[ CAS No. 121219-16-7 ]

Name: 121219-16-7|2,3-Difluorophenylboronic acid|97%
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Quality Control of [ 121219-16-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 121219-16-7 ]

Product Details of [ 121219-16-7 ]

CAS No. :	121219-16-7	MDL No. :	MFCD01863170
Formula :	C₆H₅BF₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SZYXKFKWFYUOGZ-UHFFFAOYSA-N
M.W :	157.91 g/mol	Pubchem ID :	2734333
Synonyms :

Calculated chemistry of [ 121219-16-7 ]

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 :	2.2

Safety of [ 121219-16-7 ]

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 [ 121219-16-7 ]

* 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 [ 121219-16-7 ]
Downstream synthetic route of [ 121219-16-7 ]

[ 121219-16-7 ] Synthesis Path-Upstream 1~10

1
[ 121219-16-7 ]
[ 6418-38-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;	Step 1Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H₂C>₂ (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3~difluorophenol as a brown oil.
93%	With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;	Step 1into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). 3/4<3/4 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenoI as brown oil.
93%	With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;	Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.

93%	With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;	Step 1. Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H₂O₂ (30 mL)was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.
93%	With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;	Step 1 Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H₂O₂ (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25° C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.
93%	With dihydrogen peroxide In dichloromethane at 25℃; for 2 h;	Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H₂O₂(30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25° C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93percent) of 2,3-difluorophenol as brown oil.

Reference： [1] Journal of Materials Chemistry, 1999, vol. 9, # 8, p. 1669 - 1677
[2] Journal of Organic Chemistry, 2017, vol. 82, # 10, p. 5236 - 5241
[3] Journal of the American Chemical Society, 2011, vol. 133, # 39, p. 15674 - 15685
[4] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13182 - 13187
[5] Patent: WO2012/158795, 2012, A1, . Location in patent: Page/Page column 87-88
[6] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 182-183
[7] Patent: WO2013/191965, 2013, A1, . Location in patent: Page/Page column 174
[8] Patent: WO2014/22569, 2014, A1, . Location in patent: Page/Page column 66
[9] Patent: US8673925, 2014, B1, . Location in patent: Page/Page column 215
[10] Patent: US2014/142099, 2014, A1, . Location in patent: Paragraph 0206
[11] Journal of Materials Chemistry, 2007, vol. 17, # 8, p. 766 - 782
[12] Patent: US5853613, 1998, A,
[13] Patent: US5683623, 1997, A,

2
[ 33192-09-5 ]
[ 121219-16-7 ]
[ 21524-39-0 ]

Reference： [1] Journal of Sulfur Chemistry, 2018, vol. 39, # 5, p. 507 - 515

3
[ 121219-16-7 ]
[ 21524-39-0 ]

Reference： [1] Journal of Sulfur Chemistry, 2018, vol. 39, # 5, p. 507 - 515

4
[ 688-71-1 ]
[ 367-11-3 ]
[ 121219-16-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - -70℃; for 2 h; Inert atmosphere Stage #2: at -70 - 20℃; Inert atmosphere	1,2-Difluorobenzene (40 g, 0.35 mol) and dry tetrahydrofurane (400 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, pressure-equilibrated dropping funnel and thermometer. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was cooled down to −78° C. with dry ice/acetone bath and 2.5 mol/L hexane solution of n-butyllithium (140 ml; 0.35 mol) was added dropwise, keeping the reaction temperature below −70° C. After addition of all butyllithium solution the mixture was stirred at −78° C. for 2 h and then tripropylborate (66 g, 0.35 mol) was added dropwise keeping the reaction temperature below −70° C. After addition of tripropyl borate the cooling bath was removed and the reaction mixture continuously stirred to reach the room temperature then the solvents were evaporated. The thick liquid residue was acidified and then propanol was evaporated and the remaining solid was filtered off, washed out with hexane and recrystalized from water. The white crystalline product 47 g was obtained, with 85percent of theor. yield.

Reference： [1] Patent: US2013/20532, 2013, A1, . Location in patent: Paragraph 0042
[2] Journal of Materials Chemistry C, 2014, vol. 2, # 5, p. 891 - 900

5
[ 367-11-3 ]
[ 121219-16-7 ]

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 39, p. 15674 - 15685
[2] Journal of Materials Chemistry, 1999, vol. 9, # 8, p. 1669 - 1677
[3] Patent: EP329752, 1989, A1,
[4] Patent: US6388146, 2002, B1, . Location in patent: Page column 22
[5] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13182 - 13187

6
[ 5419-55-6 ]
[ 367-11-3 ]
[ 121219-16-7 ]

Reference： [1] Patent: US5417885, 1995, A,
[2] Patent: US5683623, 1997, A,

7
[ 121-43-7 ]
[ 33863-76-2 ]
[ 121219-16-7 ]

Reference： [1] Patent: US6566372, 2003, B1,

8
[ 121-43-7 ]
[ 367-11-3 ]
[ 121219-16-7 ]

Reference： [1] Patent: US5262556, 1993, A,

9
[ 109-72-8 ]
[ 121-43-7 ]
[ 121219-16-7 ]

Reference： [1] Patent: US5853613, 1998, A,

10
[ 121-43-7 ]
[ 367-11-3 ]
[ 121219-16-7 ]

Reference： [1] Journal of Materials Chemistry, 2007, vol. 17, # 8, p. 766 - 782

[ 121219-16-7 ] Synthesis Path-Downstream 1~32

1
[ 121219-16-7 ]
[ 125962-61-0 ]
8-(2',3'-Difluoro-biphenyl-4-yl)-1,4-dioxa-spiro[4.5]decane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium carbonate In ethanol at 80℃; for 19h;

Reference： [1]Marck, Guy; Villiger, Alois; Buchecker, Richard [Tetrahedron Letters, 1994, vol. 35, # 20, p. 3277 - 3280]

2
[ 121219-16-7 ]
[ 6418-38-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;	Step 1Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2C>2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3~difluorophenol as a brown oil.
93%	With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;	Step 1into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)- boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). ¾<¾ (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenoI as brown oil.
93%	With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;	Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.

93%	With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;	Step 1. Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL)was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
93%	With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;	Step 1 Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
93%	With dihydrogen peroxide; In dichloromethane; at 25℃; for 2h;	Into a 500 mL round-bottom flask, was placed a solution of (2,3-difluorophenyl)-boronic acid (30 g, 189.98 mmol, 1.00 equiv) in dichloromethane (250 mL). H2O2 (30 mL) was added dropwise with stirring. The resulting solution was stirred for 2 h at 25 C. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to give 23 g (93%) of 2,3-difluorophenol as brown oil.
	With dihydrogen peroxide;	2,3-Difluoro-phenol (3). 10% Hydrogen peroxide (135 ml, 0.396 mol) was added dropwise to a stirred refluxing solution of compound 2 (19.8 g, 0.126 mol) in ether. The stirred mixture was heated under reflux for 2.5 h and cooled. The ether layer was separated and the aqueous layer was washed with ether. The combined etheral layers were washed with sodium hydroxide (3*150 ml, 10%) and the separated aqueous layer extracted was acidified with hydrochloric acid (90 ml, 36%). The product was extracted into ether (twice), and the combined etheral extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo. This crude product was recrystallized from petroleum spirit (40-60 C.) to give an off white solid. Yield 9.84 g (60%); mp 29.5-31.5 C.; 1 H NMR (CDCl3) d 5.35(1H, s), 6.65-6.80 (2H, m), 6.95(1H, q); IR (KCl) vmax 3700-3000, 1630, 1540, 1515, 1490, 1480, 1350, 1310, 1250, 1190, 1020 cm-1; MS m/z 130 (M+), 110, 101.
	With dihydrogen peroxide; In diethyl ether;	EXAMPLE 37 2,3-Difluorophenol Hydrogen peroxide (10%, 340 cm3, 1 mol) was added dropwise to a stirred solution of compound from Example 36 (47 g, 0.3 mol) in diethyl ether (350 cm3) heated under reflux. The stirred mixture was heated under reflux for a further 2.5 h then cooled. The ethereal layer was separated and the aqueous layer extracted with diethyl ether (2200 cm3). The combined ethereal layers were washed with sodium hydroxide (10%, 4100 cm3) and the separated aqueous layers acidified with 36% hydrochloric acid. The product was extracted into diethyl ether (3*100 cm3), and the combined ethereal extracts washed with water and dried (MgSO4). The solvent was removed in vacuo to give an off white solid. Yield=39 g (100%); m.p.=30-32 C.; 1 H NMR (CDCl3): delta5.15 (1H, d), 6.67-6.82 (2H, m), 6.90-7.00 (1H, m); IR: 3700-3000, 1630, 1535, 1513, 1492, 1482, 1360, 1310, 1255, 1182, 1025, 910, 736 cm-1; MS: 130 [M]+, 121.

Reference： [1]Journal of Materials Chemistry,1999,vol. 9,p. 1669 - 1677
[2]Journal of Organic Chemistry,2017,vol. 82,p. 5236 - 5241
[3]Journal of the American Chemical Society,2011,vol. 133,p. 15674 - 15685
[4]Chemistry - A European Journal,2011,vol. 17,p. 13182 - 13187
[5]Patent: WO2012/158795,2012,A1 .Location in patent: Page/Page column 87-88
[6]Patent: WO2012/158764,2012,A1 .Location in patent: Page/Page column 182-183
[7]Patent: WO2013/191965,2013,A1 .Location in patent: Page/Page column 174
[8]Patent: WO2014/22569,2014,A1 .Location in patent: Page/Page column 66
[9]Patent: US8673925,2014,B1 .Location in patent: Page/Page column 215
[10]Patent: US2014/142099,2014,A1 .Location in patent: Paragraph 0206
[11]Journal of Materials Chemistry,2007,vol. 17,p. 766 - 782
[12]Patent: US5853613,1998,A
[13]Patent: US5683623,1997,A

3
[ 121219-16-7 ]
[ 360575-29-7 ]
[ 861218-24-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2998 - 3001

4
[ 72537-17-8 ]
[ 121219-16-7 ]
3-(2,3-difluorophenyl)-2-fluoro-5-trifluoromethylpyridine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 4685 - 4696

5
[ 121219-16-7 ]
[ 175968-39-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrogen peroxide 2: K₂CO₃ 3: butyllithium / -78 °C 4: H₂ / Pd/C

Reference： [1]Petrenko, Alexey; Goodby, John W. [Journal of Materials Chemistry, 2007, vol. 17, # 8, p. 766 - 782]

6
[ 121-43-7 ]
[ 33863-76-2 ]
[ 121219-16-7 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In hexane;	4-Trifluoromethyl-6-(3-fluoro-5-chloro)phenyl-2(1H)-quinolinone (Compound 732, Structure 145 of Scheme XXX, Where R=H, R1=Trifluoromethyl, R2=3-Fluoro-5-chloro) 3-Chloro-5-fluorobenzeneboronic Acid (Compound 733, Structure 144 of Scheme XXX, Where R2=3-Fluoro-5-chloro): This compound was prepared according to General Procedure XXIII in Example 406 from <strong>[33863-76-2]1-bromo-3-chloro-5-fluorobenzene</strong> (20 g, 0.18 mmol), n-BuLi (8.2 M in hexane, 21 mL, 0.18 mmol), and trimethyl borate (60 mL, 0.53 mmol) to give 2,3-difluoro-benzeneboronic acid as a white solid.

Reference： [1]Patent: US6566372,2003,B1

7
[ 73583-37-6 ]
[ 121219-16-7 ]
[ 1143578-39-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; at 20 - 50℃; for 17h;	(1) 2-chloro-4-(2,3-difluorophenyl)pyridine To a solution of <strong>[73583-37-6]4-bromo-2-chloropyridine</strong> (10.0 g, 52.0 mmol), 2,3-difluorophenylboronic acid (8.21 g, 52.0 mmol), and sodium carbonate (14.4 g, 104 mmol) in methanol (104 ml) was added tetrakisphenylphosphine palladium (3.00 g, 2.60 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:hecane=1:8) to obtain the title compound (11.2 g, 96%) as a solid. 1H-NMR (CDCl3) delta: 7.21-7.24 (2H, m), 7.26-7.31 (1H, m), 7.41-7.43 (1H, m), 7.52 (1H, s), 8.48 (1H, d, J=5.2 Hz).

Reference： [1]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 41

8
[ 1052714-46-1 ]
[ 121219-16-7 ]
[ 1210418-75-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;microwave irradiation;	Synthesis of 6-(2,3-difluorophenyl)-5-fluoropicolinic acid To a solution of <strong>[1052714-46-1]6-bromo-5-fluoropicolinic acid</strong> (1.0 equiv.) in DME and 2M Na2CO3 (3:1, 0.25 M) was added 2,3-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 1N NaOH was added. The organic phase was separated and extracted three more times with 1N NaOH and once with 6N NaOH. The combined aqueous phases were filtered and acidified to pH I 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-(2,3-difluorophenyl)-5-fluoropicolinic acid in 78%. LC/MS=254.1 (M+H), Rt=0.75 min.
78%	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-(2,3-difluorophenyl)-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 2,3-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- (2,3-difluorophenyl)-5-fiuoropicolinic acid in 78%. LC/MS = 254.1 (M+H), Rt = 0.75 min.

Reference： [1]Patent: US2010/56576,2010,A1 .Location in patent: Page/Page column 40
[2]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 77

9
[ 58573-93-6 ]
[ 121219-16-7 ]
4-heptyl-2'',3''-difluoro-1,1':4',1''-terphenyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.55%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 2h;Inert atmosphere; Reflux;	General procedure: 1,2-dimethoxyethene (150 ml) and sodium carbonate (2 M, 150 ml) were added to diflouroboronic acid (4.79 g, 30.33 mmol, 158 g/mol) and 4-bromo-4′′pentylbiphenyl (7.07 g, 23.33 mmol, 303 g/mol) under dry nitrogen with continuous stirring. Tetrakis (triphenylphosphine) palladium (0) (0.1348 g, 0.11 mmol, 1156 g/mol) was added. The stirred mixture was heated under reflux (ca. 120 C) for 2 h (i.e., until g. L .c/ t. l. c. analysis revealed a complete reaction). Reaction mixture was cooled to room temperature and 100 ml water was added. The product was extracted into 200 ml ether (twice) and the combined ethereal extracts were washed with brine and dried (MgSO4), the most of it filtered off by pressure. The solvent was removed in vacuo. The dry product was purified by addition to a packed chromatography column of silica gel [silica gel, Hexane] to yield white product. Product was re-crystallised through ethanol. It was put in the desiccators overnight. Yield (6.47 g, 82.53%).M.P. 97.5 C (from EtOH). Elemental analysis: (Found: C, 82.40; H, 6.74 . Calc. for C23H22F2: C, 82.11; H, 6.59%);m/z 336 (M+), 292, 279 (100%),165, 151; transitions / C K 95.8 (25.79 J/g) SmA 108.8 (18.98 J/g) I;IR (KBr) υmax/c- 1 2927 (CH), 1473, 1398, 1264, 1216, 1100, 897, 817, 785, 721; δH(400 MHz;CDCl3) 0.80 (3H,t,J 7,CH3CH2), 1.19-.27 (8H, m), 1.57 (2H, quint, J7.7, ArCH2CH2), 2.57 (2H, t, J7.9, ArCH2), 7.02 (1H, ddd, J 6.8, 6.6, 1.5, 20H), 7.16 (1H, ddd, J 6.8, 6.4, 1.6, 19H),7.47 (2H,d,J 8.1), 7.52 (2H, dd, J 8.2, 1.5), 7.59 (2H, d, J8.2),;(δF(376; CDCl3)) - 143.30 (1F, dd, JF,F20.81, JF,H6.9), - 143.88 (1F, dd, JF,F18.5, JF,H6.9);δC(100.5;CDCl3) 14.10, 22.68, 29.20, 29.34, 31.50, 31.82, 35.64, 116.0 (d, J 16.9), 124.08 (dd, JC,F 5.4, 4.6), 125.20 (dd, JC,F 3.8, 1.5), 126.93, 127.11, 128.92, 129.27 (d JC,F 3.1), 130.83, 131.00, 133.26 (d, JC,F 4.6), 137.75, 141.00, 142.51

Reference： [1]Journal of Molecular Liquids,2012,vol. 175,p. 72 - 84
[2]Journal of Materials Chemistry,2010,vol. 20,p. 299 - 307
[3]Journal of Molecular Liquids,2012,vol. 170,p. 11 - 19

10
[ 63619-59-0 ]
[ 121219-16-7 ]
[ 151718-03-5 ]

Yield	Reaction Conditions	Operation in experiment
82.53%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 2h;Inert atmosphere; Reflux;	General procedure: 1,2-dimethoxyethene (150 ml) and sodium carbonate (2 M, 150 ml) were added to diflouroboronic acid (4.79 g, 30.33 mmol, 158 g/mol) and 4-bromo-4??pentylbiphenyl (7.07 g, 23.33 mmol, 303 g/mol) under dry nitrogen with continuous stirring. Tetrakis (triphenylphosphine) palladium (0) (0.1348 g, 0.11 mmol, 1156 g/mol) was added. The stirred mixture was heated under reflux (ca. 120 C) for 2 h (i.e., until g. L .c/ t. l. c. analysis revealed a complete reaction). Reaction mixture was cooled to room temperature and 100 ml water was added. The product was extracted into 200 ml ether (twice) and the combined ethereal extracts were washed with brine and dried (MgSO4), the most of it filtered off by pressure. The solvent was removed in vacuo. The dry product was purified by addition to a packed chromatography column of silica gel [silica gel, Hexane] to yield white product. Product was re-crystallised through ethanol. It was put in the desiccators overnight. Yield (6.47 g, 82.53%).M.P. 97.5 C (from EtOH). Elemental analysis: (Found: C, 82.40; H, 6.74 . Calc. for C23H22F2: C, 82.11; H, 6.59%);m/z 336 (M+), 292, 279 (100%),165, 151; transitions / C K 95.8 (25.79 J/g) SmA 108.8 (18.98 J/g) I;IR (KBr) upsilonmax/c- 1 2927 (CH), 1473, 1398, 1264, 1216, 1100, 897, 817, 785, 721; deltaH(400 MHz;CDCl3) 0.80 (3H,t,J 7,CH3CH2), 1.19-.27 (8H, m), 1.57 (2H, quint, J7.7, ArCH2CH2), 2.57 (2H, t, J7.9, ArCH2), 7.02 (1H, ddd, J 6.8, 6.6, 1.5, 20H), 7.16 (1H, ddd, J 6.8, 6.4, 1.6, 19H),7.47 (2H,d,J 8.1), 7.52 (2H, dd, J 8.2, 1.5), 7.59 (2H, d, J8.2),;(deltaF(376; CDCl3)) - 143.30 (1F, dd, JF,F20.81, JF,H6.9), - 143.88 (1F, dd, JF,F18.5, JF,H6.9);deltaC(100.5;CDCl3) 14.10, 22.68, 29.20, 29.34, 31.50, 31.82, 35.64, 116.0 (d, J 16.9), 124.08 (dd, JC,F 5.4, 4.6), 125.20 (dd, JC,F 3.8, 1.5), 126.93, 127.11, 128.92, 129.27 (d JC,F 3.1), 130.83, 131.00, 133.26 (d, JC,F 4.6), 137.75, 141.00, 142.51

Reference： [1]Journal of Molecular Liquids,2012,vol. 175,p. 72 - 84
[2]Journal of Materials Chemistry,2010,vol. 20,p. 299 - 307
[3]Journal of Molecular Liquids,2012,vol. 170,p. 11 - 19

11
[ 121219-16-7 ]
[ 200064-11-5 ]
[ 1202243-12-6 ]

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

12
aqueous potassium carbonate [ No CAS ]
[ 55304-73-9 ]
[ 121219-16-7 ]
[ 6163-58-2 ]
[ 1013647-52-3 ]

Yield	Reaction Conditions	Operation in experiment
	bis(triphenylphosphine)palladium(II)-chloride; In 1,4-dioxane;	Example 6A 2-Chloro-6-(2,3-difluorophenyl)nicotinaldehyde 179 mg (1.14 mmol) of 2,3-difluorophenylboronic acid and then 3.4 ml of a 2 M aqueous potassium carbonate solution are added with stirring to a solution of 200 mg (1.14 mmol) of <strong>[55304-73-9]2,6-dichloropyridine-3-carboxaldehyde</strong> in 4 ml of dioxane. After 10 min, 160 mg (0.23 mmol) of bis(triphenylphosphine)palladium(II) chloride and 69 mg (0.23 mmol) of tri-2-tolylphosphine are added and the reaction mixture is then stirred at 60 C. overnight. The mixture is worked up and purified directly by means of preparative HPLC (method 9). This affords 144 mg (50% of theory) of the target compound in a mixture with tri-2-tolylphosphine, which is reacted further in this form. 1H NMR (400 MHz, DMSO-d6): delta=7.42 (tdd, 1H), 7.65 (dtd, 1H), 7.80 (ddt, 1H), 8.06 (dd, 1H), 8.39 (d, 1H), 10.31 (s, 1H).

Reference： [1]Patent: US2010/298221,2010,A1

13
[ 106-41-2 ]
[ 121219-16-7 ]
[ 202464-01-5 ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium carbonate In 1,2-dimethoxyethane for 4h; Reflux;	9.1 Step 1 : 2',3'-Difluoro-biphenyl-4-olA mixture of 4-bromophenol (1.7 g, 10 mmol), 2,3-difluorolphenylboronic acid (3.1 g, 20 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and a 2M sodium carbonate solution (6ml ) in 40 ml of 1 ,2-dimethoxy ethane was heated at reflux for 4 hours. The mixture was cooled and was poured into an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (100ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel using 0-20% ethyl acetate/heptane to provide the title compound (0.55g, 27%).

Reference： [1]Current Patent Assignee: SANOFI - WO2011/34828, 2011, A1 Location in patent: Page/Page column 36

14
[ 156573-09-0 ]
[ 121219-16-7 ]
[ 1241535-57-8 ]

Yield	Reaction Conditions	Operation in experiment
77.8%	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In Solmix A-11; water; toluene; for 2h;Reflux; Inert atmosphere;	Third Step 4-Bromo-2,3-difluoroethoxybenzene (s-5) (45.2 g), 2, 3-difluorophenyllboronic acid (s-6) (36.1 g), potassium carbonate (79.1 g), Pd (Ph3P)2Cl2 (4.0 g), toluene (200 ml), Solmix A-11 (200 ml) and water (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and heated to reflux for 2 hours. After the reaction solution had been cooled to 25C, it was poured into water (200 ml) and toluene (200 ml) and mixed with them. The mixture was then allowed to stand until it had separated into two layers of organic and aqueous layers, and the extraction into an organic layer was carried out. The resulting organic layers were separated, and washed with water, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel as a stationary phase powder and a mixed solvent of toluene and heptane (toluene: heptane= 2:1 by volume) as an eluent, and further purified by recrystallization from Solmix A-11 and dried to give 4-ethoxy-2,2',3,3'-tetrafluoro-1,1'-biphenyl (s-7) (40.1 g).

Reference： [1]Patent: EP2479162,2012,A1 .Location in patent: Page/Page column 40-41

15
[ 207399-07-3 ]
[ 121219-16-7 ]
[ 1428582-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water; at 115℃; for 2h;Inert atmosphere;	To an oven dried pressure tube with a magnetic stir-bar were added <strong>[207399-07-3]IR-780</strong> (400 mg, 0.74 mmol), 2,3-difluoro phenyl boronic acid (1.17 g, 6.23 mmol), palladium (0) tetrakis (222 mg), 4.5 mL THF and 1.5 mL nano-pure water followed by 1.44 mL DIPEA. The reaction mixture was flashed with N2 and was heated to 115 C for 2 h. Mass spectral analysis indicated only the desired product with a very little peak corresponding to the decholinated starting material (m/z = 506). The product was purified using Teledyne's Isco CombiFlash system using dichloromethane/methanol as eluent.

Reference： [1]Patent: WO2013/44156,2013,A1 .Location in patent: Paragraph 0496

16
[ 121219-16-7 ]
[ 55557-52-3 ]
[ 1439364-54-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	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

17
[ 588-93-2 ]
[ 121219-16-7 ]
[ 126163-02-8 ]

Yield	Reaction Conditions	Operation in experiment
427 g	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 4h;Inert atmosphere; Reflux;	In a nitrogen atmosphere, 4-propyl bromobenzene (400 g), 2 M potassium carbonate aqueous solution (1100 mL), tetrakistriphenylphosphine palladium (0) (11.6 g) were dissolved in THF (1200 mL) and heated to reflux. Under reflux, a solution of 2,3-difluorophenylboronic acid (317 g) dissolved in THF (950 mL) was added, and the mixture was further stirred under reflux for 4 hours. After completion of the reflux, the reaction solution was allowed to cool, hexane was added and the organic layer was separated. Hexane was added to the remaining aqueous layer, and liquid separation was carried out, and the organic layer was separated again and combined with the organic layer which was previously fractionated. The obtained organic layer was washed twice with saturated brine. Sodium sulfate was added to the organic layer after washing, dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from ethanol to give 2,3-difluoro-4- (4-propyl Phenyl) benzene (427 g).

Reference： [1]Journal of Materials Chemistry C,2014,vol. 2,p. 891 - 900
[2]Patent: JP6019595,2016,B2 .Location in patent: Paragraph 0052; 0053

18
[ 51554-95-1 ]
[ 121219-16-7 ]
[ 121219-17-8 ]

Yield	Reaction Conditions	Operation in experiment
19.7 g	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 5h;Inert atmosphere; Reflux;	The compounds of the formula (I-3-1) A reaction vessel 20.0 g (0.0881 mol), compound 15.3 g(0.0969 mole) of the formula (I-2-1), carbonate potassium 18.3g (0.132 mol), tetrahydrofuran120mL, the water 120mL was added, and the inside of the system was replaced with nitrogen.Tetrakis (triphenylphosphine) palladium (0) 1.02 g (0.881 mmol) was added and heated to refluxfor 5 hours. Toluene was added and the aqueous was washed with brine, to give the compound19.7 g (0.0757 mole) of the formula was purified by column chromatography (silica gel) (I-3-2).

Reference： [1]Journal of Materials Chemistry C,2014,vol. 2,p. 891 - 900
[2]Patent: JP2015/110532,2015,A .Location in patent: Paragraph 0127-0128

19
[ 40400-15-5 ]
[ 121219-16-7 ]
[ 1616923-39-7 ]

Yield	Reaction Conditions	Operation in experiment
62%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In methanol; toluene; at 80℃; for 18h;Inert atmosphere;	To a suspension of (2-iodo-phenyl)-acetonitrile (Aldrich, 2.4 g, 10 mmol) and 2,3-difluorophenylboronic acid (Aldrich, 2.4 g, 15 mmol) in anhydrous methanol (10 mL) and toluene (20 mL) was added Cs2CO3 (9.8 g, 30 mmol). The mixture was degassed with nitrogen, followed by the addition of tetrakis(triphenylphosphine)palladium (1.2 g, 1 mmol). [0504] The reaction mixture was heated at 80 C. and stirred for 18 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (10-30% ethyl acetate in hexanes) to give the product ( 101) as a colorless oil (1.4 g, 62%)

Reference： [1]Patent: US2014/194431,2014,A1 .Location in patent: Paragraph 0502-0504

20
[ 60633-25-2 ]
[ 121219-16-7 ]
C₁₃H₉ClF₂O [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 1122 - 1125

21
[ 14508-49-7 ]
[ 121219-16-7 ]
[ 1613074-45-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,2-dimethoxyethane at 85℃;	3c General Procedure for Examples 3b to 3h General procedure: General Procedure for Examples 3b to 3h: [0237] Tetrakis(Triphenylphosphine)Palladium(0) (1-3% mol) is added to a mixture of 2-Chloropyrazine (1 eq), Aryl/Heteroaryl boronic acid (1 eq) and base (2 eq) suspended into the solvent. The reaction mixture is heated until the reaction is completed, the solvent is removed under reduced pressure and the residue is partitioned between water and EtOAc (or 1N aqueous NaOH and EtOAc); organic layer is separated, dried, concentrated under reduced pressure and the residue is purified by Silica gel flash chromatography using a suitable eluent.
76%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,2-dimethoxyethane; water at 85℃;	3c General procedure: Tetrakis(Triphenylphosphine)Palladium(0) (1-3% mol) is added to a mixture of 2- Chloropyrazine (1 eq), Aryl/Heteroaryl boronic acid (1 eq) and base (2 eq) suspended into the solvent. The reaction mixture is heated until the reaction is completed, the solvent isremoved under reduced pressure and the residue is partitioned between water and EtOAc (or iN aqueous NaOH and EtOAc); organic layer is separated, dried, concentrated under reduced pressure and the residue is purified by Silica gel flash chromatography using a suitable eluent.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2015/105397, 2015, A1 Location in patent: Paragraph 0237
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2015/55698, 2015, A1 Location in patent: Page/Page column 52; 53

22
[ 31462-58-5 ]
[ 121219-16-7 ]
C₁₀H₆F₂N₂ [ No CAS ]

Reference： [1]Science,2015,vol. 349,p. 1087 - 1091

23
[ 10602-01-4 ]
[ 121219-16-7 ]
C₁₅H₁₂F₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate In isopropyl alcohol for 9h; Inert atmosphere; Reflux;	7.1 The first step Under a nitrogen atmosphere, the compound (S-11) (8.00g), compound (S-12) (8.27g), sodium carbonate (7.40 g), palladium acetate (7.84mg), SPhos ligands (28 .7mg) and it was stirred 2-propanol (80 ml) placed in a reactor and heated to reflux for 9 hours. The reaction mixture was poured into water and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, washed with saturated brine, and dried with anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (volume ratio of heptane: ethyl acetate = 4: 1) was purified. Further purified by recrystallization from Solmix, compound (S-13); was obtained (7.49g 82%).
7.49 g	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate In isopropyl alcohol for 9h; Inert atmosphere; Reflux;	7.1 First Step Under a nitrogen atmosphere, compound (S-11) (8.00 g), compound (S-12) (8.27 g), sodium carbonate (7.40 g), palladium acetate (7.84 mg), an SPhos ligand (28.7 mg) and 2-propanol (80 mL) were put in a reaction vessel, and the resulting mixture was stirred, and heated under refluxing for 9 hours. The resulting reaction mixture was poured into water, and an aqueous layer was subjected to extraction with toluene. Organic layers combined were washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1 in a volume ratio). The residue was further purified by recrystallization from Solmix to give compound (S-13) (7.49 g; 820).

Reference： [1]Current Patent Assignee: CHISSO CORPORATION - JP2016/20340, 2016, A Location in patent: Paragraph 0175
[2]Current Patent Assignee: CHISSO CORPORATION - US2015/368225, 2015, A1 Location in patent: Paragraph 0218

24
[ 38573-88-5 ]
[ 121219-16-7 ]
2,3,2',3'-tetrafluorobiphenyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.1%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 6h;Inert atmosphere; Reflux;	500 mL of a three-necked flask was added 15.8 g of compound D, 19.3 g 2,3-difluorobenzene, 120 mL of toluene,60 mL of ethanol, 60mL water, 42.4 g of sodium carbonate, Under nitrogen protection, 0.5 g of Pd (PPh3) 4 was added, Heating reflux 6h, Cooled to room temperature, After adding 100 mL of water, Dispensing, 100mL toluene extraction water layer, Combined with reservoirs, After the solvent was distilled off, Column chromatography, To give 15.4 g of a white solid compound E, Yield: 68.1% GC> 98%.

Reference： [1]Patent: CN106278812,2017,A .Location in patent: Paragraph 0135; 0138; 0139

25
[ 33192-09-5 ]
[ 121219-16-7 ]
[ 21524-39-0 ]

Reference： [1]Journal of Sulfur Chemistry,2018,vol. 39,p. 507 - 515

26
[ 121219-16-7 ]
5-bromo-3-thiocyanatoindole [ No CAS ]
[ 21524-39-0 ]

Reference： [1]Journal of Sulfur Chemistry,2018,vol. 39,p. 507 - 515

27
[ 121219-16-7 ]
[ 65896-11-9 ]
2',3,3'-trifluoro-[1,1'-biphenyl]-2-amine [ No CAS ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 7607 - 7612

28
[ 121219-16-7 ]
[ 65896-11-9 ]
2,3,3'-trifluoro-2'-iodo-1,1'-biphenyl [ No CAS ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 7607 - 7612

29
[ 64248-57-3 ]
[ 121219-16-7 ]
2,3,2′,3′-tetrafluorobiphenyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 1-iodo-2,3-difluorobenzene; (2,3-difluorophenyl)boronic acid With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane; water at 20℃; for 0.0833333h; Stage #2: With potassium carbonate In 1,4-dioxane; water for 48h; Reflux;

Reference： [1]Maiti, Buddhadev; Wang, Kunlun; Bhandari, Srijana; Bunge, Scott D.; Twieg, Robert J.; Dunietz, Barry D. [Journal of Materials Chemistry C, 2019, vol. 7, # 13, p. 3881 - 3888]

30
[ 79832-89-6 ]
[ 121219-16-7 ]
[ 1253696-08-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 5h;Reflux;	Compound 1 (9.8 g, 31.6 mmol), Compound 8 (5.0 g, 31.6 mmol), tetrahydrofuran (125 mL), water (25 mL) and potassium carbonate (19.7 g, 142.4 mmol) were placed in a 500 mL reaction flask and stirred to dissolve. Nitrogen gas was introduced into the reaction flask to deoxygenate for 30 minutes. Then, tetrakis(triphenylphosphine)palladium (1.1 g, 0.949 mmol) was added, and the mixture was heated to reflux for 5 hours to carry out the reaction. After the reaction was completed, an extraction was performed by using ethyl acetate and water, and the organic phase was collected. The solvent of the collected organic phase was removed by using a rotary concentrator. Then, column chromatography was performed to obtain Compound 9. Next, 3.0 g of Compound 9 (8.77 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran to obtain a solution of Compound 9.

Reference： [1]Patent: US2019/338190,2019,A1 .Location in patent: Paragraph 0132; 0133

31
[ 121219-16-7 ]
[ 78155-74-5 ]
methyl 5-(2,3-difluorophenyl)-1H-indazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;	General procedure: To a mixture of <strong>[78155-74-5]methyl 5-bromo-1H-indazole-3-carboxylate</strong> (XIII, 1 eq.) and the proper boronic acid (XII, 2.5 eq.) in 1 ,4-dioxane, a solution of Na2C03(2 eq.) in water was added. The reaction mixture was degassed for 10 minutes and PdCl2(dppf) (0.05 eq.; 1 :1 complex with dichloromethane) was added. The reaction mixture was heated at 100 C for 3 hours under Ar stream, cooled, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried and filtered. Removal of the solvent gave a residue that was purified by column chromatography to give intermediate having general formula XIV. (0223) Methyl 5-(2,3-difluorophenyl)-1H-indazole-3-carboxylate (XlVa). The title compound was obtained according to general procedure D, step 1 using methyl 5-bromo-1 H- indazole-3-carboxylate (XIII, 1.00 g, 3.92 mmol), (2,3-difluorophenyl)boronic acid (Xllb, 1.55 g, 9.81 mmol), Na2CO3 (0.83 g, 7.83 mmol), PdCl2(dppf) (0.17 g, 0.21 mmol). The crude was purified by column chromatography (S1O2, acetone/n-hexane) to give 0.60 g of the title product. Yield = 53%.

Reference： [1]Patent: WO2019/215075,2019,A1 .Location in patent: Page/Page column 47-48

32
[ 1232038-69-5 ]
[ 121219-16-7 ]
8-bromo-3-(2,3-difluorophenyl)imidazo[1,2-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h; Microwave irradiation; Sealed tube;	27 8-bromo-3-iodoimidazo[l,2-a]pyridine (100 mg, 0.31 mmole) was combinded with (2,3-difluorophenyl)boronic acid (49 mg, 0.31 mmole), [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.05 equiv), and potassium carbonate (42 mg, 0.31 mmol) in microwave seal tube. To this mixture was added dimethylformamide (2 mL) and water (0.2 mL). The resulting mixture was stirred at 90°C for 120 min. Reaction was cooled and diluted with EtOAc and filtered through celite. The filtrate was concentrated, and solid was precipitated out of DMF/H2O mixture to give 8-bromo-3-(2,3- difluorophenyl)imidazo[l,2-a]pyridine. 309.0 (M). The precipitate used as such for the next step.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2020/10223, 2020, A1 Location in patent: Paragraph 0333

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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. 121219-16-7 ]

Quality Control of [ 121219-16-7 ]

Related Doc. of [ 121219-16-7 ]

Product Details of [ 121219-16-7 ]

Calculated chemistry of [ 121219-16-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 121219-16-7 ]

Application In Synthesis of [ 121219-16-7 ]

[ 121219-16-7 ] Synthesis Path-Upstream 1~10

[ 121219-16-7 ] Synthesis Path-Downstream 1~32

Related Functional Groups of [ 121219-16-7 ]

Organoboron

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 121219-16-7 ]