[ CAS No. 564483-19-8 ] {[proInfo.proName]}

Name: 564483-19-8|Di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine|98%
Brand: Ambeed
SKU: A360721
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2D 3D

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Quality Control of [ 564483-19-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 564483-19-8 ]

SDS Specification

Alternatived Products of [ 564483-19-8 ]

Product Details of [ 564483-19-8 ]

CAS No. :	564483-19-8	MDL No. :	MFCD06411306
Formula :	C₂₉H₄₅P	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SACNIGZYDTUHKB-UHFFFAOYSA-N
M.W :	424.64	Pubchem ID :	11618717
Synonyms :		Chemical Name :	Di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine

Calculated chemistry of [ 564483-19-8 ]

Physicochemical Properties

Num. heavy atoms :	30
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.59
Num. rotatable bonds :	7
Num. H-bond acceptors :	0.0
Num. H-bond donors :	0.0
Molar Refractivity :	142.82
TPSA :	13.59 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-2.88 cm/s

Lipophilicity

Log Po/w (iLOGP) :	5.02
Log Po/w (XLOGP3) :	8.47
Log Po/w (WLOGP) :	9.43
Log Po/w (MLOGP) :	7.73
Log Po/w (SILICOS-IT) :	10.04
Consensus Log Po/w :	8.14

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	1.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-7.64
Solubility :	0.00000966 mg/ml ; 0.0000000228 mol/l
Class :	Poorly soluble
Log S (Ali) :	-8.63
Solubility :	0.000001 mg/ml ; 0.0000000024 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-9.81
Solubility :	0.0000000653 mg/ml ; 0.0000000002 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.8

Safety of [ 564483-19-8 ]

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

Application In Synthesis of [ 564483-19-8 ]

* 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 [ 564483-19-8 ]
Downstream synthetic route of [ 564483-19-8 ]

[ 564483-19-8 ] Synthesis Path-Upstream 1~1

1
[ 13716-10-4 ]
[ 694-80-4 ]
[ 21524-34-5 ]
[ 564483-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: With magnesium In tetrahydrofuran for 2 h; Inert atmosphere; Reflux Stage #2: With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In tetrahydrofuran at 20℃; for 5.5 h; Reflux; Inert atmosphere	1L three bottles,To a solution of 32.5 g of 2,4,6-triisopropylbromobenzene,5.6 g of magnesium turnings and 300 mL of anhydrous THF,20 g of o-chlorobromobenzene was dropwise added,2,4,6-triisopropyl-2-bromobiphenyl Grignard reagent,Refluxed for 2 hours,Down to room temperature,2.4 g of tetrakis (triphenylphosphine) palladium was added,Stirred for 30 minutes,18.8 g of di-tert-butylphosphonium chloride was added dropwise at room temperature,The reaction was refluxed for 5 hours.And the mixture was added dropwise to the reaction solution under ice-water bath200 mL of saturated aqueous ammonium chloride was quenched,Liquid separation,The organic phase is dissolved,Add methanol crystallization,And filtered to obtain 41.7 g of white 2-di-tert-butylphosphine-2,4,6-triisopropylbiphenyl,Yield 94percent.

Reference： [1] Patent: CN105859774, 2016, A, . Location in patent: Paragraph 0078; 0079; 0080; 0081
[2] Journal of the American Chemical Society, 2003, vol. 125, # 22, p. 6653 - 6655

[ 564483-19-8 ] Synthesis Path-Downstream 1~66

1
[ 13716-10-4 ]
[ 694-80-4 ]
[ 21524-34-5 ]
[ 564483-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%		1L three bottles,To a solution of 32.5 g of 2,4,6-triisopropylbromobenzene,5.6 g of magnesium turnings and 300 mL of anhydrous THF,20 g of o-chlorobromobenzene was dropwise added,2,4,6-triisopropyl-2-bromobiphenyl Grignard reagent,Refluxed for 2 hours,Down to room temperature,2.4 g of tetrakis (triphenylphosphine) palladium was added,Stirred for 30 minutes,18.8 g of di-tert-butylphosphonium chloride was added dropwise at room temperature,The reaction was refluxed for 5 hours.And the mixture was added dropwise to the reaction solution under ice-water bath200 mL of saturated aqueous ammonium chloride was quenched,Liquid separation,The organic phase is dissolved,Add methanol crystallization,And filtered to obtain 41.7 g of white 2-di-tert-butylphosphine-2,4,6-triisopropylbiphenyl,Yield 94%.

Reference： [1]Patent: CN105859774,2016,A .Location in patent: Paragraph 0078; 0079; 0080; 0081
[2]Journal of the American Chemical Society,2003,vol. 125,p. 6653 - 6655

2
[ 564483-19-8 ]
C₂₉H₄₅PO [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2007,vol. 129,p. 5096 - 5101

3
potassium phosphate [ No CAS ]
[ 150-19-6 ]
[ 890315-75-0 ]
[ 564483-19-8 ]
[ 890315-26-1 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;palladium diacetate; In ethyl acetate;	Example 534 6.0 mg of palladium acetate was added to 5 mL of toluene suspension containing 0.50 g tert-butyl 2-(benzamido)-4-bromobenzoate, 0.18 mL of 3-methoxyphenol, 17 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 0.57 g of tripotassium phosphate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate = 6:1] to obtain 0.32 g of tert-butyl 2-(benzamido)-4-(3-methoxyphenoxy)benzoate as white solid. 1H-NMR (CDCl3) delta: 1.62 (9H, s), 3.80 (3H, s), 6.64-6.76 (4H, m), 7.28 (1H, t, J = 8.0 Hz), 7.48-7.59 (3H, m), 7.98 (1H, d, J = 8.8 Hz), 8.01-8.06 (2H, m), 8.63 (1H, d, J = 2.7 Hz), 12.30 (1H, s).

Reference： [1]Patent: EP1820795,2007,A1

4
potassium phosphate [ No CAS ]
[ 890315-75-0 ]
[ 554-84-7 ]
[ 564483-19-8 ]
[ 890316-67-3 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;tris-(dibenzylideneacetone)dipalladium(0); In ethyl acetate; toluene;	Example 559 31 mg of 3-nitrophenol, 79 mg of tripotassium phosphate, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 10:1] to obtain tert-butyl 2-(benzamido)-4-(3-nitrophenoxy)benzoate.

Reference： [1]Patent: EP1820795,2007,A1

5
potassium phosphate [ No CAS ]
[ 890315-75-0 ]
[ 2713-34-0 ]
[ 564483-19-8 ]
[ 890315-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;tris-(dibenzylideneacetone)dipalladium(0); In ethyl acetate; toluene;	Example 526 29 mg of 3,5-difluorophenol, 79 mg of tripotassium phosphate, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 10:1] to obtain 71 mg of tert-butyl 2-(benzamido)-4-(3,5-difluorophenoxy)benzoate as colorless oil. 1H-NMR (CDCl3) delta: 1.64 (9H, s), 6.56-6.63 (3H, m), 6.73 (1H, dd, J = 8.8, 2.4 Hz), 7.50-7.60 (3H, m), 8.01-8.07 (3H, m), 8.70 (1H, d, J = 2.4 Hz), 12.34 (1H, s).

Reference： [1]Patent: EP1820795,2007,A1

6
potassium phosphate [ No CAS ]
[ 106-44-5 ]
[ 890315-75-0 ]
[ 564483-19-8 ]
[ 890316-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;palladium diacetate; In ethyl acetate; toluene;	Example 554 0.023 mL of p-cresol, 79 mg of tripotassium phosphate, 2.4 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 0.8 mg of palladium acetate were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate = 4:1] to obtain tert-butyl 2-(benzamido)-4-(4-methylphenoxy)benzoate.

Reference： [1]Patent: EP1820795,2007,A1

7
potassium phosphate [ No CAS ]
[ 434958-85-7 ]
[ 890315-75-0 ]
[ 564483-19-8 ]
[ 890316-66-2 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;tris-(dibenzylideneacetone)dipalladium(0); In ethyl acetate; toluene;	Example 558 52 mg of <strong>[434958-85-7]tert-butyl 5-hydroxy-1H-indole-1-carboxylate</strong>, 79 mg of tripotassium phosphate, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 10:1] to obtain tert-butyl 5-(3-(benzamido)-4-(tert-butoxycarbonyl)phenoxy)-1H-indole-1-carboxylate.

Reference： [1]Patent: EP1820795,2007,A1

8
potassium phosphate [ No CAS ]
[ 13523-92-7 ]
[ 890315-74-9 ]
[ 564483-19-8 ]
[ 890315-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;tris-(dibenzylideneacetone)dipalladium(0); In ethyl acetate; toluene;	Example 537 26 mg of 5-hydroxy-1-methyl-1H-indole, 64 mg of tripotassium phosphate, 3.8 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 5.5 mg of tris(dibenzylideneacetone)dipalladium(0) were added to 1.0 mL of toluene solution containing 50 mg of methyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10percent citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 5:1] to obtain 53 mg of methyl 2-(benzamido)-4-(1-methyl-1H-indol-5-yloxy)benzoate as pale yellow solid. 1H-NMR (CDCl3) delta: 3.83 (3H, s), 3.93 (3H, s), 6.47 (1H, dd, J = 3.1, 0.9 Hz), 6.63 (1H, dd, J = 9.0, 2.6 Hz), 7.02 (1H, dd, J = 8.8, 2.2 Hz), 7.10 (1H, d, J = 2.9 Hz), 7.32-7.38 (2H, m), 7.47-7.57 (3H, m), 7.97-8.03 (3H, m), 8.58 (1H, d, J = 2.6 Hz), 12.14 (1H, s).

Reference： [1]Patent: EP1820795,2007,A1

9
[ 890315-75-0 ]
[ 120-83-2 ]
[ 564483-19-8 ]
[ 890316-80-0 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;tris-(dibenzylideneacetone)dipalladium(0); In ethyl acetate;	Example 571 91 mg of 2,4-dichlorophenol was added to 2.1 mL of toluene suspension containing 22 mg of 60% sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, 61 mg of 2,4-dichlorophenol, 15 mg of 60% sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 10 hours. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 20:1] to obtain tert-butyl 2-(benzamido)-4-(2,4-dichlorophenoxy)benzoate.

Reference： [1]Patent: EP1820795,2007,A1

10
[ 890315-75-0 ]
[ 367-27-1 ]
[ 131274-22-1 ]
[ 564483-19-8 ]
[ 890316-65-1 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;tris-(dibenzylideneacetone)dipalladium(0); palladium diacetate; In ethyl acetate; toluene;	Example 557 0.018 mL of 2,4-difluorophenol was added to 1 mL of toluene suspension containing 10 mg of 60percent sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 0.5 mL of toluene solution containing 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl, 1.7 mg of palladium acetate and 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate was added and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, 4.5 mg of 60percent sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 0.018 mL of 2,4-difluorophenol, 7.4 mg of 60percent sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 5.1 mg of tris(dibenzylideneacetone)dipalladium(0) were added, and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour and 30 minutes. 10percent citric acid aqueous solution and ethyl acetate were added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate = 4:1] to obtain tert-butyl 2-(benzamido)-4-(2,4-difluorophenoxy)benzoate.

Reference： [1]Patent: EP1820795,2007,A1

11
[ 100-02-7 ]
[ 890315-75-0 ]
[ 131274-22-1 ]
[ 564483-19-8 ]
[ 890315-31-8 ]

Yield	Reaction Conditions	Operation in experiment
	With citric acid;tris-(dibenzylideneacetone)dipalladium(0); palladium diacetate; In ethyl acetate; toluene;	Example 536 31 mg of 4-nitrophenol was added to 1.0 mL of toluene suspension containing of 8.9 mg of 60percent sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 0.5 mL of toluene solution containing 3.8 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl, 1.3 mg of palladium acetate and 56 mg of tert-butyl 2-(benzamido)-4-bromobenzoate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, 1.3 mg of tri-tert-butylphosphine tetrafluoroborate and 4.1 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, 10percent citric acid aqueous solution and ethyl acetate were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 10:1] to obtain 18 mg of tert-butyl 2-(benzamido)-4-(4-nitrophenoxy)benzoate as white solid. 1H-NMR (CDCl3) delta: 1.65 (9H, s), 6.79 (1H, dd, J = 8.8, 2.4 Hz), 7.12-7.17 (2H, m), 7.50-7.61 (3H, m), 8.01-8.06 (2H, m), 8.09 (1H, d, J = 8.8 Hz), 8.23-8.29 (2H, m), 8.74 (1H, d, J = 2.4 Hz), 12.36 (1H, s).

Reference： [1]Patent: EP1820795,2007,A1

12
[ 1206774-49-3 ]
[ 1206774-50-6 ]
[ 564483-19-8 ]
[ 108-95-2 ]
[ 1206771-42-7 ]

Yield	Reaction Conditions	Operation in experiment
48 mg (96%)	With hydrogen bromide; acetic acid;palladium diacetate; In ethyl acetate; toluene;	Example 16 3-(3-tert-Butyl-5-phenoxy-phenyl)-1H-pyridin-2-one (I-45) step 1-A mixture of 3-(3-bromo-5-tert-butyl-phenyl)-2-methoxy-pyridine (123 mg, 0.384 mmol), phenol (46 mg, 0.489 mmol), Pd(OAc)2 (4.1 mg, 0.018 mmol), 2-di-tert-butylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (9.9 mg, 0.023 mmol) and K3PO4 (167 0.787 mmol)) in a Schlenk flask was purged with argon before toluene (5 mL) was added. The reaction under an argon atmosphere was heated overnight at 115 C. The reaction was cooled to RT, filtered through CELITE, and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluding with an EtOAc/hexane gradient (0 to 2% EtOAc) to afford 40 mg (41%) of 3-(3-tert-butyl-5-phenoxy-phenyl)-2-methoxy-pyridine (124). step 2-A solution of 124 (52 mg, 0.157 mmol), 48% HBr (50 L, 0.436 mmol) and HOAc (3 mL) in sealed tube was heated at 70 C. overnight. The reaction mixture was cooled to RT, carefully poured into a cold saturated aqueous NaHCO3 and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 66% EtOAc/hexanes to afford 48 mg (96%) of I-45 as a foam.

Reference： [1]Patent: US2010/21423,2010,A1

13
[ 564483-19-8 ]
C₂₉H₄₅PO [ No CAS ]
[ 1233777-93-9 ]
[ 1233777-92-8 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 3100 - 3103

14
[ 52522-40-4 ]
[ 564483-19-8 ]
[ 1354022-32-4 ]
[ 1354022-31-3 ]

Reference： [1]Organometallics,2012,vol. 31,p. 519 - 522

15
[ 636-98-6 ]
[ 1271-03-0 ]
[ 564483-19-8 ]
[ 1358576-09-6 ]

Reference： [1]Organometallics,2012,vol. 31,p. 1073 - 1081

16
[ 74-85-1 ]
[ 1109-15-5 ]
[ 564483-19-8 ]
[ 1353897-02-5 ]

Reference： [1]Organometallics,2012,vol. 31,p. 2801 - 2809
[2]Organometallics,2012,vol. 31,p. 2801 - 2809

17
[ 1109-15-5 ]
[ 564483-19-8 ]
C₁₈⁽²⁾HBF₁₅^(1-)*C₂₉H₄₅P*⁽²⁾H⁽¹⁺⁾ [ No CAS ]

Reference： [1]Organometallics,2012,vol. 31,p. 2801 - 2809

18
[ 1109-15-5 ]
[ 564483-19-8 ]
[ 1353896-98-6 ]

Reference： [1]Organometallics,2012,vol. 31,p. 2801 - 2809

19
[ 225931-80-6 ]
[ 586-77-6 ]
[ 564483-19-8 ]
C₃₇H₅₅BrNPPd [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 19922 - 19934

20
[ 108-86-1 ]
[ 225931-80-6 ]
[ 564483-19-8 ]
C₃₅H₅₀BrPPd [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 19922 - 19934

21
[ 225931-80-6 ]
[ 623-00-7 ]
[ 564483-19-8 ]
C₃₆H₄₉BrNPPd [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 19922 - 19934

22
[ 225931-80-6 ]
[ 41492-05-1 ]
[ 564483-19-8 ]
C₃₉H₅₈BrPPd [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 19922 - 19934

23
[ 1435520-65-2 ]
[ 564483-19-8 ]
[ 1445085-66-4 ]

Reference： [1]Chemical Science,2013,vol. 4,p. 916 - 920

24
[ 225931-80-6 ]
[ 352-33-0 ]
[ 564483-19-8 ]
C₃₅H₄₉ClFPPd [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10035 - 10039
Angew. Chem.,2013,vol. 125,p. 10219 - 10223

25
[ 1013-88-3 ]
[ 1415914-94-1 ]
[ 564483-19-8 ]
[ 1415914-95-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate; In toluene;	Synthesis of the Intermediate Imines E8 Intermediate E8.1 Under argon in a sealed tube were added to a solution of (S)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(5-bromo-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate E7.1) (725 mg, 1.16 mmol) in toluene (15 ml) sodium tert-butoxide (334 mg, 3.48 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (73.8 mg, 174 mumol) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (60.0 mg, 58.0 mumol) and benzophenone imine (420 mg, 389 mul, 2.32 mmol), the tube was sealed under argon and the mixture was stirred at 105 C. for 4 h. The brown solution was extracted with ethyl acetate/water. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give a brown oil. The residue was chromatographed on 20 g silica gel with ethyl acetate 0-50% to give (S)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(difluoromethyl)-4-(5-(diphenylmethyleneamino)-2-fluorophenyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (525 mg, 723 mumol, 62.4% yield) as a yellow oil. MS (ISP): m/z=726.8 [M+H]+.

Reference： [1]Patent: US2014/80819,2014,A1 .Location in patent: Page/Page column

26
(R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine [ No CAS ]
[ 116538-96-6 ]
[ 564483-19-8 ]
[ 1600507-18-3 ]

Yield	Reaction Conditions	Operation in experiment
32%	With tris-(dibenzylideneacetone)dipalladium(0); In hexane; toluene;	Example 73 Synthesis of (R)-3-((3-(5-Amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile A microwave vial was charged with (R)-5-amino-3-(5-bromo-2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (125 mg, 0.344 mmol), 3-aminothieno[3,2-b]pyridine-6-carbonitrile (90 mg, 0.516 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (43.9 mg, 0.103 mmol), sodium tert-butoxide (93 mg, 0.964 mmol), tris(dibenzylideneacetone)dipalladium(0) (31.5 mg, 0.034 mmol), and toluene (1.72 mL). The vial was purged with argon, sealed, and irradiated in a microwave reactor at 100 C. for 1.5 hours. The reaction was diluted with water and extracted with ethyl acetate; the organic layer was concentrated. The crude product was purified via silica gel chromatography, eluting with 20-100% ethyl acetate in hexane, to the title compound (50 mg, 0.109 mmol, 32% yield). LC/MS (ESI+) m/z=458 (M+H). 1H NMR (400 MHz, DMSO-d6) 9.07 (d, J=1.9 Hz, 1H), 9.06 (d, J=1.9 Hz, 1H), 8.46 (s, 1H), 7.52 (dd, J=2.9, 7.2 Hz, 1H), 7.49 (s, 1H), 7.17-7.24 (m, 1H), 7.06 (dd, J=8.8, 11.9 Hz, 1H), 6.09 (br. s., 2H), 3.66 (d, J=15.5 Hz, 1H), 3.51 (d, J=15.5 Hz, 1H), 1.63 (s, 3H), 1.58 (s, 3H), 1.47 (s, 3H).

Reference： [1]Patent: US2014/107109,2014,A1 .Location in patent: Page/Page column

27
[ 39929-21-0 ]
[ 564483-19-8 ]
[ 1312108-97-6 ]

Reference： [1]Australian Journal of Chemistry,2014,vol. 67,p. 481 - 499
[2]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 572 - 576

28
[ 1581285-85-9 ]
[ 564483-19-8 ]
[ 1599466-89-3 ]

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 4161 - 4166

29
[ 795-87-9 ]
[ 564483-19-8 ]
C₃₈H₄₅F₁₂OP [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In dichloromethane; at -78 - 20℃;Inert atmosphere;	tBuXPhos (232 mg, 0.546 mmol) was added inone portion at -78C to a solution of ketone 1 (192 mg, 0.546mmol) in CH2Cl2 (5mL) and the resulting slurry allowed to warmto r.t. while it was stirred. The solvent was then removed undervacuum and the crude product washed with MeOH to afford 7as a white solid (321 mg, 76%).

Reference： [1]Synlett,2014,vol. 25,p. 1539 - 1541

30
[ 225931-80-6 ]
[ 564483-19-8 ]
C₆₆H₁₀₂P₂Pd₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In pentane; at 20℃; for 48h;Inert atmosphere; Glovebox;	General procedure: In a nitrogen-filled glovebox, phosphine ligand (0.21 mmol,1.00 eq.) and [(1,5-cyclooctadiene) Pd(CH2TMS)2] (80 mg,0.21 mmol, 1.00 eq.) were suspended in pentane (5.0 mL). The reaction mixture was stirred vigorously at room temperature, duringwhich time a solid precipitated from solution. After 48 h, thenon-homogenous mixture was filtered though a sintered glass frit.The filter cake was washed with pentane (10.0 mL) to yield thedesired complex. 9: Yellow-green solid (Yield: 106 mg, 79%). IR (neat): 2931,2850, 1580, 1456, 1419, 1376, 1359, 1293, 1252, 1170, 1155,1087, 1044, 1013, 929, 870, 851, 798, 746, 715 cm1.

Reference： [1]Inorganica Chimica Acta,2014,vol. 422,p. 188 - 192

31
potassium phosphate [ No CAS ]
[ 564483-19-8 ]
ethyl 1-[7-methoxy-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With tris-(dibenzylideneacetone)dipalladium(0); In methanol; chloroform; water; tert-butyl alcohol;	(2) A suspension of the compound obtained in (1) (107 g), ethyl 1H-pyrazole-4-carboxylic acid (59.22 g), tripotassium phosphate (112.14 g), 2-di-t-butylphosphino-2',4',6'-triisopropyl biphenyl (11.22 g) and tris(dibenzylideneacetone)dipalladium(0) (8.06 g) in t-butyl alcohol (1173 mL) was stirred under nitrogen atmosphere for 4 hours at 90 C. The reaction mixture was added with water and filtered, and the resulting crystals were washed with methanol. The crystals were then dissolved in chloroform, and NH-silica gel (300 mL), silica gel (300 mL) and sodium sulfate (200 g) were added, followed by filtration to remove the insoluble material. The filtrate was concentrated under reduced pressure, the residue was added with methanol. The resulting crystals were corrected by filtration to yield ethyl 1-[7-methoxy-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-1H-pyrazole-4-carboxylate (99.62 g, 69% yield) as colorless crystals. MS (ESI) m/z: 409 [M+H]+.

Reference： [1]Patent: US2015/239889,2015,A1

32
potassium phosphate [ No CAS ]
[ 37622-90-5 ]
[ 564483-19-8 ]
ethyl 1-[7-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With tris-(dibenzylideneacetone)dipalladium(0); In methanol; chloroform; tert-butyl alcohol;	(2) A suspension of the compound obtained in (1) (89.27 g), ethyl 1H-pyrazole-4-carboxylate (45.16 g), tripotassium phosphate (93.3 g), 2-di-t-butylphosphino-2',4',6'-triisopropyl biphenyl (9.33 g) and tris(dibenzylideneacetone)dipalladium(0) (6.7 g) in t-butyl alcohol (900 mL) was stirred for 2 hours at 90 C. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was added with chloroform and water. The organic layer was separated, and the aqueous layer was extracted with chloroform. The NH-silica gel (100 mL) and sodium sulfate (100 g) were added to the organic layer, and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was added with methanol. The resulting crystals were collected by filtration to yield ethyl 1-[7-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-1H-pyrazole-4-carboxylate (78.94 g, 66% yield) as colorless crystals. MS (APCI) m/z: 409 [M+H]+.

Reference： [1]Patent: US2015/239889,2015,A1

33
bis(η3-allyl-μ-chloropalladium(II)) [ No CAS ]
[ 2923-28-6 ]
[ 564483-19-8 ]
allyl(2-di-tert-butylphosphino-2‘,4‘,6‘-triisopropyl-1,1‘-biphenyl)palladium(II) triflate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In tetrahydrofuran; at 20℃; for 2h;Schlenk technique; Inert atmosphere; Darkness;	General procedure: [(allyl)PdCl]2 (183 mg, 0.50 mmol); 22 AgOTf (257 mg, 1.00 mmol); 27 tBuXPhos (425 mg, 1.00 mmol); 24 THF (10.0 mL); 2 h. Product obtained as a slightly yellow solid (708 mg, 98%); 1H NMR (400 MHz, CDCl3, delta): 7.92 (t, J=7.3 Hz, 1H), 7.59-7.47 (m, 3H), 7.42-7.40 (m, 1H), 6.79 (dd, J=3.2 Hz, 7.5 Hz, 1H), 5.72 (sept, J=7.2 Hz, 1H), 4.49 (d, J=6.7 Hz, 1H), 3.52 (dd, J=9.0 Hz, 14.0 Hz, 1H), 3.03 (quint, J=7.1 Hz, 1H), 2.93 (d, J=12.9 Hz, 1H), 2.67-2.62 (m, 1H), 2.50 (quint, J=7.1 Hz, 1H), 2.26 (quint, J=6.9 Hz, 1H), 1.49-1.40 (m, 9H), 1.40-1.28 (m, 21H), 0.96 (d, J=6.7 Hz, 3H), 0.88 (d, J=6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3, delta): 153.6, 152.7, 149.2, 146.0, 145.8, 135.1 (2 peaks), 134.9, 133.7, 133.6, 131.7, 131.6, 128.3, 128.2, 126.6, 126.2, 125.8, 122.6, 120.3 (2 peaks), 120.1 (2 peaks), 119.4, 116.2, 101.3, 101.1, 55.5, 38.3 (2 peaks), 38.2, 38.1, 33.9, 32.0, 31.7, 31.2, 31.1, 30.9, 30.8, 25.9, 25.4, 24.9, 24.5 (2 peaks), 24.1 [Observed complexity due to C-F and C-P coupling]; 19F NMR (372 MHz, CDCl3, delta): -78.1 (s, 3F); 31P NMR (162 MHz, CDCl3, delta): 70.1; Anal. calcd. for C33H50O3F3PSPd: C, 54.96; H, 6.99. Found C, 54.84; H, 7.13.

Reference： [1]Patent: US9777030,2017,B2 .Location in patent: Page/Page column 58; 59; 60; 61
[2]Journal of Organic Chemistry,2015,vol. 80,p. 6794 - 6813

34
bis[(1,2,3-η)-2-butenyl]di(μ-chloro)palladium(II) [ No CAS ]
[ 2923-28-6 ]
[ 564483-19-8 ]
[(π-crotyl)Pd(tBuXPhos)]OTf [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In 2-methyltetrahydrofuran; at 20℃; for 2h;Schlenk technique; Inert atmosphere; Darkness;	General procedure: [(crotyl)PdCl]2 (197 mg, 0.50 mmol); 22 AgOTf (257 mg, 1.00 mmol); 27 tBuXPhos (425 mg, 1.00 mmol); 2-MeTHF (10.0 mL); 2 h. Product obtained as a slightly yellow solid (722 mg, 98%); The spectral properties are complicated due to the presence of isomers. 1H NMR (400 MHz, CDCl3, delta): Complex spectrum, see FIG. 1; 13C NMR (100 MHz, CDCl3, delta): 153.4, 152.3, 152.0, 146.4, 146.2, 146.0, 145.8, 144.1, 135.0, 134.9, 134.7, 134.4, 134.1, 133.7, 133.6, 133.3, 133.2, 131.5 (2 peaks), 131.4 (2 peaks), 128.1 (2 peaks), 128.0, 127.1, 126.1, 125.7, 124.6, 124.1, 122.9, 122.8, 122.5, 121.7, 121.4, 119.3, 112.9 (2 peaks), 48.3, 38.9, 38.8, 38.3, 38.1, 37.5, 37.3, 33.8, 33.5, 32.0, 31.9, 31.7, 31.6, 31.3, 31.1 (2 peaks), 31.0 (2 peaks), 30.7 (2 peaks), 26.2, 25.6, 25.5, 25.4, 25.1, 24.9, 24.3, 24.2, 24.0 (2 peaks), 23.7, 23.4, 22.8, 16.4 (2 peaks) [Observed complexity due to C-F and C-P coupling]; 19F NMR (372 MHz, CDCl3, delta): -77.9 (s, 3F); 31P NMR (162 MHz, CDCl3, delta): 72.2, 71.7, 66.7; Anal. calcd. for C34H52O3F3PSPd: C, 55.54; H, 7.13. Found C, 55.66; H, 6.99.

Reference： [1]Patent: US9777030,2017,B2 .Location in patent: Page/Page column 58; 59; 60; 61
[2]Journal of Organic Chemistry,2015,vol. 80,p. 6794 - 6813

35
bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)] [ No CAS ]
[ 2923-28-6 ]
[ 564483-19-8 ]
[(π-cinnamyl)Pd(tBuXPhos)]OTf [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 6794 - 6813

36
[ 16836-95-6 ]
[ 564483-19-8 ]
C₃₆H₅₂AgO₃PS [ No CAS ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 340 - 354

37
cis-[Pd(pentafluorophenyl)2(THF)2] [ No CAS ]
[ 352-34-1 ]
[ 564483-19-8 ]
C₃₅H₄₉FIPPd [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 13276 - 13280
Angew. Chem.,2016,vol. 128,p. 13470 - 13474,5

38
cis-[Pd(pentafluorophenyl)2(THF)2] [ No CAS ]
[ 564483-19-8 ]
C₄₁H₄₅F₁₀PPd [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 13276 - 13280
Angew. Chem.,2016,vol. 128,p. 13470 - 13474,5

39
[ 29892-37-3 ]
[ 564483-19-8 ]
[ 1312108-97-6 ]

Reference： [1]Organic Syntheses,2016,vol. 93,p. 115 - 126
[2]Chemistry - A European Journal,2016,vol. 22,p. 14175 - 14180

40
[ 104-92-7 ]
[ 225931-80-6 ]
[ 564483-19-8 ]
C₃₆H₅₂BrOPPd [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 3177 - 3181
Angew. Chem.,2017,vol. 129,p. 3225 - 3229,5

41
[ 564483-19-8 ]
[Au(tBuXPhos)(1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea)]²⁺ [ No CAS ]