[ CAS No. 220210-56-0 ] {[proInfo.proName]}

Name: 220210-56-0|3-tert-Butoxycarbonylphenylboronic acid|98%
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Quality Control of [ 220210-56-0 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 220210-56-0 ]

CAS No. :	220210-56-0	MDL No. :	MFCD01630855
Formula :	C₁₁H₁₅BO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HVJDVHCPCSZDSR-UHFFFAOYSA-N
M.W :	222.05	Pubchem ID :	2773299
Synonyms :

Calculated chemistry of [ 220210-56-0 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.36
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	62.01
TPSA :	66.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.66
Log Po/w (WLOGP) :	0.32
Log Po/w (MLOGP) :	1.11
Log Po/w (SILICOS-IT) :	-0.11
Consensus Log Po/w :	0.6

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.28
Solubility :	1.18 mg/ml ; 0.0053 mol/l
Class :	Soluble
Log S (Ali) :	-2.68
Solubility :	0.468 mg/ml ; 0.00211 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.19
Solubility :	1.42 mg/ml ; 0.00638 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.19

Safety of [ 220210-56-0 ]

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 [ 220210-56-0 ]

* 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 [ 220210-56-0 ]
Downstream synthetic route of [ 220210-56-0 ]

[ 220210-56-0 ] Synthesis Path-Upstream 1~1

1
[ 220210-56-0 ]
[ 1083057-14-0 ]

Reference： [1] Patent: US2013/186801, 2013, A1,
[2] Patent: WO2013/185112, 2013, A1,
[3] Patent: WO2014/71122, 2014, A1,
[4] Patent: WO2015/73231, 2015, A1,
[5] Patent: US2015/231142, 2015, A1,
[6] Patent: US2016/324788, 2016, A1,
[7] Patent: WO2018/107100, 2018, A1,

[ 220210-56-0 ] Synthesis Path-Downstream 1~88

1
[ 220210-56-0 ]
[ 149418-41-7 ]
[ 850913-60-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenyl-arsane; silver(l) oxide;dichloro bis(acetonitrile) palladium(II); In tetrahydrofuran; at 50℃; for 4h;	a) 3 (3-Bromo-2-oxo-2, 5-dihvdrofuran-4-vl)-benzoic acid ter-butyl ester 3- (tert-Butoxycarbonyl)-phenylboronic acid (133mg, 0. 6mmol) and 3,4-dibromo-2 (5H) - furanone (121 mg, 0. 5mmol) were dissolved in tetrahydrofuran (5ml) under nitrogen and bis (acetonitrile) dichloropalladium (II) (13mg, 0. 05mol), triphenylarsine (31mg, 0. 1mmol) ans silver (II) oxide (348mg, 1. 5mmol) added. The mixture was stirred and heated to 50C for 4 hours. Ethyl acetate (20mi) was added and the mixture filtered through a pad of Kieselguhr. The filtrate was washed with water (x2), dried (MgS04) and evaporated. The residue was purified by chromatography on silica gel, eluting with 5-20% ethyl acetate in isohexane to give the title compound. (60mg). LC/MS Rt 3.41 min, [MH+] 339,341.

Reference： [1]Patent: WO2005/37786,2005,A1 .Location in patent: Page/Page column 39-40

2
[ 220210-56-0 ]
[ 875639-16-0 ]
[ 875639-30-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 90℃; for 0.5h;	Method 4:; Step 1: Synthesis of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid; To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.01 g, 2.21 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (20 mL total) was added (3-tert-butoxycarbonylphenyl)boronic acid (0.54 g, 2.43 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (0.90 g, 0.11 mmol) in a microwave vial. The vial was capped, flushed with N2, evacuated under vacuum, and subsequently heated in a microwave at 90 C. for 1800 seconds. The material was diluted with ethyl acetate and the organic layer was washed with H2O then dried over Na2SO4. The solution was adsorbed onto silica gel and purified by flash chromatography with a gradient of ethyl acetate and hexanes, affording 3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-benzoic acid tert-butyl ester as a white solid (1.07 g, 87% yield). 1H NMR (500 MHz, CDCl3) delta 8.68 (s, 1H), 8.17 (br s, 3H), 8.09 (s, 1H), 7.99 (m, 2H), 7.71 (d, J=6.5 Hz, 1H), 7.50 (m, 2H), 7.34 (t, J=8.0 Hz, 1H), 7.32 (d, J=6.5 Hz, 2H), 7.06 (m, 2H), 3.88 (s, 3H), 2.39 (s, 3H), 1.60 (s, 9H). MS: m/e 555.1 (M+H+).
87%	With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; acetonitrile; at 90℃; for 0.5h;Microwave irradiation;	To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-li/-pyrrolo[2,3- £]pyridine (1.01 g, 2.21 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (20 mL total) was added (3-/er?-butoxycarbonylphenyl)boronic acid (0.54 g, 2.43 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichlororhoalladium (II), complex with dichloromethane (1:1) (0.90 g, 0.11 mmol) in a microwave vial. The vial was capped, flushed with N2, evacuated under vacuum, and subsequently heated in a microwave at 90 C for 1800 seconds. The material was diluted with ethyl acetate and the organic layer was washed with H2O then dried over NaiSO,}. The solution was adsorbed onto silica gel and purified by flash chromatography with a gradient of ethyl acetate and hexanes, affording 3-[3-(2- methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H -pyrrolo[2,3-6]pyridine-5-yl]-benzoic acid ert-butyl ester as a white solid (1.07 g, 87% yield). 1H NMR (500 MHz, CDCl3) delta 8.68 (s, 1H), 8.17 (br s, 3H), 8.09 (s, 1H), 7.99 (m, 2H), 7.71 (d, J= 6.5 Hz, 1H), 7.50 (m, 2H), 7.34 (t, J= 8.0 Hz, 1H), 7.32 (d, J= 6.5 Hz, 2H), 7.06 (m, 2H), 3.88 (s, 3H), 2.39 (s, 3H), 1.60 (s, 9H). MS: m/e 555.1 (M + H+).

Reference： [1]Patent: US2006/30583,2006,A1 .Location in patent: Page/Page column 44
[2]Patent: WO2008/124849,2008,A2 .Location in patent: Page/Page column 64

3
[ 220210-56-0 ]
[ 863925-40-0 ]
[ 950594-80-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 90℃; for 6h;	Preparation 2; Tert-butyl 3-(6-(pyrrolidin-1-yl)-5,6,7,8-tetrahvdronaphthalen-2-yl}benzoateTo a solution of 1-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl) pyrrolidine (9.0 g, 28.417 mmol) In dimethoxy ethane (165 mL) was added 3-t-butoxycarbonyl phenyl boronic acid (9.465 g, 42.6255 mmol). 2 M sodium carbonate solution (71 mL) and 1,1 - bis(dirhohetiylphosphino)ferrocene palladium (II) chloride (0.23 g, 0.248) were then added to the solution. The reaction was warmed to 90 C and refluxed for 6 hours. LCMS and TLC analysis showed no starting material. The reaction was cooled to room temperature and concentrated. The reaction was diluted with ethyl acetate, washed with water x3, brine, and was dried (MgSO4), filtered, and concentrated in vacuo to give a crude yield of 13.45 g. The resulting solid was purified by flash column chromatography on 330 g silica gel, eluting with methylene chloride/methanol/ NH4OH (10:1:0.1). The pure fractions were -collected and concentrated to yield 12.23 g Tert-butyl 3-(6-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2- yl)benzoate. 400 MHz 1H NMR (CDCI3) delta 8.2 (m, 1H), 7.9 (m, 1 H), 7.7 (m, 1H)1 7.4-7.5 (m, 1H), 7.3-7.4 (m, 2H) 7.1 (m, 1H), 2.7-3.1 (m, 6H), 2.5 (brs, 1H), 2.2 (m, 1H), 1.8 (m, 3H), 1.7-18 (m, 1H)1 1.6 (s, 9H), 1. 5 (m, 3H). MS (M+1) 378.3, 379.2.

Reference： [1]Patent: WO2007/105053,2007,A2 .Location in patent: Page/Page column 18

4
[ 7752-82-1 ]
[ 220210-56-0 ]
tert-butyl 3-(2-aminopyrimidin-5-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.5%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 3h;	Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to a mixture of 5- bromopyrimidin-2-amine (0.348 g, 2.0 mmol), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (0.533 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3.0 mL) and toluene (3.0 mL). The resulting mixture was heated at 120 0C for 3 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with methanol. The precipitate was filtered and dried to give the product (399 mg, 73.5%). 272.1.

Reference： [1]Patent: WO2008/64157,2008,A1 .Location in patent: Page/Page column 68-69

5
[ 220210-56-0 ]
[ 1152274-51-5 ]
[ 1152274-55-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃;	To N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (508 mg, 1.14 mmol) in 1,2-dimethoxyethane (11 mL) was added <strong>[220210-56-0]3-(tert-butoxycarbonyl)phenylboronic acid</strong> (328 mg, 1.48 mmol), tetrakis(triphenylphosphine)palladium (0) (131 mg, 0.114 mmol), and 2 M Na2CO3 (1.71 mL, 3.41 mmol). The mixture was heated at 80 C. overnight before it was diluted with ethyl acetate (10 mL) and washed with water (20 mL). The organics were dried over Na2SO4 and evaporated. The resulting crude material was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexanes to yield tert-butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (603 mg, 97%). ESI-MS m/z calc. 544.6, found 545.3 (M+1). Retention time 2.76 minutes.

Reference： [1]Patent: US2009/143381,2009,A1 .Location in patent: Page/Page column 59

6
[ 220210-56-0 ]
[ 959918-38-8 ]
[ 959916-18-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 1.5h;Microwave irradiation;	INTERMEDIATE 62fert-Butyl 3-(4-f5.5-dimethyl-2-(mophiholin-4-yl)-7-oxo-4,5.6.7-tetrahvdrothieno\|"2.3- c"\|pyridin-3-yl]pyridin-2-yl)benzoateA mixture of Intermediate 57 (450 mg, 1.19 mmol), 3-(tert-butoxycarbonyl)- phenylboronic acid (305 mg, 1.37 mmol), potassium phosphate tribasic (375 mg, 1.77 mmol) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) in water (2.5 mL) and DME (9 mL) was heated at 1200C under microwave irradiation for 1.5 h. The reaction mixture was partitioned between EtOAc (40 mL) and sat. aqueous NaHCO3 solution (40 mL). The aqueous phase was reextracted with EtOAc (2 x 40 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-3% MeOH in DCM) to give the title compound (350 mg, 57%) as an off-white solid. deltaH (DMSO-d) 8.77 (d, J5.1 Hz, IH), 8.64 (s, IH), 8.35 (d, J7.9 Hz, IH), 8.10 (s, IH), 7.99 (d, J7.7 Hz, IH), 7.65 (t, J7.7 Hz, IH), 7.57 (s, IH), 7.48 (dd, J5.1, 1.1 Hz, IH), 3.67-3.57 (m, 4H), 2.96-2.87 (m, 4H), 2.72 (s, 2H), 1.59 (s, 9H), 1.20 (s, 6H). LCMS (ES+) 520.2 (M+H)+.

Reference： [1]Patent: WO2009/71895,2009,A1 .Location in patent: Page/Page column 122

7
[ 3430-17-9 ]
[ 220210-56-0 ]
[ 1083057-12-8 ]

Yield	Reaction Conditions	Operation in experiment
82%		Synthesis of t°rf-butyl-3-(3-methylpyridin-2-yl)benzoate (compound 4).1. toluene, 2M K2CO3tBu[00259] 2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 0C under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 0C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). <n="55"/>The organic layer is concentrated to afford crude compound 4 (82%) that is used directly in the next step.
82%		2-Bromo-3-methylpyridine (1.0 eq.) was dissolved in toluene (12 vol). K2CO3 (4.8 equivalents) and water (3.5 volumes) were added in that order. The resulting mixture was heated to 65 C under a stream of N 2 and held for 1 hour. Then 3-(t-butoxycarbonyl)phenylboronic acid (1.05 equivalents) and Pd(dppf)Cl2CH2Cl2 (0.015 eq.) were added and the mixture was heated to 80 C. After 2 hours, the heater was turned off, water (3.5 vol) was added and the layers were separated. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous m. The aqueous phase was made basic with 50% aq. EtOAc (2 EtOAc). The organic layer was concentrated to give crude 3-(3-methylpyridin-2-yl)benzoic acid butyl ester (82%) which was used directly in the next step.
		2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 0C under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 0C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). <n="24"/>The organic layer is concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that is used directly in the next step.

		2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 0C under a stream of N2 for 1 hour. 3-(?-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 0C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer is concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that is used directly in the next step.
		Preparation of tert-butyl-3-(3-methylpyridin-2-yl)benzoate 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step.
		2-Bromo-3-methylpy:ridine (1.0 eq) was dissolved in toluene (12 vol). K2C03 (4.8eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 oc under astream ofN2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (L05 eq) andPd(dppf)Ch·CH2CI2 (0.(H5 eq) were then added and the mixture was heated to 80 oc After 2hours, the heat was turned oft~ water was added (3.5 vol), and the layers were allowed toseparate. The organic phase was then washed with water (3.5 vol) and extracted with 10%)aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic withS0%1 aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer wasconcentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was useddirectly in the next step.
		[00299] 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2C03 ( 4.8 eq)was added, followed by water (3.5 vol). The resulting mixture was heated to 65 oc under astream ofN2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) andPd(dppf)Cb·CH2Cb (0.015 eq) were then added and the mixture was heated to 80 C. After 2hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed toseparate. The organic phase was then washed with water (3.5 vol) and extracted with 10%aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer wasconcentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was useddirectly in the next step.
		[00314] 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2C03 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C under a stream of N2 for 1 hour. 3-(^-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2 CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude /er^-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; toluene; at 80℃; for 2h;Inert atmosphere;	2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step. 2-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; toluene; at 80℃; for 2h;Inert atmosphere;	Preparation of tert-butyl-3-(3-methylpyridin-2-yl)benzoate 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step.
		10 g of 2-bromo-3-methyl pyridine was dissolved in 120 ml of toluene. 38.5 g ofpotassium carbonate was added followed by 35 ml of water and the mixture heated to65 C under N2 atm for 1 hour. 13.55 g (t-butoxycarbonyl)phenylboronic acid and 0.72 gPd(dppf)C12 were added. The reaction mixture was heated to 80 C. After completion ofreaction, the reaction mass was cooled, 35 ml water was added and stined for 15 mm.The layers were separated. The organic layer was washed with 35 ml water and extracted with 230 ml 10% methane sulfonic acid. The aqueous layer was basified with 50% NaOH and extracted with 100 ml ethyl acetate. The organic layer was concentrated under vacuum to afford 13 g crude tert-butyl-3(3-methylpyridin-2-yl)benzoate (83.3 % yield).

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 3662 - 3674
[2]Patent: WO2009/76142,2009,A2 .Location in patent: Page/Page column 53-54
[3]Patent: TWI636051,2018,B .Location in patent: Sheet 76; 77
[4]Patent: WO2009/73757,2009,A1 .Location in patent: Page/Page column 22
[5]Patent: WO2010/37066,2010,A2 .Location in patent: Page/Page column 12; 27
[6]Patent: US2013/186801,2013,A1 .Location in patent: Paragraph 0367; 0368
[7]Patent: WO2013/185112,2013,A1 .Location in patent: Paragraph 00567
[8]Patent: WO2014/71122,2014,A1 .Location in patent: Paragraph 00146; 00147; 00298; 00299
[9]Patent: WO2015/73231,2015,A1 .Location in patent: Paragraph 00313-00314
[10]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 1411
[11]Patent: US2016/324788,2016,A1 .Location in patent: Paragraph 0367; 0368
[12]Patent: WO2017/17696,2017,A1 .Location in patent: Page/Page column 21; 22
[13]Patent: WO2018/107100,2018,A1 .Location in patent: Paragraph 00252
[14]Patent: WO2019/18395,2019,A1 .Location in patent: Paragraph 00200

8
[ 20090-58-8 ]
[ 220210-56-0 ]
[ 1185856-26-1 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Step c: tert-Butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoateTo 4-chloro-5-methylpyrimidin-2-amine (150 mg, 1.04 mmol), tetrakistriphenylphosphine Palladium (0) (60 mg, 0.052 mmol) and <strong>[220210-56-0]3-(tert-butoxycarbonyl)phenylboronic acid</strong> (347 mg, 1.56 mmol), 1,2-DME (3 mL) and Na2CO3 (1.04 mL, 2 M, 2.08 mmol) were added and heated to 120 C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using EtOAc and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoate (148 mg, 50%). ESI-MS m/z calc. 285.1, found 286.5 (M+1)+. Retention time 1.33 minutes.

Reference： [1]Patent: US2009/221597,2009,A1 .Location in patent: Page/Page column 41

9
[ 1681-36-3 ]
[ 220210-56-0 ]
[ 1189328-78-6 ]

Yield	Reaction Conditions	Operation in experiment
71.4%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 60h;	4-Chloro-3-methylpyridine (2.00 g, 15.7 mmol), <strong>[220210-56-0]3-(tert-butoxycarbonyl)phenylboronic acid</strong> (5.42 g, 24.4 mmol), a 2M aqueous solution of potassium carbonate (31.4 mL, 62.8 mmol), and palladium tetrakis(triphenylphosphine) (Pd(PPh3)4, 0.906 g, 0.784 mmol) were suspended in 1,2-dimethoxyethane (DME, 150 mL). The resulting mixture was stirred and heated to 80 C. for 60 hours. The crude reaction mixture was cooled to room temperature and then the layers were separated. The organic layer was evaporated to dryness and then purified on 120 g of silica gel utilizing a gradient of 0-70% ethyl acetate in hexanes to yield the pure product as a pale yellow oil (3.02 g, 11.2 mmol, 71.4%).

Reference： [1]Patent: US2009/246137,2009,A1 .Location in patent: Page/Page column 42

10
[ 220210-56-0 ]
[ 915759-45-4 ]
C₂₉H₃₁F₃N₂O₆S₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 190 - 201

11
[ 220210-56-0 ]
[ 691857-51-9 ]
[ 1217339-14-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 90℃;	Ethyl 5-(3-(ter?-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-nitrobenzofuran-3- carboxylate; Cesium carbonate (1.54 g, 4.71 mmol) was added to Pd(Ph3P)4 (182 mg, 0.157 mmol), ethyl 2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (1500 mg, 3.14 mmol), 3- (tert-butoxycarbonyl)phenylboronic acid (768 mg, 3.46 mmol). Dioxane (26 mL) and water (5 mL) was added at rt. The reaction was heated to 90 0C overnight. The reaction was allowed to cool was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (BIOTAGE, EtOAc/hexanes gradient, fraction collection at lambda = 254 nm) to give to give the titled compound (1.10 g, 69%). 1H NMR (300 MHz, DMSO-d6) delta ppm 8.60 (1 H, s), 8.08 - 8.18 (2 H, m), 8.02 (1 H, s), 7.95 - 8.01 (1 H, m), 7.88 (1 H, s), 7.58 - 7.70 (2 H, m), 7.46 (2 H, t, J=8.78 Hz), 4.34 (2 H, q, J=7.20 Hz), 1.56 (9 H, s), 1.27 (3 H, t, J=7.14 Hz). LC-MS retention time: 2.13 min; m/z (MH+): parent does not ionize. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a MICROMASS Platform for LC in electrospray mode.
69%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃;	Cesium carbonate (1.54 g, 4.71 mmol) was added to Pd(Ph3P)4 (182 mg, 0.157 mmol), ethyl 2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate (1500 mg, 3.14 mmol), 3- (tert-butoxycarbonyl)phenylboronic acid (768 mg, 3.46 mmol). Dioxane (26 mL) and water (5 mL) was added at rt. The reaction was heated to 90 C overnight. The reaction was allowed to cool was diluted with EtOAc and washed with sat NaHC03, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at lambda = 254 nm) to give to give the titled compound (1.10 g, 69%). 1H NMR (300 MHz, DMSO-de) delta ppm 8.60 (1 H, s), 8.08 - 8.18 (2 H, m), 8.02 (1 H, s), 7.95 - 8.01 (1 H, m), 7.88 (1 H, s), 7.58 - 7.70 (2 H, m), 7.46 (2 H, t, J=8.78 Hz), 4.34 (2 H, q, J=7.20 Hz), 1.56 (9 H, s), 1.27 (3 H, t, J=7.14 Hz). LC-MS retention time: 2.13 min; m/z (MH+): parent does not ionize. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Reference： [1]Patent: WO2010/30592,2010,A1 .Location in patent: Page/Page column 150-151
[2]Patent: WO2011/112191,2011,A1 .Location in patent: Page/Page column 175-176

12
[ 220210-56-0 ]
[ 18680-27-8 ]
[ 1154427-21-0 ]

Yield	Reaction Conditions	Operation in experiment
> 99%	With magnesium sulfate; In diethyl ether; at 20℃; for 3h;Inert atmosphere;	(3-(tert-Butoxycarbonyl)phenyl)boronic acid (978 mg, 4,40 mmol) was suspended in 40 mL Et20 and mixed with (+)-pinanediol (750 mg, 4,40 mmol) and anhydrous MgS04 (1 gram, 8,30 mmol). The mixture was stirred at room temperature under argon for 3 hours before the inorganic material was filtered off and the filtrate concentrated under reduced pressure. This gave a sticky clear oil (1568 mg, 4.40 mmol, >99%) which solidified overnight at room temperature. 1H NMR (600 MHz, Chloroform-d) delta 8.41 (t, J- 1.5 Hz, 1H), 8.07 (dt, J= 7.8, 1.6 Hz, 1H), 7.95 (dt, J= 7.4, 1.4 Hz, 1H), 7.42 (t, J= 7.6 Hz, 1H), 4.47 (dd, J= 8.8, 1.9 Hz, 1H), 2.42 (ddt, J= 14.8, 8.8, 2.4 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.16 (t, J= 5.5 Hz, 1H), 2.05 - 1.89 (m, 2H), 1.60 (s, 10H), 1.49 (s, 3H), 1.31 (s, 3H), 1.19 (s, 1H), 0.89 (s, 3H). 13C NMR (151 MHz, CDC13) delta 166.04, 138.84, 135.78, 132.22, 131.60, 127.79, 86.62, 81.12, 78.57, 77.37, 77.16, 76.95, 66.00, 51.53, 39.67, 38.35, 35.64, 28.84, 28.37, 27.25, 26.65, 24.20, 15.43. MS (ESI positive mode): m/z 379.2 (M+Na+)
85%	In tetrahydrofuran; at 20℃; for 0.5h;	A solution of (+)- pinanediol (10.0 g, 58.7 mmole) and 3-tert-Butoxycarbonylphenylboronic acid (13.0 g, 58.7 mmole) in tetrahydrofuran (THF, 78 ml_) was stirred for 30 min at room temperature. The solution was concentrated in vacuo, and the residue chromatographed on SiO2 using a gradient of 20% dichloromethane (DCM) in hexane to 70% DCM/hexane to afford 17.76 g (85%) of the product as a slowly crystallizing white solid. Electrospray Ionization Mass Spectrum (ESI-MS) m/z

Reference： [1]Patent: WO2018/33719,2018,A1 .Location in patent: Page/Page column 154
[2]Patent: WO2009/64413,2009,A1 .Location in patent: Page/Page column 64

13
[ 220210-56-0 ]
[ 947248-68-2 ]
[ 1309593-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 15h;Reflux;	Intermediate [Example Int8.1tert-butyl 3-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)benzoateTo a stirred solution of Int1.2 (1 .2 g) in 1 -propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdCl2(PPh3 )2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1 .04 g of the title compound.1 H-NMR (300MHz, DMSO-d6): delta [ppm]= 1 .57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1 H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1 H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1 H).
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 15h;Reflux;	Intermediate Example Int11.1tert-butyl 3-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)benzoateTo a stirred solution of Int1.2 (1.2 g) in 1 -propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdCl2(PPh3)2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.04 g of the title compound. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1H)
	With potassium carbonate; triphenylphosphine;bis-triphenylphosphine-palladium(II) chloride; In propan-1-ol; for 15h;Reflux;	To a stirred solution of lnt1.2 (1.2 g) in 1-propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdCl2(PPh3)2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.04 g of the title compound. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1 H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1 H).

With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; water; for 15h;Reflux;

To a stirred solution of Int1.2 (1.2 g) in 1-propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdC[2(PPh3)2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.04 g of the title compound. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1 H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1 H).

Reference： [1]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 70
[2]Patent: WO2011/63908,2011,A1 .Location in patent: Page/Page column 68-69
[3]Patent: EP2343295,2011,A1 .Location in patent: Page/Page column 26
[4]Patent: EP2343297,2011,A1 .Location in patent: Page/Page column 35

14
[ 220210-56-0 ]
C₃₃H₂₈ClFN₂O₅S [ No CAS ]

Reference： [1]Patent: WO2011/112191,2011,A1

15
[ 220210-56-0 ]
[ 1217336-90-7 ]

Reference： [1]Patent: WO2011/112191,2011,A1

16
[ 220210-56-0 ]
[ 1217339-15-5 ]

Reference： [1]Patent: WO2011/112191,2011,A1

17
[ 220210-56-0 ]
[ 1217340-53-8 ]

Reference： [1]Patent: WO2011/112191,2011,A1

18
[ 220210-56-0 ]
[ 1217339-16-6 ]

Reference： [1]Patent: WO2011/112191,2011,A1

19
[ 220210-56-0 ]
[ 1217339-17-7 ]

Reference： [1]Patent: WO2011/112191,2011,A1

20
[ 220210-56-0 ]
[ 1217339-18-8 ]

Reference： [1]Patent: WO2011/112191,2011,A1

21
[ 220210-56-0 ]
[ 1217339-19-9 ]

Reference： [1]Patent: WO2011/112191,2011,A1

22
[ 220210-56-0 ]
[ 1338223-78-1 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

23
[ 220210-56-0 ]
[ 1338223-80-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

24
[ 220210-56-0 ]
[ 1338223-82-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

25
[ 220210-56-0 ]
C₁₆H₁₀O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

26
[ 220210-56-0 ]
3-(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)benzoic acid trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

27
[ 220210-56-0 ]
3-(4-oxo-4H-thiochromen-3-yl)benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

28
[ 49619-82-1 ]
[ 220210-56-0 ]
C₂₀H₁₈O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

29
3-bromo-1-methylquinolin-4(1H)-one [ No CAS ]
[ 220210-56-0 ]
tert-butyl 3-(1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)benzoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

30
[ 220210-56-0 ]
[ 68847-94-9 ]
tert-butyl 3-(4-oxo-4H-thiochromen-3-yl)benzoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

31
[ 38496-18-3 ]
[ 220210-56-0 ]
[ 1391833-29-6 ]

Yield	Reaction Conditions	Operation in experiment
67%		2,6-Dichloronicotinic acid (1 .20 g, 6.25 mmol), 3-(te/t-butoxycarbonyl)benzene boronic acid (2.08 g, 9.10 mmol), potassium carbonate (2.60 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol), degassed 1 ,2- dimethoxyethane (30 ml_) and water (0.5 ml_) were combined under an argon atmosphere and the mixture heated at 90 C overnight. The reaction mixture was then cooled to room temperature, diluted with water (100 ml_) and extracted with ethyl acetate (2 x 150 ml_). The aqueous layer was acidified to pH 3-4 using 2N HCI solution and extracted with ethyl acetate (2 x 200 ml_). The combined organic portions were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 20% methanol/dichloromethane) and the product containing fractions concentrated to give a solid, which was triturated with 2:1 heptane/ethyl acetate to give pure 6-(3-(tert- butoxycarbonyl)phenyl)-2-chloronicotinic acid (1 .4 g, 67 %) as an off-white foam. 1H NMR (400 MHz, CD3OD) delta ppm 8.64 (s, 1 H), 8.34 (d, 1 H), 8.29 (d, 1 H), 8.04 (d, 1 H), 7.95 (d, 1 H), 7.59 (t, 1 H), 1 .60 (s, 9H); m/z 334 [M+H].

Reference： [1]Patent: WO2012/42433,2012,A1 .Location in patent: Page/Page column 40-41

32
[ 38496-18-3 ]
[ 220210-56-0 ]
[ 1391837-01-6 ]

Reference： [1]Patent: WO2012/42433,2012,A1

33
[ 220210-56-0 ]
[ 1373125-71-3 ]
C₃₇H₄₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In water; toluene; at 90℃; for 14h;	General procedure: The arylbromide (122 mg, 0.3 mmol), 3-methoxy-phenylboronic acid (137 mg, 0.900 mmol), potassium phosphate (191 mg, 0.900 mmol), Pd2(dba)3 (6.87 mg, 0.008 mmol), and tri-tert-butylphosphonium tetrafluoroborate (8.70 mg, 0.030 mmol) were combined in a mixture of degassed toluene (0.81 ml) and water (0.09 ml) and heated to 90 C for 14 h. At this time LC-MS showed a complete reaction. The reaction was cooled, diluted with ethyl acetate, and filtered through a small pad of silica gel eluting with ethyl acetate. The crude solution was concentrated and purified by silica gel chromatography (Biotage 25 g SNAP cartridge; 0-10% ethyl acetate in hexanes) to afford a clear viscous oil (121 mg, 93%).

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2308 - 2311

34
[ 220210-56-0 ]
[ 1083057-13-9 ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: WO2013/185112,2013,A1
[3]Patent: US2015/231142,2015,A1
[4]Patent: US2016/324788,2016,A1
[5]Patent: WO2017/17696,2017,A1
[6]Patent: WO2018/107100,2018,A1
[7]Patent: WO2019/18395,2019,A1
[8]Chemistry - A European Journal,2019,vol. 25,p. 3662 - 3674

35
[ 220210-56-0 ]
[ 1083057-14-0 ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: WO2013/185112,2013,A1
[3]Patent: WO2014/71122,2014,A1
[4]Patent: WO2015/73231,2015,A1
[5]Patent: US2015/231142,2015,A1
[6]Patent: US2016/324788,2016,A1
[7]Patent: WO2018/107100,2018,A1
[8]Patent: WO2019/18395,2019,A1
[9]Chemistry - A European Journal,2019,vol. 25,p. 3662 - 3674
[10]Patent: TWI636051,2018,B

36
[ 220210-56-0 ]
[ 1160221-25-9 ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: WO2013/185112,2013,A1
[3]Patent: WO2014/71122,2014,A1
[4]Patent: WO2015/73231,2015,A1
[5]Patent: US2015/231142,2015,A1
[6]Patent: US2016/324788,2016,A1
[7]Patent: WO2017/17696,2017,A1
[8]Patent: WO2018/107100,2018,A1
[9]Patent: WO2019/18395,2019,A1
[10]Patent: TWI636051,2018,B

37
[ 220210-56-0 ]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCL salt [ No CAS ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: WO2013/185112,2013,A1
[3]Patent: WO2017/17696,2017,A1

38
[ 220210-56-0 ]
Lumacaftor [ No CAS ]

Reference： [1]Patent: US2013/186801,2013,A1
[2]Patent: US2013/186801,2013,A1
[3]Patent: WO2014/71122,2014,A1
[4]Patent: WO2014/71122,2014,A1
[5]Patent: WO2015/73231,2015,A1
[6]Patent: WO2015/73231,2015,A1
[7]Patent: US2016/324788,2016,A1
[8]Patent: US2016/324788,2016,A1
[9]Patent: WO2017/17696,2017,A1
[10]Patent: TWI636051,2018,B

39
[ 220210-56-0 ]
[ 1176954-98-5 ]
3-(3-tert-butoxycarbonylphenyl)-1-[(6-chloro-3-pyridyl)methyl]-4-oxopyrido[1,2-a]pyrimidin-1-ium-2-olate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With palladium diacetate; lithium hydroxide; N?phenyl?2?(dicyclohexylphosphino)pyrrole; In 1,2-dimethoxyethane; water; at 80℃; for 16h;	Step 1: To a suspension of 1-[(6-chloro-3-pyridyl)methyl]-3-iodo-4-oxo-pyrido[1,2-a]pyrimidin-1-ium-2-olate(850 mg, 2.06 mmol), 3-tert-butoxycarbonylphenyl)boronic acid (684 mg, 3.08 mmol), lithium hydroxide (49 mg, 2.1mmol) and palladium (II) acetate (92 mg, 0.41 mmol) in 1,2-dimethoxyethane/water (1:1, 90 mL) was added 2-(dicyclohexylphosphino)-1-phenyl-1 H-pyrrole (139 mg, 0.41 mmol) and the reaction mixture was heated at 80C for 16 h.The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and washed with asaturated solution of citric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentratedunder reduced pressure. Purification by flash chromatography eluting with a dichloromethane/methanol gradient afforded3-(3-tert-butoxycarbonylphenyl)-1-[(6-chloro-3-pyridyl)methyl]-4-oxo-pyrido[1,2-a]pyrimidin-1-ium-2-olate (180 mg,18%).

Reference： [1]Patent: EP2684879,2014,A1 .Location in patent: Paragraph 0216

40
[ 220210-56-0 ]
3-(3-carboxyphenyl)-1-[(6-chloro-3-pyridyl)methyl]-4-oxopyrido[1,2-a]pyrimidin-1-ium-2-olate [ No CAS ]

Reference： [1]Patent: EP2684879,2014,A1

41
[ 220210-56-0 ]
[ 1537219-88-7 ]

Reference： [1]Patent: EP2684879,2014,A1

42
[ 220210-56-0 ]
[ 1160221-26-0 ]

Reference： [1]Patent: WO2014/71122,2014,A1
[2]Patent: WO2015/73231,2015,A1
[3]Patent: US2015/231142,2015,A1
[4]Patent: US2016/324788,2016,A1
[5]Patent: TWI636051,2018,B

43
[ 220210-56-0 ]
[ 31462-58-5 ]
[ 1595294-71-5 ]

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 3946 - 3954

44
[ 220210-56-0 ]
[ 3959-07-7 ]
[ 1620134-55-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6165 - 6182

45
[ 220210-56-0 ]
[ 1620134-49-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6165 - 6182

46
[ 220210-56-0 ]
[ 1620134-84-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6165 - 6182

47
[ 220210-56-0 ]
[ 1620134-86-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6165 - 6182

48
[ 220210-56-0 ]
5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide [ No CAS ]
tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate [ No CAS ]
di-tert-butyl 3,3′-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridine-5,6-diyl)dibenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 65℃; for 16h;Inert atmosphere;	A mixture of 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (5.0 g, 13 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (2.75 g, 12.4 mmol). Pd(Ph3P)4 (2.26 g, 1.96 mmol) and cesium carbonate (8.49 g, 26.1 mmol) was degassed/charged with N2 and diluted with water (22 ml)/DMF (220 ml). The resultant mixture was then degassed, charged with N2, heated to an internal temperature of 65 C. and allowed to stir under N2 atmosphere for 16 h. The reaction mixture was cooled to rt then diluted with EtOAc and sat. 1M HCl. The layers were separated and the aq layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4 filtered and concentrated. The resultant solid was then flashed on SiO2 eluting with a 0-100% EtOAc in hexanes gradient over 16 CV to give tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (5.2 g, 11 mmol, 83% yield) as a slightly yellow solid contaminated with the bis-coupled product di-tert-butyl 3,3?-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridine-5,6-diyl)dibenzoate. 1H NMR (500 MHz, CHLOROFORM-d) delta 8.18 (s, 1H), 8.08-8.02 (m, 2H), 7.95-7.89 (m, 2H), 7.63 (dt, J=7.6, 1.5 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.24-7.18 (m, 2H), 6.03 (d, J=4.3 Hz, 1H), 2.99 (d, J=4.9 Hz, 3H), 1.62 (s, 9H).

Reference： [1]Patent: US2014/275154,2014,A1 .Location in patent: Paragraph 0059

49
[ 220210-56-0 ]
2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(2,2,2-trifluoroethoxy)benzofuran-5-yl trifluoromethanesulfonate [ No CAS ]
tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(2,2,2-trifluoroethoxy)benzofuran-5-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 110℃;Sealed tube; Inert atmosphere;	Preparation of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6- (2,2,2-trifluoroethoxy)benzofuran-5-yl)benzoate 2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-(2,2,2- trifiuoroethoxy)benzofuran-5-yl trifiuoro-methanesulfonate (100 mg, 0.194 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (47.4 mg, 0.213 mmol), Cs2C03 (126 mg, 0.388 mmol), dioxane (10 mL) and water (1.0 mL) were added into a sealed tube. The reaction mixture was degassed and back-filled with N2 followed by addition of tetrakis(triphenylphosphine)palladium(0) (22.42 mg, 0.019 mmol) at room temperature. The teflon screw cap of the tube was tighten, and the reaction mixture heated to 1 10C and stir it for overnight. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, filtered through a pad of celite and the celite pad washed with EtOA (50 ml). After evaporation of the solvent under vacuum, the residue was purified via Combifiash using a 40g silica column with 28% EtOAc in pet ether as an eluent to give the desired compound as an white solid. Yield: 100 mg, (95%). 1H NMR (400 MHz, CDC13): delta 1.61 (s, 9 H), 3.01 (d, J=4.9 Hz, 3 H), 4.31 (q, J=8.0 Hz, 2 H), 5.83 (br. s., 1 H), 7.14 - 7.21 (m, 3 H), 7.48 (t, J=7.7 Hz, 1 H), 7.63 - 7.71 (m, 1 H), 7.78 (s, 1 H) 7.89 - 7.96 (m, 2 H), 7.98 - 8.04 (m, 1 H), 8.14 (t, J=1.5 Hz, 1 H). LCMS (ES+) m/z = 544.3 (M+H). Column- Acquity BEH C18 (2.1 x 50 mm) 1.7 u Buffer: lOmM AmmoniumAcetate pH 5 adjusted with HCOOH Mobile phase A: BuffenMeCN (95:5) Mobile phase B: Buffer:MeCN (5:95) Flow: 0.8 ml/Min Time % A % B 0.0 95 5 1.1 5 95 1.7 5 95 Rt min: 1.24, wavelength: 220 nm
95%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 110℃;Inert atmosphere; Sealed tube;	2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-(2,2,2-trifluoroethoxy)benzofuran-5-yl trifluoro-methanesulfonate (100 mg, 0.194 mmol), (3-(tert- butoxycarbonyl)phenyl)boronic acid (47.4 mg, 0.213 mmol), CS2CO3 (126 mg, 0.388 mmol), dioxane (10 mL) and water (1.0 mL) were added into a sealed tube. The reaction mixture was degassed and back-filled with N2 followed by addition of tetrakis(triphenylphosphine)palladium(0) (22.42 mg, 0.019 mmol) at room temperature. The teflon screw cap of the tube was tighten, and the reaction mixture heated to 110C and stir it for overnight. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, filtered through a pad of celite and the celite pad washed with EtOA (50 ml). After evaporation of the solvent under vacuum, the residue was purified via Combiflash using a 40g silica column with 28% EtOAc in pet ether as an eluent to give the desired compound as an white solid. Yield: 100 mg, (95%). 1H MR (400 MHz, CDCh): delta 1.61 (s, 9 H), 3.01 (d, J=4.9 Hz, 3 H), 4.31 (q, J=8.0 Hz, 2 H), 5.83 (br. s., 1 H), 7.14 - 7.21 (m, 3 H), 7.48 (t, J=7.7 Hz, 1 H), 7.63 - 7.71 (m, 1 H), 7.78 (s, 1 H) 7.89 - 7.96 (m, 2 H), 7.98 - 8.04 (m, 1 H), 8.14 (t, J=1.5 Hz, 1 H). LCMS (ES+) m/z = 544.3 (M+H), Column- Acquity BEH C18 (2.1 x 50 mm) 1.7 um, Buffer: lOmM Ammonium Acetate pH 5 adjusted with HCOOH, Mobile phase A: BuffenMeCN (95:5), Mobile phase B: BuffenMeCN (5:95), Flow: 0.8 ml/min, Rt min: 1.24, wavelength: 220 nm.

Reference： [1]Patent: WO2014/159559,2014,A1 .Location in patent: Page/Page column 152-153
[2]Patent: WO2016/137832,2016,A1 .Location in patent: Page/Page column 25; 26

50
[ 220210-56-0 ]
2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((methylsulfonyl)-methyl)benzofuran-5-yl trifluoromethanesulfonate [ No CAS ]
tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((methylsulfonyl)-methyl)benzofuran-5-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;	Preparation of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6- ((methylsulfonyl)-methyl)benzofuran-5-yl)benzoate To a stirred solution of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6- ((methylsulfonyl)-methyl)benzofuran-5-yl trifluoromethanesulfonate (50 mg, 0.098 mmol) in dioxane (2mL) was added (3-(tert- butoxycarbonyl)phenyl)boronic acid (32.7 mg, 0.147 mmol) and Cs2C03 (96 mg, 0.294 mmol). The mixture was degassed and then added with (PPh3)4Pd(0) (11.35 mg, 9.81 muiotaetaomicron) and water (0.2ml). The mixture was purged with N2 for 10 min and then stirred for overnight at 90C. After completion of the reaction, the mixture was filtered through celite and solvent was evaporated. Ice-cold water was added to the crude reaction mixture, solid precipitated was filtered and dried to obtain the desired product. It was triturated in n-hexane and used for the next step without any purification. Yield: 50 mg. LCMS (ES+) m/z = 538.2 (M+H), 482 (M+H of the corresponding acid). Column- ACQUITY UPLC BEH CI 8 (50X2. lmm; 1.7mupiiota) M phase A : 0.1% TFA in water M phase B : Acetonitrile Flow: 0.8 ml/Min Time % A % B 0.0 98 2 1.0 2 98 1.6 2 98 Rt min: 1.19, wavelength: 220 nm

Reference： [1]Patent: WO2014/159559,2014,A1 .Location in patent: Page/Page column 177

51
[ 220210-56-0 ]
5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide [ No CAS ]
tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 65℃; for 16h;Inert atmosphere;	Step 1 : Preparation of tert-butyl 3 -(6-chloro-2-(4-fluorophenyl)-3- (m thylcarbamoyl)furo[2,3-]pyridin-5-yl)benzoate Chemical Formula: C26H22CIFN204 Molecular Weight: 480.92 A mixture of 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine- 3-carboxamide (5.0 g, 13 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (2.75 g, 12.4 mmol), Pd(Ph3P)4 (2.26 g, 1.96 mmol) and cesium carbonate (8.49 g, 26.1 mmol) was degassed/charged with N2 and diluted with water (22 ml)/DMF (220 ml). The resultant mixture was then degassed, charged with N2, heated to an internal temperature of 65 C and allowed to stir under N2 atmosphere for 16 h. The reaction mixture was cooled to rt then diluted with EtOAc and sat. 1M HC1. The layers were separated and the aq layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water, brine, dried over Na2S04 filtered and concentrated. The resultant solid was then flashed on Si02 eluting with a 0 - 100 % EtOAc in hexanes gradient over 16 CV to give tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3- (methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (5.2 g, 11 mmol, 83% yield) as a slightly yellow solid contaminated with the bis-coupled product di-tert-butyl 3,3'-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridine-5,6- diyl)dibenzoate. 1H NMR (500MHz, CHLOROFORM-d) delta 8.18 (s, 1H), 8.08 - 8.02 (m, 2H), 7.95 - 7.89 (m, 2H), 7.63 (dt, J=7.6, 1.5 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.24 - 7.18 (m, 2H), 6.03 (d, J=4.3 Hz, 1H), 2.99 (d, J=4.9 Hz, 3H), 1.62 (s, 9H)

Reference： [1]Patent: WO2014/159559,2014,A1 .Location in patent: Page/Page column 248-249

52
[ 220210-56-0 ]
4-(3-bromo-2-(quinolin-2-ylethynyl)imidazo[1,2-b]pyridazin-8-yl)morpholine [ No CAS ]
tert-butyl 3-(8-morpholino-2-(quinolin-2-ylethynyl)imidazo[1,2-b]pyridazin-3-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	To a stirred solution of compound 18b (51 mg, 0.12 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (39 mg, 0.18 mmol), and cesium carbonate (0.12 g, 0.36 mmol) in degassed 1,4-dioxane (4 mL) and water (0.5 mL) under Argon was added dichloro(diphenylphosphinoferrocene)palladium (II) (4.3 mg, 0.0059 mmol). The resulting mixture was heated at 80 C. for 2 h, allowed to cool to rt, and treated with EtOAc (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel (20-100% EtOAc/heptane) to give compound 18c as a brown oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H29N5O3: 532.2 (M+H). found: 532.5.

Reference： [1]Patent: US2014/364413,2014,A1 .Location in patent: Paragraph 0588; 0589

53
[ 220210-56-0 ]
[ 65-85-0 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 9807 - 9816

54
[ 220210-56-0 ]
N-(4-bromonaphthalen-1-yl)-2,3,5,6-tetramethylbenzenesulfonamide [ No CAS ]
tert-butyl 3-(4-(2,3,5,6-tetramethylphenylsulfonamido)naphthalen-1-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 85℃; for 5h;	1 b) tert-butyl 3-(4-(2,3,5,6-tetramethylphenylsulfonamido)naphthalen-1-yl)benzoate To a solution of N-(4-bromonaphthalen-1-yl)-2,3,5,6-tetramethylbenzene-sulfonamide (75 mg, 0.18 mmol) in dioxane (1.6 mL) were added <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)-boronic acid</strong> (48 mg, 0.22 mmol), PdCl2(dppf)·CH2Cl2 complex (8 mg, 0.009 mmol) and sodium carbonate (0.4 mL, 1mol/l aqueous solution). The reaction mixture was stirred at 85C for 5 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (10 mL), and washed with NH4Cl (saturated aqueous solution). The organic phase was dried over sodium sulfate, filtered and then concentrated in vacuo. The resulting residue was purified via silica gel flash chromatography with n-heptane / ethyl acetate (2% to 30%) as eluent to yield 40 mg (43 %) of the title compound as a white powder.

Reference： [1]Patent: EP2998294,2016,A1 .Location in patent: Paragraph 0127; 0128

55
[ 220210-56-0 ]
[ 20191-76-8 ]
methyl 3-(4-amino-3-bromo-1-naphthyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;	To a solution of <strong>[20191-76-8]2,4-dibromonaphthalen-1-amine</strong> (100 mg, 0.3 mmol) in dioxane (2 mL) were added (3-(tert-butoxycarbonyl)phenyl)boronic acid (64 mg, 0.287 mmol), PdCl2(dppf)·CH2Cl2 complex (12 mg, 0.014 mmol) and sodium carbonate (0.57 mL, 1mol/l aqueous solution). The reaction mixture was stirred at 90C for 4 h. After cooling to room temperature, H2O (5 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with H2O, dried over sodium sulfate, filtered and then concentrated in vacuo. Purification of the residue by high performance liquid chromatography (RP silica gel, acetonitrile/water/ trifluoroacetic acid) and lyophilization of the product fractions provided 50 mg (44 %) of the title compound as a white powder.

Reference： [1]Patent: EP2998294,2016,A1 .Location in patent: Paragraph 0150; 0151

56
[ 220210-56-0 ]
[ 20191-76-8 ]
tert-butyl 3-(2-bromo-4-(2,3,5,6-tetramethylphenylsulfonamido)naphthalen-1-yl)benzoate [ No CAS ]

Reference： [1]Patent: EP2998294,2016,A1

57
[ 220210-56-0 ]
[ 2298-07-9 ]
3-[4-[(2,4-dimethoxyphenyl)sulfonylamino]-1-naphthyl]benzoic acid [ No CAS ]

Reference： [1]Patent: EP2998294,2016,A1

58
[ 220210-56-0 ]
[ 2298-07-9 ]
tert-butyl 3-(4-aminonaphthalen-1-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;	To a solution of 4-bromonaphthalen-1-amine (100 mg, 0.45 mmol) in dioxane (20 mL) were added <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (120 mg, 0.54 mmol), PdCl2(dppf)·CH2Cl2 complex (19 mg, 0.023 mmol) and sodium carbonate (0.9 mL, 1mol/l aqueous solution). The reaction mixture was stirred at 90C for 4 h. After cooling to room temperature, dichloromethane (10 mL) and H2O were added. The organic phase was separated and washed with H2O, dried over sodium sulfate, filtered and concentrated in vacuo to afford 150 mg (quantitative yield) of the title compound, which was used in the next step 2b) without further purification.

Reference： [1]Patent: EP2998294,2016,A1 .Location in patent: Paragraph 0132; 0133

59
[ 220210-56-0 ]
[ 25016-01-7 ]
3'-formyl-4'-methoxybiphenyl-3-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 692 - 696

60
[ 220210-56-0 ]
C₂₁H₂₄O₄ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 692 - 696

61
[ 220210-56-0 ]
C₂₀H₂₂O₄ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 692 - 696

62
[ 220210-56-0 ]
4'-methoxy-3'-prop-2-ynyl-biphenyl-3-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 692 - 696

63
[ 220210-56-0 ]
C₂₇H₃₀N₄O₃ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 692 - 696

64
[ 220210-56-0 ]
6-ethyl-5-[3-(2-methoxy-5-(3-carboxyphenyl)-phenyl)prop-1-ynyl]-pyrimidine-2,4-diamine trifluoroacetate salt [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 692 - 696

65
[ 220210-56-0 ]
((1-(3-bromophenyl)cyclopropyl)methoxy)(tert-butyl)dimethylsilane [ No CAS ]
C₂₇H₃₈O₃Si [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 8723 - 8727
Angew. Chem.,2016,vol. 128,p. 8865 - 8869,5

66
[ 220210-56-0 ]
6-(ethoxy-1,1,2,2,2-d5)-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate [ No CAS ]
tert-butyl-3-(6-(ethoxy-1,1,2,2,2-d5)-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.57%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,3-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube;	A mixture of 6-(ethoxy-l,l,2,2,2-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (70 mg, 0.150 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (40.0 mg, 0.180 mmol) and CS2CO3 (98 mg, 0.300 mmol) in dioxane (10 mL)/water (1.0 mL) in a sealed tube capped with a rubber septum at room temperature was degassed and back filled with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (17.34 mg, 0.015 mmol) was added to the mixture. The reaction mixture was heated to 100C and stirred at same temperature for 16 hr. After cooling to room temperature, completion of the reaction was confirmed by TLC. The reaction mixture was filtered through a celite pad, which was then washed with EtOAc. The filtrate was concentrated under reduced pressure, and the crude product purified via Combiflash using a 12g silica gel column with 24% EtOAc in pet. ether as an eluent to afford the desired compound as a white solid. Yield: 65 mg, (87.57%). 1H MR (300MHz, CHLOROFORM-d) delta ppm = 8.19 (t, J= 1.6 Hz, 1 H), 8.01 - 7.99 (m, 1 H), 7.99 - 7.94 (m, 2 H), 7.72 - 7.70 (m, 2 H), 7.48 (t, J= 7.7 Hz, 1 H), 7.19 (t, J= 8.7 Hz, 2 H), 7.13 (s, 1 H), 5.88 (bs, 1H), 3.03 (d, J= 4.9 Hz, 3 H), 1.63 (s, 9 H). LCMS: (ES+) m/z = 495.4 (M+H)+, Column- ACQUITY UPLC BEH C8 (50X2.1mm; 1.7muiotaeta), Moblie phase A : lOmM Ammonium Acetate pH-5 adjusted with HCOOH : MeCN (95:5), Mobile phase B : lOmM Ammonium Acetate pH-5 adjusted with HCOOH : MeCN (5:95), Flow : 0.8ml/min, Rt: 1.31 min, wavelength: 220nm

Reference： [1]Patent: WO2016/137832,2016,A1 .Location in patent: Page/Page column 21; 39; 40

67
[ 220210-56-0 ]
Fmoc-4-bromo-L-phenylalanine [ No CAS ]
(2S)-3-(4-{3-[(tert-butoxy)carbonyl]phenyl}phenyl)-2-([(9H-fluoren-9-yl)methoxy]carbonyl}amino)propanoic acid [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 9499 - 9506

68
[ 220210-56-0 ]
C₂₀H₂₈BrClN₂O₂ [ No CAS ]
C₃₁H₄₁ClN₂O₄ [ No CAS ]

Reference： [1]Patent: US2016/194290,2016,A1 .Location in patent: Paragraph 0993

69
[ 220210-56-0 ]
tert-butyl-3-(6-chloro-3-methylpyridine-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2017/17696,2017,A1

70
[ 45644-21-1 ]
[ 220210-56-0 ]
tert-butyl 3-(6-aminopyridin-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 18h;Inert atmosphere;	Example 73A tert-butyl 3-(6-aminopyridin-2-yl)benzoate A mixture of 6-chloropyrid-2-amine (259.6 mg, 2.019 mmol) and <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (491.8 mg, 2.215 mmol) in dimethoxyethane (5 mL) and water (2.5 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (621.0 mg, 4.49 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (88.5 mg, 0.125 mmol) were added, and the mixture stirred at 80 C. for 18 hours. Water was then added to the reaction mixture (35 mL), and it was extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane (Rf=0.43), to provide the title compound (340.5 mg, 62%). 1H NMR (400 MHz, DMSO-d6) delta 8.50 (t, J=1.7 Hz, 1H), 8.16 (dt, J=7.9, 1.4 Hz, 1H), 7.88 (dt, J=7.8, 1.3 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.45 (d, J=8.2 Hz, 1H), 6.05 (s, 2H), 1.56 (s, 9H): MS (ESI+) m/z 271 (M+H)+.

Reference： [1]Patent: US2017/15675,2017,A1 .Location in patent: Paragraph 1113

71
[ 220210-56-0 ]
3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}pyridin-2-yl)benzoic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

72
[ 220210-56-0 ]
tert-butyl 3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}pyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

73
[ 220210-56-0 ]
3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-5-methylpyridin-2-yl)benzoic acid [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

74
[ 220210-56-0 ]
2-(3-(tert-butoxycarbonyl)phenyl)-5-methylpyridine 1-oxide [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

75
[ 220210-56-0 ]
tert-butyl 3-(6-amino-5-methylpyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

76
[ 220210-56-0 ]
tert-butyl 3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-5-methylpyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

77
[ 220210-56-0 ]
3-(3-chloro-6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}pyridin-2-yl)benzoic acid [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

78
[ 220210-56-0 ]
2-(3-(tert-butoxycarbonyl)phenyl)-3-chloropyridine 1-oxide [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

79
[ 220210-56-0 ]
tert-butyl 3-(6-amino-3-chloropyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

80
[ 220210-56-0 ]
tert-butyl 3-(3-chloro-6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}pyridin-2-yl)benzoate [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

81
[ 3510-66-5 ]
[ 220210-56-0 ]
tert-butyl 3-(5-methylpyridin-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃;	Example 84A tert-butyl 3-(5-methylpyridin-2-yl)benzoate 2-Bromo-5-methylpyridine (0.688 g, 4 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (0.888, 4 mmol), potassium carbonate (1.16 g, 8.4 mmol), and PdCl2dppf (0.146 g, 0.2 mmol) were mixed in dimethoxyethane (8.5 mL) and water (4.7 mL), and the mixture was heated overnight at 80 C. After this time, the mixture was diluted with ether (75 mL), washed with a solution of 0.25 mL CH3SO3H in 12 mL water, followed by washing with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude oil was purified by silica gel chromatography (0 to 25% ethyl acetate-heptanes, eluent) to afford the title compound as a yellow oil (0.445 g, 41% yield). 1H NMR (400 MHz, CDCl3) delta 8.61-8.49 (m, 2H), 8.20 (dt, J=7.8, 1.4 Hz, 1H), 8.02 (dt, J=7.7, 1.5 Hz, 1H), 7.65-7.46 (m, 2H), 7.14-7.04 (m, 1H), 2.43 (s, 3H), 1.63 (s, 9H). MS (DCI+) m/z 270.0 (M+H).

Reference： [1]Patent: US2017/15675,2017,A1 .Location in patent: Paragraph 1137

82
[ 220210-56-0 ]
[ 96424-68-9 ]
tert-butyl 3-(3-chloropyridin-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃;	Example 95A tert-butyl 3-(3-chloropyridin-2-yl)benzoate 2-Bromo-3-chloropyridine (0.8 g, 4.16 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (0.923 g, 4.16 mmol), potassium carbonate (1.207 g, 8.73 mmol), and PdCl2dppf (0.152 g, 0.208 mmol) were mixed in dimethoxyethane (9 mL) and water (5 mL), and the mixture was heated overnight at 80 C. After this time, the mixture was diluted with ether (50 mL), then washed with a solution of 0.25 mL CH3SO3H in 12 mL water, followed by washing with brine (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel chromatography (0 to 30% ethyl acetate-heptanes, eluent) to afford the title compound (0.856 g, 71% yield). 1H NMR (500 MHz, DMSO-d6) delta 8.67 (dd, J=4.6, 1.5 Hz, 1H), 8.19 (t, J=1.8 Hz, 1H), 8.09 (dd, J=8.3, 1.5 Hz, 1H), 8.07-7.84 (m, 2H), 7.64 (t, J=7.8 Hz, 1H), 7.49 (dd, J=8.2, 4.6 Hz, 1H), 1.56 (s, 9H).

Reference： [1]Patent: US2017/15675,2017,A1 .Location in patent: Paragraph 1161

83
[ 220210-56-0 ]
(7R)-N-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide [ No CAS ]
3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-4-methylpyridin-2-yl)benzoic acid [ No CAS ]

Reference： [1]Patent: US2017/15675,2017,A1

84
[ 220210-56-0 ]
(7R)-N-(6-chloro-4-methylpyridin-2-yl)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide [ No CAS ]
tert-butyl 3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-4-methylpyridin-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃;	Example 103B tert-butyl 3-(6-[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-4-methylpyridin-2-yl)benzoate The product from Example 103A (0.080 g, 0.209 mmol), <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (0.046 g, 0.209 mmol), PdCl2dppf (10.71 mg, 0.015 mmol), and potassium carbonate (0.066 g, 0.481 mmol) in dimethoxyethane (0.8 mL) and water (0.4 mL) were heated at 80 C. overnight. The mixture was diluted with ethyl acetate (10 mL) and washed with water (35 mL) and with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC on a Waters Nova-Pak HR C18 6 mum 60 A Prep-Pak cartridge column (40 mm100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/minute to yield the title compound (0.055 g, 50%). 1H NMR (500 MHz, DMSO-d6) delta 10.03 (s, 1H), 8.58 (t, J=1.8 Hz, 1H), 8.28 (dt, J=7.9, 1.3 Hz, 1H), 7.95 (dt, J=7.6, 1.4 Hz, 1H), 7.84 (t, J=1.0 Hz, 1H), 7.71-7.57 (m, 3H), 7.05 (s, 1H), 5.13 (d, J=9.3 Hz, 1H), 4.44 (d, J=9.2 Hz, 1H), 2.39 (s, 3H), 1.74 (s, 3H), 1.59 (s, 9H). MS (ESI+) m/z 525.1 (M+H).

Reference： [1]Patent: US2017/15675,2017,A1 .Location in patent: Paragraph 1186

85
[ 220210-56-0 ]
5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide [ No CAS ]
tert-butyl 3-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate [ No CAS ]
di-tert-butyl 3,3′-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridine-5,6-diyl)dibenzoate [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 796 - 806
[2]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 771 - 774

86
[ 220210-56-0 ]
[ 753-90-2 ]
5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide [ No CAS ]
tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoate [ No CAS ]

Reference： [1]MedChemComm,2017,vol. 8,p. 796 - 806

87
[ 220210-56-0 ]
tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 771 - 774

88
[ 220210-56-0 ]
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoic acid [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 771 - 774

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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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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

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[ 220210-56-0 ] Synthesis Path-Upstream 1~1

[ 220210-56-0 ] Synthesis Path-Downstream 1~88

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