[ CAS No. 144025-03-6 ] {[proInfo.proName]}

Name: 144025-03-6|2,4-Difluorophenylboronic acid|97%
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Quality Control of [ 144025-03-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 144025-03-6 ]

Product Details of [ 144025-03-6 ]

CAS No. :	144025-03-6	MDL No. :	MFCD01318998
Formula :	C₆H₅BF₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QQLRSCZSKQTFGY-UHFFFAOYSA-N
M.W :	157.91	Pubchem ID :	2734334
Synonyms :

Calculated chemistry of [ 144025-03-6 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	36.18
TPSA :	40.46 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.03
Log Po/w (WLOGP) :	0.48
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	0.13
Consensus Log Po/w :	0.56

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.81
Solubility :	2.47 mg/ml ; 0.0156 mol/l
Class :	Very soluble
Log S (Ali) :	-1.47
Solubility :	5.35 mg/ml ; 0.0339 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.83
Solubility :	2.31 mg/ml ; 0.0147 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.16

Safety of [ 144025-03-6 ]

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 [ 144025-03-6 ]

* 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 [ 144025-03-6 ]
Downstream synthetic route of [ 144025-03-6 ]

[ 144025-03-6 ] Synthesis Path-Upstream 1~10

1
[ 144025-03-6 ]
[ 367-27-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With dihydrogen peroxide In water at 20℃;	General procedure: In a 50 mL round-bottomed flask, a mixture of arylboronic acid(1 mmol), H2O2 (30percent aq, 0.2 mL), ZnO nanocatalyst (5 molpercent; sampleZnO-1) and 2 mL of water were stirred at room temperature under aerobic condition. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with 20 mL of water and extracted with (3×20) mL of diethyl ether. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed in a rotary evaporator under reduced pressure. The crude product was purified by column chromatography (hexane/ ethylacetate, 9:1) on silica (100–200mesh) to get the desired product. The products were identified by 1HNMR and 13C NMR.
91%	With dihydrogen peroxide In water at 20℃; for 0.166667 h; Green chemistry	General procedure: In a 50mL round-bottomed flask, a mixture of arylboronic acid (1mmol), H₂O₂ (30percent aq, 0.2mL), bio-silica (5mg) and 2mL of water was added and stirred at room temperature in aerobic condition. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with 20mL of water and extracted with (3×20) mL of diethylether and the combined organic layer was washed with brine and dried over by Na₂SO₄ and evaporated in a rotary evaporator under reduced pressure. The crude was purified by column chromatography (hexane/ethylacetate, 9:1) on mesh silica (100–200) to get the desired product. The products were confirmed by ¹H NMR, ¹³C NMR, FT-IR spectroscopy and mass spectrometry.

Reference： [1] Applied Catalysis A: General, 2018, vol. 562, p. 58 - 66
[2] Tetrahedron Letters, 2015, vol. 56, # 14, p. 1780 - 1783
[3] Journal of Organic Chemistry, 2001, vol. 66, # 2, p. 633 - 634

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[ 144025-04-7 ]
[ 144025-03-6 ]

Yield	Reaction Conditions	Operation in experiment
84.3%	With sulfuric acid In tetrahydrofuran; water	B) Trimethylborate (25.98 g; 0.25 moles--Fluka) and a solution of 2,4-difluorophenylmagnesiumbromide (0.25 moles) in tetrahydrofuran (200 ml) were contemporaneously added, in 1 hour, into a reactor containing tetrahydrofuran (125 ml) under nitrogen while keeping the temperature at -15° C. At the end of the addition, the reaction mixture was kept under stirring at -15° C. for 15 minutes. After bringing the temperature to 0° C., water (17.5 ml) and 10percent sulfuric acid (125 ml) were added in 10 minutes and in 15 minutes respectively. After adding further water (250 ml) up to complete dissolution, the solution was extracted with ethyl ether (3*150 ml). The collected organic phases were evaporated to dryness obtaining a crude 2,4-difluorophenylboronic acid (36.98 g; titre 90percent; 84.3percent yield) which was used in the subsequent cross-coupling reaction without any further purification.
84.3%	With sulfuric acid In tetrahydrofuran; water	B) Trimethylborate (25.98 g; 0.25 moles - Fluka) and a solution of 2,4-difluorophenylmagnesiumbromide (0.25 moles) in tetrahydrofuran (200 ml) were contemporaneously added, in 1 hour, into a reactor containing tetrahydrofuran (125 ml) under nitrogen while keeping the temperature at -15°C. At the end of the addition, the reaction mixture was kept under stirring at -15°C for 15 minutes. After bringing the temperature to 0°C, water (17.5 ml) and 10percent sulfuric acid (125 ml) were added in 10 minutes and in 15 minutes respectively. After adding further water (250 ml) up to complete dissolution, the solution was extracted with ethyl ether (3 x 150 ml). The collected organic phases were evaporated to dryness obtaining a crude 2,4-difluorophenylboronic acid (36.98 g; titre 90percent; 84.3percent yield) which was used in the subsequent cross-coupling reaction without any further purification.
40%	Stage #1: at -60℃; for 5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0℃; Inert atmosphere	Embodiment 1: the Synthesis of Di-(4,6-Difluorophenyl Pyridine-N, C2) Pyridine Formyl Iridium/FIrPic.Step One: After the reaction triggered by 11 g of magnesium powder, iodine, and a small amount of 2,4-Difluoro Bromobenzene, dripped in a solution of 77.2 g of 2,4-Difluoro Bromobenzene and 400 ml of THF. The temperature was kept between 28° C. and 35° C. and maintained for the whole reaction. And the solution appeared gray.Then after 5 hours of reaction at room temperature, then stop if no raw material was detected by pointing board. Added 54 g of Trimethoxy-boron and 400 ml of THF in the reaction bulb, then introduced in the nitrogen gas. When the temperature reached -60° C., dripped in the Grignard reagent. In less than a minute, green light appeared in the solution. With the Grignard reagent dripped in, the solution turned murky gray. When the dripping ended, the solution turned gray. With gradually lowered to room temperature, more solid substances can be seen. Overnight after, the solid substances disappeared, and the solution turned yellow turbidity.When cooled to 0° C. and dripped in 2M of hydrochloric acid, the solution appeared white turbidity which disappeared soon, and then turned transparent yellow green, and pH value is 1. After stirred for 2 hours, the solution was separated. By using 1 L of acetic ester as solvent, and after rinsed by water for twice, 24.76G of white solid substances were obtained by followed extracting and column chromatography processes, and the yield rate was up by 40percent.¹HMNR (CDCl₃, 400Hz): 7.83 (1H, m), 6.94 (1H, m), 6.8 (1H, m).

Reference： [1] Patent: US5312975, 1994, A,
[2] Patent: EP494419, 1992, A2,
[3] Patent: US5312975, 1994, A,
[4] Patent: EP494419, 1992, A2,
[5] Patent: US2012/309971, 2012, A1, . Location in patent: Page/Page column 2-3

3
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Reference： [1] Patent: US2016/164006, 2016, A1,

4
[ 348-57-2 ]
[ 121-43-7 ]
[ 144025-03-6 ]

Reference： [1] Zeitschrift fur Anorganische und Allgemeine Chemie, 2002, vol. 628, # 13, p. 2827 - 2833

5
[ 512198-16-2 ]
[ 7732-18-5 ]
[ 144025-03-6 ]

Reference： [1] Zeitschrift fur Anorganische und Allgemeine Chemie, 2002, vol. 628, # 13, p. 2827 - 2833
[2] Zeitschrift fur Anorganische und Allgemeine Chemie, 2002, vol. 628, # 13, p. 2827 - 2833

6
[ 871300-65-1 ]
[ 144025-03-6 ]

Reference： [1] Journal of Organic Chemistry, 2008, vol. 73, # 12, p. 4662 - 4670

7
[ 109-04-6 ]
[ 144025-03-6 ]
[ 391604-55-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium carbonate In tetrahydrofuran; water at 70℃; for 24 h;	2-Bromopyridine (2.01 mL, 21.1 mmol), 2,4-difluorophenylboronic acid (4.00 g, 25.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.732 g, 0.633 mmol) were added to round-bottomed flask with reflux condenser and dissolved to 50 mL of THF. After 30 mL of aqueous 2N Na₂CO₃was introduced, the reaction mixture was heated at 70° C. for 1 day. After cooling, the crude mixture was poured into water, extracted with CH₂C1₂(50 mL x 3 times), and dried over magnesium sulfate. The product was purified by silica column (n-hexane:EtOAc=4:1) to give dfppy 1 as colorless liquid (3.90 g, 97percent).
93%	Stage #1: With potassium carbonate In 1,2-dimethoxyethane for 0.5 h; Stage #2: at 90℃; for 18 h; Heating / reflux	2-bromopyridine (1 mmol), 2,4-difluorophenylboronic acid (1.2 mmol), potassium carbonate (2.7 mmol), and dimethoxyethane (1.5 mL) were put together in a round bottom flask, to which nitrogen was injected, followed by stirring for 30 minutes. Tetrakis(triphenylphosphine)palladium (0.05 mmol) was added and a reflux condenser was connected thereto, followed by reflux at 90° C. for 18 hours. After confirming the reaction by TLC, the solvent was removed by distillation under reduced pressure at high vacuum. After extracting with ethyl acetate, the residue was purified by fresh column chromotography to give compound (C). The yield was 93percent.
93%	Stage #1: With potassium carbonate In 1,2-dimethoxyethane for 0.5 h; Stage #2: at 90℃; for 18 h; Heating / reflux	2-bromopyridine (1 mmol), 2,4-difluorophenylboronic acid (1.2 mmol), potassium carbonate (2.7 mmol), and dimethoxyethane (1.5 mL) were put together in a round bottom flask, to which nitrogen was injected, followed by stirring for 30 minutes. Tetrakis(triphenylphosphine)palladium (0.05 mmol) was added and a reflux condenser was connected thereto, followed by reflux at 90°C for 18 hours. After confirming the reaction by TLC, the solvent was removed by distillation under reduced pressure at high vacuum. After extracting with ethyl acetate, the residue was purified by fresh column chromotography to give compound (C). The yield was 93percent.

90%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In ethanol; water; toluene at 80℃; for 15 h; Inert atmosphere	(1.03 g, 6.5 mmol) and tetrakis (triphenylphosphine) palladium (0.370 g, 0.32 mmol) were weighed out by adding 2-bromopyridine (1.0 g, 6.37 mmol), 2,4-difluorobenzeneboronic acid 50mL two-necked flask, the vacuum drum nitrogen cycle three times, followed by injection of toluene (9mL), saturated K₂CO₃(Aq) (3 mL), ethanol (3 mL), and refluxed at 80 ° C for 15 hours.Cooled to room temperature, extracted with dichloromethane and distilled water, and the organic phases were combined and dried under reduced pressure to give 1.12 g of product in 90percent yield.
87%	With palladium diacetate; sodium carbonate; triphenylphosphine In ethanol; water; toluene at 105℃; for 21 h; Inert atmosphere; Reflux	2,4-difluorophenylboronic acid (2.00 g, 12.7 mmol), Pd (OAc) 2 (143 mg, 63.5 mmol), PPh3 (656 mg, 2.50 mmol), Na2 CO3 (2.65 g, 250 mmol)And 2-bromopyridine (1.74 g, 11.0 mmol) were dissolved in a mixture of toluene (30 ml), ethanol (30 ml) and water (15 ml). The mixture was heated under reflux at 105 ° C. for 21 hours under an inert atmosphere.After cooling the mixture to room temperature, the organic layer of the mixture was not observed and ethyl acetateIt was extracted with chill. The solution was dried over magnesium sulfate and evaporated. The obtained crude product was purified by SiO 2 chromatography using hexane: ethyl acetate = 9: 1 to obtain dfppy represented by the formula (xii) (1.83 g, 9.57 mmol, 87percent)
83%	With potassium carbonate In tetrahydrofuran; water at 80℃; for 24 h; Heating / reflux	5.0 g of 2,4-difluorophenyl boronic acid (0.0285 mol), 3.0 g of 2-bromopyridine (0.019 mol), 150 ml of tetrahydrofuran, and a 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and then palladium tetrakistriphenylphosphine(Pd(PPh₃)₄; 0.7 g, 3 molpercent) as a catalyst was added. The mixture was refluxed at 80°C for 24 hours, and the reaction was terminated. 500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 150 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by distillation under reduced pressure. The yield was 83percent. Further, an ¹H-NMR of the prepared 2,4-difluoro phenyl pyridine is illustrated in the accompanying Fig. 3.
83%	With potassium carbonate In tetrahydrofuran; water at 80℃; for 24 h;	PREPARATIVE EXAMPLE 2Iridium(2-(4'-difluorophenyl-4-yl)pyridine) (2-(2-(phenylpyridine))₂; In order to prepare 2,4-difluoro phenyl pyridine, 5.0 g of 2,4-difluorophenyl boronic acid (0.0285 mol), 3.0 g of 2-bromopyridine (0.019 mol), 150 ml of tetrahydrofuran, and a 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and then palladium tetrakistriphenylphosphine(Pd(PPh₃)₄; 0.7 g, 3 mol percent) as a catalyst was added.The mixture was refluxed at 80° C. for 24 hours, and the reaction was terminated. 500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 150 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by distillation under reduced pressure. The yield was 83percent. Further, an ¹H-NMR of the prepared 2,4-difluoro phenyl pyridine is illustrated in the accompanying FIG. 3.Next, 1 g of bromo iridium complex (0.0014 mol), 0.5 g of 2,4-difluoro phenyl boronic acid (0.0021 mol), 150 ml of tetrahydrofuran, and 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and palladium tetrakistriphenylphosphine (Pd(PPh₃)₄; 0.07 g, 3 mol percent) as a catalyst was added. The mixture was refluxed at 80° C. for 24 hours, and the reaction was terminated500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 200 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by rotary evaporation. Finally, iridium(2-(4'-difluorophenyl-4-yl)pyridine) (2-(2-(phenylpyridine))₂was prepared as in Formula 3, and the yield was 86percent. Further, an ¹H-NMR of the prepared iridium(2-(4'-difluorophenyl-4-yl)pyridine)(2-(2-(phenylpyridine)) is illustrated in the accompanying FIG. 4.
83.5%	With potassium carbonate In tetrahydrofuran at 61℃; for 4 h; Inert atmosphere	Step Two: Added 200 ml of THF, 24.76 g of 2,4-Difluoro Boric acid and 22 g of 2-Bromopyridine to 1 L of four-neck flask, the solution appeared light tawny. Then added 52 g of Potassium carbonate in the solution, and yellow turbidity appeared. Then the Nitrogen gas was introduced in for 15 minutes. Added 1 g of Tetraphenyl-Phosphine-Palladium to the solution and heated, then refluxed when warmed to 61° C. As heated for 4 hours, the solution turned brown. Then the cooling and separating process, water layer was extracted with 300 ML of Ethyl Acetate, and then followed with merging and distillation steps. Finally, 25 g of white solid products can be reached by column chromatography with petroleum ether as solvent. The yield rate reached 83.5percent.¹HNMR (CDCl₃, 400Hz): 6.89 (m, 1H), 7.1 (m, 1H), 7.28 (m, 1H), 7.75 (m, 2H), 8.00 (m, 1H), 8.71 (d, 1H).
76.18%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In tetrahydrofuran at 65℃; for 24 h;	2-bromopyridine (4.17g, 26.39mmol), 2,4- difluorophenyl boronic acid (5.00g, 31.66mmol), phosphorus tetrakistriphenylphosphine palladium (0.91g, 0.79mmol) and sodium carbonate (6.36g, 60.00mmol ) was dissolved in 100mL of tetrahydrofuran, 65 for 24 hours, cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain primary ligand (3.84g, yield 76.18percent). The primary ligand (2.50g, 13.08mmol) and iridium chloride (2.30g, 6.23mmol) was dissolved in 15mL ethoxyethanol, the reaction mixture was 130 ° C 12h, then was added pyridine phosphate (2.72g, 12.46mmol) and sodium carbonate (3.30g, 31.15mmol), continue 130 reaction 24h. System cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain a yellow solid Ir1-001 (1.06g, yield: 21.5percent).
76.18%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In tetrahydrofuran at 65℃; for 24 h;	2-bromopyridine (4.17g, 26.39mmol), 2,4- difluorophenyl boronic acid (5.00g, 31.66mmol), phosphorus tetrakistriphenylphosphine palladium (0.91g, 0.79mmol) and sodium carbonate (6.36g, 60.00mmol ) was dissolved in 100mL of tetrahydrofuran, 65 for 24 hours, cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain primary ligand (3.84g, yield 76.18percent).The primary ligand (2.50g, 13.08 mmol) and iridium chloride (2.30g, 6.23mmol) was dissolved in ethoxyethanol 15mL2-, the reaction mixture was 130 12h, phosphoric acid was then added pyridine (2.72g, 12.46mmol) and sodium carbonate (3.30g, 31.15mmol), continue 130 reaction 24h.System cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain a yellow solid BIr1-001 (1.06g, yield: 21.5percent).
76.18%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In tetrahydrofuran for 24 h; Reflux	The first host ligand in Example 1 was prepared as follows:2-Bromopyridine (4.17 g, 26.39 mmol),2,4-difluorobenzeneboronic acid (5.00 g, 31.66 mmol),Tetrakistriphenylphosphine palladium (0.91 g, 0.79 mmol) and sodium carbonate were added(6.36 g, 60.00 mmol) was dissolved in 100 mL of tetrahydrofuran,The reaction was refluxed for 24 hours,Cool, add water and methylene chloride,The organic layer was concentrated by column chromatography as the firstA primary ligand of an aromatic ring linked azetidin(3.84 g, yield 76.18percent).The aromatic rhizariazole (2.50 g, 13.08 mmol) as the first host ligand,And iridium trichloride (2.30 g, 6.23 mmol) were dissolved in 15 mL of ethoxyethanol,The mixture was refluxed for 12h,Iridium dimeric bridged complex was obtained.Then pyridine sulfonic acid (1.36 g, 6.23 mmol) and potassium carbonate (2.60 g, 18.70 mmol)To the above iridium dimeric bridged complex,At 120. Continue reflux 18h.Cooling system,Add water and methylene chloride,The organic phase was concentrated and subjected to column chromatography to obtain a iridium complex (1.01 g, yield: 21.5percent) as a yellow solid.
57.8%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; toluene for 24 h; Inert atmosphere; Reflux	In a 100mL one-neck flask, were successively added 2-bromopyridine 5. 6g i.e. 25. 7mmol, 2, 4- difluorophenyl boronic acid 4. 5gI.e., 28. Ommol, i.e. sodium carbonate solution 20mL 2M, 20mL of toluene and 20mL of methanol and tetrakis (triphenylphosphine) palladium 0 · 80g i.e. 0. 7mmol, the reaction was heated to reflux under nitrogen for 24h. Cooling to room temperature, the reaction solution was poured into 100mL water and extracted three times each with 25mL of dichloromethane, the organic layers combined, dried over anhydrous magnesium sulfate overnight. Filtration, vacuum spin solvent, the crude product to 200-300 mesh silica gel as the stationary phase, the volume ratio of methylene chloride: petroleum ether 1: 1 mixture as an eluent to column chromatography to obtain 4.08g brown liquid a yield of 57.8percent

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[ 391604-55-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With O₄P^(3-)3K⁽¹⁺⁾5H₂O; tri(1-adamantyl)phosphine; {2-[((acetyl-κO)amino)phenyl-κC](tri-1-adamantylphosphine)palladium}(p-toluenesulfonate) In tetrahydrofuran at 70℃; for 4 h;	To a mixture of 2-chloropyridine (47 .iL, 0.50 mmol, 1 equiv), 2,4-difluorophenylboronic acid (118 mg, 0.75 mmol, 1.5 equiv), and K3P045H20 (0.45 mg, 1.5 mmol, 3 equiv) was added THF (400 tL) then a THF stock solution of 3 and PAd3 (100 1iL, 0.25 tmol of Pd/PAd3). The mixture was stirred at 70 °C for 4 h. The reaction mixture was diluted with ethyl acetate thenextracted with water. The combine organic layers were evaporated and the crude product waspurified by flash chromatography. After drying, 89 mg (93percent) of 37 was obtained as a colorless oil. NMR spectroscopic data agreed with literature values.
74%	With palladium diacetate; sodium carbonate; triphenylphosphine In ethanol; water; toluene at 90℃; for 6 h; Inert atmosphere	In the round-bottom flask is sequentially added in the sodium carbonate (5.30g, 50mmol), 2, 4 - difluorobenzoic acid (4.35g, 27 . 5mmol), 2 - chloro pyridine (3.95g, 25mmol), Pd (OAc)₂ (0.3350g,0 . 5mmol), Ph₃ P (0.5250g, 2mmol), toluene (50 ml), ethanol (25 ml) and deionized water (25 ml), pump the nitrogen 1h, stirring under nitrogen protection, for 90 °C in oil bath reaction 5h. Cooling to room temperature, liquid, aqueous phase of ethyl acetate (3 × 50 ml) extraction, the combined organic phase, using anhydrous MgSO₄ Drying, filtering, evaporate the solvent after the neutral aluminium oxide chromatography separation (elution agent is V_PE : V_EA =20:1), to obtain the colorless transparent liquid 2 - (2, 4 - difluorophenyl) pyridine (3.54g, 18 . 5mmol), yield 74percent.
74%	With palladium diacetate; sodium carbonate; triphenylphosphine In ethanol; water; toluene at 90℃; for 6 h; Inert atmosphere	Sodium carbonate (5.30 g, 50 mmol) was added in turn to a round bottom flask.2,4-Difluorophenylboronic acid (4.35 g, 27.5 mmol),2-chloropyridine (3.95 g, 25 mmol), Pd(OAc) 2 (0.3350 g, 0.5 mmol),Ph3P (0.5250 g, 2 mmol), toluene (50 mL), ethanol (25 mL) andDeionized water (25 mL) was bubbled with nitrogen for 1 h and stirred under nitrogen.The reaction was carried out in a 90°C oil bath for 5 h. Cool to room temperature, separate,The aqueous phase is extracted with ethyl acetate (3 x 50 mL) and the organic phases are combined,Dry with anhydrous MgSO4, suction filtration, solvent distillation and separation by neutral alumina column chromatography(eluent: VPE:VEA=20:1), colorless transparent liquid was isolated2-(2,4-Difluorophenyl)pyridine (3.54 g, 18.5 mmol), 74percent yield.

56%

With palladium diacetate; potassium carbonate; triphenylphosphine In 1,2-dimethoxyethaneInert atmosphere; Reflux

General procedure: To a two necked, 100 mL round bottom flask equipped with a magnetic stir bar were added 2-chloropyridine (1 equiv), phenylboronic acid (1.2 equiv), triphenylphosphine (0.1 equiv), 2 M potassium carbonate (2.7 equiv) and ethylene glycol dimethyl ether(0.9 M). The mixture was degased with Ar for 15 min. Then Pd(OAc)₂ (2.5 molpercent) was added to the reaction mixture and degassing continued for 15 more minutes and then the outlet was removed. The reaction mixture was heated to reflux. The progress of reaction was monitored by TLC (hexane:EtOAc 90:10). Upon completion (typically 18-24 h), reaction mixture was cooled to room temperature and then extracted with DCM (3x20 mL). The combined organic portion was washed with water (3x20 mL) and brine (1 20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. The crude material was purified by flash chromatography to obtain pure ligand.

Reference： [1] Journal of the American Chemical Society, 2016, vol. 138, # 20, p. 6392 - 6395
[2] Patent: WO2017/75581, 2017, A1, . Location in patent: Page/Page column 29; 30
[3] Patent: CN104262404, 2017, B, . Location in patent: Paragraph 0035; 0036; 0037
[4] Patent: CN104163835, 2017, B, . Location in patent: Paragraph 0028; 0029; 0030
[5] Journal of Nanoscience and Nanotechnology, 2012, vol. 12, # 7, p. 5613 - 5618
[6] Journal of Nanoscience and Nanotechnology, 2013, vol. 13, # 5, p. 3441 - 3445
[7] Molecular Crystals and Liquid Crystals, 2007, vol. 462, # 1, p. 179 - 188
[8] Molecular Crystals and Liquid Crystals, 2010, vol. 520, p. 97 - 107
[9] Molecular Crystals and Liquid Crystals, 2009, vol. 504, # 1, p. 59 - 66
[10] Journal of Organometallic Chemistry, 2015, vol. 776, p. 51 - 59

9
[ 52334-81-3 ]
[ 144025-03-6 ]
[ 387827-64-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With palladium diacetate; potassium carbonate; triphenylphosphine In 1,2-dimethoxyethaneInert atmosphere; Reflux	General procedure: To a two necked, 100 mL round bottom flask equipped with a magnetic stir bar were added 2-chloropyridine (1 equiv), phenylboronic acid (1.2 equiv), triphenylphosphine (0.1 equiv), 2 M potassium carbonate (2.7 equiv) and ethylene glycol dimethyl ether(0.9 M). The mixture was degased with Ar for 15 min. Then Pd(OAc)₂ (2.5 molpercent) was added to the reaction mixture and degassing continued for 15 more minutes and then the outlet was removed. The reaction mixture was heated to reflux. The progress of reaction was monitored by TLC (hexane:EtOAc 90:10). Upon completion (typically 18-24 h), reaction mixture was cooled to room temperature and then extracted with DCM (3x20 mL). The combined organic portion was washed with water (3x20 mL) and brine (1 20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. The crude material was purified by flash chromatography to obtain pure ligand.

Reference： [1] Journal of Organometallic Chemistry, 2015, vol. 776, p. 51 - 59
[2] Journal of Organic Chemistry, 2016, vol. 81, # 16, p. 6988 - 6994
[3] Journal of the American Chemical Society, 2017, vol. 139, # 47, p. 17186 - 17192
[4] Chemistry - A European Journal, 2018, vol. 24, # 44, p. 11314 - 11318

10
[ 144025-03-6 ]
[ 50488-42-1 ]
[ 387827-64-7 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 43, p. 14090 - 14094[2] Angew. Chem., 2018, vol. 130, p. 14286 - 14290,5
[3] Angewandte Chemie - International Edition, 2016, vol. 55, # 34, p. 9969 - 9973[4] Angew. Chem., 2016, vol. 128, # 34, p. 10123 - 10127,5
[5] Journal of the American Chemical Society, 2018, vol. 140, # 2, p. 741 - 747
[6] Organic Letters, 2018,
[7] European Journal of Inorganic Chemistry, 2009, # 32, p. 4850 - 4859

[ 144025-03-6 ] Synthesis Path-Downstream 1~88

1
[ 16321-99-6 ]
[ 144025-03-6 ]
9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-(2,4-difluorophenyl)purine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In toluene at 100℃; for 8h;

Reference： [1]Hocek, Michal; Holý, Antonín; Votruba, Ivan; Dvořáková, Hana [Journal of Medicinal Chemistry, 2000, vol. 43, # 9, p. 1817 - 1825]

2
[ 42861-71-2 ]
[ 144025-03-6 ]
acetic acid 2',4'-difluoro-biphenyl-3-yl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 355 - 374

3
[ 89-55-4 ]
[ 144025-03-6 ]
[ 22494-42-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 2-[5-(4-methylphenyl)isoxazol-3-yl]-5-(5-phenylisoxazol-3-yl)-1,3,4-oxadiazole·2PdCl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 0.0166667h;	General procedure: A 0.01 solution of L1-4·PdCl2 (0.2 mol % Pd) in DMF (0.1-0.2 ml)(or 0.8-4 mg of the respective Pd/Fe composite) was addedto a mixture of aryl(hetaryl)boronic acid (1.20 mmol), aryl-(hetaryl) bromide (1.00 mmol), Bu4NBr (3.2 mg, 0.01 mmol,used in the case of aryl halides that were insoluble in water),and K2CO3 (0.35 g, 2.5 mmol) in 2 (10 ml) (or in 10 mlof 1:1 methanol-water mixture). The reaction mixture wasvigorously stirred at the indicated temperature until fullconversion was obtained. The reaction progress wascontrolled by TLC method (eluent hexane-Et2O, 2:1). In thecase of activated aryl bromides, the reaction was veryexothermic, therefore it was important to use an effectivereflux condenser for larger scale syntheses. In the cases when the reaction products were aryl(hetaryl)benzoic acids, analytically pure samples were obtainedby diluting the reaction mixture with water, heating, filteringin order to remove an insignificant amount (~0.2 mol %) ofpalladium black and the homocoupling product, diluted with10-15% (v/v) of ethanol, heated to ~50C, and slowly,while stirring, acidified with 5% HCl to pH 2-3. Theprecipitate that formed after cooling was easily filtered, andpure compounds were isolated without a need forchromatographic separation. In the case when Pd/Fe wasused, the catalyst was separated after the completion of thereaction with the aid of an external magnet and the reactionmixture was used as described above. The recovered Pd/Fecatalyst could be used again after washing with water andacetone. In the case of biaryls (heterobiaryls) that wereinsoluble in water, the reaction mixture was diluted withsaturated NaCl solution, extracted with Et2O or EtOAc, theextract was dried over Na2SO4 and filtered through a thinsilica gel layer. The solvent was evaporated on a rotaryevaporator, and the residue, as a rule, had a purity of atleast 99%. Analytically pure samples were obtained by recrystallization of biaryls from a minimal amount ofaqueous alcohol (10-20% (v/v) 2) or by converting theamines to hydrochlorides. The residual palladium contentin the target products was in the range from 0.5 to 2.2 ppmaccording to the results of atomic absorption spectroscopy.
98.37%	With potassium carbonate; palladium dichloride; In water; N,N-dimethyl-formamide; at 75℃;Sonication; Cooling;	120ml of distilled water,120ml of N,N-dimethylformamide mixed into the ultrasonic reactor and ultrasonically mixed to form solution A,Add 53.2 mg of PdCl2 (0.03 mmol) in a cold water bath and disperse evenly. Add 7.2 g of 2,4-difluorophenylboronic acid (45 mmol).6.51g 5-bromosalicylic acid (30 mmol) was dissolved and dispersed in a cold water bath.Finally, 3.36 g of K2CO3 (60 mmol) was added to dissolve and disperse.The reaction was carried out in an ultrasonic reactor at a temperature of 75 C and an ultrasonic power of 175 W for 100 min.After the reaction is completed, the liquid filtration catalyst after the reaction isTo the filtrate, a concentration of 1 mol/L of HCl was added and the mixture was shaken until the precipitated flocculent precipitate no longer disappeared, and 2000 ml of distilled water was added to the filtrate, and the mixture was allowed to stand.The flocculent precipitate of fluorophenylsalicylic acid was completely precipitated and filtered to obtain a white cake.The filter cake was dissolved in 200 ml of ethyl acetate, and washed with deionized water for 3 times.The upper organic phase was taken, dried over 45 g of anhydrous sodium sulfate, filtered over anhydrous sodium sulfate, and evaporated under vacuo to give a white solid.Recrystallization temperature 5 C, recrystallization time 10 h,Filtration to obtain a refined product of fluorophenylsalicylic acid,Product yield is 98.37%,The product purity is 99.89%.
97%	With C11H8Cl4N2O3Pd; potassium carbonate; In methanol; water; N,N-dimethyl-formamide; at 100℃; for 0.0833333h;	General procedure: To a mixture of 1.20 mmol of arylboronic acid, 1.00 mmol of aryl(hetaryl) bromide, 3.2 mg (0.01 mmol) of Bu4NBr (for water insoluble aryl halides) and 0.35 g (2.5 mmol) K2CO3 in 5 mL of H2O (or in 5 mL of equal volumes of water and methanol) pre-heated to 80C was added 0.1 mL of a suspension of L1-4PdCl2 complexes (0.1 mol % Pd) in methanol-DMF mixture (0.01 M). The reaction mixture was stirred vigorously at the same temperature (Table 4) to complete conversion. The reaction progress was monitored by TLC (eluent hexane-Et2O, 3 : 1). In the case of activated aryl bromides the reaction was highly exothermic that should be considered at the synthesis scaling. If the reaction products were aryl(hetaryl)benzoic acids, to obtain ananalytically pure sample the reaction mixture was diluted with water, heated, and filtered from mino ramounts (~ 0.1 mol %) of palladium black. Then about 10-15 vol % of alcohol was added, the mixture wa sheated to ~50C and acidified carefully with 10% HCl to adjusting pH = 2-3. As a result, the formed precipitate was filtered off and dried to provide analytically pure samples without the use of chromatographic methods. In the case of water-insoluble biaryls (heterobiaryls), the reaction mixture was diluted with a saturated solution of NaCl, extracted with Et2O or EtOAc, the extract was dried with Na2SO4 and filtered through a bed of silica gel. The solvent was removed to give the target compound with a purity ? 99% .Analytically pure sample was obtained by recrystallization from the minimum amount of aqueous alcohol (about 10-20 vol % of 2), or by conversion of amines to hydrochlorides.

90%	With potassium carbonate; In water; at 20℃; for 6h;Green chemistry;	General procedure: A 50 mL flask was charged with an aryl halide (1.0 mmol), anaryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocatalyst(0.05 mol% Pd) and deionized water (5 mL). The reactionwas stirred at room temperature for 4 h. The progress ofthe reaction was monitored by thin-layer chromatography After the reaction was completed, distilled water (25 mL) wasadded to the mixture and dilute 2 mol/L HCl was added dropwiseto pH 3.0-4.0 with stirring, and the mixture was heatedto 100 C for 10 min. The white solid that had formed wasfiltered off and washed with hot water. After drying, it wasdissolved in ether (5 mL) and was rapidly separated using asilica gel column. Elution with ether left behind small amountsof impurities and traces of palladium black to give a crudeproduct. The ether solution was evaporated to 3-5 mL andrecrystallized to obtain a pure product. All the products 3a-uare known compounds and were characterized by comparingtheir melting points and 1H NMR spectra with those preparedrecently by using a water-soluble glycine-based Pd catalyst,PdCl2(NH2CH2CO2H)2.10 The melting points and 1H NMRdata of 3a-u are listed in the supplemental material.
86.97%	With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 4h;	The 15mmol2,4-difluorophenyl boronic acid, 10mmol5- bromine salicylic acid, 0.1mmol o-phenylenediamine condensation of benzaldehyde bis Schiff base complexes of palladium catalyst, 20mmol of potassium carbonate were added to 80ml volume percentage of 50% of N, N - dimethylformamide an aqueous solution of, the reaction mixture was stirred at 150 240 minutes, the reaction was stopped, cooled to room temperature, the catalyst was recovered by filtration, to the filtrate was added 800ml of deionized water, boiled for 20 minutes, cooled to room temperature and mass fraction 37.5% of the HCl reaction mixture was adjusted to pH 3 and stirred to precipitate Diflunsial flocculent precipitate completely, filtration, distillation of the reaction solvent recovered in the filtrate, and the filter cake was added diethyl ether mass 5:1 the filter cake was dissolved, together with 50mL of deionized water three times to remove water-soluble impurities, to take the upper organic phase was dried over anhydrous sodium sulfate, anhydrous sodium sulfate was filtered off, the filtrate was evaporated to give the crude product Diflunsial, then in = 3/1 by volume ethanol - aqueous solution at 2 recrystallized from 12 hours to obtain Diflunsial products, by IR, 1 HNMR and HPLC analysis, the yield was Diflunsial to 86.97%.

Reference： [1]Chemistry of Heterocyclic Compounds,2017,vol. 53,p. 1340 - 1349
Khim. Geterotsikl. Soedin.,2017,vol. 53,p. 1340 - 1349,10
[2]Patent: CN108610253,2018,A .Location in patent: Paragraph 0015; 0016; 0017; 0018; 0019; 0020; 0021-0039
[3]Russian Journal of General Chemistry,2016,vol. 86,p. 68 - 81
Zh. Obshch. Khim.,2016,vol. 86,p. 75 - 88,14
[4]Journal of Organic Chemistry,2004,vol. 69,p. 7919 - 7927
[5]Tetrahedron Letters,2010,vol. 51,p. 5392 - 5394
[6]Journal of Chemical Research,2019,vol. 43,p. 50 - 52
[7]Patent: CN105254485,2016,A .Location in patent: Paragraph 0019-0021; 0039; 0040
[8]ACS Combinatorial Science,2015,vol. 17,p. 32 - 38

4
[ 30363-03-2 ]
[ 144025-03-6 ]
2,4,6-tris-(2',4'-difluoro-biphenyl-4-yl)-[1,3,5]triazine [ No CAS ]

Reference： [1]Chemistry Letters,2004,vol. 33,p. 1244 - 1245

5
[ 109-04-6 ]
[ 144025-03-6 ]
[ 391604-55-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 70℃; for 24h;	2-Bromopyridine (2.01 mL, 21.1 mmol), 2,4-difluorophenylboronic acid (4.00 g, 25.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.732 g, 0.633 mmol) were added to round-bottomed flask with reflux condenser and dissolved to 50 mL of THF. After 30 mL of aqueous 2N Na2CO3 was introduced, the reaction mixture was heated at 70 C. for 1 day. After cooling, the crude mixture was poured into water, extracted with CH2C12 (50 mL x 3 times), and dried over magnesium sulfate. The product was purified by silica column (n-hexane:EtOAc=4:1) to give dfppy 1 as colorless liquid (3.90 g, 97%).
93%		2-bromopyridine (1 mmol), 2,4-difluorophenylboronic acid (1.2 mmol), potassium carbonate (2.7 mmol), and dimethoxyethane (1.5 mL) were put together in a round bottom flask, to which nitrogen was injected, followed by stirring for 30 minutes. Tetrakis(triphenylphosphine)palladium (0.05 mmol) was added and a reflux condenser was connected thereto, followed by reflux at 90 C. for 18 hours. After confirming the reaction by TLC, the solvent was removed by distillation under reduced pressure at high vacuum. After extracting with ethyl acetate, the residue was purified by fresh column chromotography to give compound (C). The yield was 93%.
93%		2-bromopyridine (1 mmol), 2,4-difluorophenylboronic acid (1.2 mmol), potassium carbonate (2.7 mmol), and dimethoxyethane (1.5 mL) were put together in a round bottom flask, to which nitrogen was injected, followed by stirring for 30 minutes. Tetrakis(triphenylphosphine)palladium (0.05 mmol) was added and a reflux condenser was connected thereto, followed by reflux at 90C for 18 hours. After confirming the reaction by TLC, the solvent was removed by distillation under reduced pressure at high vacuum. After extracting with ethyl acetate, the residue was purified by fresh column chromotography to give compound (C). The yield was 93%.

90%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 80℃; for 15h;Inert atmosphere;	(1.03 g, 6.5 mmol) and tetrakis (triphenylphosphine) palladium (0.370 g, 0.32 mmol) were weighed out by adding 2-bromopyridine (1.0 g, 6.37 mmol), 2,4-difluorobenzeneboronic acid 50mL two-necked flask, the vacuum drum nitrogen cycle three times, followed by injection of toluene (9mL), saturated K2CO3(Aq) (3 mL), ethanol (3 mL), and refluxed at 80 C for 15 hours.Cooled to room temperature, extracted with dichloromethane and distilled water, and the organic phases were combined and dried under reduced pressure to give 1.12 g of product in 90% yield.
87%	With palladium diacetate; sodium carbonate; triphenylphosphine; In ethanol; water; toluene; at 105℃; for 21h;Inert atmosphere; Reflux;	2,4-difluorophenylboronic acid (2.00 g, 12.7 mmol), Pd (OAc) 2 (143 mg, 63.5 mmol), PPh3 (656 mg, 2.50 mmol), Na2 CO3 (2.65 g, 250 mmol)And 2-bromopyridine (1.74 g, 11.0 mmol) were dissolved in a mixture of toluene (30 ml), ethanol (30 ml) and water (15 ml). The mixture was heated under reflux at 105 C. for 21 hours under an inert atmosphere.After cooling the mixture to room temperature, the organic layer of the mixture was not observed and ethyl acetateIt was extracted with chill. The solution was dried over magnesium sulfate and evaporated. The obtained crude product was purified by SiO 2 chromatography using hexane: ethyl acetate = 9: 1 to obtain dfppy represented by the formula (xii) (1.83 g, 9.57 mmol, 87%)
83%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 80℃; for 24h;Heating / reflux;	5.0 g of 2,4-difluorophenyl boronic acid (0.0285 mol), 3.0 g of 2-bromopyridine (0.019 mol), 150 ml of tetrahydrofuran, and a 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and then palladium tetrakistriphenylphosphine(Pd(PPh3)4; 0.7 g, 3 mol%) as a catalyst was added. The mixture was refluxed at 80C for 24 hours, and the reaction was terminated. 500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 150 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by distillation under reduced pressure. The yield was 83%. Further, an 1H-NMR of the prepared 2,4-difluoro phenyl pyridine is illustrated in the accompanying Fig. 3.
83%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 80℃; for 24h;	PREPARATIVE EXAMPLE 2Iridium(2-(4'-difluorophenyl-4-yl)pyridine) (2-(2-(phenylpyridine))2 ; In order to prepare 2,4-difluoro phenyl pyridine, 5.0 g of 2,4-difluorophenyl boronic acid (0.0285 mol), 3.0 g of 2-bromopyridine (0.019 mol), 150 ml of tetrahydrofuran, and a 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and then palladium tetrakistriphenylphosphine(Pd(PPh3)4; 0.7 g, 3 mol %) as a catalyst was added.The mixture was refluxed at 80 C. for 24 hours, and the reaction was terminated. 500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 150 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by distillation under reduced pressure. The yield was 83%. Further, an 1H-NMR of the prepared 2,4-difluoro phenyl pyridine is illustrated in the accompanying FIG. 3.Next, 1 g of bromo iridium complex (0.0014 mol), 0.5 g of 2,4-difluoro phenyl boronic acid (0.0021 mol), 150 ml of tetrahydrofuran, and 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and palladium tetrakistriphenylphosphine (Pd(PPh3)4; 0.07 g, 3 mol %) as a catalyst was added. The mixture was refluxed at 80 C. for 24 hours, and the reaction was terminated500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 200 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by rotary evaporation. Finally, iridium(2-(4'-difluorophenyl-4-yl)pyridine) (2-(2-(phenylpyridine))2 was prepared as in Formula 3, and the yield was 86%. Further, an 1H-NMR of the prepared iridium(2-(4'-difluorophenyl-4-yl)pyridine)(2-(2-(phenylpyridine)) is illustrated in the accompanying FIG. 4.
83.5%	With potassium carbonate;tetraphenyl-phosphine-palladium; In tetrahydrofuran; at 61℃; for 4h;Inert atmosphere;	Step Two: Added 200 ml of THF, 24.76 g of 2,4-Difluoro Boric acid and 22 g of 2-Bromopyridine to 1 L of four-neck flask, the solution appeared light tawny. Then added 52 g of Potassium carbonate in the solution, and yellow turbidity appeared. Then the Nitrogen gas was introduced in for 15 minutes. Added 1 g of Tetraphenyl-Phosphine-Palladium to the solution and heated, then refluxed when warmed to 61 C. As heated for 4 hours, the solution turned brown. Then the cooling and separating process, water layer was extracted with 300 ML of Ethyl Acetate, and then followed with merging and distillation steps. Finally, 25 g of white solid products can be reached by column chromatography with petroleum ether as solvent. The yield rate reached 83.5%.1HNMR (CDCl3, 400Hz): 6.89 (m, 1H), 7.1 (m, 1H), 7.28 (m, 1H), 7.75 (m, 2H), 8.00 (m, 1H), 8.71 (d, 1H).
76.18%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; at 65℃; for 24h;	2-bromopyridine (4.17g, 26.39mmol), 2,4- difluorophenyl boronic acid (5.00g, 31.66mmol), phosphorus tetrakistriphenylphosphine palladium (0.91g, 0.79mmol) and sodium carbonate (6.36g, 60.00mmol ) was dissolved in 100mL of tetrahydrofuran, 65 for 24 hours, cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain primary ligand (3.84g, yield 76.18%). The primary ligand (2.50g, 13.08mmol) and iridium chloride (2.30g, 6.23mmol) was dissolved in 15mL ethoxyethanol, the reaction mixture was 130 C 12h, then was added pyridine phosphate (2.72g, 12.46mmol) and sodium carbonate (3.30g, 31.15mmol), continue 130 reaction 24h. System cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain a yellow solid Ir1-001 (1.06g, yield: 21.5%).
76.18%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; at 65℃; for 24h;	2-bromopyridine (4.17g, 26.39mmol), 2,4- difluorophenyl boronic acid (5.00g, 31.66mmol), phosphorus tetrakistriphenylphosphine palladium (0.91g, 0.79mmol) and sodium carbonate (6.36g, 60.00mmol ) was dissolved in 100mL of tetrahydrofuran, 65 for 24 hours, cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain primary ligand (3.84g, yield 76.18%).The primary ligand (2.50g, 13.08 mmol) and iridium chloride (2.30g, 6.23mmol) was dissolved in ethoxyethanol 15mL2-, the reaction mixture was 130 12h, phosphoric acid was then added pyridine (2.72g, 12.46mmol) and sodium carbonate (3.30g, 31.15mmol), continue 130 reaction 24h.System cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain a yellow solid BIr1-001 (1.06g, yield: 21.5%).
76.18%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; for 24h;Reflux;	The first host ligand in Example 1 was prepared as follows:2-Bromopyridine (4.17 g, 26.39 mmol),2,4-difluorobenzeneboronic acid (5.00 g, 31.66 mmol),Tetrakistriphenylphosphine palladium (0.91 g, 0.79 mmol) and sodium carbonate were added(6.36 g, 60.00 mmol) was dissolved in 100 mL of tetrahydrofuran,The reaction was refluxed for 24 hours,Cool, add water and methylene chloride,The organic layer was concentrated by column chromatography as the firstA primary ligand of an aromatic ring linked azetidin(3.84 g, yield 76.18%).The aromatic rhizariazole (2.50 g, 13.08 mmol) as the first host ligand,And iridium trichloride (2.30 g, 6.23 mmol) were dissolved in 15 mL of ethoxyethanol,The mixture was refluxed for 12h,Iridium dimeric bridged complex was obtained.Then pyridine sulfonic acid (1.36 g, 6.23 mmol) and potassium carbonate (2.60 g, 18.70 mmol)To the above iridium dimeric bridged complex,At 120. Continue reflux 18h.Cooling system,Add water and methylene chloride,The organic phase was concentrated and subjected to column chromatography to obtain a iridium complex (1.01 g, yield: 21.5%) as a yellow solid.
57.8%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; for 24h;Inert atmosphere; Reflux;	In a 100mL one-neck flask, were successively added 2-bromopyridine 5. 6g i.e. 25. 7mmol, 2, 4- difluorophenyl boronic acid 4. 5gI.e., 28. Ommol, i.e. sodium carbonate solution 20mL 2M, 20mL of toluene and 20mL of methanol and tetrakis (triphenylphosphine) palladium 0 · 80g i.e. 0. 7mmol, the reaction was heated to reflux under nitrogen for 24h. Cooling to room temperature, the reaction solution was poured into 100mL water and extracted three times each with 25mL of dichloromethane, the organic layers combined, dried over anhydrous magnesium sulfate overnight. Filtration, vacuum spin solvent, the crude product to 200-300 mesh silica gel as the stationary phase, the volume ratio of methylene chloride: petroleum ether 1: 1 mixture as an eluent to column chromatography to obtain 4.08g brown liquid a yield of 57.8%
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; for 8h;Inert atmosphere; Reflux;	2-bromopyridine (4.5 g, 28.48 mmol), 2,4-difluorophenyl boronic acid (5 g, 31.33 mmol), and K2CO3 (4.32 g, 31.33 mmol) were added into a 500 mL reaction bottle. Next, dimethoxyethane (180 ml), water (90 ml), and a catalyst amount of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) were added into the reaction bottle. After removing moisture and purging nitrogen gas several times, the mixture was heated to reflux. After reacting for 8 hr and then cooling to room temperature, NaHCO3 (aq) was added into the reaction bottle to adjust the pH value to a weak base condition. Next, the result was extracted three times using ethyl acetate (EA) and water as the extraction solvent. Next, an organic phase was separated and dried, and then purified by column chromatography, obtaining compound (1). The synthesis pathway of the above reaction was as follows: (0030) The physical measurement of the compound (1) is listed below: 1H NMR (200 MHz, CDCl3, 294 K): delta 8.71 (d, 1H), 8.00 (q, 1H), 7.777.74 (m, 2H), 7.26 (q, 1H), 7.066.86 (m, 2H).
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux;	A 500 mL flask was provided,And 2-bromopyridine was added(2-bromopyridine, 4.5 g (28.48 mmol)),Difluorophenylboronic acid(2,4-difluorophenyl bronic acid,5 g (31.33 mmol)),And potassium carbonate (K2CO3, 4.32 g (31.33 mmol)),Followed by addition of 180 mL of dimethoxyethane,And 90 mL of water as solvent,Then four additional catalyst quantities were added(Triphenylphosphine) palladium (Pd (PPh3) 4).In the processRepeated water removalOxygen drying after filling nitrogen,The reaction was then heated to reflux.After reaction overnight,The reaction was returned to room temperature,Adding sodium bicarbonate (NaHCO3) aqueous solution and the reaction to weak base,Ethyl acetate (EA)And water for extraction three times,And the collected organic layer was dried three times and filtered,After drying with a cyclotron,And purified by column chromatography,Compound 1 was obtained.The reaction formula of the above reaction is as follows:
	With palladium diacetate; potassium carbonate; In ethanol; water; at 80℃;	General procedure: A mixture of 2-bromopyridine derivatives (1 mmol),1.5 equiv. of arylboronic acid, 2 equiv. of K2CO3, Pd(OAc)2 (1.5 mol%), ethanol/water (3:1 v/v) was stirred at 80 C in air for the indicated time. The reaction mixture was added to brine (20 mL) and extracted with dichloromethane. The solvent was concentrated under vacuum, and the product was isolated by column chromatography.

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[33]Tetrahedron,2019,vol. 75

6
[ 621-38-5 ]
[ 144025-03-6 ]
N-(2',4'-difluorobiphenyl-3-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6128 - 6139

7
[ 109-09-1 ]
[ 144025-03-6 ]
[ 391604-55-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With O4P(3-)3K(1+)5H2O; tris(1-adamantyl)phosphine; {2-[((acetyl-kappaO)amino)phenyl-kappaC](tri-1-adamantylphosphine)palladium}(p-toluenesulfonate); In tetrahydrofuran; at 70℃; for 4h;	To a mixture of 2-chloropyridine (47 .iL, 0.50 mmol, 1 equiv), 2,4-difluorophenylboronic acid (118 mg, 0.75 mmol, 1.5 equiv), and K3P045H20 (0.45 mg, 1.5 mmol, 3 equiv) was added THF (400 tL) then a THF stock solution of 3 and PAd3 (100 1iL, 0.25 tmol of Pd/PAd3). The mixture was stirred at 70 C for 4 h. The reaction mixture was diluted with ethyl acetate thenextracted with water. The combine organic layers were evaporated and the crude product waspurified by flash chromatography. After drying, 89 mg (93%) of 37 was obtained as a colorless oil. NMR spectroscopic data agreed with literature values.
74%	With palladium diacetate; sodium carbonate; triphenylphosphine; In ethanol; water; toluene; at 90℃; for 6h;Inert atmosphere;	In the round-bottom flask is sequentially added in the sodium carbonate (5.30g, 50mmol), 2, 4 - difluorobenzoic acid (4.35g, 27 . 5mmol), 2 - chloro pyridine (3.95g, 25mmol), Pd (OAc)2 (0.3350g,0 . 5mmol), Ph3 P (0.5250g, 2mmol), toluene (50 ml), ethanol (25 ml) and deionized water (25 ml), pump the nitrogen 1h, stirring under nitrogen protection, for 90 C in oil bath reaction 5h. Cooling to room temperature, liquid, aqueous phase of ethyl acetate (3 × 50 ml) extraction, the combined organic phase, using anhydrous MgSO4 Drying, filtering, evaporate the solvent after the neutral aluminium oxide chromatography separation (elution agent is VPE : VEA =20:1), to obtain the colorless transparent liquid 2 - (2, 4 - difluorophenyl) pyridine (3.54g, 18 . 5mmol), yield 74%.
74%	With palladium diacetate; sodium carbonate; triphenylphosphine; In ethanol; water; toluene; at 90℃; for 6h;Inert atmosphere;	Sodium carbonate (5.30 g, 50 mmol) was added in turn to a round bottom flask.2,4-Difluorophenylboronic acid (4.35 g, 27.5 mmol),2-chloropyridine (3.95 g, 25 mmol), Pd(OAc) 2 (0.3350 g, 0.5 mmol),Ph3P (0.5250 g, 2 mmol), toluene (50 mL), ethanol (25 mL) andDeionized water (25 mL) was bubbled with nitrogen for 1 h and stirred under nitrogen.The reaction was carried out in a 90C oil bath for 5 h. Cool to room temperature, separate,The aqueous phase is extracted with ethyl acetate (3 x 50 mL) and the organic phases are combined,Dry with anhydrous MgSO4, suction filtration, solvent distillation and separation by neutral alumina column chromatography(eluent: VPE:VEA=20:1), colorless transparent liquid was isolated2-(2,4-Difluorophenyl)pyridine (3.54 g, 18.5 mmol), 74% yield.

56%

With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,2-dimethoxyethane;Inert atmosphere; Reflux;

General procedure: To a two necked, 100 mL round bottom flask equipped with a magnetic stir bar were added 2-chloropyridine (1 equiv), phenylboronic acid (1.2 equiv), triphenylphosphine (0.1 equiv), 2 M potassium carbonate (2.7 equiv) and ethylene glycol dimethyl ether(0.9 M). The mixture was degased with Ar for 15 min. Then Pd(OAc)2 (2.5 mol%) was added to the reaction mixture and degassing continued for 15 more minutes and then the outlet was removed. The reaction mixture was heated to reflux. The progress of reaction was monitored by TLC (hexane:EtOAc 90:10). Upon completion (typically 18-24 h), reaction mixture was cooled to room temperature and then extracted with DCM (3x20 mL). The combined organic portion was washed with water (3x20 mL) and brine (1 20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. The crude material was purified by flash chromatography to obtain pure ligand.

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[3]Patent: CN104262404,2017,B .Location in patent: Paragraph 0035; 0036; 0037
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[10]Journal of Organometallic Chemistry,2015,vol. 776,p. 51 - 59

8
[ 16681-59-7 ]
[ 144025-03-6 ]
[ 872327-70-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium carbonate; triphenylphosphine;palladium diacetate; In 1,2-dimethoxyethane; water;	Step 2 To a 500 mL round flask was added N-methyl-2-bromoimidazole (6.50 g, 40 mmol),2,4-diflurophenylboronic acid (7.89g, 50 mmol), palladium(II) acetate (0.28 g, 1.25 mmol), triphenylphosphine (1.31 g, 5 mmol), sodium carbonate (14.31 g, 135 mmol), and 200 mL of DME and 100 mL of water. The reaction was heated to reflux and stirred under a nitrogen atmosphere for 12 hours. The mixture was extracted with ethyl acetate and further purified by a silica gel column. Distillation of the product at 150 C. gave N-methyl-2-(2,4-difluorophenyl)imidazole as a colorless oil (6.60 g, 85% yield), characterized by 1H-NMR and MS.

Reference： [1]Patent: US2006/8670,2006,A1

9
[ 1006-33-3 ]
[ 144025-03-6 ]
[ 705563-34-4 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium hydroxide;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 60℃; for 12h;	A stirred solution of <strong>[1006-33-3]2-bromo-5-fluoroacetophenone</strong> (11.72 g, 54 MMOL) and 2, 4-DIFLUOROPHENYLBORONIC acid (8.53 g, 54 MMOL) in tetrahydrofuran (600 mL) was treated under nitrogen with [1, 1APOS;-BIS (DIPHENYLPHOSPHINO) ferrocene] DICHLOROPALLADIUM (II) complex with DICHLOROMETHANE (2.20 g, 2.69 mmol, 5 molepercent) and a 5 N sodium hydroxide solution (21.6 mL, 108 MMOL). The reaction was heated at 60 °C for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in diethyl ether, filtered through a short column of silica gel, and the solvent EVAPORATED IN VACUO to a crude brown oil (11.72 g). The crude oil was purified by preparative liquid chromatography on a BIOTAGE 40 Mi column of pre-packed silica gel (90 g), ELUTING with a gradient of between 3percent and 10percent methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford, after evaporation of the solvent, the title compound as a purified, colorless oil (7.11 g, 28.4 mmol, 52percent); HRMS [ (+ESI), M/Z] : 251.06705 [M+H] +. Calcd for C14HGF3O : 251.06783 ; IR (FILM), VMAX : 2918,1695, 1604,1481, 1424,1267, 1186,1139, 1100,962, 850,814 CM-1 ; 1H NMR (400 MHz, DMSO-D6) B : 2.44 (s, 3H), 7.16 (tdd, J = 8. 5,2. 5,0. 9 Hz, 1 H), 7.28 (ddd, J = 10. 5,9. 4,2. 6 Hz, 1 H), 7.37-7. 45 (m, 2H), 7.50 (td, J = 8. 5,2. 7 Hz, 1 H), 7.75 (dd, J = 9. 4,2. 7 Hz, 1 H) ; Anal. calcd for C14HGF3O : C, 67.20 ; H, 3.63 ; N, 0.00. Found: C, 67.37 ; H, 3.46 ; N, 0.00.

Reference： [1]Patent: WO2004/50631,2004,A1 .Location in patent: Page 147-148

10
[ 31250-80-3 ]
[ 144025-03-6 ]
[ 660432-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;palladium diacetate; (R)-tol-BINAP; In methanol; water; toluene; for 18.0h;Heating / reflux;	Reflux a mixture of [1-BENZYL-2,] 4, [5-TRIBROMOIMIDAZOLE] (1.043 g, 2.42 mmol), 2,4- difluorophenyl boronic acid (0.682 g, 4.32 mmol), palladium acetate (0.027 g, 0.12 mmol), R (+) -2, 2'-bis [(DI-P-TOLYL-PHOSPHINO) 1, 1'-BINAPHTHYL] (0.098 g, 0.14 mmol), 2 M sodium carbonate (3.6 [ML,] 4.83 mmol), methanol (3.6 [ML)] and toluene (36 mL) for [18] hours. Cool to ambient temperature and dilute with ethyl acetate. Wash with saturated sodium carbonate, saturated sodium chloride, dry with magnesium sulfate and purify the residue on silica gel eluting with hexane/ethyl acetate mixtures to provide [1-BENZYL-4,] 5- [DIBROMO-2- (2, 4-DIFLUORO-PHENYL)-LH-IMIDAZOLE] (0.39 g). MS [(ES+)] : [NILZ] = 461.1 (M+H) [+]

Reference： [1]Patent: WO2004/14900,2004,A1 .Location in patent: Page 40

11
[ 13720-06-4 ]
[ 144025-03-6 ]
[ 889686-60-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;palladium diacetate; tris-(o-tolyl)phosphine; In 1,2-dimethoxyethane; water; at 80℃;	Step 1: 2-Bromo-6-(2,4-difluorophenyl)naphthalene; A mixture of <strong>[13720-06-4]2,6-dibromonaphthalene</strong> (12.49 g, 43.7 mmol), 2,4-difluorobenzeneboronic acid (3.44 g, 21.8 mmol), sodium carbonate (4.63 g, 45.7 mmol), palladium acetate (245 mg, 1.09 mmol) and tri-o- tolylphosphine (667 mg, 2.19 mmol) in water (15 mL) and ethylene glycol dimethyl ether (90 mL) was degassed and heated to 800C overnight. The cooled reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with isohexane, to give 2-bromo-6-(2,4-difluorophenyl)naphthalene (1.24 g, contains 10% <strong>[13720-06-4]2,6-dibromonaphthalene</strong>). 1H NMR (500 MHz, CDCl3) delta 8.04 (1 H, s), 7.93 (1 H, s), 7.82 (1 H, d, J = 8.5 Hz), 7.75 (1 H, d, J = 8.6 Hz), 7.62 (2 H, dd, J = 8.4, 31.8 Hz), 7.50 (1 H, m ), 7.04-6.91 (2 H, m).

Reference： [1]Patent: WO2006/59149,2006,A1 .Location in patent: Page/Page column 14

12
[ 106-41-2 ]
[ 497-19-8 ]
[ 144025-03-6 ]
[ 59089-68-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; triphenylphosphine;palladium on charcoal; In toluene;	B) 2,4-Difluorophenylboronic acid (1.99 g; 12.6 mmoles), prepared as described in example 20, and ethanol (3 ml) were added to a mixture of 5% palladium on charcoal (0.0134 g; 0.0063 mmoles), toluene (12 ml), triphenylphosphine (0.0066 g; 0.0252 mmoles), 4-bromophenol (1.09 g; 6.3 mmoles) and a 2M aqueous sodium carbonate solution (6 ml), kept under stirring at 20 C. and under nitrogen. The reaction mixture was heated under reflux and stirring for 20 hours. While keeping at 60 C., 37% hydrochloric acid (1.7 ml) was added dropwise to the reaction mixture. The mixture was filtered at 50 C. by washing with acetone (2*10 ml) at 50 C. After separation of the phases, the aqueous phase was washed with toluene (5 ml). The collected organic phases were evaporated to dryness under reduced pressure obtaining 4-(2,4-difluorophenyl)-phenol (1.34 g; titre 87%; 90% yield).
90%	With hydrogenchloride; triphenylphosphine;palladium on charcoal; In toluene;	B) 2,4-Difluorophenylboronic acid (1.99 g; 12.6 mmoles), prepared as described in example 20, and ethanol (3 ml) were added to a mixture of 5% palladium on charcoal (0.0134 g; 0.0063 mmoles), toluene (12 ml), triphenylphosphine (0.0066 g; 0.0252 mmoles), 4-bromophenol (1.09 g; 6.3 mmoles) and a 2M aqueous sodium carbonate solution (6 ml), kept under stirring at 20C and under nitrogen. The reaction mixture was heated under reflux and stirring for 20 hours. While keeping at 60C, 37% hydrochloric acid (1.7 ml) was added dropwise to the reaction mixture. The mixture was filtered at 50C by washing with acetone (2 x 10 ml) at 50C. After separation of the phases, the aqueous phase was washed with toluene (5 ml). The collected organic phases were evaporated to dryness under reduced pressure obtaining 4-(2,4-difluorophenyl)-phenol (1.34 g; titre 87%; 90% yield).
78%	With hydrogenchloride; triphenylphosphine;palladium on charcoal; In toluene;	C) 2,4-Difluorophenylboronic acid (1.1 g; 6.97 mmoles), prepared as described in example 20, and ethanol (3 ml) were added to a mixture of 5% palladium on charcoal (0.0134 g; 0.0063 mmoles), toluene (12 ml), triphenylphosphine (0.0066 g; 0.0252 mmoles), 4-bromophenol (1.09 g; 6.3 mmoles) and a 2M aqueous sodium carbonate solution (6 ml), kept under stirring at 20 C. and under nitrogen. The reaction mixture was heated under reflux and stirring for 20 hours. While keeping at 60 C., 37% hydrochloric acid (1.7 ml) was added dropwise to the reaction mixture. The mixture was filtered at 50 C. by washing with acetone (2*10 ml) at 50 C. After separation of the phases, the aqueous phase was washed with toluene (5 ml). The collected organic phases were evaporated to dryness under reduced pressure obtaining 4-(2,4-difluorophenyl)-phenol (1.25 g; titre 81%; 78% yield).

78%

With hydrogenchloride; triphenylphosphine;palladium on charcoal; In toluene;

C) 2,4-Difluorophenylboronic acid (1.1 g; 6.97 mmoles), prepared as described in example 20, and ethanol (3 ml) were added to a mixture of 5% palladium on charcoal (0.0134 g; 0.0063 mmoles), toluene (12 ml), triphenylphosphine (0.0066 g; 0.0252 mmoles), 4-bromophenol (1.09 g; 6.3 mmoles) and a 2M aqueous sodium carbonate solution (6 ml), kept under stirring at 20C and under nitrogen. The reaction mixture was heated under reflux and stirring for 20 hours. While keeping at 60C, 37% hydrochloric acid (1.7 ml) was added dropwise to the reaction mixture. The mixture was filtered at 50C by washing with acetone (2 x 10 ml) at 50C. After separation of the phases, the aqueous phase was washed with toluene (5 ml). The collected organic phases were evaporated to dryness under reduced pressure obtaining 4-(2,4-difluorophenyl)-phenol (1.25 g; titre 81%; 78% yield).

Reference： [1]Patent: US5312975,1994,A
[2]Patent: EP494419,1992,A2
[3]Patent: US5312975,1994,A
[4]Patent: EP494419,1992,A2

13
[ 4316-97-6 ]
[ 144025-03-6 ]
4-chloro-6-(2,4-difluorophenyl)-5-methylpyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; water;	(1) The compound produced by the method of the Reference Example 15 (6.2g, 38mmol) was dissolved in THF (100ml), followed by addition of 2,4-difluorophenylboronic acid (7.2g, 45.6mmol), tetrakis(triphenylphosphine)palladium (2.3g, 2mmol), potassium carbonate (12.6g, 91.3mmol) and water (30ml), and the mixture was refluxed under heating for 4 hours. 2,4-Difluorophenylboronic acid (2.4g, 15mmol) and tetrakistriphenylphosphine palladium (0.8g, 0.7mmol) were additionally added, and the mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated, and water was added to the residue, followed by extraction with chloroform. The extract was washed with water, dried and concentrated by evaporationg the solvent. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5:1) to obtain 4-chloro-6-(2,4-difluorophenyl)-5-methylpyrimidine (4.6g, oil). 1H-NMR(CDCl3) delta 2.30(3H, s), 6.90-7.10(2H, m), 7.43-7.52(1H, m), 8.89(1H, s)

Reference： [1]Patent: EP1333029,2003,A1

14
[ 40134-18-7 ]
[ 144025-03-6 ]
[ 929541-51-5 ]

Yield	Reaction Conditions	Operation in experiment
92.71%		Intermediate 4. 2-(2,4-Difluoro-phenyl)-nicotinic acid methyl ester. ; To a stirred solution of Intermediate 3 (1.00 g, 5.83 mmol) in THF (20 ml_) was added the 2,4- difluorophenyl boronic acid (1.38 g, 8.74 mmol) followed by Pd(PPh3)4 (0.337 g, 0.291 mmol). The mixture was then heated to reflux for 1 hour and then the 2.0 N Na2CO3 (5.83 ml_, 11.7 mmol) was added. The reaction was allowed to stir overnight at reflux. The suspension was cooled to room temperature. The mixture was poured into H2O (50 mL) and extracted four times with 15 ml CH2CI2. The organic extracts were combined, dried over Na2SO4, filtered and concentrated down under reduced pressure. The oil was purified by silica chromatography using a gradient of hexanes:EtOAc (100:0) to hexanes:EtOAc (75:25) to yield 1.35 g (92.71percent) of Intermediate 4 as a yellow oil.

Reference： [1]Patent: WO2007/31828,2007,A2 .Location in patent: Page/Page column 35

15
[ 657408-07-6 ]
[ 890315-98-7 ]
[ 144025-03-6 ]
[ 890316-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;palladium diacetate; In hexane; di-isopropyl ether; toluene;	Referential Example 32 To 15 mL of toluene solution containing 1.5 g of tert-butyl 4-chloro-2-nitrobenzoate, 1.1 g of 2,4-difluorophenylboronic acid, 2.8 g of cesium carbonate, 27 mg of palladium acetate and 25 mg of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl were added sequentially, and the resulting mixture was heated to reflux under nitrogen atmosphere for 8 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and added a saturated sodium hydrogen carbonate aqueous solution. 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. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.95 g of tert-butyl 4-(2,4-difluorophenyl)-2-nitrobenzoate as white solid. 1H-NMR (DMSO-d6) delta: 1.52 (9H, s), 7.26-7.31 (1H, m), 7.44-7.51 (1H, m), 7.72-7.79 (1H, m), 7.93 (1H, d, J = 7.9 Hz), 7.98 (1H, d, J = 7.9 Hz), 8.17 (1H, s).

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

16
[ 499-44-5 ]
[ 144025-03-6 ]
2,4-F₂PhB(OH)(4-isopropyltropolone-H) [ No CAS ]

Reference： [1]Inorganica Chimica Acta,2005,vol. 358,p. 3355 - 3361

17
[ 363-52-0 ]
[ 144025-03-6 ]
[ 365458-32-8 ]

Reference： [1]Journal of the Electrochemical Society,2004,vol. 151,p. A1429-A1435

18
[ 1996-23-2 ]
[ 144025-03-6 ]
[ 365458-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene byproducts: H2O; (Ar or under vac.); mixed in toluene; heated to reflux; water removed byazeotropic distillation; after 4 h, solvent evapd. under reduced pressu re; sublimed at 125°C;

Reference： [1]Lee; Ma; Yang; Sun; McBreen [Journal of the Electrochemical Society, 2004, vol. 151, # 9, p. A1429-A1435]

19
[ 192869-80-0 ]
[ 144025-03-6 ]
7-benzyl-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110℃; for 10h;	To <strong>[192869-80-0]7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine</strong> (Step B, 1.61 g, 6.22 mmol) in toluene (25 mL) were sequentially added 2,4-difluorophenylboronic acid (1.18 g, 7.46 mmol), 2M aq potassium carbonate (6.2 mL, 12.4 mmol), ethanol (3.1 mL) and tetrakis(triphenylphosphine)palladium (0.36 g, 0.31 mmol) under an argon atmosphere. The contents were heated at 110 C. for 10 hour, cooled to room temperature, concentrated under reduced pressure and partitioned between ethyl acetate (2×150 mL) and water (50 mL). The ethyl acetate layer was extracted with aq. HCl (1N, 100 mL×3) and the aqueous portion was cooled with ice bath and neutralized with aq. NaOH (10N) to pH 12, saturated with NaCl and extracted with dichloromethane (4×100 mL). The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound c (0.81 g, 38% two steps) as a dark oil. LCMS [M+H]+ 338.11.

Reference： [1]Patent: US2008/275052,2008,A1 .Location in patent: Page/Page column 45-46

20
[ 38557-72-1 ]
[ 144025-03-6 ]
[ 1092372-30-9 ]

Yield	Reaction Conditions	Operation in experiment
39%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; for 0.166667h;Microwave irradiation;	Next, a synthesis method of a ligand of the present invention, 2-(2,4-difuluorophenyl)-3,5-dimethylpyrazine is described. 2.14 g of<strong>[38557-72-1]2-chloro-3,5-dimethylpyrazine</strong> which was obtained as the intermediate described above, 2.37 g of 2,4-difluorophenyl boronic acid, 1.59 g of sodium carbonate, 0.069 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation : Pd(PPh3)2Cl2), 15 mL of water, and 15 mL of acetonitrile were put in an eggplant flask equipped with a reflux pipe, and the inside thereof was substituted by argon. This reaction container was subjected to irradiation with microwave (2.45 GHz, 100W) for 10 minutes to be heated. Then, water was added to this solution, and extraction using dichloromethane was conducted to separate an organic layer. The organic layer obtained was washed with water and dried with magnesium sulfate. After the drying, the solution was filtrated. A solvent of this solution was distilled off, and then the residue obtained by the distillation was purified by silica gel column chromatography which uses dichloromethane as a developing solvent; thereby obtaining an objective pyrazine derivative, HdmF2ppr (white powder, yield of 39 %). A synthetic scheme of Step 1 is shown by the following (a-2).

Reference： [1]Patent: WO2008/149828,2008,A1 .Location in patent: Page/Page column 81; 82

21
[ 479691-42-4 ]
[ 144025-03-6 ]
[ 1143577-33-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 20 - 100℃;	(3) Tert-butyl 4-[4-(2,4-difluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylate To a mixture of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (1.0 g, 3.35 mmol), 2,4-difluorophenylboric acid (793 mg, 5.02 mmol), 2N aqueous sodium carbonate solution (13.4 ml) and toluene (33 ml) was added tetrakistriphenylphosphine palladium (464 mg, 0.402 mmol) at room temperature under nitrogen atmosphere, and the mixture was stirred at 100 C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (894 mg, 71%) as an oily material. 1H NMR (CDCl3) delta: 1.50 (9H, s), 3.46-3.58 (4H, m), 3.85-3.93 (4H, m), 6.83-7.08 (3H, m), 8.08-8.22 (1H, m), 8.39 (1H, d, J=5.3 Hz).
71%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; at 100℃;Inert atmosphere;	General procedure: A mixture of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (1.80g, 6.02mmol), (2,4-difluorophenyl)boronic acid (1.43g, 9.04mmol), 1M aq Na2CO3 (24 mL, 48.2 mmol), tetrakis(triphenylphosphine)palladium (0) (835mg, 0.723mmol), and toluene (60mL) was stirred at 100C overnight under N2 atmosphere. The mixture was diluted with water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 8 (907mg, 40%) as a colorless viscous oil.

Reference： [1]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 20
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1468 - 1478

22
[ 73583-37-6 ]
[ 144025-03-6 ]
[ 1143578-31-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; at 20 - 50℃; for 17h;Inert atmosphere;	To a solution of <strong>[73583-37-6]4-bromo-2-chloropyridine</strong> (30.0g, 156mmol), (2,4-difluorophenyl)boronic acid (24.6g, 156mmol), and sodium carbonate (43.1g, 312mmol) in MeOH (195mL) was added tetrakis(triphenylphosphine)palladium (0) (9.01g, 7.79mmol) at room temperature under N2 atmosphere, and the mixture was stirred at 50C for 17h. The reaction mixture was cooled to room temperature and the resulting solid was filtered. The filtrate was dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 33 (31.9g, 91%) as a colorless powder. 1H NMR (300MHz, CDCl3) delta: 6.95-7.05 (2H, s), 7.37-7.39 (1H, m), 7.43-7.47 (1H, m), 7.49 (1H, br s), 8.47 (1H, d, J=13.2Hz).
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; at 20 - 50℃; for 17h;	(1) 2-chloro-4-(2,4-difluorophenyl)pyridine To a solution of <strong>[73583-37-6]4-bromo-2-chloropyridine</strong> (30 g, 156 mmol), 2,4-difluorophenyl boronic acid (24.6 g, 156 mmol), and sodium carbonate (43.1 g, 312 mmol) in methanol (195 ml) was added tetrakisphenylphosphine palladium (9.01 g, 7.79 mmol) at room temperature under nitrogen atmosphere, and the mixture was stirred at 50 C. for 17 hours. The reaction was cooled to room temperature and the resulting solid was filtered. The filtrate was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:8) to obtain the title compound (31.9%, 91%) as a solid. 1H-NMR (CDCl3) delta: 6.95-7.05 (2H, s), 7.37-7.39 (1H, m), 7.43-7.47 (1H, m), 7.49 (1H, br s), 8.47 (1H, d, J=13.2 Hz).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1468 - 1478
[2]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 40

23
[ 39856-56-9 ]
[ 144025-03-6 ]
[ 934477-86-8 ]

Yield	Reaction Conditions	Operation in experiment
3 g (80%)	With potassium carbonate;Pd(PPh3)4; In 1,2-dimethoxyethane; dichloromethane; water;	(2) Synthesis of 2-(2,4-difluorophenyl)-5-dimethylamino-pyridine <strong>[39856-56-9]2-bromo-5-dimethylaminopyridine</strong> (3.2 g, 16 mmol), 2,4-difluorophenylboronic acid (4.8 g, 30 mmol), K2CO3 (13 g, 94 mmol) and Pd(PPh3)4 (400 mg, 0.35 mmol) in a degassed mixture of DME/H2O (60/50 ml) were refluxed 24 hours under nitrogen. After being cooled to room temperature, the organic layer was separated and the aqueous phase extracted with EtOAc (100 ml). The combined organic fractions were washed with brine, dried over MgSO4 and evaporated to dryness. The crude compound was purified by column chromatography (SiO2, CH2Cl2 then CH2Cl2/MeOH: 97/3). The resulting brown solid was dissolved in CH2Cl2 and decolorized with charcoal. Filtration and evaporation of the solvent afford 3 g (80%) of the desired compound as a slightly yellow crystalline solid. 1H-NMR (CDCl3, 298K, 200 MHz, delta ppm) delta 3.03 (s, 6H), 6.9-7.1 (m, 3H), 7.60 (dd, J=2.5*9 Hz, 1H), 7.95 (m, 1H), 8.24 (d, J=2.5 Hz, 1H).

Reference： [1]Patent: US2009/200920,2009,A1

24
[ 35486-42-1 ]
[ 144025-03-6 ]
[ 1202278-21-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃;Inert atmosphere;	[00170] A solution of <strong>[35486-42-1]3,5-dibromopyridin-2-amine</strong> (2.95 g, 11.71 mmol) and 2,4- diflurophenylboronic acid (1.85 g, 11.71 mmol) in toluene was degassed via nitrogen bubble for 20 mins. The mixture was then added Pd(PPh3)4 (0.677 g, 0.585 mmol), K3PO4 (2 M, 11.8 mL, 23.4 mmol) and Ethanol (1 mL) and heated at 80 0C overnight. The reaction was cooled, poured into ethyl acetate (150 mL), washed with <n="67"/>brine, separated, dried over Na2SO4 and concentrated to give a crude 5-bromo-3-(2,4- difluorophenyl)pyridin-2-amine (3) which was used directly in next step without purification.
	With potassium phosphate; water;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃;Inert atmosphere;	A solution of <strong>[35486-42-1]3,5-dibromopyridin-2-amine</strong> (2.95 g, 11.71 mmol) and 2,4- diflurophenylboronic acid (1.85 g, 11.71 mmol) in toluene was degassed via nitrogen bubble for 20 mins. The mixture was then added Pd(PPh3)4 (0.677 g, 0.585 mmol), K3PO4 (2 M, 11.8 mL, 23.4 mmol) and ethanol (1 mL) and heated at 80 0C overnight. The reaction was cooled, poured into ethyl acetate (150 mL), washed with brine, <n="77"/>separated, dried over Na2SO4 and concentrated to give a crude 5-bromo-3-(2,4- difluorophenyl)pyridin-2-amine (3) which was used directly in next step without purification

Reference： [1]Patent: WO2009/155389,2009,A1 .Location in patent: Page/Page column 65-66
[2]Patent: WO2009/155388,2009,A1 .Location in patent: Page/Page column 75-76

25
[ 1052714-46-1 ]
[ 144025-03-6 ]
[ 1210418-87-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.5h;Microwave irradiation;	Synthesis of 6-(2,4-difluorophenvD-5-fluoropicolinic acid To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in DME and 2M Na2C03 (3: 1, 0.25 M) was added 2,4-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) in a microwave vial. The vial was heated in the microwave at 120 C for 30 minutes. The mixture was diluted with ethyl acetate and IN NaOH was added. The organic phase was separated and extracted three more times with IN NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH 1 by the addition of concentrated HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 6- (2,4-difluorophenyl)-5-fiuoropicolinic acid in 79% yield. LC/MS = 254.1 (M+H), Rt = 0.75 min.

Reference： [1]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 78

26
[ 108-86-1 ]
[ 144025-03-6 ]
[ 37847-52-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 90℃;Inert atmosphere;	Synthesis 18; 2',4'-Difluorobiphenylsulfonyl chloride2,4-Difluorophenylboronic acid (15 g, 129 mmol) was added to a solution of bromobenzene (19.8 g, 126 mmol) in DME (500 mL). To this was added a solution of sodium carbonate (55.8 g, 520 mmol) in water (260 mL). The solution was degassed by bubbling argon through the mixture and then stirred under argon. Pd(dppf)CI2 (1.5 g,2.1 mmol) was added and the flask was flushed with argon and heated at 900C overnight. The mixture was then cooled to room temperature and water (150 mL) and ethyl acetate (500 mL) were added. The layers were separated and the organic layer washed with 2 M NaOH (100 mL), water (100 mL) and brine (100 mL). The black ethyl acetate layer was dried over MgSO4, charcoal was added, and the mixture was filtered through a short pad of silica. Evaporation of the solvents gave 2,4-difluorobiphenyl as a brown oil, which crystallised on standing (21.2 g).
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;	Synthesis 42',4'-Difluorobiphenylsulfonyl chloride2,4-Difluorophenylboronic acid (15 g, 129 mmol) was added to a solution of bromobenzene (19.8 g, 126 mmol) in DME (500 ml_). To this was added a solution of sodium carbonate (55.8 g, 520 mmol) in water (260 ml_). The solution was degassed by bubbling argon through the mixture and then stirred under argon. Pd(dppf)CI2 (1.5 g, 2.1 mmol) was added and the mixture heated overnight at 900C under argon. The mixture was cooled to room temperature and water (150 mL) and ethyl acetate (500 ml.) were added. The layers were separated and the organic layer was washed with 2 M NaOH (100 mL), water (100 mL) and brine (100 mL). The black ethyl acetate layer was dried over MgSO4, charcoal was added, and the mixture was filtered through a short pad of silica. Evaporation of the solvents gave 2,4-difluorobiphenyl as a brown oil, which crystallised on standing (21.2 g).

Reference： [1]ChemCatChem,2015,vol. 7,p. 2475 - 2479
[2]Patent: WO2010/32010,2010,A1 .Location in patent: Page/Page column 86
[3]Patent: WO2010/32009,2010,A1 .Location in patent: Page/Page column 90

27
[ 200064-11-5 ]
[ 144025-03-6 ]
[ 1202243-15-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6578 - 6581

28
[ 144025-03-6 ]
[ 50488-42-1 ]
[ 387827-64-7 ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 14090 - 14094
Angew. Chem.,2018,vol. 130,p. 14286 - 14290,5
[2]Journal of the American Chemical Society,2019,vol. 141,p. 16590 - 16594
[3]Angewandte Chemie - International Edition,2016,vol. 55,p. 9969 - 9973
Angew. Chem.,2016,vol. 128,p. 10123 - 10127,5
[4]Journal of the American Chemical Society,2018,vol. 140,p. 741 - 747
[5]Organic Letters,2018,vol. 20,p. 6794 - 6798
[6]Inorganic Chemistry,2019,vol. 58,p. 855 - 860
[7]European Journal of Inorganic Chemistry,2009,p. 4850 - 4859

29
[ 591-50-4 ]
[ 144025-03-6 ]
[ 37847-52-2 ]

Reference： [1]Chemical Communications,2010,vol. 46,p. 6524 - 6526

30
[ 1448-87-9 ]
[ 144025-03-6 ]
[ 930781-41-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 24h;	General procedure: 2-Phenylquinoxaline (pqx) was prepared from a reaction of <strong>[1448-87-9]2-chloroquinoxaline</strong> and phenylboronic acid. <strong>[1448-87-9]2-Chloroquinoxaline</strong>(3.00 g, 18.2 mmol), phenylboronic acid (2.44 g,20.0 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.98 g, 0.85 mmol) were added to 50 mL of THF. After adding 5 mL of aqueous 4 M K2CO3, the reaction mixture was heated to 80 C for 24 h. The cooled crude mixture was poured into water, extracted with CH2Cl2 (50 mL × 3 times)and dried over anhydrous magnesium sulfate. Finally, silica column purification (n-hexane:EtOAc = 5:1) gave 3.15 g of a white solid in quantitative yield (84%).

Reference： [1]Bulletin of the Korean Chemical Society,2010,vol. 31,p. 2309 - 2314
[2]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 167 - 173

31
[ 58481-11-1 ]
[ 144025-03-6 ]
[ 1251843-62-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2,4-difluorophenylboronic acid (4.14 g, 26.23 mmol), potassium carbonate (1.812 g, 13.11 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The orange MTBE layer was treated with hydrogen chloride (4 M in dioxane, 4.37 mL, 17.48 mmol) and stirred for 1 h at room temperature. The formed solid was collected by filtration. Methyl 2-(2,4-difluorophenyl)isonicotinate hydrochloride (4.0 g, 80percent) was isolated as a slightly orange solid. MS m/z 250 (M+H)+

Reference： [1]Patent: US2010/261755,2010,A1 .Location in patent: Page/Page column 23

32
[ 1000577-94-5 ]
[ 144025-03-6 ]
[ 1264712-20-0 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 53 - 57

33
[ 540-38-5 ]
[ 144025-03-6 ]
[ 59089-68-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate;palladium(0)bis(tricyclohexylphosphine); In water; N,N-dimethyl-formamide;Inert atmosphere; Reflux;	Part IPreparation of Preferred Intermediates 2',4'-Difluoro-biphenyl-4-ol2,4-Difluoro-phenyl-boronic acid (1.29 g, 8.18 mmol) and 4-iodophenol (0.60 g, 2.7 mmol) were suspended in DMF (60 mL) and 6 mL H2O (6 mL). The mixture was degassed with nitrogen. Finely ground potassium carbonate (1.13 g, 8.18 mmol) and bis(tricyclohexylphosphine) palladium(0) (91 mg, 0.13 mmol) were added. The reaction was stirred at reflux overnight under nitrogen and cooled. The mixture was filtered through a plug of silica gel/Celite and evaporated. The residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate (2×20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 0-25% ethyl acetate in hexanes to yield 2',4'-difluoro-biphenyl-4-ol (0.61 g, 100%). LR-MS (ES) calculated for C12H8F2O, 206.19; found m/z 205 [M-H]-.

Reference： [1]Patent: US7939569,2011,B1 .Location in patent: Page/Page column 14

34
[ 123-91-1 ]
Ba(OH)2.8H₂O [ No CAS ]
[ 7732-18-5 ]
[ 144025-03-6 ]
[ 396092-82-3 ]
2-(2,4-difluorophenyl)-4-N,N-dimethylaminopyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Pd(PPh3)4;	3-5. Synthesis of 2-(2',4'-Difluorophenyl)-4-(dimethylamino)pyridine (28) 2,4-Difluorophenyl boronic acid (1.1 g, 6.9 mmol), Ba(OH)2.8H2O (6.5 g, 20.6 mmol) and Pd(PPh3)4 (0.4 g, 0.3 mmol) were placed in a 100 mL one-neck round bottom flask equipped with a condenser. The flask was evacuated and filled with N2 gas. 1,4-Dioxane/H2O=1/3 (34.3 ml) and <strong>[396092-82-3]2-bromo-4-(dimethylamino)pyridine</strong> (1.2 g, 6.9 mmol) were added. The reaction mixture was refluxed for 30 h under N2 gas and cooled to room temperature. The dioxane was removed by evaporation and the contents were poured into dichloromethane (30 ml), the precipitate was removed through filter paper, and the organic layer washed with saturated aqueous NaCl (30 ml), and dried over sodium sulfate. After evaporation of the solvent, purification of the product by column chromatography (solvent: ethyl acetate/hexane=1/2) provided 2-(2',4'-difluorophenyl)-4-(dimethylamino)-pyridine (28, 1.2 g, 5.0 mmol, 72%), as the yellow oil.

Reference： [1]Patent: US2012/25177,2012,A1

35
[ 83741-35-9 ]
[ 144025-03-6 ]
[ 1370002-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	With copper diacetate; triethylamine; In dichloromethane; at 20℃; for 19h;	Preparation 46B: 4-Bromo-l- 2,4-difluorophenyl)-lH-benzo[d]imidazole[00149] A vial charged with molecular sieves, 4A (200 mg, 2.030 mmol) was flame- dried, then allowed to cool to room temperature. To this vial were added 4-bromo-lH- benzo[d]imidazole (0.400 g, 2.030 mmol), copper (II) acetate (0.553 g, 3.05 mmol), and 2,4-difluorophenylboronic acid (0.962 g, 6.09 mmol) followed by (¾(¾ (Volume: 10.15 ml) and triethylamine (0.736 ml, 5.28 mmol). The heterogeneous green reaction was stirred at room temperature. After 19 h, the reaction was filtered through a disposable filter funnel and the filter cake rinsed with (¾(¾. The filtrate was concentrated to afford a green residue. The crude material was dissolved in a minimal amount of CH2CI2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (12 g column, 30 mL/min, 0-45% EtOAc in hexanes over 15 min, tr = 10.5 min) gave Preparation 46B (7.5 mg, 0.024 mmol, 1.195% yield) as a yellow solid. MS (ESI) : m/z = 31 1.0 [M+H]+. HPLC Peak tr = 1.73 minutes. HPLC conditions: Column:Luna CI 8 4.6x30mm 3u A: 10:90 H20:ACNNH4OAc/B: 10:90 H20:ACN NH4OAc; 0%-95%B in 2 min; 4mL/min flow.

Reference： [1]Patent: WO2012/44537,2012,A1 .Location in patent: Page/Page column 59

36
[ 83741-35-9 ]
[ 144025-03-6 ]
[ 1370001-86-7 ]

Reference： [1]Patent: WO2012/44537,2012,A1

37
[ 51376-06-8 ]
[ 144025-03-6 ]
[ 1395071-76-7 ]

Reference： [1]Russian Chemical Bulletin,2011,vol. 60,p. 2306 - 2314
Izv. Akad. Nauk, Ser. Khim.,2011,p. 2262 - 2269,8

38
[ 128055-74-3 ]
[ 144025-03-6 ]
[ 1425942-30-8 ]

Reference： [1]Journal of Materials Chemistry C,2013,vol. 1,p. 2183 - 2192

39
[ 144025-03-6 ]
[ 55557-52-3 ]
[ 1439364-59-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃;Inert atmosphere;	General procedure: In a degassed solution of DME/H2O (2:1) (12mL/mmol of diazine), were successively introduced S-Phos (10mol%) and Pd(OAc)2 (5mol%). The solution was heated at 80C for 10min then sodium carbonate (4.0equiv), appropriate boronic acid (1.05 or 1.5equiv) and appropriate diazine (1.0equiv) were added. The solution was then refluxed (15min or overnight) under Ar. The resulting mixture was filtered on Celite and washed with ethyl acetate and water. The aqueous phase was then extracted three times with ethyl acetate. The combined organic phase was dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography (eluent: PE/EtOAc) to give the desired product.

Reference： [1]Tetrahedron,2013,vol. 69,p. 5393 - 5400

40
[ 2005-43-8 ]
[ 144025-03-6 ]
[ 512180-22-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 70℃; for 18h;	<strong>[2005-43-8]2-Bromoquinoline</strong> (5g, 24.0mmol), 2,4-difluorophenyl boronic acid (3.8g, 24.0mmol) and tetrakis(triphenylphosphine) palladium(0) (Pd(PPh3)4, 1.39g, 1.20mmol) were added to 2-neck flask and dissolved in tetrahydrofuran (50ml). Aqueous sodium carbonate solution (2M, 50ml) was put into the solution and the solution was stirred at 70C for 18h. The solution was cooled to room temperature and was poured into water followed by extraction with methylene chloride three times. The extract was dried over anhydrous magnesium sulfate and purified by column chromatography over silica using ethyl acetate: n-hexane (1:10) as an eluent to yield a pure white solid (5.1g). Yield: 88%. 1H-NMR (200MHz, CDCl3); 8.23-8.06 (m, 3H), 7.84 (d, J=8.0Hz, 2H), 7.74 (t, J=8.0Hz, 1H), 7.55 (t, J=8Hz, 1H), 7.10-6.90 (m, 2H)

Reference： [1]Organic electronics,2013,vol. 14,p. 1504 - 1509
[2]Organic Letters,2019,vol. 21,p. 3631 - 3634

41
[ 144025-03-6 ]
[ 396092-82-3 ]
2-(2,4-difluorophenyl)-4-N,N-dimethylaminopyridine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 8054 - 8064

42
[ 144025-03-6 ]
[ 396092-82-3 ]
[Ir(2-(2,4-difluoro-3-(trifluoromethyl)-phenyl)-4-methylpyridine)₂Cl]₂ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 8054 - 8064

43
[ 63927-22-0 ]
[ 144025-03-6 ]
8-(2,4-difluorophenyl)isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
312 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 100℃; for 18h;Inert atmosphere;	General procedure: In an argon gas atmosphere, tetrakis(triphenylphosphine)palladium (83 mg) and a 2 M aqueous sodium carbonate solution (2.2 mL) were added to a mixture of <strong>[63927-22-0]8-bromoisoquinoline</strong> (300 mg), 2,4-difluorophenylboronic acid (342 mg), 1,2-dimethoxyethane (10 mL), and ethanol (1 mL), followed by stirring for 18 hours at an oil temperature of 100° C. The reaction liquid was cooled to room temperature, and then water and ethyl acetate were added thereto to perform liquid separation. The organic layer was washed with saturated brine and then dried, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining 8-(2,4-difluorophenyl)isoquinoline (312 mg).

Reference： [1]Patent: US2013/317010,2013,A1 .Location in patent: Paragraph 0167

44
[ 34941-91-8 ]
[ 144025-03-6 ]
[ 871245-90-8 ]

Yield	Reaction Conditions	Operation in experiment
50%	With palladium diacetate; potassium carbonate; triphenylphosphine In 1,2-dimethoxyethane at 80℃; for 12h; Inert atmosphere; Schlenk technique;	2.5.1. Synthesis of 2-(2',4'-difluorophenyl)-4-fluoropyridine(4-F-dfppy) General procedure: A mixture of 2-chloro-4-fluoropyridine (0.66 g,5 mmol), 2,4-difluorophenylboronic acid (0.79 g, 5 mmol),Pd(OAc)2 (0.023 g, 0.1 mmol), PPh3 (0.105 g, 0.4 mmol) and K2CO3(1.1 g, 8 mmol) in 10 ml of 1,2-dimethoxyethane was refluxed at 80°C for 12 h under argon atmosphere.After cooled to room temperature, the mixture was poured into water, extracted with CHCl3 and dried over anhydrous Na2SO4. The product was purified by column chromatography on silica gel using 1: 10 (v:v) ethyl acetate/petroleum as eluent to give a white solid. Yield: 50%.1H NMR(300 MHz, CDCl3) δ[ppm]: 8.68-8.63 (m, 1H), 8.10-8.02(m, 1H), 7.51 (d, J= 10.2 Hz, 1H), 7.03-6.88 (m, 3H).13CNMR (75 MHz, CDCl3) δ [ppm]: 170.34, 166.88, 165.05,164.89, 162.25, 162.10, 161.71, 161.55, 158.89, 158.74,154.87, 151.51, 151.43, 131.97, 131.90, 122.36, 111.75,111.60, 111.50, 111.36, 110.02, 109.80, 104.46, 104.11,103.76. MS (EI,m/z): [M]+calcd for C11H6F3N, 209.05;found, 209.03. Anal. calcd for C11H6F3N (%): C 63.16, H2.89, N 6.70; found: C 63.35, H 3.01, N 6.95.

Reference： [1]Fan, Cong; Zhu, Liping; Jiang, Bei; Zhong, Cheng; Ma, Dongge; Qin, Jingui; Yang, Chuluo [Organic electronics, 2013, vol. 14, # 12, p. 3163 - 3171]

45
[ 58530-53-3 ]
[ 144025-03-6 ]
[ 917495-77-3 ]

Yield	Reaction Conditions	Operation in experiment
30%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; for 48h;Inert atmosphere; Schlenk technique; Reflux;	A mixture of <strong>[58530-53-3]2,4-dibromopyridine</strong> (7.1 g, 30 mmol), 2,4-difluorophenylboronic acid (4.7 g, 30 mmol), Pd(PPh3)4(22 mg, 5% mmol), Na2CO3(3.8 g, 36 mmol) in 20 ml of tetrahydrofuran (THF) and 5 ml of distilled water was refluxed for 2 days under argon. The mixture was extracted with CHCl3 and dried over anhydrous Na2SO4. The product was purified by column chromatography on silica gel using1: 10 (v:v) ethyl acetate/petroleum as eluent to give a white solid. Yield: 30%.1H NMR (300 MHz, CDCl3) delta[ppm]: 8.49 (d, J= 5.1 Hz, 1H), 8.02-7.91 (m, 2H), 7.41-7.39 (m, 1H), 7.01-6.86 (m, 2H).13C NMR (75 MHz, CDCl3) delta[ppm]: 165.13, 164.97, 162.20, 162.04, 161.79, 161.62,158.69, 153.47, 150.10, 133.01, 132.11, 132.03, 127.19,127.05, 125.48, 122.31, 122.16, 112.01, 111.73, 104.67,104.33, 103.98. MS (EI,m/z): [M]+calcd for C11H6BrF2N,268.97; found, 268.98. Anal. calcd for C11H6BrF2N (%): C48.92, H 2.24, N 5.19; found: C 49.01, H 2.04, N 5.22.

Reference： [1]Organic electronics,2013,vol. 14,p. 3163 - 3171

46
[ 176317-02-5 ]
[ 144025-03-6 ]
[ 1531637-30-5 ]

Reference： [1]Russian Chemical Bulletin,2013,vol. 62,p. 657 - 660
Izv. Akad. Nauk, Ser. Khim.,2013,vol. 3,p. 656 - 659,4

47
[ 327-75-3 ]
[ 144025-03-6 ]
[ 1531637-31-6 ]

Reference： [1]Russian Chemical Bulletin,2013,vol. 62,p. 657 - 660
Izv. Akad. Nauk, Ser. Khim.,2013,vol. 3,p. 656 - 659,4

48
[ 144025-03-6 ]
[ 2265-93-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With iodine; potassium carbonate; In acetonitrile; at 80℃; for 14h;Inert atmosphere; Schlenk technique; Sealed tube;	General procedure: Arylboronic acid 1 (0.5 mmol) and K2CO3 (1 mmol, 138.0mg) were added to a 20 mL Schlenk-tube equipped with amagnetic stir bar. The tube was evacuated twice and backfilledwith N2. MeCN (2 mL) and I2 (0.75 mmol, 191 mg)were added to the tube at r.t. under a stream of N2, and thetube was sealed and placed into a pre-heated oil bath at 80 Cfor 8-12 h. The resulting solution was cooled to r.t. and H2O(10 mL) was added. The aq layer was extracted with EtOAc (3 × 5 mL). For products 2s and 2t, HCl (1 M) was added tothe aq solution until pH 2 before extraction. The combinedorganic phase was dried over anhydrous Na2SO4, filteredand concentrated by rotary evaporation. Purification of theresidue by column chromatography on silica gel providedthe desired product 2a-v

Reference： [1]Synlett,2014,vol. 25,p. 995 - 1000

49
[ 71759-89-2 ]
[ 144025-03-6 ]
4⁽⁵⁾-(2,4-difluorophenyl)-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; N-benzyl-N,N,N-triethylammonium chloride; cesium fluoride; In water; toluene; at 110℃; for 1h;Microwave irradiation; Inert atmosphere;	General procedure: Method A: In a20 mL microwave Biotage tube, a mixture of <strong>[71759-89-2]4-iodo-1H-imidazole</strong>(1a) (0.194 g, 1.0 mmol), a boronic acid 2(2.0 mmol), CsF (0.456 g,3.0 mmol), PdCl2(dppf)(0.041 g, 0.05 mmol) and BnEt3NCl(0.011 g, 0.05 mmol) in toluene(7 mL) and water (7 mL)was purged with argon andheated under microwaveirradiation. When the reaction was complete, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to provide compounds 3a-3i and 3k-3o in yields ranging from 40 to 91%. Time and temperaturereactions were collected in Table 1.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 6347 - 6350

50
[ 144025-03-6 ]
[ 644985-24-0 ]
2,2',3,4'-tetrafluorobiphenyl-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.49 g	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; toluene; at 100℃; for 16h;Inert atmosphere;	[1488] (2,4-Difluorophenyl)boronic acid (5.39 g), dicyclohexyl (2 6'-dimethoxybiphenyl-2-yl)phosphine (1.40 g), 2 M aqueous sodium carbonate solution (34.1 mL) and tris(dibenzylideneacetone)dipalladium(0) (1.46 g) were added to a solution of <strong>[644985-24-0]4-bromo-2,3-difluorobenzaldehyde</strong> (5.03 g) in toluene (150 mL) at room temperature, and the resultant was stirred 16 hours at 100C in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the filtrate was extracted using ethyl acetate. The obtained organic layer was sequentially washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the title compound (5.49 g). 1H NMR (300 MHz, CDC13) delta 6.93-7.06 (2H, m), 7.23-7.30 (1H, m), 7.35-7.44 (1H, m), 7.70 (1H, ddd, J = 8.1, 6.2, 1.8 Hz), 10.39 (lH, d, J = 0.6 Hz).
5.49 g	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; toluene; at 100℃; for 16h;Inert atmosphere;	(2,4-Difluorophenyl)boronic acid (5.39 g), a 2 M aqueous sodium carbonate solution (34.1 mL), tris(dibenzylideneacetone)dipalladium(0) (1.46 g), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (1.40 g) were added at room temperature to a toluene (150 mL) solution of <strong>[644985-24-0]4-bromo-2,3-difluorobenzaldehyde</strong> (5.03 g), and the mixture was stirred at 100 C for 16 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The organic layer was separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.49 g). 1H NMR (300 MHz, CDCl3) delta 6.93-7.06 (2H, m), 7.23-7.30 (1H, m), 7.35-7.44 (1H, m), 7.70 (1H, ddd, J=8.1, 6.2, 1.8 Hz), 10.39 (1H, d, J=0.6 Hz).

Reference： [1]Patent: WO2014/142363,2014,A1 .Location in patent: Paragraph 1488
[2]Patent: US2015/119412,2015,A1 .Location in patent: Paragraph 0414; 0415

51
[ 18179-39-0 ]
[ 144025-03-6 ]
C₁₄H₁₀F₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; toluene; at 100℃; for 2h;	[1477] A mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (22.0 g), (2,4-difluorophenyl)boronic acid (25.0 g), dicyclohexyl (2 6'-dimethoxybiphenyl-2-yl)phosphine (4.87 g), 2 M aqueous sodium carbonate solution (119 mL), tris(c benzyUdeneacetone)dipaUadium(0) (5.07 g) and toluene (150 mL) was stirred 2 hours at 100C. The reaction mixture was poured into water at room temperature, it was filtered using celite, and then the filtrate was extracted using ethyl acetate. The obtained organic layer was washed with a saturated saline solution, it was passed through a short column of a silica gel (NH), and the solvent was distilled off under reduced pressure, benzylbromide (10.4 mL) was added to a mixture of the obtained residue, potassium carbonate (21.9 g) and DMF (100 mL), the resultant was stirred for 1 hour at 70C in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and extraction thereof was performed using ethyl acetate. The obtained organic layer was sequentially washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the title compound (30.5 g). 1H NMR (300 MHz, CDC13) delta 3.92 (3H, s), 5.22 (2H, s), 6.85-7.02 (2H, m), 7.09-7.19 (2H, m), 7.28-7.45 (3H, m), 7.47-7.56 (2H, m), 7.62 (1H, dd, J = 6.8, 2.9 Hz), 7.90 (1H, d, J = 8.0 Hz).
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; toluene; at 100℃; for 2h;	A mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (22 g), 2,4-difluorophenylboronic acid (25 g), a 2 M aqueous sodium carbonate solution (119 mL), tris(dibenzylideneacetone)dipalladium(0) (5.07 g), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.87 g) in toluene (150 mL) was stirred at 100 C for 2 hours. The reaction mixture was poured to water, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a basic silica gel, and the solvent was distilled off under reduced pressure. Benzyl bromide (10.4 mL) was added at room temperature to a mixture of the obtained residue, potassium carbonate (21.9 g), and DMF (100 mL), and the mixture was stirred at 70 C for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (30.5 g)

Reference： [1]Patent: WO2014/142363,2014,A1 .Location in patent: Paragraph 1474
[2]Patent: US2015/119412,2015,A1 .Location in patent: Paragraph 0372

52
[ 43192-33-2 ]
[ 144025-03-6 ]
2',4'-difluoro-3-methoxybiphenyl-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 g	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; toluene; at 100℃; for 2h;	[1251] 4-Bromo-2-methoxybenzaldehyde (1.50 g), (2,4-difluorophenyl)boronic acid (1.65 g), dicyclohexyl (2 6'-a^emoxybiphenyl-2-yl)phosphine (430 mg), s(dibenzylideneacetone)dipalladium(0) (447 mg) and 2 M aqueous sodium carbonate solution (10 mL) were added to toluene (30 mL), and the resultant was stirred for 2 hours at 100C. The reaction mixture was cooled to room temperature, it was poured into water, and extraction thereof was performed using ethyl acetate. The obtained organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was crystalized (ethanol/water), thereby obtaining the title compound (1.00 g). NMR (300 MHz, DMSO-cfc) delta 3.98 (3H, s), 7.21-7.30 (2H, m), 7.32-7.37 (1H, m), 7.39-7.49 (1H, m), 7.67-7.82 (2H, m), 10.39 (1H, s).

Reference： [1]Patent: WO2014/142363,2014,A1 .Location in patent: Paragraph 1251

53
[ 98027-84-0 ]
[ 144025-03-6 ]
2,6-dichloro-4-(2,4-difluorophenyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 90℃; for 1h;Inert atmosphere;	Intermediate Example 5. N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)cycloprdpanesulfonamidea) 2,6-dichloro-4-(2,4-difluorophenyl)pyridineA solution of <strong>[98027-84-0]2,6-dichloro-4-iodopyridine</strong> (1.5 g, 5.49 mmol) in 1,2-dimethoxy- ethane (15 ml) was degassed by N2 bubbling for 5 mm. 2,4-Difluorophenylboronic acid (0.86 g, 5.49 mmol, 1 eq) was added and the mixture was degassed for another 5 mm. Pd(dppf)C12 (0.358 g, 0.43 mmol, 0.08 eq) and aqueous sodium carbonate (1.45 g, 13.7 mmol, 2.5 eq) were added sequentially using the procedure of Intermediate Example 1 and the mixture was heated at 90 C for 16 h. The reaction mixture was quenched and extracted as in Intermediate Example 1. The solvent was distilled off to afford the cruderesidue which was purified by column chromatography (60-120 silica gel, 3 % ethyl acetate in hexane) to yield the title product in 98.5 % yield (1.4 g).

Reference： [1]Patent: WO2014/162039,2014,A1 .Location in patent: Page/Page column 33; 34

54
[ 52334-81-3 ]
[ 144025-03-6 ]
[ 387827-64-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,2-dimethoxyethane;Inert atmosphere; Reflux;	General procedure: To a two necked, 100 mL round bottom flask equipped with a magnetic stir bar were added 2-chloropyridine (1 equiv), phenylboronic acid (1.2 equiv), triphenylphosphine (0.1 equiv), 2 M potassium carbonate (2.7 equiv) and ethylene glycol dimethyl ether(0.9 M). The mixture was degased with Ar for 15 min. Then Pd(OAc)2 (2.5 mol%) was added to the reaction mixture and degassing continued for 15 more minutes and then the outlet was removed. The reaction mixture was heated to reflux. The progress of reaction was monitored by TLC (hexane:EtOAc 90:10). Upon completion (typically 18-24 h), reaction mixture was cooled to room temperature and then extracted with DCM (3x20 mL). The combined organic portion was washed with water (3x20 mL) and brine (1 20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. The crude material was purified by flash chromatography to obtain pure ligand.

Reference： [1]Journal of Organometallic Chemistry,2015,vol. 776,p. 51 - 59
[2]Journal of Organic Chemistry,2016,vol. 81,p. 6988 - 6994
[3]Journal of the American Chemical Society,2017,vol. 139,p. 17186 - 17192
[4]Chemistry - A European Journal,2018,vol. 24,p. 11314 - 11318

55
[ 18179-39-0 ]
[ 100-39-0 ]
[ 144025-03-6 ]
methyl 3-(benzyloxy)-2',4'-difluorobiphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.5 g	Stage #1: methyl 4-iodosalicylate; 2,4-difluorophenylboronic acid With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium carbonate In water; toluene at 100℃; for 2h; Stage #2: benzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 1h; Inert atmosphere;	66.A A) Methyl 3-(benzyloxy)-2',4'-difluorobiphenyl-4-carboxylate A mixture of methyl 2-hydroxy-4-iodobenzoate (22 g), (2,4-difluorophenyl)boronic acid (25 g), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.87 g), a 2 M aqueous sodium carbonate solution (119 mL), tris(dibenzylideneacetone)dipalladium(0) (5.07 g), and toluene (150 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured to water at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. Benzyl bromide (10.4 mL) was added to a mixture of the obtained residue, potassium carbonate (21.9 g), and DMF (100 mL), and the resultant mixture was stirred at 70° C. for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (30.5 g). 1H NMR (300 MHz, CDCl3) δ 3.92 (3H, s), 5.22 (2H, s), 6.85-7.02 (2H, m), 7.09-7.19 (2H, m), 7.28-7.45 (3H, m), 7.47-7.56 (2H, m), 7.62 (1H, dd, J=6.8, 2.9 Hz), 7.90 (1H, d, J=8.0 Hz).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2015/99777, 2015, A1 Location in patent: Paragraph 0699; 0700

56
[ 1416013-62-1 ]
[ 144025-03-6 ]
3-amino-2,2',4'-trifluoro-[1,1'-biphenyl]-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.9%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16.0h;Inert atmosphere;	3-Amino-2,2',4'-trifluoro-[1,1'-biphenyl]-4-carboxylic acid A mixture of <strong>[1416013-62-1]2-amino-4-bromo-3-fluorobenzoic acid</strong> (400 mg, 1.71 mmol), (2,4-difluorophenyl)boronic acid (405 mg, 1.5 mmol), Pd(PPh3)4 (197 mg, 0.171 mmol) and Na2CO3 (725 mg, 6.84 mmol ) in 1,4-dioxane/H2O (10 mL/2 mL) was stirred at 100 oC under argon for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane / methanol = 20:1) to yield the desired product (374 mg, 81.9% yield) as an off-white solid. ESI-MS m/z: 268.1 [M + H]+

Reference： [1]Patent: WO2015/54572,2015,A1 .Location in patent: Page/Page column 276

57
[ 3510-66-5 ]
[ 144025-03-6 ]
[ 583052-21-5 ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 16590 - 16594
[2]Angewandte Chemie - International Edition,2015,vol. 54,p. 9591 - 9595
Angew. Chem.,2015,vol. 127,p. 9727 - 9731,5

58
[ 50488-34-1 ]
[ 144025-03-6 ]
[ 583052-24-8 ]

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 9591 - 9595
Angew. Chem.,2015,vol. 127,p. 9727 - 9731,5

59
[ 105170-27-2 ]
[ 144025-03-6 ]
2-(2,4-difluorophenyl)-5-(methoxy)pyridine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 11938 - 11941

60
[ 634-47-9 ]
[ 144025-03-6 ]
2-(2,4-difluorophenyl)-4-methylquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 110℃; for 16h; Inert atmosphere;	2.1.1. Synthesis of ligand 1 A mixture containing 2-chloro-4-methylquinoline (2.03 g,11.3 mmol), 2,4-difluorophenyl boronic acid (2.66 g, 16.9 mmol),sodium carbonate (2.12 g), toluene (30 mL), ethanol (10 mL), andwater (10 mL) was placed in a 100 mL of round-bottom flask. Themixture was deoxygenated before and after the addition oftetrakis(triphenylphosphine)palladium(0) (910 mg, 0.79 mmol).The mixture was refluxed at 110°C for 16 h under argon. Aftercooled, water (30 mL) was added and the two layers were formedand separated. The aqueous layer was extracted with diethyl ether(3 30 mL). All the organic portions were combined, washed withbrine (30 mL), dried over anhydrous sodium sulfate, and filtered.The filtrate was collected and the solvent was removed in vacuo.The oil was purified by column chromatography over silica usingethyl acetate/hexane (1:20) as eluent to give 1 (2.83 g, 98%) as colorlessgum-like solid. 1H NMR (400 MHz, CDCl3) d 2.77 (s, 3H), 6.94(m, 1H), 7.04 (m, 1H), 7.58 (t, J = 8.3, 1H), 7.69 (d, J = 2.1, 1H), 7.73(d, J = 8.4, 1H), 8.20-8.00 (m, 3H). m/z [ESI+]: 256.1 ([M + H]+). Anal.Cal. For C16H11F2N: C, 75.3; H, 4.3; N, 5.5. Found: C, 75.7; H, 4.4; N,5.7.
	Inert atmosphere; Schlenk technique;

Reference： [1]Xu, Danni; Chu, Qianqian; Wu, Zhuangzhi; Chen, Qingyun; Fan, Sheng-Qiang; Yang, Guan-Jun; Fang, Baizeng [Journal of Catalysis, 2015, vol. 325, p. 118 - 127]
[2]Tao, Peng; Li, Wei-Ling; Zhang, Jing; Guo, Song; Zhao, Qiang; Wang, Hua; Wei, Bin; Liu, Shu-Juan; Zhou, Xin-Hui; Yu, Qi; Xu, Bing-She; Huang, Wei [Advanced Functional Materials, 2016, vol. 26, # 6, p. 881 - 894]

61
[ 89284-11-7 ]
[ 144025-03-6 ]
5-bromo-6-(2,4-difluorophenyl)pyridin-2-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8292 - 8308

62
[ 3164-13-4 ]
[ 144025-03-6 ]
2-(2',4'-difluoro[biphenyl]-4-yl)benzo[d]oxazole [ No CAS ]

Reference： [1]New Journal of Chemistry,2015,vol. 39,p. 6025 - 6033

63
[ 144025-03-6 ]
[ 4373-60-8 ]
(2-(3-(2,4-difluorophenyl)-phenyl)-pyridine) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 6h;Inert atmosphere;	Step 3, synthesis of the intermediate 3 (2-(3-(2,4-difluorophenyl)-phenyl)-pyridine) includes: (0070) adding the intermediate 2 of 1.28 mmol, 2,4-difluorobenzeneboronic acid of 1.41 mmol and tetrakis(triphenylphosphine)palladium of 0.03 mmol into a dual-port flask through three cycles of evacuation-nitrogen purge-evacuation; finally, protecting the reaction system with nitrogen, then injecting a deoxidized and mixed solvent having a mixing ration of 3:1:1 (toluene:ethanol:sodium carbonate solution, V/V/V) with a syringe; reacting the reaction system under 80° C. for 6 hours; after the reaction stopped, extracting with dichloromethane and water by three times, then combining organic phase; removing the solvent by using the rotary evaporator; separating white solid by using the column chromatography. (0071) The obtained intermediate 3 (2-(3-(2,4-difluorophenyl)-phenyl)-pyridine) is examined through 1H NMR, and has a correct structure revealed in the 1H NMR spectra data as follows: (0072) 1H NMR (400 MHz, CDCl3) delta(ppm)=8.71 (dt, J=8.4, 1.6 Hz, 1H), 8.14 (s, 1H), 8.04-7.94 (m, 1H), 7.77 (dd, J=3.6, 1.2 Hz, 2H), 7.55 (d, J=5.2 Hz, 2H), 7.49 (dt, J=6.4, 8.8 Hz, 1H), 7.31-7.20 (m, 1H), 7.02-6.88 (m, 2H).

Reference： [1]Patent: US9312503,2016,B2 .Location in patent: Page/Page column 10

64
[ 640-60-8 ]
[ 144025-03-6 ]
[ 37847-52-2 ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 2072 - 2076

65
[ 122918-25-6 ]
[ 144025-03-6 ]
6-(2,4-difluorophenyl)picolinonitrile [ No CAS ]

Reference： [1]Journal of Materials Chemistry C,2016,vol. 4,p. 2560 - 2565
[2]Chemical Communications,2019,vol. 55,p. 501 - 504

66
[ 89167-24-8 ]
[ 144025-03-6 ]
6-(2,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine [ No CAS ]

Reference： [1]Arkivoc,2016,vol. 2016,p. 268 - 278

67
[ 69249-22-5 ]
[ 144025-03-6 ]
6-(2,4-difluorophenyl)-1,2,4-triazine-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 90℃;	6-l3romo- 1 ,2,4-triazine-3-amine (0.5 g, 2.857 mmol), 2,4-difluorophenylboronic acid (0.68 g, 4.286 mmol), 2N sodium carbonate and [1,1 ?-bis(diphenylphosphine)ferrocene]dichloropalladium(II) complex with dichloromethane (0.28 g, 0.343 mmol) were added to 1,2- dimethoxyethane (28.6 ml) and agitated at 90 C. overnight. Afier the temperature of the reaction mixture was cooled to room temperature, the reaction mixture was filtrated with CelliteTM pad, and the solvent was concentrated under reduced pressure, and then washed with ethyl acetate and filtrated to obtain yellow solid, 6-(2,4-difluorophenyl)- 1,2,4- triazine-3-amine (amount: 0.82 g, yield: 46%).

Reference： [1]Patent: US2016/251361,2016,A1 .Location in patent: Paragraph 1004; 1007

68
[ 2103-94-8 ]
[ 144025-03-6 ]
4-(2',4'-difluorobiphenyl-4-yl)thiazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane at 90 - 100℃; for 8h;	3.2. Synthesis of 4-(2,4-difluorobiphenyl-4-yl)-1,3-thiazol-2-amine(2) In a screw capped reaction tube 4-phenyl-1,3-thiazol-2-amine(100 mg, 0.48 mmol), 4-phenyl-1,3-thiazol-2-amine, Pd(PPh3)4 (8 mg, 1.5 mol%), 2,4-diflurophenyl boronic acid (153 mg,0.724 mmol) and K3PO4 (153 mg, 0.724 mmol) were added to 3 mLof dioxane solvent. The resulting reaction mixturewas flushed withdry nitrogen gas for few minutes. The reaction mixture was heatedat 90e100 C for 8 h. After the completion of the reaction, 20 mL ofwater was added. After cooling at room temperature, organic andthe aqueous layers were separated and the latter was extractedwith ethyl acetate three times (3 15 mL). The obtained residuewas then purified through column chromatography and compound(2) was isolated as light yellow crystalline solid (146 mg, 90%).

Reference： [1]Adeel, Muhammad; Braga, Ataualpa A.C.; Tahir, Muhammad Nawaz; Haq, Fazal; Khalid, Muhammad; Halim, Mohammad A. [Journal of Molecular Structure, 2017, vol. 1131, p. 136 - 148]

69
[ 81167-60-4 ]
[ 144025-03-6 ]
[ 583052-24-8 ]

Reference： [1]Organic electronics,2016,vol. 39,p. 91 - 99

70
[ 79669-50-4 ]
[ 144025-03-6 ]
C₁₅H₁₂F₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;	Step 1 (0576) 2 mol/L potassium carbonate aqueous solution (22.7mL, 45.4mmol), 2,4-difluorobenzeneboronic acid (7.17g, 45.4mmol) and Pd (PPh3)4 were added into DMF (50mL) solution of Compound iii-48 (5.2g, 22.7mmol) under nitrogen atmosphere, and the mixture was stirred at 100C for 2 hours. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-49 (5.6g, 94%). LC/MS (ESI): 263 (M+1)

Reference： [1]Patent: EP3192794,2017,A1 .Location in patent: Paragraph 0575; 0576

71
[ 307353-32-8 ]
[ 144025-03-6 ]
C₁₅H₁₂F₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium dihydrogenphosphate; In toluene; at 140℃; for 0.5h;Inert atmosphere; Microwave irradiation;	Step 1 (0579) Compound iii-51 (300mg, 1.22mmol), (2,4-difluorophenyl)boronic acid (290mg, 1.84mmol), PdCl2 (dppf) (90mg, 0.12mmol) and potassium phosphate (780mg, 3.67mmol) were dissolved into toluene (12mL) under nitrogen atmosphere under microwave irradiation, and the mixture was stirred at 140C for 30 minutes. After the reaction mixture was filtrated by Celite, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-52 (304mg, 89%). 1H-NMR (CDCl3) delta: 8.09-8.05 (m, 2H), 7.72 (d, J = 1.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.00-6.91 (m, 2H), 4.82 (d, J = 5.8 Hz, 2H), 3.94 (s, 3H), 1.83 (t, J = 5.9 Hz, 1H).

Reference： [1]Patent: EP3192794,2017,A1 .Location in patent: Paragraph 0578; 0579

72
[ 307353-32-8 ]
[ 144025-03-6 ]
C₁₆H₁₄F₂O₅S [ No CAS ]

Reference： [1]Patent: EP3192794,2017,A1

73
[ 18511-71-2 ]
[ 144025-03-6 ]
4,4'-bis(2,4-difluorophenyl)-2,2'-bipyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 36h;Inert atmosphere; Reflux;	<strong>[18511-71-2]4,4'-dibromo-2,2'-bipyridine</strong> (3.45 g, 11 mmol)2,4-difluorobenzeneboronic acid (3.82 g, 24.2 mmol)K2CO3 (3.04 g, 22 mmol),Tetrakis (triphenylphosphine) palladium (0.76 g, 0.66 mmol) in a three-necked flask,80 mL of toluene was added,20 mL of deionized water,Repeated gas three times,Under nitrogen protection,Heated to reflux for 36 h.After stopping the reaction,Cooled to room temperature, washed with organic phase three times, separated, organic phase with anhydrous MgSO4 drying.After removal of toluene by filtration, the residue was recrystallized from CH2Cl2,The petroleum ether was washed twice to give a white product of 4.72 g in 65% yield.

Reference： [1]Patent: CN106946944,2017,A .Location in patent: Paragraph 0013; 0032-0034

74
[ 2363-16-8 ]
[ 144025-03-6 ]
[ 1047624-83-8 ]

Yield	Reaction Conditions	Operation in experiment
60.3%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;	A mixture of <strong>[2363-16-8]methyl 4-bromo-3-nitrobenzoate</strong> (750 mg, 2.88 mmol), (2,4- difluorophenyl)boronic acid (683 mg, 4.33 mmol), tetraki s(triphenylphosphine)palladium(0)(333 mg, 0.288 mmol), and sodium carbonate (611 mg, 5.77 mmol) were combined in dioxane (15 mL) and water(4 mL), sparged with nitrogen gas for 10 minutes, and heated at 90 C under nitrogen for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with diatornaceousearth, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-100 % ethyl acetate in petroleum ether) to provide the title compound (510 mg, 1.739 mmol,60.3 % yield).

Reference： [1]Patent: WO2017/177955,2017,A1 .Location in patent: Paragraph 00329

75
[ 126728-20-9 ]
[ 144025-03-6 ]
2-chloro-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 6368 - 6371

76
[ 126728-20-9 ]
[ 144025-03-6 ]
C₁₃H₆ClF₂N₃ [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 6368 - 6371

77
[ 374633-36-0 ]
[ 144025-03-6 ]
2-(2,4-difluorophenyl)-3-fluoro-6-methylpyridine [ No CAS ]

Reference： [1]Green Chemistry,2018,vol. 20,p. 3436 - 3443

78
[ 119-30-2 ]
[ 144025-03-6 ]
[ 22494-42-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With C₃₂H₂₆Cl₂N₈O₄Pd₂; potassium carbonate In methanol; lithium hydroxide monohydrate for 0.0833333h; Reflux;
98%	With potassium carbonate In lithium hydroxide monohydrate for 0.0833333h; Reflux;	Suzuki reaction catalyzed by Pd-M(Ni,Co,Fe,Cu) - Pro/Al2O3 composites (general procedure) General procedure: To a mixture of 1.20 mmol of arylboronic acid, 1.00 mmol of aryl bromide, and 0.35 g (2.50 mmol) of K2CO3 in 5 mL of H2O (or 50% aqueous methanol) was added a catalyst (10 mg 1-4, 6, 3.3 mg 5, 0.1 mol % Pd). The reactor was placed in a silicon bath preheated to 120°C (for reactions in aqueous methanol) or to 160°C (for reactions in water), the reaction mixture was intensively stirred for 15-20 min at reflux (yields of the cross-coupling product are given in Table 1). The reactions progress was monitored by TLC (eluent hexane-Et2O, 3 : 1) using calibration solutions of the corresponding biaryl and aryl bromide (at a molar ratio of 1 : 1 and 9 : 1). After the reaction completion, the catalyst was separated by centrifugation (3000 rpm)and, after washing with water and ethanol, was reused. The centrifugate was diluted with water, filtered, 10- 15 vol % ethanol was added, heated to ~50°C, and slowly acidified with 5% HCl to pH 2-3 with stirring. As a result, well filterable precipitates were formed, and analytically pure samples of the cross-coupling product were obtained without the use of chromatographic methods. Yields in exp. 1, 4, 10 (Table 1) were also determined by 1H NMR using tetrachloroethane (0.5 mmol) as an internal standard.
52%	With trimethyl-(2-hydroxyethyl)ammonium chloride; palladium diacetate; anhydrous sodium carbonate; propane-1,2,3-triol at 60℃; for 5h;

Reference： [1]Bumagin, Nikolay A.; Dikusar, Evgenij A.; Ivashkevich, Ludmila S.; Kletskov, Alexey V.; Kolesnik, Iryna A.; Lyakhov, Alexander S.; Petkevich, Sergey K.; Potkin, Vladimir I. [Inorganic Chemistry, 2020]
[2]Bumagin, N. A. [Russian Journal of General Chemistry, 2022, vol. 92, # 5, p. 832 - 840][Zh. Obshch. Khim., 2022, vol. 92, # 5, p. 769 - 778]
[3]Dilauro, Giuseppe; García, Sergio Mata; Tagarelli, Donato; Vitale, Paola; Perna, Filippo M.; Capriati, Vito [ChemSusChem, 2018, vol. 11, # 19, p. 3495 - 3501]

79
[ 2178-24-7 ]
[ 144025-03-6 ]
C₁₆H₁₄F₂O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 138 - 142

80
[ 6165-68-0 ]
[ 1295502-53-2 ]
[ 144025-03-6 ]
4-(2,4-difluorophenyl)-7-(thiophene-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 15029 - 15042

81
[ 148893-10-1 ]
[ 144025-03-6 ]
5-(2,4-difluorobenzyl)-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃;	5-(bromomethyl)-N-(2-(5-fluoro-1 H-indol-3-yI)ethyl)isoxazole-3-carboxamide (0.150 g; 0.409 mmol) was dissolved in DME (3 mL) and water (1 mL) with (2,4-difluorophenyl)boronic acid (0.068 g; 0.430 mmol), sodium carbonate (0.086 g; 0.430 mmol),Tetrakis(triphenylphosphine)palladium(0) (0.024 g; 0.020 mmol) and heated overnight at90C. After cooling to RT, the reaction mixture was diluted with water and ethyl acetate, the organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography on silica (eluent ethyl acetate 0 to 10 % in dichloromethane) to yield 0.0462 g (28%) of 5-(2,4-difluorobenzyl)-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a white solid. 1H NMR (300 MHz, DMSQ-d6): 10.92 (br. s., 1 H); 8.82 (t, 1 H); 7.39 - 7.57 (m, 1 H); 7.21 - 7.36 (m, 4H); 7.11 (td, 1H); 6.90 (td, 1H); 6.50 (s, 1H); 4.24 (s, 2H); 3.49 (q, 2H); 2.89 (t, 2H). ESIIAPCI(+): 400 (M+H).ESI/APCI(-): 398 (M-H).

Reference： [1]Patent: WO2018/206760,2018,A1 .Location in patent: Page/Page column 28; 29

82
[ 144025-03-6 ]
[ 852054-42-3 ]
7-(2,4-difluorophenyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine-5-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 908℃;Schlenk technique; Inert atmosphere;	General procedure: 50 mL Schlenk tube was charged with (5-formylfuran-2-yl)boronic acid (0.140 g, 1 mmol)and [Pd(PPh3)4] (0.113 g, 0.01 mmol). Dimethoxy ethane (8 mL) and 2m aqueous sodiumcarbonate (2 mL) were added, and the tube was purged with argon gas with fiveevacuate/refill cycles. Compound 5a (0.534 g, 1 mmol) was subsequently added as a neatliquid. The tube was sealed and heated at 908C for 18 h. Upon cooling to ambienttemperature, the organic compounds were extracted into dichloromethane (3× 30 mL) fromwater (30 mL). The combined organic layers were washed with water (1×30 mL) and brine(1×30 mL), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure.The crude product was preadsorbed onto silica gel and purified by column chromatography(9:1 hexane/ethyl acetate) to give 6a (0.395 g, 74%).

Reference： [1]Molecules,2019,vol. 24

83
[ 13195-50-1 ]
[ 144025-03-6 ]
2-(2,4-difluorophenyl)-5-nitrothiophene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019

84
[ 29509-91-9 ]
[ 144025-03-6 ]
4-(2,4-difluorophenyl)-2,6-diphenylpyrimidine [ No CAS ]

Reference： [1]Journal of Materials Chemistry C,2020,vol. 8,p. 2196 - 2204

85
[ 608-33-3 ]
[ 144025-03-6 ]
3-bromo-2’,4’-difluoro-[1,1‘-biphenyl]-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; for 12h;Inert atmosphere; Reflux;	2,4-difluorobenzeneboronic acid (11.9 g, 75.4 mmol), <strong>[608-33-3]2,6-dibromophenol</strong> (20.0 g, 79.4 mmol), Pd(PPh3)4 (2.7 g, 2.4 mmol), sodium carbonate (14.4 g, 136.0 mmol), THF (500 mL) and H2O (50 mL) were added to a 1000 mL round-bottomed flask. N2 replacement three times and N2 protection. Then put into a heating jacket, stir and reflux for 12h. The solution was cooled to room temperature, extracted with EA and washed with brine three times, dried with anhydrous magnesium sulfate, the combined organic layers were concentrated. The crude product was purified by column-chromatography, eluting with 10% (v/v) EA/PE to obtain 3-bromo-2?,4?-difluoro-[1,1?-biphenyl]-2-ol as white solid (18.3 g, 88% yield),

Reference： [1]Patent: US2020/91442,2020,A1 .Location in patent: Paragraph 0134-0136

86
[ 144025-03-6 ]
[ 192447-58-8 ]
2,6-bis(2,4-difluorophenyl)-N,N-dimethylpyridin-4-amine [ No CAS ]

Reference： [1]Chemistry - A European Journal,2020,vol. 26,p. 15718 - 15726

87
[ 144025-03-6 ]
[ 55928-90-0 ]
5-(2,4-difluorophenyl)pyridazin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous sodium carbonate; In water monomer; N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;	General procedure: Under N2, to a solution of compound 2 (1.7 g, 10.0 mmol) in a mixture of DMF(30 mL) and H2O (5 mL) were added the appropriate compound 3 (14.0 mmol), sodiumcarbonate (2.1 g, 20.0 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol). The mixture wasstirred at 100 C for 2 h. The mixture was diluted with water (60 mL) and extractedwith ethyl acetate (3100 mL). The organic layer was washed with brine, dried andconcentrated under reduced pressure. The residue was purified by flash chromatography(CH2Cl2:MeOH, 20:1 - 10:1) to provide the target compound.

Reference： [1]Organic Preparations and Procedures International,2022

88
[ 121219-03-2 ]
[ 144025-03-6 ]
C₁₂H₇F₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With palladium diacetate; triphenylphosphine at 80℃; Inert atmosphere;	2 Synthesis of Compound No. 17 Under the protection of nitrogen, 17-A1 (1.7 g, 11 mmol, commercially available), 17-A2 (2 g, 10 mmol), palladium acetate (21.5 mg, 0.1 mmol), triphenylphosphine (39 mg, 0.15 mmol) and potassium carbonate (2.8, 20 mmol) were dissolved in dioxane (20 ml) and water (2 ml). The temperature was increased to 80°C and stirring was performed overnight. After the completion of the reaction, suction filtration through celite was performed followed by concentration. The sample was mixed and subjected to column chromatography separation (100-200 mesh silica gel, n-heptane:EA=5:1) to obtain the product 17-A3 (900 mg, 40%) as a white solid. 1H-NMR (300MHz, DMSO) δ10.17 (s, 1H), 7.55-7.08 (m, 3H), 6.79-6.50 (m, 3H). LCMS: Calculated 224.0, found 222.6 [(M-H)-].
40%	With palladium diacetate; triphenylphosphine at 80℃; Inert atmosphere;	2 Synthesis of Compound No. 17 Under the protection of nitrogen, 17-A1 (1.7 g, 11 mmol, commercially available), 17-A2 (2 g, 10 mmol), palladium acetate (21.5 mg, 0.1 mmol), triphenylphosphine (39 mg, 0.15 mmol) and potassium carbonate (2.8, 20 mmol) were dissolved in dioxane (20 ml) and water (2 ml). The temperature was increased to 80°C and stirring was performed overnight. After the completion of the reaction, suction filtration through celite was performed followed by concentration. The sample was mixed and subjected to column chromatography separation (100-200 mesh silica gel, n-heptane:EA=5:1) to obtain the product 17-A3 (900 mg, 40%) as a white solid. 1H-NMR (300MHz, DMSO) δ10.17 (s, 1H), 7.55-7.08 (m, 3H), 6.79-6.50 (m, 3H). LCMS: Calculated 224.0, found 222.6 [(M-H)-].

Reference： [1]Current Patent Assignee: ASCENTAWITS PHARMACEUTICALS - EP3971194, 2022, A1 Location in patent: Paragraph 0071; 0163-0164
[2]Current Patent Assignee: ASCENTAWITS PHARMACEUTICALS - EP3971194, 2022, A1 Location in patent: Paragraph 0071; 0163-0164

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(3-Fluorophenyl)boronic acid

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

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

[ CAS No. 144025-03-6 ] {[proInfo.proName]}

Quality Control of [ 144025-03-6 ]

Related Doc. of [ 144025-03-6 ]

Product Details of [ 144025-03-6 ]

Calculated chemistry of [ 144025-03-6 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 144025-03-6 ]

Application In Synthesis of [ 144025-03-6 ]

[ 144025-03-6 ] Synthesis Path-Upstream 1~10

[ 144025-03-6 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 144025-03-6 ]

Fluorinated Building Blocks

Organoboron

Aryls

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 144025-03-6 ]