. :	MFCD12028565
Formula :	C₁₅H₂₁BO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NDSHAELUPJMEBM-UHFFFAOYSA-N
M.W :	260.14	Pubchem ID :	43811034
Synonyms :

Calculated chemistry of [ 1002727-88-9 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.6
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	77.07
TPSA :	27.69 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.57 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.27
Log Po/w (WLOGP) :	2.31
Log Po/w (MLOGP) :	1.92
Log Po/w (SILICOS-IT) :	2.62
Consensus Log Po/w :	2.03

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.68
Solubility :	0.0543 mg/ml ; 0.000209 mol/l
Class :	Soluble
Log S (Ali) :	-3.53
Solubility :	0.0775 mg/ml ; 0.000298 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.57
Solubility :	0.007 mg/ml ; 0.0000269 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.12

Safety of [ 1002727-88-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1002727-88-9 ]

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

Upstream synthesis route of [ 1002727-88-9 ]
Downstream synthetic route of [ 1002727-88-9 ]

[ 1002727-88-9 ] Synthesis Path-Upstream 1~4

1
[ 67856-45-5 ]
[ 73183-34-3 ]
[ 1002727-88-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5.16667 h;	Step 3:A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI₂dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 95⁰C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO₄ and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield).
84%	With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5.16 h;	A solution of the 6-iodochroman 11c (1.O g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI₂dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 95⁰C for about 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO₄ and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield).
84%	Stage #1: With potassium acetate In N,N-dimethyl-formamide for 0.0833333 h; Stage #2: at 95℃; for 5.08 h;	A solution of the 6-ιodochroman 11c (1 0 g, 3 85 mmol), bιs[pιnocolato]dιborane (1 22 g, 4 81 mmol) and potassium acetate (1 10 g, 11 5 mmol) in DMF (36 mL) is degassed with Ar for 5 mm followed by the addition of the PdCI₂dppf-DCM complex (314 mg, 0 38 mmol) The reaction mixture is then degassed for an additional 5 mm before being heated to 95⁰C for 5 h The reaction is then cooled to RT The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL) The combined organics are washed with water (100 mL) and brine (100 mL) The organic phase is then dried over MgSO₄ and filtered and concentrated The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield)

Reference： [1] Patent: WO2009/62285, 2009, A1, . Location in patent: Page/Page column 66-67
[2] Patent: WO2009/62308, 2009, A1, . Location in patent: Page/Page column 76
[3] Patent: WO2009/62288, 2009, A1, . Location in patent: Page/Page column 72-73

2
[ 493-08-3 ]
[ 73183-34-3 ]
[ 1002727-88-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5 h;	A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI₂dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 95⁰C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO₄ and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield).

Reference： [1] Patent: WO2009/62289, 2009, A1, . Location in patent: Page/Page column 79; 80

3
[ 3875-78-3 ]
[ 73183-34-3 ]
[ 1002727-88-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium acetate In N,N-dimethyl-formamide at 95℃; for 3 h; Inert atmosphere	Step 1. 2-(Chroman-6-yl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolaneTo a solution of 6-bromochroman (400 mg, 1.88 mmol) in N,N-dimethylformamide (50 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (620 mg, 2.44 mmol), KOAc (552.1 mg, 5.63 mmol) and Pd(dppf)Cl2 (155 mg, 0.19 mmol) with stirring for 3 h at 95°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was diluted with water, extracted with ethyl acetate (80 mL x 3) and the organic layers combined, dried over anhydrous magnesium sulfate, concentrated under vacuum to give the residue, which was applied onto a silica gel column with 1 percent ethyl acetate in petroleum ether to afford 2-(chroman-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as colorless oil (320 mg, 59percent).*H-NMR (300 MHz, CDC1₃): δ 7.54 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 4.19 - 4.23 (t, J = 5.4 Hz, 2H), 2.78 - 2.83 (t, J = 6.3 Hz, 2H), 1.98 - 2.05 (m, 2H), 1.28 (s,12H)

Reference： [1] Patent: WO2012/119046, 2012, A2, . Location in patent: Page/Page column 72

4
[ 491-37-2 ]
[ 1002727-88-9 ]

Reference： [1] Patent: WO2009/62289, 2009, A1,

[ 1002727-88-9 ] Synthesis Path-Downstream 1~88

1
[ 67856-45-5 ]
[ 73183-34-3 ]
[ 1002727-88-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 95℃; for 5.16667h;	Step 3:A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84% yield).
84%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 95℃; for 5.16h;	A solution of the 6-iodochroman 11c (1.O g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 950C for about 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84% yield).
84%		A solution of the 6-iotaodochroman 11c (1 0 g, 3 85 mmol), biotas[piotanocolato]diotaborane (1 22 g, 4 81 mmol) and potassium acetate (1 10 g, 11 5 mmol) in DMF (36 mL) is degassed with Ar for 5 mm followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0 38 mmol) The reaction mixture is then degassed for an additional 5 mm before being heated to 950C for 5 h The reaction is then cooled to RT The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL) The combined organics are washed with water (100 mL) and brine (100 mL) The organic phase is then dried over MgSO4 and filtered and concentrated The crude mixture is further purified by CombiFlash Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84% yield)

Reference： [1]Patent: WO2009/62285,2009,A1 .Location in patent: Page/Page column 66-67
[2]Patent: WO2009/62308,2009,A1 .Location in patent: Page/Page column 76
[3]Patent: WO2009/62288,2009,A1 .Location in patent: Page/Page column 72-73

2
[ 1002727-88-9 ]
[ 1154741-28-2 ]
C₂₉H₃₂N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 80℃; for 2h;	In the 8 ml vial, the boronic ester 11d (14.5 mg, 0.06 mmol), intermediate 40b (30 mg, 0.06 mmol), K2CO3 (25.3 mg, 0.18 mmol) and Pd(PPh3)4 (0) (7 mg, 0.006 mmol) are mixed and the vial is flushed with Ar. To the reaction mixture, water (1 ml_) and DMF (3 ml.) are added and then heated to 800C for about 2 h. The mixture is neutralized with 1 N HCI and concentrated under reduced pressure. The residue is dissolved in the mixture of THF (1.5 ml.) and MeOH (0.5 ml) and then 1 N NaOH solution (0.9 ml_, 0.9 mmol) is added. The reaction is stirred at 550C for about 12 h, then neutralized with 1 N HCI and concentrated under reduced pressure. The residue is dissolved in a mixture of 0.5 ml_ of AcOH and 1 ml. of DMSO and purified with preparative reversed phase LCMS (H2O/Acetonitrile + 0.06% TFA). The pure fractions are pooled, frozen and lyophilized to afford compound 1029 as a white solid (19.5 mg, 66% yield).

Reference： [1]Patent: WO2009/62308,2009,A1 .Location in patent: Page/Page column 106; 107; 116

3
[ 493-08-3 ]
[ 73183-34-3 ]
[ 1002727-88-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 95℃; for 5h;	A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84% yield).

Reference： [1]Patent: WO2009/62289,2009,A1 .Location in patent: Page/Page column 79; 80

4
[ 1002727-88-9 ]
[ 1155288-13-3 ]
[ 1155288-15-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 110℃; for 0.25h;Microwave irradiation;	In a microwave vessel is added ether 44b (36 mg, 0.07 mmol), the boronic ester 11d (24 mg, 0.09 mmol), K2CO3 (29 mg, 0.21 mmol) and the catalyst Pd(PPh3)4 (8.3 mg, 0.01 mmol) all dissolved in DMF/H2O(1 mL/0.1 mL). The vessel is capped and submitted to microwave conditions at 11O0C for 15 min. The reaction mixture is diluted with EtOAc and subsequently washed with water. The organic phase is further washed with brine, dried (MgSO4), filtered and concentrated. The material is purified by CombiFlash Companion to afford the methyl ester of the desired product (23 mg, 63% yield) as a white solid. This material is dissolved in THF (1 mL) and MeOH (0.6 mL) and NaOH (1 N, 0.33 mL, 0.33 mmol) is added. The mixture is stirred at 500C for 16 h. The mixture is concentrated in vacuo before being purified by reversed phase preparative HPLC to afford after lyophilization compound 2005 as a yellow amorphous solid (13.5 mg, 60% yield).It would be obvious to those skilled in the art that intermediate 44a can be used with other nucleophiles to displace the primary bromide (as in the preparation of 44b from <n="117"/>44a), followed by Suzuki coupling with any boronate fragment described in this application to produce a variety of other compounds (for example, the production of compound 2005 from 44b).

Reference： [1]Patent: WO2009/62289,2009,A1 .Location in patent: Page/Page column 115-116

5
[ 1002727-88-9 ]
[ 1364598-02-6 ]
[ 76-05-1 ]
[ 1364598-12-8 ]

Yield	Reaction Conditions	Operation in experiment
39%		Methyl 2-tert-butoxy-2-(3-(3-chlorophenyl)-7-(chroman-6-yl)-5-methylpyrazolo[l,5- a]pyrimidin-6-yl)acetate, TFA salt.; To a 2-5 mL microwave tube was added methyl 2-tert-butoxy-2-(7-chloro-3-(3chlorophenyl)-5-methylpyrazolo[l,5-a]pyrimidin-6- yl)acetate (25 mg, 0.059 mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 muiotaetaomicron), 2-(chroman-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (15 mg, 0.059 mmol), dioxane (1.5 mL), followed by 2M K3P04 solution(77uL). The reaction mixture was heated in a microwave reactor at 130C for 30 min. The reaction was filtered and the filtrate was purified by preparative HPLC to afford (12mg, 39%) of the title compound as the TFA salt. Preparative HPLC condition: Phenomenex Luna C18 30 x 100mm S10, 30 to 100% B over 17 mingradient, 5 min hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA. Flow rate: 40mL/min. Compound used as is in the next step.

Reference： [1]Patent: WO2012/33735,2012,A1 .Location in patent: Page/Page column 154-155

6
[ 1002727-88-9 ]
[ 1364597-01-2 ]
[ 76-05-1 ]
methyl 2-tert-butoxy-2-(7-(chroman-6-yl)-5-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		Methyl 2-tert-butoxy-2-(7-(chroman-6-yl)-5-methyl-3-phenylpyrazolo[l,5- a]pyrimidin-6-yl)acetate, TFA salt.; To a 2-5 mL microwave tube was added methyl 2-tert-butoxy-2-(7-chloro-5-methyl-3-phenylpyrazolo[l,5-a]pyrimidin-6-yl)acetate (20 mg, 0.052 mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 muiotaetaomicron), 2-(chroman-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (20 mg, 0.077 mmol), dioxane (1.5 mL), followed by 2M K3PO4 solution(77uL). The reaction mixture was heated in a microwave reactor at 130C for 30 min. The reaction was filtered and the filtrate was purified by preparative HPLC to afford (13mg, 52%) of the title compound as the TFA salt. Preparative HPLC condition: Phenomenex Luna CI 8 30 x 100mm S 10, 30 to 100% B over 17 mingradient, 5 min hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA. Flow rate: 40mL/min. ¾-NMR (500 MHz, MeOD) delta ppm 0.99 (9 H, s), 2.2 (2 H, m), 2.74 (2 H, s), 2.81 (3 H, s), 3.8 (3 H, s), 4.26 (2 H, m), 5.24 (1 H, s), 6.97 (1 H, s), 7.22 (1 H, s), 7.32 - 7.42 (3 H, m), 8.10 (2 H, s), 8.37 (1 H, s).

Reference： [1]Patent: WO2012/33735,2012,A1 .Location in patent: Page/Page column 80-81

7
[ 1002727-88-9 ]
[ 1364598-75-3 ]
methyl 2-(tert-butoxy)-2-(3-chloro-7-(chroman-6-yl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 130℃; for 0.5h;Microwave irradiation;	Methyl 2-(tert-butoxy)2-(3-chloro- 7-(chroman-6-yl)-2, 5-dimethylpyrazolof 1, 5- a]pyrimidin-6-yl)acetate, TFA salt. ; To a 2-5 mL microwave tube was added added methyl 2-tert-butoxy-2-(3,7-dichloro-2,5-dimethylpyrazolo[l,5-a]pyrimidin-6- yl)acetate. (25 mg, 0.069 mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 muiotaetaomicron), 2-(chroman-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (18 mg, 0.069 mmol), dioxane (1.5 mL), followed by 2M K3P04 solution(77uL). The reaction mixture was heated in a microwave reactor at 130C for 30 min. The reaction was filtered and the filtrate was purified by preparative HPLC to afford (7 mg, 22%) of the title compound as the TFA salt. Preparative HPLC condition:Phenomenex Luna C18 30 x 100mm S 10, 30 to 100% B over 17 mingradient, 5 min hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA. Flow rate: 40mL/min. Compound used as is in the next step.

Reference： [1]Patent: WO2012/33735,2012,A1 .Location in patent: Page/Page column 191-192

8
[ 1002727-88-9 ]
[ 1396750-69-8 ]

Reference： [1]Patent: WO2012/119046,2012,A2

9
[ 1002727-88-9 ]
[ 1268867-67-9 ]
[ 1396750-76-7 ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; for 4h;Inert atmosphere;	Step 2. Methyl 2-(chroman-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylateTo a solution of 2-(chroman-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (320 mg, 1.23 mmol) in dioxane (5.0 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 180 mg, 0.61 mmol), K3PO4 (392 mg, 1.86 mmol), Pd(PPh3)4 (35.8 mg, 0.03 mmol) and water (3 drops) with stirring for 4 h at 95C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was applied onto a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(chroman-6-yl)-3- (isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (130 mg, 51%).LC/MS(ES, m/z): [M+H]+ 392.0'H-NMR (300 MHz, CDCI3): delta 8.76 (s, 1H), 8.07 - 8.16 (m, 2H), 7.71 (s, 1H), 7.62 (d, / = 8.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.42 - 4.47 (t, J = 6.6 Hz, 1H), 4.27 - 4.30 (t, 7 = 5.1 Hz, 2H), 4.00 (s, 3H), 2.88 - 2.94 (m, 5H), 2.05 - 2.12 (m, 2H), 1.16 (d, / = 6.60 Hz, 6H)

Reference： [1]Patent: WO2012/119046,2012,A2 .Location in patent: Page/Page column 73

10
[ 1002727-88-9 ]
[ 1402890-80-5 ]
[ 1402890-72-5 ]

Reference： [1]Patent: EP2511273,2012,A1

11
[ 1002727-88-9 ]
[ 1402890-99-6 ]
[ 1402891-00-2 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃;	Step 4: Preparation of intermediate ethyl 2-(tert-butoxy)-2-[7-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]acetate (7d) To a solution of ethyl 2-(7-bromo-2,3-dihydro-1,4-benzodioxin-6-yl)-2-(tert-butoxy)acetate (7c) (85 mg, 0.23 mmol) in mixture of ethanol (0.6 mL), toluene (1.26mL) and water (0.5 mL) were added sodium carbonate (96 mg, 0.91 mmol) and <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (106 mg, 0.41 mmol). After 5 minutes of nitrogen bubbling, tetrakis(triphenylphosphine)palladium (13 mg, 0.01 mmol) was added and the mixture was heated at 95C overnight. The mixture was then cooled at room temperature and water (5 mL) was added. The aqueous layer was extracted with toluene (3 x 10 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20) to provide ethyl 2-(tert-butoxy)-2-[7-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]acetate (7d) (52 mg, 0.12 mmol, 53%). 1H NMR (300 MHz, CDCl3) delta0.99 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H), 1.99-2.08 (m, 2H), 2.76-2.84 (m, 2H), 4.07-4.17 (m, 4H), 4.26 (s, 4H), 5.05 (s, 1H), 6.71 (s, 1H), 6.80 (d, J = 8.2 Hz, 1H), 7.04-7.10 (m, 2H), 7.18 (s, 1H).
53%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃;Inert atmosphere;	To a solution of ethyl 2-(7-bromo-2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-(ferf- butoxy)acetate (6c) (85 mg, 0.23 mmol) in mixture of ethanol (0.6 mL), toluene (1 .26mL) and water (0.5 mL) were added sodium carbonate (96 mg, 0.91 mmol) and 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (106 mg, 0.41 mmol). After 5 minutes of nitrogen bubbling, tetrakis(triphenylphosphine)palladium (13 mg, 0.01 mmol) was added and the mixture was heated at 95 C overnight. The mixture was then cooled at room temperature and water (5 mL) was added. The aqueous layer was extracted with toluene (3 x 10 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20) to provide ethyl 2-(ferf-butoxy)-2-[7-(3,4- dihydro-2/- -1 -benzopyran-6-yl)-2,3-dihydro-1 ,4-benzodioxin-6-yl]acetate (6d) (52 mg, 0.12 mmol, 53%).1 H NMR (300 MHz, CDCI3) delta 0.99 (s, 9H), 1 .23 (t, J = 7.2 Hz, 3H), 1 .99-2.08 (m, 2H), 2.76-2.84 (m, 2H), 4.07-4.17 (m, 4H), 4.26 (s, 4H), 5.05 (s, 1 H), 6.71 (s, 1 H), 6.80 (d, J = 8.2 Hz, 1 H), 7.04-7.10 (m, 2H), 7.18 (s, 1 H).

Reference： [1]Patent: EP2511273,2012,A1 .Location in patent: Page/Page column 54
[2]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 75-77

12
[ 1002727-88-9 ]
[ 1402890-78-1 ]
[ 1402890-79-2 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 18h;Reflux;	Step 4: Preparation of intermediate methyl 2-(tert-butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)phenyl]acetate (1d) To a solution of methyl 2-(2-bromophenyl)-2-(tert-butoxy)acetate (1c) (60 mg, 0.20 mmol) in toluene (1.1 mL) was added sodium carbonate (84 mg, 0.79 mmol), water (0.48 mL), palladium tetrakis(triphenylphospine) (12 mg, 0.01 mmol) and a solution of <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (93 mg, 0.36 mmol) in ethanol (0.55 mL). The mixture was refluxed for 18 hours. The mixture was then cooled at room temperature and water (5 mL) was added. The aqueous layer was extracted with toluene (2 x 5 mL). The organic layers were washed with a 1 M sodium hydroxide aqueous solution (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 90/10) to provide methyl 2-(tert butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)phenyl]acetate (1d) (43 mg, 0.12 mmol, 60%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 0.99 (s, 9H), 2.04-2.07 (m, 2H), 2.80-2.86 (m, 2H), 3.68 (s, 3H), 4.24 (dd, J = 4.8, 6.0 Hz, 2H), 5.21 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 7.12 (dd, J = 1.6, 8.4 Hz, 1H), 7.21 (dd, J = 1.6, 7.2 Hz, 1H), 7.28-7.36 (m, 2H), 7.66 (dd, J = 1.6, 7.2 Hz, 1H). MS m/z ([M+Na]+) 377.
60%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 18h;Reflux;	To a solution of methyl 2-(2-bromophenyl)-2-(ferf-butoxy)acetate (1 c) (60 mg, 0.20 mmol) in toluene (1 .1 mL) was added sodium carbonate (84 mg, 0.79 mmol), water (0.48 mL), palladium tetrakis(triphenylphospine) (12 mg, 0.01 mmol) and a solution of 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (93 mg, 0.36 mmol) in ethanol (0.55 mL). The mixture was refluxed for 18 hours. The mixture was then cooled at room temperature and water (5 mL) was added. The aqueous layer was extracted with toluene (2 x 5 mL). The organic layers were washed with a 1 M sodium hydroxide aqueous solution (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide methyl 2-(fert-butoxy)-2-[2-(3,4-dihydro-2H-1 -benzopyran-6- yl)phenyl]acetate (1d) (43 mg, 0.12 mmol, 60%) as a white solid. 1 H NMR (400 MHz, CDCI3) J0.99 (s, 9H), 2.04-2.07 (m, 2H), 2.80-2.86 (m, 2H), 3.68 (s, 3H), 4.24 (dd, J = 4.8, 6.0 Hz, 2H), 5.21 (s, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 1 .6 Hz, 1 H), 7.12 (dd, J = 1 .6, 8.4 Hz, 1 H), 7.21 (dd, J = 1 .6, 7.2 Hz, 1 H), 7.28-7.36 (m, 2H), 7.66 (dd, J = 1.6, 7.2 Hz, 1 H).MS m/z ([M+Na]+) 377.

Reference： [1]Patent: EP2511273,2012,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 61-63

13
[ 1002727-88-9 ]
[ 1402890-80-5 ]
[ 1402890-81-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 18h;Reflux;	Step 2: Preparation of intermediate methyl 2-(tert-butoxy)-2-[1-(3,4-dihydro-2H-1-benzopyran-6-yl)naphthalen-2-yl]acetate (2b) To a solution of methyl 2-(1-bromonaphthalen-2-yl)-2-(tert-butoxy)acetate (2a) (60 mg, 0.17 mmol) in toluene (1.1 mL) was added sodium carbonate (72 mg, 0.68 mmol), water (0.48 mL), palladium tetrakis(triphenylphospine) (10 mg, 0.085 mmol) and a solution of <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (80 mg, 0.31 mmol) in ethanol (0.55 mL). The mixture was refluxed for 18 hours. The mixture was then cooled at room temperature and water (5 mL) was added. The aqueous layer was extracted with toluene (2 x 5 mL). The organic layers were washed with a 1 M sodium hydroxide aqueous solution (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95/5) to provide methyl 2-(tert-butoxy)-2-[1-(3,4-dihydro-2H-1-benzopyran-6-yl)naphthalen-2-yl]acetate (2b) (46 mg, 0.11 mmol, 66%) as a white solid and a mixture of atropoisomers. 1H NMR (300 MHz, CDCl3) delta1.06 (s, 9H), 2.08-2.13 (m, 2H), 2.73-2.89 (m, 2H), 3.63 and 3.65 (2s, 3H), 4.27-4.32 (m, 2H), 5.11 and 5.12 (2s, 1H), 6.90-7.15 (m, 3H), 7.33-7.52 (m, 3H), 7.77-7.87 (m, 3H). MS m/z ([M+Na]+) 427.

Reference： [1]Patent: EP2511273,2012,A1 .Location in patent: Page/Page column 45

14
[ 1002727-88-9 ]
[ 1402890-92-9 ]
[ 1402890-93-0 ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;	A mixture of methyl 2-(ferf-butoxy)-2-(2-chloro-5-nitro-4-phenoxyphenyl)acetate (4e) (69 mg, 0.175 mmol), sodium carbonate (74 mg, 0.7 mmol), 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)chroman (68 mg, 0.26 mmol) and palladium tetrakis(triphenylphospine) (10mg, 0.08mmol) in degassed A/JV-dimethylformamide (1 .5 mL) and water (0.5 mL) was heated at 100 C for 4 hours. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 ml_). The organic layer was washed with brine (2 x 5 ml_), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 90/10) to provide methyl 2-(ferf-butoxy)-2-[2-(3,4-dihydro-2H-1 -benzopyran-6-yl)-5-nitro-4- phenoxyphenyl]acetate (4f) (29 mg, 0.059 mmol, 33%) as a yellow oil.1 H NMR (300 MHz, CDCI3) J 1 .03 (s, 9H), 1 .99-2.07 (m, 2H), 2.76-2.81 (m, 2H), 3.72 (s, 3H), 4.20-4.24 (m, 2H), 5.12 (s, 1 H), 6.81 -6.84 (m, 2H), 6.95 (d, J = 2.0 Hz, 1 H), 7.00 (dd, J = 2.0 8.2 Hz, 1 H), 7.06-7.09 (m, 2H), 7.13-7.18 (m, 1 H), 7.33-7.38 (m, 2H), 8.30 (s, 1 H).
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 4h;	Step 6: Preparation of intermediate methyl 2-(tert-butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-5-nitro-4-phenoxyphenyl]acetate (5f) A mixture of methyl 2-(tert-butoxy)-2-(2-chloro-5-nitro-4-phenoxyphenyl)acetate (5e) (69 mg, 0.175 mmol), sodium carbonate (74 mg, 0.7 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (68 mg, 0.26 mmol) and palladium tetrakis(triphenylphospine) (10mg, 0.08mmol) in degassed N,N-dimethylformamide (1.5 mL) and water (0.5 mL) was heated at 100C for 4 hours. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 mL). The organic layer was washed with brine (2 x 5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 90/10) to provide methyl 2-(tert-butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-5-nitro-4-phenoxyphenyl]acetate (5f) (29 mg, 0.059 mmol, 33%) as a yellow oil. 1H NMR (300 MHz, CDCl3) delta1.03 (s, 9H), 1.99-2.07 (m, 2H), 2.76-2.81 (m, 2H), 3.72 (s, 3H), 4.20-4.24 (m, 2H), 5.12 (s, 1H), 6.81-6.84 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 2.0 8.2 Hz, 1H), 7.06-7.09 (m, 2H), 7.13-7.18 (m, 1H), 7.33-7.38 (m, 2H), 8.30 (s, 1H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 69; 71-72
[2]Patent: EP2511273,2012,A1 .Location in patent: Page/Page column 51

15
[ 1002727-88-9 ]
[ 1403382-22-8 ]
[ 18107-18-1 ]
[ 1403382-23-9 ]

Yield	Reaction Conditions	Operation in experiment
77%		A degassed solution of ethyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6- (trifluoromethyl)phenyl}-2-oxoacetate (34d) (478 mg, 1 .16 mmol), potassium carbonate (641 mg, 4.64 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)chroman (392 mg, 1 .51 mmol) and palladium tetrakis(triphenylphosphine) (134 mg, 0.12 mmol) in dioxane (10 mL) and water (2 mL) was heated at 85 C overnight. Water (10 mL) was added and dioxane was evaporated in vacuo. Diethyl ether (10 mL) was added and the layers were separated. The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (10 mL). The combined aqueous layers were acidified with 37% hydrochloric acid until pH 2 then extracted with diethyl ether (2x20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in cyclohexane (5 mL) and methanol (2.5 mL) at 0C and a 2M solution of trimethylsilyldiazomethane in diethyl ether (4 mL, 8 mmol) was added. The mixture was stirred at room temperature for 15 minutes, cooled at 0C and acetic acid was added until the end of bubbling. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL), washed with a saturated solution of sodium hydrogenocarbonate (10 mL), brine (10 mL) , dried over sodium sulfate and concentrated in vacuo to provide methyl 2-[2-(3,4- dihydro-2 - -1 -benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl) phenyl]-2-oxoacetate (34e) (343 mg, 0.90 mmol, 77%) as a yellow solid which was used without further purification.1 H NMR (400 MHz, CDCI3) 1 .98-2.04 (m, 2H), 2.77 (t, J = 6.4 Hz, 2H), 3.57 (s, 3H), 4.19-4.22 (m, 2H), 6.81 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 1 .0 Hz, 1 H), 6.95 (dd, J = 1 .0 Hz, J = 8.4 Hz, 1 H), 7.35 (t, J = 8.6 Hz, 1 H), 7.73 (dd, J = 4.8 Hz, J = 8.6 Hz, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 156; 158

16
[ 1002727-88-9 ]
[ 1403381-18-9 ]
[ 1403381-19-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃;	A mixture of methyl 2-(2-bromo-3-methylphenyl)-2-(ferf-butoxy)acetate (11 c) (72 mg, 0.23 mmol), sodium carbonate (97 mg, 0.91 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (104 mg, 0.41 mmol) and palladium tetrakis(triphenylphosphine) (13 mg, 0.01 1 mmol) in a mixture of toluene (1 .1 mL), water (0.55 mL) and ethanol (0.48 mL) was heated at 85C overnight. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with toluene (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to provide methyl 2-(ferf-butoxy)-2-[2-(3,4-dihydro-2H-1 -benzopyran-6-yl)-3- methylphenyl]acetate (11d) (66 mg, 0.18 mmol, 78%) as a colorless oil.1 H NMR (300 MHz, CDCI3) S- .02 and 1 .03 (s, 9H), 2.04-2.09 (m, 5H), 2.76-2.85 (m, 2H), 3.61 and 3.62 (s, 3H), 4.22-4.26 (m, 2H), 4.89 and 4.90 (s, 1 H), 6.83-6.94 (m, 3H), 7.17-7.27 (m, 2H), 7.50 (t, J = 8.1 Hz, 1 H).MS m/z ([M+Na]+) 391 .

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 86; 88

17
[ 1002727-88-9 ]
[ 1403381-21-4 ]
[ 1403381-22-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃;	A mixture of ethyl 2-ethoxy-2-{2-[(trifluoromethane) sulfonyloxy]naphthalen-1 - yljacetate (12c) (82 mg, 0.20 mmol), sodium carbonate (86 mg, 0.81 mmol), 6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (94 mg, 0.36 mmol) and palladium tetrakis(triphenylphospine) (12 mg, 0.010 mmol) in toluene (1 .1 mL), water (0.55 mL) and ethanol (0.48 mL) was heated at 85 C overnight. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with toluene (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to provide ethyl 2-[2-(3,4-dihydro-2H-1 -benzopyran-6-yl)naphthalen-1 -yl]-2-ethoxyacetate (12d) (55 mg, 0.14 mmol, 69%) as a colorless oil.1 H NMR (300 MHz, CDCI3) £1 .08-1 .13 (m, 6H), 2.04-2.10 (m, 2H), 2.84 (t, J = 6.4 Hz, 2H), 3.28-3.35 (m, 1 H), 3.46-3.54 (m, 1 H), 4.04 (dq, J = 10.7 7.1 Hz, 1 H), 4.17-4.27 (m, 3H), 5.48 (s, 1 H), 6.86 (d, J = 8.3 Hz, 1 H), 7.16 (broad s, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.44-7.52 (m, 2H), 7.95-7.85 (m, 2H), 8.45 (d, J = 8.2 Hz, 1 H).MS m/z ([M+Na]+) 413.

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 89-90

18
[ 1002727-88-9 ]
[ 1403381-24-7 ]
[ 1403381-25-8 ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃;	A mixture of methyl 2-(ferf-butoxy)-2-(2-chloro-5-nitrophenyl)acetate (13b) (48 mg, 0.16 mmol), sodium carbonate (67 mg, 0.64 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (74 mg, 0.29 mmol) and palladium tetrakis(triphenylphospine) (9 mg, 0.008 mmol) in toluene (1 .1 mL), water (0.55 mL) and ethanol (0.48 mL) was heated at 85C overnight. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with toluene (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide methyl 2-(ferf-butoxy)-2-[2-(3,4-dihydro-2 - -1 -benzopyran-6-yl)-5-nitrophenyl]acetate (13c) (29 mg, 0.072 mmol, 45%) as a yellow oil.1 H NMR (300 MHz, CDCI3) 1 .02 (s, 9H), 2.03-2.1 1 (m, 2H), 2.81 -2.86 (m, 2H), 3.70 (s, 3H), 4.24-4.28 (m, 2H), 5.21 (s, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 7.09 (dd, J = 2.4 8.4 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 8.14 (dd, J = 2.4 8.4 Hz, 1 H), 8.56 (d, J = 2.4 Hz, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 91-92

19
[ 1002727-88-9 ]
[ 1403381-28-1 ]
[ 1403381-29-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃;Inert atmosphere;	A mixture of methyl 2-(fert-butoxy)-2-{3-[(trifluoromethane)sulfonyloxy]naphthalen-2- yljacetate (14b) (90 mg, 0.21 mmol), sodium carbonate (91 mg, 0.86 mmol), and 6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (100 mg, 0.39 mmol) ) in a mixture of toluene (1 .26 ml_), ethanol (0.6 ml.) and water (0.5 ml.) was bubbled with nitrogen for 5 minutes. Palladium tetrakis(triphenylphospine) (12 mg, 0.01 mmol) was added and the reaction mixture was heated at 95 C overnight. After cooling to room temperature, water (2 ml.) was added. The aqueous layer was extracted with toluene (2 x 8 ml_). The organic layers were washed with brine (5 ml_), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to provide methyl 2-(ferf-butoxy)-2-[3- (3,4-dihydro-2 - -1 -benzopyran-6-yl)naphthalen-2-yl] acetate (14c) (70 mg, 0.17 mmol, 81 %).1 H NMR (300 MHz, CDCI3) J1 .05 (s, 9H), 2.04-2.12 (m, 2H), 2.80-2.89 (m, 2H), 3.67 (s, 3H), 4.27 (t, J = 5.2 Hz, 2H), 5.53 (s, 1 H), 6.89 (d, J = 8.3 Hz, 1 H) 7.14-7.22 (m, 2H), 7.44-7.48 (m, 2H), 7.69 (s, 1 H), 7.77-7.80 (m, 1 H), 7.85-7.91 (m, 1 H), 8.16 (s, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 94-95

20
[ 1002727-88-9 ]
[ 1403381-32-7 ]
[ 1403381-33-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃;	A mixture of 2-(methoxymethoxy)-2-{2-[(trifluoromethane)sulfonyloxy]naphthalen-1 - yljacetate (15c) (150 mg, 0.36 mmol), sodium carbonate (151 mg, 1 .42 mmol), 6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (166 mg, 0.64 mmol) and palladium tetrakis(triphenylphospine) (21 mg, 0.018 mmol) in a mixture of toluene (1 .1 mL), water (0.55 mL) and ethanol (0.48 mL) was heated at 95 C overnight. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with toluene (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 90/10) to provide ethyl 2-(methoxymethoxy)-2-[2-(3,4-dihydro-2 - -1 -benzopyran-6- yl)naphthalen-1 -yl]acetate (15d) (69 mg, 0.17 mmol, 48%) as a colorless oil.1 H NMR (300 MHz, CDCI3) J1 .14 (t, J = 7.1 Hz, 3H), 2.03-2.1 1 (m, 2H), 2.84 (t, J = 6.4Hz, 2H), 3.18 (s, 3H), 4.00-4.27 (m, 4H), 4.57 (d, J = 6.6Hz, 1 H), 4.74 (d, J = 6.6Hz, 1 H), 5.80 (s, 1 H), 6.87 (d, J = 8.4Hz, 1 H), 7.16-7.19 (m, 2H), 7.37 (d, J = 8.4Hz, 1 H), 7.47-7.56 (m, 2H), 7.80-7.87 (m, 2H), 8.41 (d, J = 8.3Hz, 1 H).MS m/z ([M+Na]+) 429.

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 96-98

21
[ 1002727-88-9 ]
[ 1403381-37-2 ]
[ 1403381-38-3 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 20h;	To a solution of ethyl 2-(ferf-butoxy)-2-{2-[(trifluoromethane)sulfonyloxy]cyclohex-1 - en-1 -yl}acetate (16c) (265 mg, 0.682 mmol) in a mixture of toluene (2.65 ml.) and ethanol (0.7 ml.) was added a solution of sodium carbonate 2M (0.682 ml_, 1 .36 mmol), palladium tetrakis(triphenylphosphine) (39.4 mg, 0.05 mmol) and 6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (195.2 mg, 0.75 mmol). The mixture was heated at 80 C for 20 hours. The mixture was then cooled at room temperature and water was added. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 90/10) to give ethyl 2-(ferf-butoxy)-2-[2-(3,4-dihydro-2H-1 - benzopyran-6-yl)cyclohex-1 -en-1 -yl]acetate (16d) (131 mg, 0.352 mmol, 52%).1 H NMR (400 MHz, CDCI3) 1 .01 -1 .02 (m, 9H), 1 .31 -1 .36 (m, 4H), 1 .65-1 .74 (m, 3H), 1 .96-2.44 (m, 6H), 2.78-2.85 (m, 2H), 4.17-4.27 (m, 4H), 4.70 (s, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.97-6.99 (m, 2H).MS m/z ([M+Na]+) 395.

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 100-102

22
[ 1002727-88-9 ]
[ 1403381-41-8 ]
[ 1403381-42-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 20h;Reflux;	To a solution of ethyl 2-(ferf-butoxy)-2-{4-[(trifluoromethane)sulfonyloxy]-2 - -chromen- 3-yl}acetate (17c) (171 mg, 0.39 mmol) in a mixture of toluene (1 .60 ml.) and ethanol (0.4 ml.) was added a solution of sodium carbonate 2M (0.39 ml_, 0.78 mmol), palladium tetrakis(triphenylphosphine) (22.5 mg, 0.05 mmol) and 6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (1 1 1 .6 mg, 0.429 mmol). The mixture was refluxed for 20 hours. The mixture was then cooled at room temperature and water was added. The aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 90/10) to give ethyl 2-(ferf-butoxy)-2-[4-(3,4-dihydro-2H-1 -benzopyran-6-yl)-2H-chromen-3- yl]acetate (1d) (129 mg, 0.306 mmol, 78%).1 H NMR (400 MHz, CDCI3) delta 1 .09 (s, 9H), 1 .29-1 .36 (m, 3H), 2.09 (m, 2H), 2.85 (m, 2H), 4.19-4.30 (m, 4H), 4.71 (s, 1 H), 4.82 (d, J = 14.8 Hz, 1 H), 5.08 (d, J = 14.0 Hz, 1 H), 6.74-6.91 (m, 5H), 7.04-7.08 (m, 1 H), 7.15 (dt, J = 1 .7,6.3 Hz, 1 H).MS m/z ([M+Na]+) 445.

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 102; 104

23
[ 1002727-88-9 ]
[ 1403381-55-4 ]
[ 1403381-56-5 ]

Yield	Reaction Conditions	Operation in experiment
14%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110℃; for 4h;	To a solution of ethyl 2-(fert-butoxy)-2-[2-methyl-4-(trifluoromethane)sulfonyloxy)-1 ,3- benzoxazol-5-yl]acetate (19g) (86 mg, 0.195 mmol), sodium carbonate (83 mg, 0.78 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (92 mg, 0.35 mmol) and palladium tetrakis(triphenylphosphine) (23 mg, 0.02 mmol) in a mixture of toluene (1 .1 mL), water (0.55 mL) and ethanol (0.48 mL) was heated at 1 10C for 4 hours. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) then by preparative TLC to provide ethyl 2-(ferf-butoxy)-2-[4-(3,4-dihydro-2H-1 - benzopyran-6-yl)-2-methyl-1 ,3-benzoxazol-5-yl]acetate (19h) (12 mg, 0.028 mmol, 14%) as a colorless oil.1 H NMR (300 MHz, CDCI3) J1 .00 (s, 9H), 1 .21 (t, J = 7.1 Hz, 3H), 2.01 -2.10 (m, 2H), 2.58 (s, 3H), 2.75-2.94 (m, 2H), 4.06-4.19 (m, 2H), 4.22-4.26 (m, 2H), 5.20 (s, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 7.16-7.20 (m, 2H), 7.43 (d, J = 8.6 Hz, 1 H), 7.65 (d, J = 8.6 Hz, 1 H).MS m/z ([M+H]+) 424.

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 109; 112-113

24
[ 1002727-88-9 ]
[ 1403381-59-8 ]
[ 1403381-60-1 ]

Yield	Reaction Conditions	Operation in experiment
39%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;	Under argon atmosphere, sodium carbonate (88.6 mg, 0.84 mmol), water (5 ml_), and 2-(6-bromoquinolin-5-yl)-2-hydroxyacetate (20e) (225 mg, 0.76 mmol) were added to a solution of 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (217 mg, 0.84 mmol) in A/,A/-dimethylformamide (15 ml_). The solution was degassed under argon and palladium tetrakis(triphenylphosphine) (263 mg, 0.23 mmol) was added. The mixture was heated at 100C for 4 hours. The mixture was then cooled at room temperature, water was added and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5 to 6/4), to give methyl 2-[6-(3,4-dihydro-2H-1 -benzopyran-6-yl)quinolin-5-yl]-2-hydroxyacetate (20f) (105 mg, 0.30 mmol, 39%).1 H NMR (400 MHz, CDCI3) £2.04-2.10 (m, 2H), 2.84-2.87 (m, 2H), 3.66 (s, 3H), 4.24- 4.26 (m, 2H), 5.76 (s, 1 H), 6.88 (d, J = 8.3 Hz, 1 H), 7.16-7.23 (m, 2H), 7.53-7.58 (m, 1 H), 7.84-7.90 (m, 1 H), 8.15-8.19 (m, 1 H), 8.52-8.57 (m, 1 H), 8.90-8.92 (m, 1 H). MS m/z ([M+H]+) 350.

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 114; 116

25
[ 1002727-88-9 ]
[ 1403381-64-5 ]
[ 1403381-65-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; irradiated 200W;	A mixture of methyl 2-(2-bromo-3-trifluoromethylphenyl)-2-(ferf-butoxy)acetate (21 c) (137 mg, 0.37 mmol), sodium carbonate (157 mg, 1 .48 mmol), 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)chroman (145 mg, 0.56 mmol) and palladium tetrakis(triphenylphosphine) (21 mg, 0.02 mmol) in dioxane (3 mL) and water (1 .5 mL) was irradiated (200W, 80C) for 1 hour. The mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to provide methyl 2-(ferf-butoxy)-2-[2-(3,4-dihydro-2/- -1 -benzopyran-6- yl)-3-trifluoromethylphenyl]acetate (21 d) (1 14 mg, 0.26 mmol, 70%) as a yellow oil. 1 H NMR (400 MHz, CDCI3) delta 1 .03 and 1 .05 (s, 9H), 2.05-2.08 (m, 2H), 2.79-2.83 (m, 2H), 3.61 (s, 3H), 4.24-4.26 (m, 2H), 4.83 and 4.84 (s, 1 H), 6.82-6.94 (m, 3H), 7.43- 7.50 (m, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.87-7.93 (m, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 118-120

26
[ 1002727-88-9 ]
[ 1049093-75-5 ]
[ 1403381-69-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene;Reflux;	A mixture of 5-(benzyloxy)-2-formylphenyl trifluoromethanesulfonate (23a) (1 .45 g, 4.02 mmol), sodium carbonate (1 .70 g, 16.08 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (1 .57 g, 6.04 mmol) and palladium tetrakis(triphenylphosphine) (232 mg, 0.20 mmol) in a mixture of toluene (19 mL) ethanol (8 mL) and water (10 mL) was refluxed overnight. The mixture was poured into water (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to provide methyl 4-(benzyloxy)-2-(3,4-dihydro-2 - -1 - benzopyran-6-yl)benzaldehyde (23b) (1 .18 g, 3.42 mmol, 85%) as a white solid.1 H NMR (400 MHz, CDCI3) 2.03-2.07 (m, 2H), 2.84 (t, J = 8.0 Hz, 2H), 4.23-4.26 (m, 2H), 5.16 (s, 2H), 6.87 (d, J = 8.0 Hz, 1 H), 6.95 (d, J = 1 .0 Hz, 1 H), 7.01 -7.04 (m, 2H), 7.09 (dd, J = 1 .0 Hz, J= 8.0 Hz, 1 H), 7.35-7.45 (m, 5H), 7.99 (d, J = 8.0 Hz, 1 H), 10.13 (s, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 123-124

27
[ 1002727-88-9 ]
[ 1403381-86-1 ]
[ 1403381-87-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;	Under argon atmosphere, methyl 2-(4-benzyl-6-bromo-5-oxo-2,3,4,5-tetrahydro-1 ,4- benzoxazepin-7-yl)-2-(ferf-butoxy)acetate (25i) (49 mg, 0.10 mmol), 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (28.1 mg, 0.1 1 mmol) and sodium carbonate (1 1 .4 mg, 0.1 1 mmol) were dissolved in A/,A/-dimethylformamide/H20 (2.3 ml./ 0.7 ml_). The solution was degassed under Argon and palladium tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol) was added. The mixture was heated at 100 C for 16 hours. The mixture was then cooled at room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 60/40) to afford methyl 2-[4-benzyl-6-(3,4-dihydro-2H-1 - benzopyran-6-yl)-5-oxo-2,3,4,5-tetrahydro-1 ,4-benzoxazepin-7-yl]-2-(ferf- butoxy)acetate (25j) (20 mg, 0.04 mmol, 36%).1 H NMR (400 MHz, CDCI3) 0.98 and 1 .01 (s, 9H), 2.02-2.1 1 (m, 2H), 2.69-2.93 (m, 2H), 3.28-3.61 (m, 2H), 3.63 and 3.66 (s, 3H), 4.00-4.17 (m, 2H), 4.22-4.26 (m, 2H), 4.51 -4.58 (m, 1 H), 4.80-4.86 (m, 1 H), 5.07 and 5.08 (s, 1 H), 6.81 -6.84 (m, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 7.03 (d, J = 8.1 Hz, 1 H), 7.16-7.21 (m, 1 H), 7.22-7.34 (m, 5H), 7.70 (dd, J = 8.6 and 9.7 Hz, 1 H). MS m/z ([M+H]+) 530.

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 128; 132-133

28
[ 1002727-88-9 ]
[ 1403381-95-2 ]
[ 1403381-96-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 1h;irradiated 200W;	A mixture of 2-formyl-3,6-dimethylphenyltrifluoromethanesulfonate (27b) (300 mg, 1 .06 mmol), sodium carbonate (449 mg, 4.2 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (359 mg, 1 .38 mmol) and palladium tetrakis(triphenylphosphine) (62 mg, 0.053 mmol) in a mixture of toluene (3 mL), ethanol (1 mL) and water (1 .5 mL) was irradiated (200W, 80C) for 1 hour. The mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to provide 2-(3,4- dihydro-2 - -1 -benzopyran-6-yl)-3,6-dimethylbenzaldehyde (27c) (160 mg, 0.60 mmol, 57%) as a yellow oil.1 H NMR (400 MHz, CDCI3) delta 1 .98-2.05 (m, 2H), 2.10 (s, 3H), 2.58 (s, 3H), 2.78-2.82 (m, 2H), 4.20-4.24 (m, 2H), 6.83-6.90 (m, 3H), 7.14 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 9.80 (s, 1 H).
57%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 80℃; for 1h;Irradiation;	Step 3: Preparation of intermediate 2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3,6-dimethyl benzaldehyde (62c) A mixture of 2-formyl-3,6-dimethylphenyltrifluoromethanesulfonate (62b) (300 mg, 1.06 mmol), sodium carbonate (449 mg, 4.2 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (359 mg, 1.38 mmol) and palladium tetrakis(triphenylphosphine) (62 mg, 0.053 mmol) in a mixture of toluene (3 mL), ethanol (1 mL) and water (1.5 mL) was irradiated (200 W, 80 C.) for 1 hour. The mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2*10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to provide 2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3,6-dimethylbenzaldehyde (62c) (160 mg, 0.60 mmol, 57%) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 1.98-2.05 (m, 2H), 2.10 (s, 3H), 2.58 (s, 3H), 2.78-2.82 (m, 2H), 4.20-4.24 (m, 2H), 6.83-6.90 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 9.80 (s, 1H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 137-138
[2]Patent: US2016/152543,2016,A1 .Location in patent: Paragraph 1197; 1202; 1203

29
[ 1002727-88-9 ]
[ 1403382-02-4 ]
[ 1403382-03-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 3h;irradiated 200W;	A mixture of methyl 2-bromo-3-[1 -(terf-butoxy)-2-methoxy-2-oxoethyl]benzoate (28e) (300 mg, 0.835 mmol), sodium carbonate (354 mg, 3.54 mmol), 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (304 mg, 1 .17 mmol) and palladium tetrakis(triphenylphosphine) (48 mg, 0.041 mmol) in dioxane (3.6 mL) and water (1 .4 mL) was irradiated (200W, 80 C) for 3 x 1 hour. The mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide methyl 3-[1 -(ferf-butoxy)-2-methoxy-2- oxoethyl]-2-(3,4-dihydro-2H-1 -benzopyran-6-yl)benzoate (28f) (339 mg, 0.821 mmol, 98%) as a yellow oil.1 H NMR (400 MHz, CDCI3) 1 .00 (s, 9H), 1 .95-2.10 (m, 2H), 2.60-2.85 (m, 2H), 3.59 and 3.60 (s, 3H), 3.62 and 3.64 (s, 3H), 4.22-4.25 (m, 2H), 4.98 and 5.01 (s, 1 H), 6.78-6.88 (m, 2H), 6.97-7.08 (m, 1 H), 7.38-7.43 (m, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.80-87 (m, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 141; 143

30
[ 1002727-88-9 ]
[ 1403382-06-8 ]
[ 1403382-07-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85℃;	A mixture of methyl 2-(2-bromo-3-formylphenyl)-2-(ferf-butoxy)acetate (31a) (126 mg, 0.38 mmol), sodium carbonate (162 mg, 1 .53 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (149 mg, 0.57 mmol) and palladium tetrakis(triphenylphosphine) (44 mg, 0.04 mmol) in a mixture of dioxane (2 mL) and water (1 mL) was heated at 85C overnight. The mixture was poured into water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide methyl 2-(ferf-butoxy)-2-[2-(3,4-dihydro-2 - -1 -benzopyran-6-yl)-3- formylphenyl]acetate (31 b) (103 mg, 0.27 mmol, 70%) as a yellow oil.1 H NMR (300 MHz, CDCI3) 1 .01 -1 .05 (m, 9H), 2.02-2.10 (m, 2H), 2.70-2.85 (m, 2H), 3.65 and 3.66 (s, 3H), 4.24-4.28 (m, 2H), 5.01 -5.04 (m, 1 H), 6.84-7.14 (m, 3H), 7.46-7.50 (m, 1 H), 7.90-7.96 (m, 2H), 9.71 (s, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 147-148

31
[ 1002727-88-9 ]
[ 1403382-10-4 ]
2-1-benzopyran-6-yl-3,3-dimethyl-cyclohex-1-ene carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With tetrabutylammomium bromide; potassium carbonate;palladium diacetate; In ethanol; water; at 70℃; for 3h;Inert atmosphere;	Under a nitrogen atmosphere, a solution of 2-chloro-3,3-dimethyl-cyclohex-1 - enecarbaldehyde (32a) (520 mg, 3.01 mmol), potassium carbonate (416 mg, 3.01 mmol), palladium diacetate (107 mg, 0.51 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (781 mg, 3.01 mmol) and tetrabutylammonium bromide (965 mg, 3.01 mmol) in ethanol (7 mL) and water (10 mL) was stirred at 70C for 3 hours. The mixture was then cooled at room temperature and diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane) to provide 2-1 -benzopyran-6-yl-3,3-dimethyl-cyclohex-1 - enecarbaldehyde (32b) (400 mg, 1 .48 mmol, 49%).1 H NMR (400 MHz, CDCI3) delta 1 .03 (s, 3H), 1 .04 (s, 3H), 1 .60-1 .66 (m, 2H), 1 .69-1 .77 (m, 2H), 1 .98-2.06 (m, 2H), 2.25-2.30 (m, 2H), 2.75-2.79 (m, 2H), 4.18-4.22 (m, 2H), 6.72-6.82 (m, 3H), 9.22 (s, 1 H).MS m/z ([M+H]+) 271 .

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 150-151

32
[ 1002727-88-9 ]
[ 1403382-18-2 ]
[ 1403382-19-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85℃; for 16h;Inert atmosphere;	A degassed solution of ethyl 2-(ferf-butoxy)-2-{2-[(trifluoromethane)sulfonyloxy]-6- (trifluoromethyl)phenyl}acetate (33f) (70 mg, 0.15 mmol), potassium carbonate (86 mg, 0.62 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (52 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine) (18 mg, 0.02 mmol) in dioxane (1 mL) and water (0.25 mL) was heated at 85 C for 16 hours. Water (3 mL) was added and the mixture was extracted with ethyl acetate (2x5 mL). The organic layer was washed with brine (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified twice by preparative TLC (cyclohexane/ethyl acetate 95/5 then 80/20) to provide ethyl 2-(ferf-butoxy)-2-[2-(3,4-dihydro-2H-1 -benzopyran-6-yl)-6- (trifluoromethyl)phenyl]acetate (33g) (49 mg, 0.1 1 mmol, 72%) as a colorless oil. 1 H NMR (300 MHz, CDCI3) 0.93 (s, 9H), 1 .25 (t, J = 7.2 Hz, 3H), 2.02-2.07 (m, 2H), 2.78 (t, J = 6.4 Hz, 2H), 4.17-4.25 (m, 4H), 5.23 (s, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 7.04-7.09 (m, 2H), 7.36-7.43 (m, 2H), 7.69 (dd, J = 2.1 Hz, J = 7.3 Hz, 1 H).

Reference： [1]Patent: WO2012/140243,2012,A1 .Location in patent: Page/Page column 147-148

33
[ 1002727-88-9 ]
[ 1403382-18-2 ]
[ 1403381-04-3 ]

Reference： [1]Patent: WO2012/140243,2012,A1

34
[ 1002727-88-9 ]
[ 27006-76-4 ]
[ 1402144-68-6 ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 85℃; for 24h;	Step 1 : Preparation of intermediate of 5-(3,4-dihydro-2/-/-1 -benzopyran-6-yl)-1 ,3- di methyl- 1 H-pyrazole-4-carbaldehyde (27a)A solution of 5-chloro-1 ,3-dimethyl-1 H-pyrazole-4-carboxaldehyde (200 mg, 1 .26 mmol), sodium carbonate (282 mg, 2.66 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (426 mg, 1 .64 mmol) and palladium tetrakis(triphenylphosphine) (73 mg, 0.063 mmol) in a mixture of dimethoxyethane (4 mL) and water (1 .35 mL) was heated at 85 C for 24 hours. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20 then 50/50) to provide the desired product (27a) (1 10 mg, 0.43 mmol, 34%) as a beige solid.1H NMR (400 MHz, CDCI3) 2.03-2.09 (m, 2H), 2.51 (s, 3H), 2.84 (t, J =6.4 Hz, 2H), 3.72 (s, 3H), 4.25-4.27 (m, 2H), 6.91 (d, J = 8.3 Hz, 1 H), 7.05-7.10 (m, 2H), 9.61 (s, 1 H).MS m/z ([M+H]+) 257.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 123

35
[ 1002727-88-9 ]
[ 1402144-69-7 ]

Reference： [1]Patent: WO2012/137181,2012,A1

36
[ 1002727-88-9 ]
[ 1402144-70-0 ]

Reference： [1]Patent: WO2012/137181,2012,A1

37
[ 1002727-88-9 ]
[ 1402144-71-1 ]

Reference： [1]Patent: WO2012/137181,2012,A1

38
[ 1002727-88-9 ]
[ 1402144-67-5 ]

Reference： [1]Patent: WO2012/137181,2012,A1

39
[ 1002727-88-9 ]
[ 1402143-79-6 ]
[ 1402143-80-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃; for 4.08333h;Inert atmosphere;	Step 10: Preparation of intermediate methyl 2-(terf-butoxy)-2-[2-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-5-phenylthiophen-3-yl]acetate (11j)A solution of methyl 2-(2-bromo-5-phenylthiophen-3-yl)-2-(terf-butoxy)acetate (11 i) (77 mg, 0.20 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (94 mg, 0.36 mmol) and sodium carbonate (85 mg, 0.80 mmol) in a mixture of toluene (1 .26 mL), ethanol (0.6 mL) and water (0.5 mL) was bubbled with nitrogen for 5 minutes. Palladium tetrakis(triphenylphosphine) (12 mg, 0.01 mmol) was added and the reaction mixture was heated a 95 C for 4h. After cooling to room temperature, water (2 mL) was added. The aqueous layer was extracted with toluene (2 x 8 mL). The organic layers were washed with brine (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 85/15) to provide the desired product (11j) (60 mg, 0.14 mmol, 68%).1H NMR (300 MHz, CDCI3) delta 1 .06 (s, 9H), 2.02-2.10 (m 2H), 2.82-2.89 (m 2H), 3.77 (s, 3H), 4.23-4.26 (m, 2H), 5.16 (s, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 7.23-7.38 (m, 5H), 7.46 (s, 1 H), 7.58-7.63 (m, 2H).

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 73-74

40
[ 1002727-88-9 ]
[ 1402143-84-3 ]
[ 1402143-85-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 2h;Inert atmosphere;	Step 4: Preparation of intermediate methyl 2-[2-(3,4-dihydro-2/-/-1-benzopyran-6-yl)- 1-methyl-1 H-indol-3-yl]pentanoate (12d)Under a nitrogen atmosphere, sodium carbonate (370 mg, 3.5 mmol), water (20 mL), palladium tetrakis(triphenylphosphine) (620 mg, 0.54 mmol) and 6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (904 mg, 3.48 mmol) were added to a solution of methyl 2-(2-bromo-1-methyl-1 /-/-indol-3-yl)pentanoate (1.13 g, 3.4 mmol) in N, /V-dimethylformamide (80 mL). The mixture was heated at 110C for 2 hours, concentrated in vacuo and water (40 mL) was added. The aqueous layer was extracted with ethyl acetate (2x20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired product (12d) as a white solid (1.1 g, 2.91 mmol, 86%). 1H NMR (400 MHz, CDCI3) 0.74 (t, J= 7.3 Hz, 3H), 1.04-1.18 (m, 2H), 1.87-1.99 (m, 1H), 2.03-2.15 (m, 3H), 2.82-2.90 (m, 2H), 3.55 (s, 3H), 3.63 (s, 3H), 3.71 (dd, J = 6.8 Hz, J=8.7 Hz, 1H), 4.25-4.31 (m, 2H), 6.90 (d, J=8.3 Hz, 1H), 7.05-7.15 (m, 3H), 7.21 (t, J=7.0 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H).MS m/z ([M+H]+) 378.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 76-77

41
[ 1002727-88-9 ]
[ 1402144-01-7 ]
[ 1402144-02-8 ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 1h;Inert atmosphere;	Step 8: Preparation of intermediate methyl 2-(terf-butoxy)-2-[3-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)thieno[2,3-£>]pyridin-2-yl]acetate (14h)Under a nitrogen atmosphere, sodium carbonate (16 mg, 0.15 mmol), water (1 ml_), palladium tetrakis(triphenylphosphine) (27 mg, 0.02 mmol) and 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)chroman (40 mg, 0.15 mmol) were added to a solution of methyl 2-{3-bromothieno[2,3-fc]pyridin-2-yl}-2-(te f-butoxy)acetate (14g) (55 mg, 0.15 mmol) in Lambda/,/V-dimethylformamide (4 ml_). The mixture was heated at 1 10C for 1 hour. The mixture was then cooled at room temperature, concentrated and water (20 ml_) was added. The aqueous layer was extracted with ethyl acetate (2 x 20 ml_). The organic layer was washed with brine (20 ml_), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 90/10) to afford the desired product (14h) as a white solid (30 mg, 0.07 mmol, 49%).1H NMR (400 MHz, CDCI3) 1.11 (s, 9H), 2.04-2.13 (m, 2H), 2.78-2.93 (m, 2H), 3.74(s, 3H), 4.25-4.31 (m, 2H), 5.39 (s, 1H), 6.93 (d, J= 8.3 Hz, 1H), 7.10-7.15 (m, 2H),7.23 (dd, J =4.7 Hz, J=8.1 Hz, 1H), 7.78 (dd, J= 1.6 Hz, J=8.1 Hz, 1H), 8.54 (dd, J= 1.6 Hz, J=4.7 Hz, 1H).MS m/z([M+H]+)412.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 83-84

42
[ 1002727-88-9 ]
[ 1402144-07-3 ]
[ 1402144-08-4 ]

Yield	Reaction Conditions	Operation in experiment
61%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 1h;Inert atmosphere;	Step 5: Preparation of intermediate methyl 2-(terf-butoxy)-2-[5-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-2-methyl-1 ,3-thiazol-4-yl]acetate (15e)Under a nitrogen atmosphere, sodium carbonate (22 mg, 0.21 mmol), water (1 mL), palladium tetrakis(triphenylphosphine) (32 mg, 0.03 mmol) and 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)chroman (55 mg, 0.21 mmol) were added to a solution of methyl 2-(5-bromo-2-methyl-1 ,3-thiazol-4-yl)-2-(teri-butoxy)acetate (15d) (70 mg, 0.21 mmol) in Lambda/,/V-dimethylformamide (4 mL). The mixture was heated at 1 10C for 1 hour. The mixture was then cooled at room temperature, concentrated and water (20 mL) was added. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 90/10) to afford the desired product as a white solid (48 mg, 0.13 mmol, 61 %).1H NMR (400 MHz, CDCI3) 1 .06 (s, 9H), 1 .99-2.09 (m, 2H), 2.67 (s, 3H), 2.78-2.86 (m, 2H), 3.76 (s, 3H), 4.20-4.26 (m, 2H), 5.21 (s, 1 H), 6.82 (d, J = 8.3 Hz, 1 H), 7.19- 7.25 (m, 2H).MS m/z ([M+H]+) 376.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 86-87

43
[ 1002727-88-9 ]
[ 1402144-18-6 ]
[ 1402144-19-7 ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;	Step 10: Preparation of intermediate methyl 2-(terf-butoxy)-2-[1 -(3,4-dihydro-2/-/-1 - benzopyran-6-yl)thieno[3,2- ]quinolin-2-yl]acetate (16j)Under argon atmosphere, sodium carbonate (15.7 mg, 0.15 mmol), water (0.8 ml_), and methyl 2-{1 -bromothieno[3,2- ]quinolin-2-yl}-2-(ieri-butoxy)acetate (16i) (55 mg, 0.14 mmol) were added to a solution of 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)chroman (38.5 mg, 0.15 mmol) in Lambda/,/V-dimethylformamide (3 ml_). The solution was degassed under argon and palladium tetrakis(triphenylphosphine) (47 mg, 0.04 mmol) was added. The mixture was heated at 100C for 4 hours. The mixture was then cooled at room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 70/30) to afford the desired product (16j) (19 mg, 0.04 mmol, 31 %). 1H NMR (400 MHz, CDCI3) 1 .14-1 .15 (m, 9H), 2.05-2.18 (m, 2H), 2.79-2.90 (m, 2H), 3.69-3.72 (m, 3H), 4.29-4.37 (m, 2H), 5.19-5.21 (m, 1 H), 6.94-7.08 (m, 2H), 7.12-7.17 (m, 2H), 7.85 (d, J = 9.1 Hz, 1 H), 7.99 (d, J = 9.1 Hz, 1 H), 8.08 (d, J= 9.0 Hz, 1 H), 8.80 (dd, J= 1 .6 Hz, 4.3 Hz, 1 H).MS m/z ([M+H]+) 462.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 92-93

44
[ 1002727-88-9 ]
[ 1402144-21-1 ]
[ 1402144-22-2 ]

Yield	Reaction Conditions	Operation in experiment
38%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 110℃; for 1h;Inert atmosphere;	Step 4: Preparation of intermediate ethyl 2-[4-(3,4-dihydro-2/-/-1 -benzopyran-6-yl)- 2,5-dimethyl thiophen-3-yl]-2-oxoacetate (17d)Under a nitrogen atmosphere, sodium carbonate (78 mg, 0.7 mmol), palladium tetrakis(triphenylphosphine) (81 mg, 0.07 mmol) and 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (182 mg, 0.7 mmol) were added to a solution of ethyl (4- bromo-2,5-dimethyl-thiophen-3-yl)-oxo-acetate (17c) (200 mg, 0.69 mmol) in a mixture of water (3.5 mL) and Lambda/,/V-dimethylformamide (1 1 mL). The mixture was heated at 1 10C for 1 hour. The mixture was then cooled at room temperature, concentrated in vacuo and water (30 mL) was added. The aqueous layer was extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product (17d) as a white solid (90 mg, 0.26 mmol, 38%). 1H NMR (300 MHz, CDCI3) delta 1 .08 (t, J = 7.1 Hz, 3H), 1 .96-2.07 (m, 2H), 2.26 (s, 3H), 2.64 (s, 3H), 2.77 (t, J = 6.4 Hz, 2H), 3.70 (q, J = 7.1 Hz, 2H), 4.16-4.21 (m, 2H), 6.76-6.83 (m, 2H), 6.93 (dd, J = 2.2 Hz, 8.3 Hz, 1 H).MS m/z ([M+H]+) 345.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 95-96

45
[ 1002727-88-9 ]
[ 1402144-21-1 ]
[ 1402145-08-7 ]

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 150

46
[ 1002727-88-9 ]
[ 1402144-34-6 ]
[ 1402144-35-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃; for 24h;	Step 4: Preparation of intermediate ethyl 2-(terf-butoxy)-2-[2-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-1 -benzofuran-3-yl]acetate (20d)A mixture of ethyl 2-(2-bromo-1 -benzofuran-3-yl)-2-(terf-butoxy)acetate (20c) (100 mg, 0.28 mmol), sodium carbonate (120 mg, 1 .13 mmol), 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)chroman (132 mg, 0.51 mmol) and palladium tetrakis(triphenylphosphine) (16 mg, 0.01 mmol) in toluene (1 .26 mL), water (0.50 mL) and ethanol (0.60 mL) was heated at 95 C for 24 hours. After cooling to room temperature, the mixture was poured into water (2 mL). The aqueous layer was extracted with toluene (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide the desired product (20d) (61 mg, 0.15 mmol, 53%). 1H NMR (300 MHz, CDCI3) delta lambda .lambda lambda (s, 9H), 1 .27 (t, J = 7.1 Hz, 3H), 2.05-2.1 1 (m, 2H), 2.84-2.91 (m, 2H), 4.20-4.28 (m, 4H), 5.32 (s, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 7.21 -7.35 (m, 4H), 7.52-7.59 (s, 2H).

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 103-104

47
[ 1002727-88-9 ]
methyl (3-bromo-benzo[b]thiophen-2-yl)-tert-butoxy-acetate [ No CAS ]
[ 1402144-40-4 ]

Yield	Reaction Conditions	Operation in experiment
54%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 110℃; for 1h;Inert atmosphere;	Step 5: Preparation of intermediate methyl 2-(terf-butoxy)-2-[3-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-1 -benzothiophen-2-yl]acetate (21e)Under a nitrogen atmosphere, sodium carbonate (33 mg, 0.3 mmol), palladium tetrakis(triphenylphosphine) (35 mg, 0.03 mmol) and 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (78 mg, 0.3 mmol) were added to a solution of methyl (3- bromo-benzo[fc]thiophen-2-yl)-ieri-butoxy-acetate (21 d) (100 mg, 0.28 mmol) in a mixture of water (1 ml_) and Lambda/,/V-dimethylformamide (3 ml_). The mixture was heated at 1 10C for 1 hour. The mixture was then cooled at room temperature, concentrated and water (30 ml_) was added. The aqueous layer was extracted with ethyl acetate (2 x 30 ml_). The organic layer was washed with brine (30 ml_), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product as a white solid (60 mg, 0.15 mmol, 54%). 1H NMR (400 MHz, CDCI3) 1 .10 (s, 9H), 2.05-2.13 (m, 2H), 2.78-2.93 (m, 2H), 3.73 (s, 3H), 4.25-4.30 (m, 2H), 5.37 (s, 1 H), 6.92 (d, J = 8.3 Hz, 1 H), 7.10-7.16 (m, 2H), 7.26-7.35 (m, 2H), 7.51 (d, J = 7.2 Hz, 1 H), 7.84 (d, J = 7.2 Hz, 1 H).

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 106-107

48
[ 1002727-88-9 ]
[ 1402144-51-7 ]
[ 1402144-52-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere;	Step 10: Preparation of intermediate methyl 2-(terf-butoxy)-2-[3-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-4-methyl-1 -benzothiophen-2-yl]acetate (23j)Under a nitrogen atmosphere, sodium carbonate (33 mg, 0.3 mmol), palladium tetrakis(triphenylphosphine) (35 mg, 0.03 mmol) and 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (78 mg, 0.3 mmol) were added to a solution of methyl (3- bromo-4-methyl-benzo[fc]thiophen-2-yl)-ie f-butoxy-acetate (23i) (100 mg, 0.28 mmol) in a mixture of water (1 mL) and /V,/V(-dimethylformamide (3 mL). The mixture was heated at 100C for 1 hour. The mixture was then cooled at room temperature, concentrated in vacuo and water (30 mL) was added. The aqueous layer was extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (23j) as a white solid (65 mg, 0.15 mmol, 57%). 1H NMR (400 MHz, CDCI3) £ 1 .1 1 (s, 9H), 1 .99 (s, 3H), 2.04-2.12 (m, 2H), 2.75-2.87 (m, 2H), 3.67 and 3.69 (2s, 3H), 4.23-4.31 (m, 2H), 5.12 and 5.13 (2s, 1 H), 6.74-6.80 (m, 1 H), 6.89-7.02 (m, 3H), 7.12 (t, J = 7.2 Hz, 1 H), 7.69 (d, J = 7.2 Hz, 1 H).MS m/z ([M+Na]+) 447.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 113

49
[ 1002727-88-9 ]
[ 1402144-60-8 ]
[ 1402144-61-9 ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃;	Step 5: Preparation of intermediate methyl 2-(terf-butoxy)-2-[3-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)imidazo[1 ,2-a]pyridin-2-yl]acetate (25e)To a solution of methyl 2-{3-bromoimidazo[1 ,2-a]pyridin-2-yl}-2-(terf-butoxy)acetate (25d) (60 mg, 0.175 mmol), sodium carbonate (75 mg, 0.70 mmol), 6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (82 mg, 0.32 mmol) and palladium tetrakis(triphenylphosphine) (20 mg, 0.018 mmol) in a mixture of toluene (1 .1 mL), water (0.55 mL) and ethanol (0.48 mL) was heated at 85 C overnight. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 50/50). The residue containing target compound was dissolved in ethyl acetate (5 mL) and washed with 1 M hydrochloric acid aqueous solution (5 mL). The acidic layer was basified with a saturated solution of sodium hydrogenocarbonate and extracted with ethyl acetate (2x5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired product (25e) (31 mg, 0.078mmol, 45%). 1H NMR (300 MHz, CDCI3) 1 .10 (s, 9H), 2.02-2.09 (m, 2H), 2.76-2.92 (m, 2H), 3.70 (s, 3H), 4.23-4.26 (m, 2H), 5.27 (s, 1 H), 6.68 (t, J =6.8 Hz, 1 H), 6.92 (d, J =9.0 Hz, 1 H), 7.08-7.14 (m, 1 H), 7.19-7.23 (m, 2H), 7.60 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 6.9 Hz, 1 H).MS m/z ([M+H]+) 395.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 117-118

50
[ 1002727-88-9 ]
[ 1402144-63-1 ]
[ 1402144-66-4 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃;Inert atmosphere;	Step 7: Preparation of intermediate ethyl 2-(terf-butoxy)-2-[3-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-4-methyl-1 -benzofuran-2-yl]acetate (26g)A solution of ethyl 2-(ie f-butoxy)-2-{4-methyl-3-[(trifluoromethane)sulfonyloxy]-1 - benzofuran-2-yl}acetate (26f) (60 mg, 0.137 mmol), sodium carbonate (58 mg, 0.246 mmol), and 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (64 mg, 0.246 mmol) in a mixture of toluene (0.6 mL), ethanol (0.3 mL) and water (0.3 mL) was bubbled with nitrogen for 5 minutes. Palladium tetrakis(triphenylphosphine) (8 mg, 0.007 mmol) was added and the reaction mixture was heated a 95 C overnight. Water (3 mL) was added and aqueous layer was extracted with toluene (2 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide the desired product (26g) (30 mg, 0.07 mmol, 52%). 1H NMR (400 MHz, CDCI3) delta 1 .10 (s, 9H), 1 .21 -1 .30 (m, 3H), 2.02-2.1 1 (m, 2H), 2.15 (s, 3H), 2.76-2.89 (m, 2H), 4.16-4.26 (m, 2H), 4.26 (t, J = 5.2 Hz, 2H), 5.06 (s, 1 H), 6.81 -6.90 (m, 1 H), 6.94 (d, J = 7.3 Hz, 1 H), 7.05-7.16 (m, 1 H), 7.13-7.21 (m, 2H), 7.38 (d, J = 8.2 Hz, 1 H).

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 121-122

51
[ 1002727-88-9 ]
[ 57805-14-8 ]
4-1-benzopyran-6-yl-3-methyl-2-oxo-2,3-dihydro-thiazole-5-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With tetrabutylammomium bromide; potassium carbonate;palladium diacetate; In ethanol; water; at 70℃; for 3h;Inert atmosphere;	Step 3: Preparation of intermediate 4-1 -benzopyran-6-yl-3-methyl-2-oxo-2,3-dihydro- thiazole-5-carbaldehyde (33c)Under a nitrogen atmosphere, a solution of 4-chloro-3-methyl-2-oxo-2,3-dihydro- thiazole- 5-carbaldehyde (33b) (500 mg, 2.82 mmol), potassium carbonate (390 mg, 2.82 mmol), palladium diacetate (100 mg, 0.48 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (732 mg, 2.82 mmol) and tetrabutylammonium bromide (910 mg, 2.82 mmol) in ethanol (7 ml_) and water (10 ml_) was stirred at 70 C for 3 hours. The mixture was then cooled at room temperature and diluted with ethyl acetate (30 ml_) and water (30 ml_). The organic layer was washed with water (30 ml_), brine (30 ml_), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product as a white solid (270 mg, 0.98 mmol, 35%).1H NMR (400 MHz, CDCI3) £2.03-2.1 1 (m, 2H), 2.84 (t, J = 6.4 Hz, 2H), 3.22 (s, 3H), 4.25-4.30 (m, 2H), 6.93 (d, J = 8.4 Hz, 1 H), 7.08-7.14 (m, 2H), 9.36 (s, 1 H).MS m/z ([M+H]+) 276.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 137

52
[ 1002727-88-9 ]
[ 1402145-18-9 ]
[ 1402145-19-0 ]

Yield	Reaction Conditions	Operation in experiment
54%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 85℃; for 8.16667h;Inert atmosphere;	Step 5: Preparation of intermediate ethyl 2-(terf-butoxy)-2-[5-chloro-4-(3,4-dihydro- 2/-/-1 -benzopyran-6-yl)-2-methylthiophen-3-yl]acetate (44e)Under argon atmosphere, ethyl 2-(4-bromo-5-chloro-2-methylthiophen-3-yl)-2-(tert- butoxy)acetate (44d) (500 mg, 1 .35 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)chroman (351 .8 mg, 1 .35 mmol), sodium carbonate (429 mg, 4.05 mmol) were dissolved in dioxane (28 mL) and water (4 mL). The solution was degassed under argon for 10 minutes and bis(triphenylphosphine)palladium (II) dichloride (142 mg, 0,20 mmol) was added. The reaction was heated and shaken at 85 C for 8 hours. After cooling at room temperature, the mixture was filtered through celite, rinsed with methanol. The filtrate was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 97/3) to give the desired product (44e) (308 mg, 0.73 mmol, 54%).1H NMR (400 MHz, CDCI3) «51 .00 (s, 9H), 1 .24 (t, J = 7.1 Hz, 3H), 2.03-2.08 (m, 2H), 2.50 (s, 3H), 2.79-2.84 (m, 2H), 4.09-4.18 (m, 2H), 4.24 (t, J = 5.2 Hz, 2H), 4.80 (s, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 7.04-7.06 (m, 2H).

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 156-157

53
[ 1002727-88-9 ]
[ 1402063-97-1 ]
[ 1402063-98-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 2h;	Step 4: Preparation of intermediate methyl 2-(terf-butoxy)-2-[2-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-1 -benzothiophen-3-yl]acetate (4d) To a solution of methyl 2-(2-bromo-1 -benzothiophen-3-yl)-2-(terf-butoxy)acetate (4c) (40 mg, 0.1 1 mmol) in Lambda/,/V-dimethylformamide (2 mL) were successively added sodium carbonate (13 mg, 0.12 mmol), water (500 muIota_), palladium tetrakis(triphenylphosphine) (18.3 mg, 0.016 mmol) and 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)chroman (29 mg, 0.1 1 mmol). The mixture was heated at 100C for 2 hours. After cooling to room temperature, water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (4d) as a white solid (25 mg, 0.061 mmol, 55%). 1H NMR (400 MHz, CDCI3) 1 .01 (s, 9H), 2.05-2.10 (m, 2H), 2.84-2.88 (m, 2H), 3.73 (s, 3H), 4.24-4.28 (m, 2H), 5.41 (s, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 7.26-7.40 (m, 4H), 7.76 (d, J = 7.5 Hz, 1 H), 8.23 (d, J = 7.5 Hz, 1 H).MS m/z ([M+Na]+) 433.
55%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 2h;	Step 4: preparation of intermediate methyl 2-(tert-butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-benzothiophen-3-yl]acetate (4d) To a solution of methyl 2-(2-bromo-1-benzothiophen-3-yl)-2-(tert-butoxy)acetate (4c) (40 mg, 0.11 mmol) in N, N-dimethylformamide (2 mL) were successively added sodium carbonate (13 mg, 0.12 mmol), water (500 muL), palladium tetrakis(triphenylphospine) (18.3 mg, 0.016 mmol) and <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (29 mg, 0.11 mmol). The mixture was heated at 100C for 2 hours. After cooling to room temperature, water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2 * 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 90/10) to afford the desired product (4d) as a white solid (25 mg, 0.061 mmol, 55%). 1H NMR (400 MHz, CDCl3) delta 1.01 (s, 9H), 2.05-2.10 (m, 2H), 2.84-2.88 (m, 2H), 3.73 (s, 3H), 4.24-4.28 (m, 2H), 5.41 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 7.26-7.40 (m, 4H), 7.76 (d, J = 7.5 Hz, 1H), 8.23 (d, J = 7.5 Hz, 1H). MS m/z ([M+Na]+) 433.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 53-54
[2]Patent: EP2508511,2012,A1 .Location in patent: Paragraph 0097; 0101

54
[ 1002727-88-9 ]
[ 1402143-53-6 ]
[ 1402143-54-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	Step 5: Preparation of intermediate methyl 2-(terf-butoxy)-2-[5-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-2-phenyl-1 ,3-thiazol-4-yl]acetate (6d)Under a nitrogen atmosphere, sodium carbonate (8.5 mg, 0.08 mmol), water (500 mu), palladium tetrakis(triphenylphosphine) (13 mg, 0.012 mmol) and 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (21 mg, 0.078 mmol) were added to a solution of methyl 2-(5-bromo-2-phenyl-1 ,3-thiazol-4-yl)-2-(terf-butoxy)acetate (30 mg, 0.078 mmol) in N, N-dimethylformamide (2 mL). The mixture was heated at 120C for 2 hours. The mixture was then cooled at room temperature and water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2x10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (6d) as a white solid (24 mg, 0.055 mmol, 70%).1H NMR (400 MHz, CDCI3) delta 1 .1 1 (s, 9H), 2.01 -2.10 (m, 2H), 2.81 -2.88 (m, 2H), 3.74 (s, 3H), 4.22-4.28 (m, 2H), 5.47 (s, 1 H), 6.86 (d, J = 8.3 Hz, 1 H), 7.28-7.35 (m, 2H), 7.39-7.45 (m, 3H), 7.99-8.04 (m, 2H).MS m/z ([M+H]+) 438.

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 58-59

55
[ 1002727-88-9 ]
[ 1402143-71-8 ]
[ 1402143-73-0 ]

Yield	Reaction Conditions	Operation in experiment
82%		Step 5: Preparation of intermediate ethyl 2-(terf-butoxy)-2-[3-(3,4-dihydro-2/-/-1 - benzopyran-6-yl)-5-phenylthiophen-2-yl]acetate (10e)A solution of ethyl 2-(3-bromo-5-phenylthiophen-2-yl)-2-(teri-butoxy)acetate (10d) (86 mg, 0.22 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (101 mg, 0.39 mmol) and sodium carbonate (92 mg, 0.87 mmol) in a mixture of toluene (1 .26 ml_), ethanol (0.6 ml_) and water (0.5 ml_) was bubbled with nitrogen for 5 minutes. Palladium tetrakis(triphenylphosphine) (12 mg, 0.01 mmol) was added and the reaction mixture was heated at 95 C overnight. After cooling to room temperature, water (2 ml_) was added. The aqueous layer was extracted with toluene (2 x 8 ml_). The organic layers were washed with brine (5 ml_), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to provide the desired product (10e) (80 mg, 0.18 mmol, 82%).1H NMR (300 MHz, CDCI3) 1 .1 1 (s, 9H), 1 .27 (t, J = 7.1 Hz, 3H), 2.01 -2.1 1 (m, 2H), 2.80-2.89 (m, 2H), 4.17-4.28 (m, 4H), 5.34 (s, 1 H), 7.14-7.22 (m, 3H), 7.23-7.30 (m, 2H), 7.32-7.40 (m, 2H), 7.58-7.63 (m, 2H).

Reference： [1]Patent: WO2012/137181,2012,A1 .Location in patent: Page/Page column 69

56
bis(triphenylphosphine)palladium(II) dichloride [ No CAS ]
[ 1002727-88-9 ]
[ 1402145-18-9 ]
[ 1402145-19-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In 1,4-dioxane; water;	Step 5: Preparation of intermediate ethyl 2-(tert-butoxy)-2-[5-chloro-4-(3,4-dihydro-2H-11-benzopyran-6-yl)-2-methylthiophen-3-yl]acetate (1e) Under argon atmosphere, ethyl 2-(4-bromo-5-chloro-2-methylthiophen-3-yl)-2-(tert-butoxy)acetate (1d) (500 mg, 1.35 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (351.8 mg, 1.5 mmol), sodium carbonate (429 mg, 4.05 mmol) were dissolved in dioxane (28 mL) and water (4 mL). The solution was degassed under argon for 10 minutes and bis(triphenylphosphine)palladium (II) dichloride (142 mg, 0.20 mmol) was added. The reaction was heated and shaken at 85C, for 8 hours. After cooling at room temperature, the mixture was filtered through celite, rinsed with methanol. The filtrate was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 97/3) to give ethyl 2-(tert-butoxy)-2-[5-chloro-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-methylthiophen-3-yl]acetate (1e) (308 mg, 0.73 mmol, 54%). 1H NMR (400 MHz, CDCl3) delta 1.00 (s, 9H), 1.24 (t, J= 7.1 Hz, 3H), 2.03-2.08 (m, 2H), 2.50 (s, 3H), 2.79-2.84 (m, 2H), 4.09-4.18 (m, 2H), 4.24 (t, J = 5.2 Hz, 2H), 4.80 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 7.04-7.06 (m, 2H).

Reference： [1]Patent: EP2716639,2014,A1 .Location in patent: Page/Page column

57
[ 1002727-88-9 ]
[ 1403382-26-2 ]

Reference： [1]Patent: EP2719685,2014,A1
[2]Patent: EP2821104,2015,A1

58
[ 1002727-88-9 ]
[ 1403382-27-3 ]

Reference： [1]Patent: EP2719685,2014,A1
[2]Patent: EP2821104,2015,A1

59
[ 1002727-88-9 ]
[ 1596341-39-7 ]

Reference： [1]Patent: EP2719685,2014,A1

60
[ 1002727-88-9 ]
[ 1596341-40-0 ]

Reference： [1]Patent: EP2719685,2014,A1

61
[ 1002727-88-9 ]
methyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6-(trifluoromethyl)phenyl}-2-oxoacetate [ No CAS ]
[ 1596341-32-0 ]

Reference： [1]Patent: EP2719685,2014,A1 .Location in patent: Paragraph 0093

62
[ 1002727-88-9 ]
[ 1403382-22-8 ]
[ 1596341-32-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 85℃; for 20h;Inert atmosphere;	Step 5: Preparation of intermediate 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetic acid (1e) A degassed solution of ethyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6-(trifluoromethyl)phenyll-2-oxoacetate (1d) (8.0 g, 19.41 mmol), potassium carbonate (10.73 g, 77.63 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (6.56 g, 25.23 mmol) and palladium tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) in dioxane (167 mL) and water (33.5 mL) was heated at 85C for 20 hours. Water (30 mL) was added and the reaction mixture was heated at 85C for 1h more. Water (170 mL) was added and dioxane was evaporated in vacuo. Diethyl ether (2x80 mL) was added and the layers were separated. The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (170mL). The combined aqueous layers were acidified with 2N hydrochloric acid until pH 2 then extracted with diethyl ether (2x170 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetic acid (1e) (6.09g, 16.54 mmol, 85%) as a orange oil which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 1.97-2.04 (m, 2H), 2.77 (t, J = 6.5 Hz, 2H), 4.21 (t, J = 5.2 Hz, 2H), 6.81 (s, 1H), 6.92 (m, 2H), 7.39 (t, J = 8.6 Hz, 1H), 7.73 (dd, J = 8.6, 4.8 Hz, 1H).
85%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 85℃; for 21h;	Step 5: Preparation of intermediate 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetic acid (2e) A degassed solution of ethyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6-(trifluoromethyl)phenyl}-2-oxoacetate (2d) (8.0 g, 19.41 mmol), potassium carbonate (10.73 g, 77.63 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (6.56 g, 25.23 mmol) and palladium tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) in dioxane (167 mL) and water (33.5 mL) was heated at 85 C. for 20 hours. Water (30 mL) was added and the reaction mixture was heated at 85 C. for 1h more. Water (170 mL) was added and dioxane was evaporated in vacuo. Diethyl ether (280 mL) was added and the layers were separated. The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (170 mL). The combined aqueous layers were acidified with 2N hydrochloric acid until pH 2 then extracted with diethyl ether (2170 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetic acid (2e) (6.09g, 16.54 mmol, 85%) as a orange oil which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 1.97-2.04 (m, 2H), 2.77 (t, J=6.5 Hz, 2H), 4.21 (t, J=5.2 Hz, 2H), 6.81 (s, 1H), 6.92 (m, 2H), 7.39 (t, J=8.6 Hz, 1H), 7.73 (dd, J=8.6, 4.8 Hz, 1H).
	With tetrakis(triphenylphosphine) palladium(0); water; potassium carbonate; In 1,4-dioxane; at 85℃; for 0.25h;	A degassed solution of ethyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6- (trifluoromethyl)phenyl}-2-oxoacetate (1d) (478 mg, 1 .16 mmol), potassium carbonate (641 mg, 4.64 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (392 mg, 1.51 mmol) and palladium tetrakis(triphenylphosphine) (134 mg, 0.12 mmol) in dioxane (10 mL) and water (2 mL) was heated at 85C overnight. Water (10 mL) was added and dioxane was evaporated in vacuo. Diethyl ether (10 mL) was added and the layers were separated. The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (10 mL). The combined aqueous layers were acidified with 37% hydrochloric acid until pH 2 then extracted with diethyl ether (2x20 mL

Reference： [1]Patent: EP2719685,2014,A1 .Location in patent: Paragraph 0061; 0093
[2]Patent: US2016/152543,2016,A1 .Location in patent: Paragraph 0357; 0366; 0367
[3]Patent: WO2014/57103,2014,A1 .Location in patent: Page/Page column 112

63
[ 1002727-88-9 ]
[ 1403382-23-9 ]

Reference： [1]Patent: EP2719685,2014,A1

64
[ 1002727-88-9 ]
[ 1596341-66-0 ]

Reference： [1]Patent: EP2719685,2014,A1

65
[ 1002727-88-9 ]
[ 1596341-67-1 ]

Reference： [1]Patent: EP2719685,2014,A1

66
[ 1002727-88-9 ]
[ 1596341-29-5 ]

Reference： [1]Patent: EP2719685,2014,A1

67
[ 1002727-88-9 ]
C₂₅H₁₉F₃O₅ [ No CAS ]

Reference： [1]Patent: EP2719685,2014,A1

68
[ 1002727-88-9 ]
C₂₇H₁₉F₃N₂O₄ [ No CAS ]

Reference： [1]Patent: EP2719685,2014,A1

69
[ 1002727-88-9 ]
[ 1403382-28-4 ]

Reference： [1]Patent: EP2719685,2014,A1

70
[ 1002727-88-9 ]
[ 1596341-33-1 ]

Reference： [1]Patent: EP2719685,2014,A1

71
[ 1002727-88-9 ]
[ 1596341-34-2 ]

Reference： [1]Patent: EP2719685,2014,A1

72
[ 1002727-88-9 ]
[ 1596341-35-3 ]

Reference： [1]Patent: EP2719685,2014,A1

73
[ 1002727-88-9 ]
[ 1596341-13-7 ]

Reference： [1]Patent: EP2719685,2014,A1

74
[ 1002727-88-9 ]
[ 1596367-39-3 ]
[ 1596367-40-6 ]

Yield	Reaction Conditions	Operation in experiment
79%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃;	To a degassed mixture of methyl 2-(3-benzyloxy-2-bromo-6-methylphenyl)-2- hydroxyacetate (34f) (383 mg, 1.05 mmol), sodium carbonate (333 mg, 3.15 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (327 mg, 1 .26 mmol) in dioxane (4 mL) and water (0.8 mL) was added palladium tetrakis(triphenylphosphine) (121 mg, 0.10 mmol). The mixture was heated at 120C overnight. Water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20) to provide methyl 2-[3-benzyloxy-2-(3,4- dihydro-2H-1 -benzopyran-6-yl)-6-methylphenyl]-2-hydroxyacetate (34g) (347 mg, 0.83 mmol, 79%) as a yellow foam. 1H NMR (300 MHz, CDCI3) delta 2.01-2.08 (m, 2H), 2.26 and 2.28 (s, 3H), 2.78-2.82 (m, 2H), 3.09 and 3.1 1 (d, J = 2.8 Hz, 1 H), 3.70 and 3.72 (s, 3H), 4.21 -4.26 (m, 2H), 4.97 (s, 2H), 5.26 (d, J = 2.8 Hz, 1 H), 6.81-6.89 (m, 2H), 6.98-7.16 (m, 5H), 7.22-7.30 (m, 3H).
79%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃;	Step 7: Preparation of intermediate methyl 2-[3-benzyloxy-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-6-methylphenyl]-2-hydroxyacetate (1g) To a degassed mixture of methyl 2-(3-benzyloxy-2-bromo-6-methylphenyl)-2-hydroxyacetate (1f) (383 mg, 1.05 mmol), sodium carbonate (333 mg, 3.15 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (327 mg, 1.26 mmol) in dioxane (4 mL) and water (0.8 mL) was added palladium tetrakis(triphenylphosphine) (121 mg, 0.10 mmol). The mixture was heated at 120 C. overnight. Water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2*10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20) to provide methyl 2-[3-benzyloxy-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-6-methylphenyl]-2-hydroxyacetate (1g) (347 mg, 0.83 mmol, 79%) as a yellow foam. 1H NMR (300 MHz, CDCl3) delta 2.01-2.08 (m, 2H), 2.26 and 2.28 (s, 3H), 2.78-2.82 (m, 2H), 3.09 and 3.11 (d, J=2.8 Hz, 1H), 3.70 and 3.72 (s, 3H), 4.21-4.26 (m, 2H), 4.97 (s, 2H), 5.26 (d, J=2.8 Hz, 1H), 6.81-6.89 (m, 2H), 6.98-7.16 (m, 5H), 7.22-7.30 (m, 3H). MS m/z ([M+H-H2O]+) 401.
	In 1,4-dioxane; water;	Step 7: Preparation of intermediate methyl 2-[3-benzyloxy-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-6-methylphenyl]-2-hydroxyacetate (1g) To a degassed mixture of methyl 2-(3-benzyloxy-2-bromo-6-methylphenyl)-2-hydroxyacetate (1f) (383 mg, 1.05 mmol), sodium carbonate (333 mg, 3.15 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (327 mg, 1.26 mmol) in dioxane (4 mL) and water (0.8 mL) was added palladium tetrakis(triphenylphosphine) (121 mg, 0.10 mmol). The mixture was heated at 120C overnight. Water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20) to provide methyl 2-[3-benzyloxy-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-6-methylphenyl]-2-hydroxyacetate (1g) (347 mg, 0.83 mmol, 79%) as a yellow foam. 1H NMR (300 MHz, CDCl3) d 2.01-2.08 (m, 2H), 2.26 and 2.28 (s, 3H), 2.78-2.82 (m, 2H), 3.09 and 3.11 (d, J = 2.8 Hz, 1 H), 3.70 and 3.72 (s, 3H), 4.21-4.26 (m, 2H), 4.97 (s, 2H), 5.26 (d, J = 2.8 Hz, 1 H), 6.81-6.89 (m, 2H), 6.98-7.16 (m, 5H), 7.22-7.30 (m, 3H). MS m/z ([M+H-H2O]+) 401.

Reference： [1]Patent: WO2014/57103,2014,A1 .Location in patent: Page/Page column 155; 158
[2]Patent: US2016/152543,2016,A1 .Location in patent: Paragraph 0324; 0339; 0340
[3]Patent: EP2821104,2015,A1 .Location in patent: Page/Page column

75
[ 1002727-88-9 ]
[ 1403382-22-8 ]
C₂₀H₁₆F₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 85℃; for 20h;	A degassed solution of ethyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6- (trifluoromethyl)phenyl}-2-oxoacetate (1d) (8.0 g, 19.41 mmol), potassium carbonate (10.73 g, 77.63 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)chroman (6.56 g, 25.23 mmol) and palladium tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) in dioxane (167 mL) and water (33.5 mL) was heated at 85C for 20 hours

Reference： [1]Patent: WO2014/57103,2014,A1 .Location in patent: Page/Page column 97; 99; 112; 190; 192

76
[ 179897-93-9 ]
[ 1002727-88-9 ]
C₁₈H₁₇NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.2 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 14h;Inert atmosphere;	Second Step Synthesis of Compound (22) [1012] Compound (21) (50 g, 183 mmol), <strong>[1002727-88-9]2-(chroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane</strong> (57.8 g, 220 mmol) and Cs2CO3 (178 g, 550 mmol) were dissolved in dioxane (400 mL)-water (80 mL), and Pd(dppf)Cl2 (2 g, 2.4 mmol) was added under a nitrogen atmosphere, and then the mixture was heated and stirred at 90 C. for 14 hours. After cooling to room temperature, ethyl acetate and water were added, and the organic layer was washed with saturated saline, dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1), thereby obtaining compound (22) (47.2 g). [1013] LC-MS (ESI): m/z=328 [M+H]+.
47.2 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 14h;Inert atmosphere;	Second Step Synthesis of Compound (107) (0758) Compound (106) (50 g, 183 mmol), 2-(chromane-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57.8 g, 220 mmol) and Cs2 CO3 (178 g, 550 mmol) were dissolved in a solution of dioxane (400 mL) and water (80 mL), and Pd(dppf)Cl2 (2 g, 2.4 mmol) was added thereto under a nitrogen atmosphere at room temperature, and the mixture was stirred with heating at 90C for 14 hours. The mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate. The result was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 8:1) to obtain Compound (107) (47.2g). LC-MS (ESI): m/z=328[M+H]+.

Reference： [1]Patent: US2014/249306,2014,A1 .Location in patent: Paragraph 1009; 1012-1013
[2]Patent: EP2952503,2015,A1 .Location in patent: Paragraph 0758

77
[ 1002727-88-9 ]
[ 1403382-22-8 ]
[ 144-55-8 ]
[ 1596341-32-0 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; diethyl ether; water;	Step 5: Preparation of intermediate 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetic acid (2e) A degassed solution of ethyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6-(trifluoromethyl)phenyl}-2-oxoacetate (2d) (8.0 g, 19.41 mmol), potassium carbonate (10.73 g, 77.63 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (6.56 g, 25.23 mmol) and palladium tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) in dioxane (167 mL) and water (33.5 mL) was heated at 85C for 20 hours. Water (30 mL) was added and the reaction mixture was heated at 85C for 1h more. Water (170 mL) was added and dioxane was evaporated in vacuo. Diethyl ether (2x80 mL) was added and the layers were separated. The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (170mL). The combined aqueous layers were acidified with 2N hydrochloric acid until pH 2 then extracted with diethyl ether (2x170 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetic acid (2e) (6.09 g, 16.54 mmol, 85%) as a orange oil which was used without further purification. 1H NMR (300 MHz, CDCl3) d 1.97-2.04 (m, 2H), 2.77 (t, J = 6.5 Hz, 2H), 4.21 (t, J = 5.2 Hz, 2H), 6.81 (s, 1 H), 6.92 (m, 2H), 7.39 (t, J = 8.6 Hz, 1 H), 7.73 (dd, J = 8.6, 4.8 Hz, 1H).

Reference： [1]Patent: EP2821104,2015,A1 .Location in patent: Page/Page column

78
[ 1002727-88-9 ]
(S)-methyl 2-(8-bromo-2-(3-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-7-yl)-2-(tert-butoxy)acetate [ No CAS ]
(S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-8-(chroman-6-yl)-6-methylimidazo[1,2-a]pyridin-7-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In water; N,N-dimethyl-formamide; at 60℃; for 1h;Inert atmosphere;	Step 2: (S)-Methyl 2-(8-bromo-2-(3 -chlorophenyl)-6-methylimidazo [1,2- a]pyridin-7-yl)-2-(tert-butoxy)acetate (80 mg, 0.17 mmol) was then combined with 2- (chroman-6-yl)-4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolane (63 mg, 0.24 mmol), cesiumcarbonate (112 mg, 0.344 mmol), PdC12(dppf) (12 mg, 0.017 mmol) in DMF (3.1 mL) and Water (0.31 mL) at rt. The mixture was degassed, backfilled with N2 and warmed to 60 C. The reaction mixture was allowed to stir at this temp for 1 h. The reaction mixture was then concentrated, adsorbed onto Celite and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at 2 = 254 nm) to give theexpected product (S)-methyl 2-(tert-butoxy)-2-(2-(3 -chlorophenyl)-8-(chroman-6-yl)-6-methylimidazo[1,2-a]pyridin-7-yl)acetate (46 mg, 0.089 mmol, 52 % yield). ?HNMR (500MHz, CDC13) oe 7.94 - 7.82 (m, 2H), 7.82 - 7.69 (m, 2H), 7.48 - 7.37 (m,1H), 7.31 - 7.19 (m, 3H), 6.95 (m, 1H), 5.38 (br. s., 1H), 4.28 (m, 2H), 3.79 (s, 3H),2.81 (m, 2H), 2.36 (s, 3H), 2.16 - 2.04 (m, 2H), 1.04 - 0.90 (m, 9H). LC-MSretention time: 1.20 mm; mlz (MH+): 520. LC data was recorded on a ShimadzuLC-1OAS liquid chromatograph equipped with a Waters Aquity BEH C18 2.1 X 50mm 1.7 um column using a SPD-1OAV UV-Vis detector at a detector wave length of220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of98% solvent A / 2% solvent B to 98% solvent A / 2% solvent B, a gradient time of1.5 mm, a hold time of 0.5 mm, and an analysis time of 2 mm where solvent A was10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20/ 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using aMicromass Platform for LC in electrospray mode.

Reference： [1]Patent: WO2015/126765,2015,A1 .Location in patent: Page/Page column 17; 44; 45

79
[ 1002727-88-9 ]
C₁₅H₂₂BrNO₃ [ No CAS ]
C₂₄H₃₁NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl acetamide; water; at 130℃; for 1.5h;Inert atmosphere;	Fifth Step Synthesis of Compound (43) (0647) Compound (42) (4.80g, 13.9mmol) was dissolved in a mixutre of DMA (24 mL) and water (2.4 mL), and <strong>[1002727-88-9]2-(chroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane</strong> (5.44 g, 20.9 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene] palladium dichloride (1.82 g, 2.79 mmol) and potassium carbonate (3.85g, 2.79mmol) were added thereto, and the mixture was stirred under a nitrogen atmosphere at 130C for 1.5 hours. Water (200 mL) was added thereto and the mixture was extracted with ethyl acetate (200 mL). The obtained organic layer was washed with water (150 mL×2) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound (43) (5.04 g, 91%) as a brown foam. MS: m/z = 398.3 [M+H] +

Reference： [1]Patent: EP2952503,2015,A1 .Location in patent: Paragraph 0647

80
[ 1002727-88-9 ]
methyl (S)-2-(3-benzyloxy-2-bromo-6-methylphenyl)-2-(tert-butoxy)-acetate [ No CAS ]
methyl (S)-2-(tert-butoxy)-2-[3-benzyloxy-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-6-methylphenyl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 16h;Sealed tube; Inert atmosphere;	Step 4: Preparation of intermediate methyl (S)-2-(tert-butoxy)-2-[3-benzyloxy-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-6-methylphenyl]acetate (13d) In a sealed round bottom flask, to a degassed solution of methyl (S)-2-(3-benzyloxy-2-bromo-6-methylphenyl)-2-(tert-butoxy)-acetate (13c) (330 mg, 0.783 mmol) and chroman-6-boronic acid, pinacol ester (224 mg, 0.862 mmol) in dioxane (4 mL) was added a solution of sodium carbonate (249 mg, 2.35 mmol) in water (0.8 mL) followed by palladium tetrakis(triphenylphosphine) (91 mg, 0.078 mmol). The mixture was heated at 120 C. for 16 hours. The mixture was cooled at room temperature. Water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (3*10 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide methyl (S)-2-(tert-butoxy)-2-[3-benzyloxy-2-(3,4-dihydro-2H-1-benzopyran-6-yl)-6-methyl phenyl]acetate (13d) (816 mg, 1.71 mmol, 100%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 0.96 (s, 9H), 2.00-2.09 (m, 2H), 2.35 and 2.36 (s, 3H), 2.72-2.82 (m, 2H), 3.70 and 3.71 (s, 3H), 4.22-4.26 (m, 2H), 4.88-5.01 (m, 2H), 5.16 and 5.18 (s, 1H), 6.81-6.87 (m, 2H), 6.99-7.29 (m, 8H).

Reference： [1]Patent: US2016/152543,2016,A1 .Location in patent: Paragraph 0492; 0499; 0500

81
[ 1002727-88-9 ]
tert-butoxy-(7-cyclopropyl-6-trifluoromethane sulfonyloxy-quinolin-5-yl)-acetic acid ethyl ester [ No CAS ]
tert-butoxy-(6-chroman-6-yl-7-cyclopropyl-quinolin-5-yl)-acetic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With tetrakis(triphenylphosphine) palladium(0); potassium phosphate monohydrate; In 1,4-dioxane; at 160℃; for 7h;Inert atmosphere; Microwave irradiation;	Step 11: Preparation of intermediate tert-butoxy-(6-chroman-6-yl-7-cyclopropyl-quinolin-5-yl)-acetic acid ethyl ester (42k) Under argon atmosphere, tert-butoxy-(7-cyclopropyl-6-trifluoromethanesulfonyloxy-quinolin-5-yl)-acetic acid ethyl ester (42j) (758 mg, 1.59 mmol), chroman-6-boronic acid, pinacol ester (498 mg, 1.91 mmol), potassium phosphate tribasic monohydrate (732 mg, 3.18 mmol) and dioxane (6.8 mL) were added in a microwave vial Biotage (10-20 mL) with a magnetic stirrer. The mixture was degassed under argon for 10 minutes and palladium tetrakis(triphenylphosphine) (111 mg, 0.10 mmol) was added. The vial was sealed and heated in a Biotage Initiator 2.5 Microwave Synthetizer at 160 C. for 7 hours. The mixture was diluted with ethyl acetate, filtered over Celite (several washings with ethyl acetate were made) and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 85/15) to provide tert-butoxy-(6-chroman-6-yl-7-cyclopropyl-quinolin-5-yl)-acetic acid ethyl ester (42k) (277 mg, 0.60 mmol, 38%), as a mixture of atropoisomers. 1H NMR (400 MHz, CDCl3) delta 0.77-0.87 (m, 4H), 1.04 (s, 9H), 1.10-1.18 (m, 3H), 1.56-1.61 (m, 1H), 2.07-2.11 (m, 2H), 2.81-2.87 (m, 2H), 3.95-4.19 (m, 2H), 4.26-4.30 (m, 2H), 5.35-5.39 (m, 1H), 6.86-7.07 (m, 2H), 7.14-7.18 (m, 1H), 7.31 (dd, J=8.62 Hz, J=4.2 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H), 8.81 (dd, J=1.6 Hz, J=4.2 Hz, 1H), 9.01-9.04 (m, 1H). MS m/z ([M+H]+) 460.

Reference： [1]Patent: US2016/152543,2016,A1 .Location in patent: Paragraph 0876; 0907; 0908; 0909

82
[ 1002727-88-9 ]
(6-cyclopropyl-3-methyl-4-nitro-2-vinyl-phenyl) trifluoromethanesulfonate [ No CAS ]
6-(6-cyclopropyl-3-methyl-4-nitro-2-vinyl-phenyl)chromane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetrakis(triphenylphosphine) palladium(0); potassium phosphate monohydrate; In water; toluene; at 120℃;Sealed tube; Inert atmosphere;	Step 6: Preparation of intermediate 6-(6-cyclopropyl-3-methyl-4-nitro-2-vinyl-phenyl)chromane (48f) In a sealed round bottom flask, a solution of (6-cyclopropyl-3-methyl-4-nitro-2-vinyl-phenyl) trifluoromethanesulfonate (48e) (1.86 g, 5.29 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (1.51 g, 5.82 mmol) in toluene (6 mL) and water (2 mL) was degassed by bubbling argon for 10 minutes. Potassium phosphate (2.44 g, 10.59 mmol) and tetrakis(triphenylphosphine)palladium (0) (306 mg, 0.26 mmol) were added and the mixture was heated at 120 C. overnight. The mixture was diluted with toluene (20 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/dichloromethane 50/50) to provide 6-(6-cyclopropyl-3-methyl-4-nitro-2-vinyl-phenyl)chromane (48f) (1.63 g, 4.86 mmol, 91%) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 0.60-0.68 (m, 2H), 0.76-0.82 (m, 2H), 1.55-1.62 (m, 1H), 2.01-2.08 (m, 2H), 2.44 (s, 3H), 2.79 (t, J=6.5 Hz, 2H), 4.23 (dd, J=5.9 Hz, J=4.5 Hz, 2H), 5.07 (dd, J=17.9 Hz, J=1.7 Hz, 1H), 5.37 (dd, J=11.5 Hz, J=1.7 Hz, 1H), 6.31 (dd, J=17.9 Hz, J=11.5 Hz, 1H), 6.76-6.87 (m, 3H), 7.21 (s, 1H). MS m/z ([M+H]+) 336.

Reference： [1]Patent: US2016/152543,2016,A1 .Location in patent: Paragraph 0998; 1014; 1015; 1016

83
[ 1002727-88-9 ]
[ 1403382-22-8 ]
[ 1403382-23-9 ]

Yield	Reaction Conditions	Operation in experiment
77%		Step 5: Preparation of intermediate methyl 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetate (63e) A degassed solution of ethyl 2-{3-fluoro-2-[(trifluoromethane)sulfonyloxy]-6-(trifluoromethyl)phenyl}-2-oxoacetate (63d) (478 mg, 1.16 mmol), potassium carbonate (641 mg, 4.64 mmol), <strong>[1002727-88-9]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman</strong> (392 mg, 1.51 mmol) and palladium tetrakis(triphenylphosphine) (134 mg, 0.12 mmol) in dioxane (10 mL) and water (2 mL) was heated at 85 C. overnight. Water (10 mL) was added and dioxane was evaporated in vacuo. Diethyl ether (10 mL) was added and the layers were separated. The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (10 mL). The combined aqueous layers were acidified with 37% hydrochloric acid until pH 2 then extracted with diethyl ether (2*20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in cyclohexane (5 mL) and methanol (2.5 mL) at 0 C. and a 2M solution of trimethylsilyldiazomethane in diethyl ether (4 mL, 8 mmol) was added. The mixture was stirred at room temperature for 15 minutes, cooled at 0 C. and acetic acid was added until the end of bubbling. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL), washed with a saturated solution of sodium hydrogenocarbonate (10 mL), brine (10 mL), dried over sodium sulfate and concentrated in vacuo to provide methyl 2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-fluoro-6-(trifluoromethyl)phenyl]-2-oxoacetate (63e) (343 mg, 0.90 mmol, 77%) as a yellow solid which was used without further purification. 1H NMR (400 MHz, CDCl3) delta 1.98-2.04 (m, 2H), 2.77 (t, J=6.4 Hz, 2H), 3.57 (s, 3H), 4.19-4.22 (m, 2H), 6.81 (d, J=8.4 Hz, 1H), 6.86 (d, J=1.0 Hz, 1H), 6.95 (dd, J=1.0 Hz, J=8.4 Hz, 1H), 7.35 (t, J=8.6 Hz, 1H), 7.73 (dd, J=4.8 Hz, J=8.6 Hz, 1H).

Reference： [1]Patent: US2016/152543,2016,A1 .Location in patent: Paragraph 1213; 1222; 1223

84
[ 491-37-2 ]
[ 1002727-88-9 ]

Reference： [1]Patent: WO2009/62289,2009,A1

85
[ 1002727-88-9 ]
[ 1155288-13-3 ]
[ 1155288-14-4 ]

Reference： [1]Patent: WO2009/62289,2009,A1

86
[ 1002727-88-9 ]
ethyl 2‐(tert‐butoxy)‐2‐(1,3‐dichloroisoquinolin‐4‐yl)acetate [ No CAS ]
ethyl 2‐(tert‐butoxy)‐2‐(1,3‐di(chroman‐6‐yl)isoquinolin‐4‐yl)acetate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 215 - 220

87
[ 1002727-88-9 ]
ethyl 2‐(tert‐butoxy)‐2‐(3‐chloro‐1‐phenylisoquinolin‐4‐yl)acetate [ No CAS ]
ethyl 2‐(tert‐butoxy)‐2‐(3‐(chroman‐6‐yl)‐1‐phenylisoquinolin‐4‐yl)acetate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 215 - 220

88
[ 1002727-88-9 ]
ethyl 2‐(tert‐butoxy)‐2‐(3‐chloro‐1‐(3‐methoxyphenyl)isoquinolin‐4‐yl)acetate [ No CAS ]
ethyl 2‐(tert‐butoxy)‐2‐(3‐(chroman‐6‐yl)‐1‐(3‐methoxyphenyl)isoquinolin‐4‐yl)acetate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 215 - 220

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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. 1002727-88-9 ] {[proInfo.proName]}

Quality Control of [ 1002727-88-9 ]

Related Doc. of [ 1002727-88-9 ]

Product Details of [ 1002727-88-9 ]

Calculated chemistry of [ 1002727-88-9 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1002727-88-9 ]

Application In Synthesis of [ 1002727-88-9 ]

[ 1002727-88-9 ] Synthesis Path-Upstream 1~4

[ 1002727-88-9 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 1002727-88-9 ]

Organoboron

Related Parent Nucleus of [ 1002727-88-9 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1002727-88-9 ]

Related Parent Nucleus of
[ 1002727-88-9 ]