[ CAS No. 399-94-0 ] {[proInfo.proName]}

Name: 399-94-0|1-Bromo-2,5-difluorobenzene|98%
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SKU: A357950
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Quality Control of [ 399-94-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 399-94-0 ]

Product Details of [ 399-94-0 ]

CAS No. :	399-94-0	MDL No. :	MFCD00000345
Formula :	C₆H₃BrF₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XCRCSPKQEDMVBO-UHFFFAOYSA-N
M.W :	192.99	Pubchem ID :	67862
Synonyms :		Chemical Name :	1-Bromo-2,5-difluorobenzene

Calculated chemistry of [ 399-94-0 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.06
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.11
Log Po/w (XLOGP3) :	3.11
Log Po/w (WLOGP) :	3.57
Log Po/w (MLOGP) :	3.91
Log Po/w (SILICOS-IT) :	3.38
Consensus Log Po/w :	3.21

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.49
Solubility :	0.0626 mg/ml ; 0.000324 mol/l
Class :	Soluble
Log S (Ali) :	-2.78
Solubility :	0.321 mg/ml ; 0.00167 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.81
Solubility :	0.0298 mg/ml ; 0.000155 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.44

Safety of [ 399-94-0 ]

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 [ 399-94-0 ]

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

Upstream synthesis route of [ 399-94-0 ]
Downstream synthetic route of [ 399-94-0 ]

[ 399-94-0 ] Synthesis Path-Upstream 1~16

1
[ 399-94-0 ]
[ 124-38-9 ]
[ 2991-28-8 ]

Reference： [1] Journal of Organic Chemistry, 1990, vol. 55, # 2, p. 773 - 775

2
[ 540-36-3 ]
[ 399-94-0 ]

Reference： [1] Journal of the American Chemical Society, 2004, vol. 126, # 48, p. 15770 - 15776

3
[ 108-86-1 ]
[ 1072-85-1 ]
[ 399-94-0 ]
[ 1073-06-9 ]
[ 348-61-8 ]
[ 460-00-4 ]

Yield	Reaction Conditions	Operation in experiment
0.06 mmol	at 0 - 25℃; Cooling with ice	General procedure: A FEP or PFA reactor equipped with a Teflon-lined magnetic stir bar and connected to a gas-washing bottle was charged with substituted benzene (0.95–1.10 mmol), 1,1,1,3,3-pentafluorobutane (1–2 mL per mmol of C6H5R), and BF3 · Et2O (1.3–1.5 mmol per mmol of C6H5R). The mixture was stirred for 10–15 min at 0–5°C (ice bath), and XeF2 (1.2–1.3 mmol per mmol of C6H5R) was added in portions. After addition of each portion, the mixture was stirred for 3–5 min at 22–25°C and cooled again. When the addition was complete the dark solution was stirred for 15–30 min at 22–25°C, 10percent aqueous KHCO3 was added, and the upper organic layer was separated, passed through a short column charged with silica gel (40–60 μm), and dried over MgSO4. The solution was analyzed by 19F NMR and GC/MS. The main products are given in table, and the others are listed below (GC/MS data).

Reference： [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1400 - 1407[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1412 - 1419,8

4
[ 540-36-3 ]
[ 399-94-0 ]
[ 327-51-5 ]

Reference： [1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 1593; engl. Ausg. S. 1566
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 153[3] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
[4] Green Chemistry, 2012, vol. 14, # 9, p. 2380 - 2383

5
[ 540-36-3 ]
[ 399-94-0 ]
[ 327-51-5 ]
[ 128259-70-1 ]
[ 128259-69-8 ]

Reference： [1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 393 - 406

6
[ 108-86-1 ]
[ 1072-85-1 ]
[ 399-94-0 ]
[ 1073-06-9 ]
[ 348-61-8 ]
[ 460-00-4 ]

Yield	Reaction Conditions	Operation in experiment
0.06 mmol	at 0 - 25℃; Cooling with ice	General procedure: A FEP or PFA reactor equipped with a Teflon-lined magnetic stir bar and connected to a gas-washing bottle was charged with substituted benzene (0.95–1.10 mmol), 1,1,1,3,3-pentafluorobutane (1–2 mL per mmol of C6H5R), and BF3 · Et2O (1.3–1.5 mmol per mmol of C6H5R). The mixture was stirred for 10–15 min at 0–5°C (ice bath), and XeF2 (1.2–1.3 mmol per mmol of C6H5R) was added in portions. After addition of each portion, the mixture was stirred for 3–5 min at 22–25°C and cooled again. When the addition was complete the dark solution was stirred for 15–30 min at 22–25°C, 10percent aqueous KHCO3 was added, and the upper organic layer was separated, passed through a short column charged with silica gel (40–60 μm), and dried over MgSO4. The solution was analyzed by 19F NMR and GC/MS. The main products are given in table, and the others are listed below (GC/MS data).

Reference： [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1400 - 1407[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1412 - 1419,8

7
[ 540-36-3 ]
[ 399-94-0 ]
[ 327-51-5 ]

8
[ 540-36-3 ]
[ 399-94-0 ]
[ 327-51-5 ]
[ 128259-70-1 ]
[ 128259-69-8 ]

Reference： [1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 393 - 406

9
[ 399-94-0 ]
[ 167415-27-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sulfuric acid; nitric acid In dichloromethane at 20℃; for 3.5 h; Cooling with ice	Reference Example-50 Concentrated sulfuric acid (57 mL) was cooled in an ice bath, and 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25 minutes, whereby a mixed acid was prepared. To this mixed acid, a solution of 2-bromo-1,4-difluorobenzene (50 g, 254 mmol) in dichloroethane (125 mL) was slowly added dropwise over 1.5 hours under ice-cooling. After the reaction was completed, the reaction solution was further stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was added little by little to ice water (500 g), and the resultant product was extracted with ether (300 mL*2). The organic layer was washed sequentially with water (300 mL), a saturated sodium hydrogencarbonate aqueous solution (300 mL), and a saturated saline solution (300 mL), and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane:chloroform=4:1), whereby 1-bromo-2,5-difluoro-4-nitrobenzene (56 g, yield: 93percent) was obtained as a pale yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ7.59 (dd, J=9.5 and 5.5 Hz, 1H), 7.89 (dd, J=7.3 and 6.5 Hz, 1H). ¹⁹F-NMR (376 MHz, CDCl₃): δ-120.1 (d, J=15.2 Hz, 1F), -107.9 (d, J=15.2 Hz, 1F).
93%	With sulfuric acid; nitric acid In 1,2-dichloro-ethane for 3.92 h; Cooling with ice	Concentrated sulfuric acid (57 mL) was cooled inan ice bath, and 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25minutes to prepare a mixed acid. To this mixed acid, under ice-cooling, dichloroethane(125mL) solution of 2-bromo-1,4-difluoro-benzene (50g, 254mmol) was droppedslowly over a period of 1.5 hours. After completion of the dropwise addition,the reaction solution was further stirred for 2 hours at room temperature.After completion of the reaction, the reaction solution was added in portionsto ice-water (500 g), then extracted with ether (300mL × 2). The organic layerwas washed successively with water (300mL), saturated aqueous sodium hydrogencarbonate solution (300mL), saturated brine (300mL), and then dried overanhydrous magnesium sulfate, and the solvent was evaporated under reducedpressure. The resulting crude product was purified by silica gel chromatography(hexane: chloroform = 4/1) to give a pale yellow solid of 1-bromo-2,5-difluoro-4-nitrobenzene(56 g, yield: 93percent ).
93%	at 20℃; for 3.5 h; Cooling with ice	Concentrated sulfuric acid (57 mL) was cooled in an ice bath, 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25 minutes to prepare a mixed acid. In this mixed acid under ice-cooling 2-bromo-1,4-difluorobenzene (50g, 254mmol) was dropped slowly over a period of 1.5 hours of dichloroethane (125mL) solution . After completion of the dropwise addition, the reaction solution was further stirred for 2 hours at room temperature. After completion of the reaction, added little by little the reaction solution into ice water (500g), then ether (300mL ×And extracted with 2). The organic layer was washed with water (300mL), saturated aqueous sodium hydrogen carbonate solution (300mL), was washed successively with saturated brine (300mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography - (hexane: chloroform = 4/1) to give 1-bromo-2,5-difluoro-4-nitrobenzene as a pale yellow solid (56 g, yield: 93percent ) was obtained.

80%	at 5 - 20℃; for 1.5 h;	Nitric acid (d 1.42) (26.2 g, 286.81 mmol) was slowly added dropwise to conc. sulfuric acid (102 g, 1042.96 mmol) over 1 hr under ice water, while the mixture was maintained at 10°C or below. Then, 2-bromo-1,4-difluorobenzene (50.32 g, 260.74 mmol) was slowly added thereto over 3 hr while the mixture was maintained at 10°C or below. The reaction mixture was stirred at 5°C for 30 min, and then at room temperature for 1 hr. The reaction mixture was poured into ice (about 600 g), and the mixture was extracted three times with a mixed solvent of Et2O/THF (3:1). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 20percent ethyl acetate/hexane) to give 1-bromo-2,5-difluoro-4-nitrobenzene (49.64 g, 209 mmol, 80percent) as a pale yellow solid.
78.1%	at 0 - 20℃; for 16 h;	INTERMEDIATE 6 1-((3S,5S)-1 -Oxaspiror2.5loctan-5-ylmethyl)-5-fluoro-1 H-benzo[d]imidazole-6- carbonitrile1-Bromo-2,5-difluoro-4-nitrobenzene To a stirred solution of 2-bromo-1 ,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H₂S0₄ was added KN0₃ by portions at 0 °C. After this addition, the mixture was allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated to give 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 78.1 percent yield) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) δ 7.91-7.87 (dd, 1 H), 7.52-7.57 (dd, 1 H).
78.1%	at 0 - 20℃;	1-Bromo-2,5-difluoro-4-nitrobenzeneTo a stirred solution of 2-bromo-1 ,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H₂S0₄ was added KN0₃ by portions at 0 °C. After this addition, the mixture was allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated to give 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 78.1 percent yield) as a yellow solid. H NMR (400 MHz, CDCI₃) δ 7.91-7.87 (dd, 1 H), 7.52-7.57 (dd, 1 H).
89%	With KNO₃ In conc. H₂ SO₄	1-Bromo-2,5-difluoro-4-nitrobenzene: To a stirred solution of 1-bromo-2,5-difluorobenzene (1.000 g, 5.181 mmol, Aldrich, used as received) in conc. H₂ SO₄ (8.0 mL) at 0° C., KNO₃ (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to 28° C. and stirred at 28° C. overnight. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na₂ SO₄, removed under vacuum, and the resulting white solid was dried further under vacuum to afford 1.102 g (89percent) of the title compound as a white powder; m.p. 58°-60° C.; ¹ H NMR (CDCl₃): δ7.591 (dd, 1H, J₁ =9.6 Hz, J₂ =5.4 Hz), 7.891 (t, 1H, J=6.9 Hz).

Reference： [1] Patent: US2016/24110, 2016, A1, . Location in patent: Paragraph 0809; 0810
[2] Patent: JP2016/56157, 2016, A, . Location in patent: Paragraph 0164; 0168
[3] Patent: JP2016/60742, 2016, A, . Location in patent: Paragraph 0251
[4] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379
[5] Journal of Organic Chemistry, 1995, vol. 60, # 18, p. 5838 - 5842
[6] Patent: TW2016/2105, 2016, A, . Location in patent: Paragraph 0979
[7] Patent: WO2012/174342, 2012, A1, . Location in patent: Page/Page column 44
[8] Patent: WO2013/12500, 2013, A1, . Location in patent: Page/Page column 60
[9] Patent: US5631373, 1997, A,
[10] Patent: WO2005/54176, 2005, A1, . Location in patent: Page/Page column 88

10
[ 399-94-0 ]
[ 79-10-7 ]
[ 112898-33-6 ]

Reference： [1] Russian Journal of Organic Chemistry, 1997, vol. 33, # 4, p. 563 - 564

11
[ 399-94-0 ]
[ 146447-18-9 ]

Reference： [1] Patent: US2016/24110, 2016, A1,
[2] Patent: JP2016/56157, 2016, A,
[3] Patent: JP2016/60742, 2016, A,

12
[ 399-94-0 ]
[ 172921-32-3 ]

Reference： [1] Patent: WO2012/174342, 2012, A1,
[2] Patent: WO2013/12500, 2013, A1,

13
[ 399-94-0 ]
[ 1218935-59-1 ]

Reference： [1] Patent: WO2011/6074, 2011, A1,
[2] Patent: US2017/281632, 2017, A1,
[3] Patent: CN108101820, 2018, A,

14
[ 399-94-0 ]
[ 1218935-60-4 ]

Reference： [1] Patent: WO2011/6074, 2011, A1,

15
[ 399-94-0 ]
[ 1223405-08-0 ]

Reference： [1] Patent: US2017/281632, 2017, A1,

16
[ 399-94-0 ]
[ 179737-33-8 ]

Reference： [1] European Journal of Organic Chemistry, 2011, # 2, p. 327 - 340

[ 399-94-0 ] Synthesis Path-Downstream 1~62

1
[ 540-36-3 ]
[ 399-94-0 ]
[ 327-51-5 ]

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 1593; engl. Ausg. S. 1566
[2]Green Chemistry,2012,vol. 14,p. 2380 - 2383

2
[ 399-94-0 ]
[ 124-38-9 ]
[ 2991-28-8 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 773 - 775

3
[ 540-36-3 ]
[ 399-94-0 ]
[ 327-51-5 ]
[ 128259-70-1 ]
[ 128259-69-8 ]

Reference： [1]Journal of Fluorine Chemistry,1990,vol. 46,p. 393 - 406

4
[ 399-94-0 ]
[ 167415-27-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sulfuric acid; nitric acid; In dichloromethane; at 20℃; for 3.5h;Cooling with ice;	Reference Example-50 Concentrated sulfuric acid (57 mL) was cooled in an ice bath, and 69% nitric acid (25.5 g, 279 mmol) was added dropwise over 25 minutes, whereby a mixed acid was prepared. To this mixed acid, a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (50 g, 254 mmol) in dichloroethane (125 mL) was slowly added dropwise over 1.5 hours under ice-cooling. After the reaction was completed, the reaction solution was further stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was added little by little to ice water (500 g), and the resultant product was extracted with ether (300 mL*2). The organic layer was washed sequentially with water (300 mL), a saturated sodium hydrogencarbonate aqueous solution (300 mL), and a saturated saline solution (300 mL), and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (hexane:chloroform=4:1), whereby 1-bromo-2,5-difluoro-4-nitrobenzene (56 g, yield: 93%) was obtained as a pale yellow solid. 1H-NMR (400 MHz, CDCl3): delta7.59 (dd, J=9.5 and 5.5 Hz, 1H), 7.89 (dd, J=7.3 and 6.5 Hz, 1H). 19F-NMR (376 MHz, CDCl3): delta-120.1 (d, J=15.2 Hz, 1F), -107.9 (d, J=15.2 Hz, 1F).
93%	With sulfuric acid; nitric acid; In 1,2-dichloro-ethane; for 3.92h;Cooling with ice;	Concentrated sulfuric acid (57 mL) was cooled inan ice bath, and 69% nitric acid (25.5 g, 279 mmol) was added dropwise over 25minutes to prepare a mixed acid. To this mixed acid, under ice-cooling, dichloroethane(125mL) solution of <strong>[399-94-0]2-bromo-1,4-difluoro-benzene</strong> (50g, 254mmol) was droppedslowly over a period of 1.5 hours. After completion of the dropwise addition,the reaction solution was further stirred for 2 hours at room temperature.After completion of the reaction, the reaction solution was added in portionsto ice-water (500 g), then extracted with ether (300mL × 2). The organic layerwas washed successively with water (300mL), saturated aqueous sodium hydrogencarbonate solution (300mL), saturated brine (300mL), and then dried overanhydrous magnesium sulfate, and the solvent was evaporated under reducedpressure. The resulting crude product was purified by silica gel chromatography(hexane: chloroform = 4/1) to give a pale yellow solid of 1-bromo-2,5-difluoro-4-nitrobenzene(56 g, yield: 93% ).
93%	With sulfuric acid; nitric acid; at 20℃; for 3.5h;Cooling with ice;	Concentrated sulfuric acid (57 mL) was cooled in an ice bath, 69% nitric acid (25.5 g, 279 mmol) was added dropwise over 25 minutes to prepare a mixed acid. In this mixed acid under ice-cooling <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (50g, 254mmol) was dropped slowly over a period of 1.5 hours of dichloroethane (125mL) solution . After completion of the dropwise addition, the reaction solution was further stirred for 2 hours at room temperature. After completion of the reaction, added little by little the reaction solution into ice water (500g), then ether (300mL ×And extracted with 2). The organic layer was washed with water (300mL), saturated aqueous sodium hydrogen carbonate solution (300mL), was washed successively with saturated brine (300mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography - (hexane: chloroform = 4/1) to give 1-bromo-2,5-difluoro-4-nitrobenzene as a pale yellow solid (56 g, yield: 93% ) was obtained.

90.8%	With sulfuric acid; potassium nitrate; at 5℃; for 1h;Large scale;	1208 g of 2,5-difluorobromobenzene was added to the reaction vessel. Add 5000 mL of concentrated sulfuric acid, The ice water bath control temperature is about 5 degrees, then add 462 g of potassium nitrate. After the addition, the reaction was incubated for 1 h and the GC was followed until the reaction was over. Ice water water analysis, suction filtration, filter cake drying, A yellow solid was obtained in an amount of 1463 g, a content of 98%, and a yield of 90.8%.
80%	With sulfuric acid; nitric acid; at 5 - 20℃; for 1.5h;	Nitric acid (d 1.42) (26.2 g, 286.81 mmol) was slowly added dropwise to conc. sulfuric acid (102 g, 1042.96 mmol) over 1 hr under ice water, while the mixture was maintained at 10C or below. Then, <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (50.32 g, 260.74 mmol) was slowly added thereto over 3 hr while the mixture was maintained at 10C or below. The reaction mixture was stirred at 5C for 30 min, and then at room temperature for 1 hr. The reaction mixture was poured into ice (about 600 g), and the mixture was extracted three times with a mixed solvent of Et2O/THF (3:1). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 20% ethyl acetate/hexane) to give 1-bromo-2,5-difluoro-4-nitrobenzene (49.64 g, 209 mmol, 80%) as a pale yellow solid.
78.1%	With sulfuric acid; potassium nitrate; at 0 - 20℃; for 16h;	INTERMEDIATE 6 1-((3S,5S)-1 -Oxaspiror2.5loctan-5-ylmethyl)-5-fluoro-1 H-benzo[d]imidazole-6- carbonitrile1-Bromo-2,5-difluoro-4-nitrobenzene To a stirred solution of 2-bromo-1 ,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H2S04 was added KN03 by portions at 0 C. After this addition, the mixture was allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to give 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 78.1 % yield) as a yellow solid. 1H NMR (400 MHz, CDCI3) delta 7.91-7.87 (dd, 1 H), 7.52-7.57 (dd, 1 H).
78.1%	With sulfuric acid; potassium nitrate; at 0 - 20℃;	1-Bromo-2,5-difluoro-4-nitrobenzeneTo a stirred solution of 2-bromo-1 ,4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H2S04 was added KN03 by portions at 0 C. After this addition, the mixture was allowed to warm to RT and stirred for additional 16 h. The mixture was poured onto ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to give 1-bromo-2,5-difluoro-4-nitro-benzene (95 g, 78.1 % yield) as a yellow solid. H NMR (400 MHz, CDCI3) delta 7.91-7.87 (dd, 1 H), 7.52-7.57 (dd, 1 H).
1.102 g (89%)	With KNO3; In conc. H2 SO4;	1-Bromo-2,5-difluoro-4-nitrobenzene: To a stirred solution of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (1.000 g, 5.181 mmol, Aldrich, used as received) in conc. H2 SO4 (8.0 mL) at 0 C., KNO3 (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to 28 C. and stirred at 28 C. overnight. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2 SO4, removed under vacuum, and the resulting white solid was dried further under vacuum to afford 1.102 g (89%) of the title compound as a white powder; m.p. 58-60 C.; 1 H NMR (CDCl3): delta7.591 (dd, 1H, J1 =9.6 Hz, J2 =5.4 Hz), 7.891 (t, 1H, J=6.9 Hz).
	With sulfuric acid; nitric acid; at 0 - 20℃;	Step A 1-brom-2, 5-difluoro-4-nitrobenzene; To a solution of 2-brom-1, 4-difluorobenzene (10 g, 51.8 mmol) in 40 ml of sulfuric acid at 0C is added dropwise 35 ml of nitric acid while maintaining an internal temperature below 20C. The mixture is then poured into ice and extracted with ether (3x100 ml). The organic phase is washed with NaHCO3 (3 times), dried over MgS04 and evaporated. The crude is purificated by silica gel chromatogaphy (hexane/acetone 10: 1) to afford 11.25 g of the title compound.

Reference： [1]Patent: US2016/24110,2016,A1 .Location in patent: Paragraph 0809; 0810
[2]Patent: JP2016/56157,2016,A .Location in patent: Paragraph 0164; 0168
[3]Patent: JP2016/60742,2016,A .Location in patent: Paragraph 0251
[4]Patent: CN109369412,2019,A .Location in patent: Paragraph 0009; 0010; 0013; 0014
[5]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379
[6]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[7]Patent: TW2016/2105,2016,A .Location in patent: Paragraph 0979
[8]Patent: WO2012/174342,2012,A1 .Location in patent: Page/Page column 44
[9]Patent: WO2013/12500,2013,A1 .Location in patent: Page/Page column 60
[10]Patent: US5631373,1997,A
[11]Patent: WO2005/54176,2005,A1 .Location in patent: Page/Page column 88

5
[ 399-94-0 ]
[ 21740-23-8 ]
[ 307306-06-5 ]
[ 307306-05-4 ]

Reference： [1]Canadian Journal of Chemistry,2000,vol. 78,p. 1081 - 1088

6
[ 540-36-3 ]
[ 399-94-0 ]

Yield	Reaction Conditions	Operation in experiment
92.7%	With N-Bromosuccinimide; sulfuric acid; at 30 - 40℃; for 1h;Large scale;	Add 1000 g of p-difluorobenzene to the reaction vessel, 5000 mL of sulfuric acid, controlled to 30 C in a water bath. 1620 g of N-bromosuccinimide was slowly added with stirring. Do not exceed 40 C during the addition. After the addition, the reaction was incubated for 1 h and the GC was followed until the reaction was over. After the reaction, the reaction product was poured into ice water to precipitate a solid, which was suction filtered. 1568 g of 2,5-difluorobromobenzene was obtained as a pale yellow powdery solid, the content was 98%, and the yield was 92.7%.

Reference： [1]Journal of the American Chemical Society,2004,vol. 126,p. 15770 - 15776
[2]Patent: CN109369412,2019,A .Location in patent: Paragraph 0009; 0013

7
[ 399-94-0 ]
[ 201230-82-2 ]
[ 6638-79-5 ]
[ 198967-26-9 ]

Reference： [1]Organic Letters,2006,vol. 8,p. 4843 - 4846
[2]Journal of Organic Chemistry,2008,vol. 73,p. 7102 - 7107

8
[ 399-94-0 ]
[ 4883-70-9 ]
3-[4-(2,5-difluorophenyl)-4-hydroxycyclohexyl]propanoic acid [ No CAS ]
3-[4-(2,5-difluorophenyl)-4-hydroxycyclohexyl]propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-bromo-1,4-difluorobenzene With isopropylmagnesium chloride In tetrahydrofuran at -30 - -10℃; for 1.58333h; Stage #2: 3-(4-oxocyclohexyl)propanoic acid With isopropylmagnesium chloride In tetrahydrofuran for 1h; cooling; Further stages.;

Reference： [1]Davies, Antony J.; Scott, Jeremy P.; Bishop, Brian C.; Brands, Karel M. J.; Brewer, Sarah E.; DaSilva, Jimmy O.; Dormer, Peter G.; Dolling, Ulf-H.; Gibb, Andrew D.; Hammond, Deborah C.; Lieberman, David R.; Palucki, Michael; Payack, Joseph F. [Journal of Organic Chemistry, 2007, vol. 72, # 13, p. 4864 - 4871]

9
[ 872-85-5 ]
[ 399-94-0 ]
[ 558466-01-6 ]

Yield	Reaction Conditions	Operation in experiment
65%		Referential Example 36: 2,5-Difluorophenyl-4-pyridylmethanol A tetrahydrofuran (30 ml) solution of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (1.08 ml, 9.60 mmol) was stirred at -78C, followed by the addition of a hexane solution (7.32 ml, 11.5 mmol) of n-butyl lithium.. To the resulting mixture was added a tetrahydrofuran (10 ml) solution of 4-pyridinecarboxyaldehyde (0.764 ml, 8.00 mmol) at -78C and the mixture was stirred at the same temperature for 30 minutes.. After the temperature of the reaction mixture was raised to room temperature, diethyl ether was added thereto.. The mixture was washed with a saturated aqueous solution of sodium bicarbonate.. The organic layer was then dried over anhydrous sodium sulfate.. After filtration, the filtrate was concentrated under reduced pressure.. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=7:3 elude was concentrated under reduced pressure.. The resulting solid was washed with diisopropyl ether and then collected by filtration, whereby the title compound (1.15 g, 5.20 mmol, 65%) was obtained as a white powder.1H-NMR (400MHz, CDCl3) delta: 4.25(1H,br s), 6.09(1H,s), 6.89-7.05(2H,m), 7.14-7.23(1H,m), 7.34(2H,d,J=5.4Hz), 8.44(2H,d,J=5.4Hz).
65%	With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃; for 0.5h;	A tetrahydrofuran (30 ml) solution of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (1.08 ml, 9.60 mmol) was stirred at -78C, followed by the addition of a hexane solution (7.32 ml, 11.5 mmol) of n-butyl lithium. To the reaction mixture was added a tetrahydrofuran (10 ml) solution of 4-pyridinecarboxyaldehyde(0.764 ml, 8.00 mmol) at -78C. The resulting mixture was stirred at the same temperature for 30 minutes. After the temperature of the reaction mixture was raised to room temperature, diethyl ether was added thereto. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=7:3 eluate was concentrated under reduced pressure. The solid thus obtained was washed with diisopropyl ether and then collected by filtration to give the title compound (1.15 g, 5.20 mmol, 65%) as a white powder. 1H-NMR (400MHz, CDCl3) delta: 4.25 (1H,brs), 6.09 (1H,s), 6.89-7.05(2H,m), 7.14-7.23 (1H,m), 7.34 (2H,d, J=5.4Hz), 8.44(2H,d,J=5.4Hz).

Reference： [1]Patent: EP1466898,2004,A1 .Location in patent: Page 138; 139
[2]Patent: EP1640366,2006,A1 .Location in patent: Page/Page column 23

10
[ 399-94-0 ]
[ 118794-70-0 ]
[ 558466-13-0 ]

Yield	Reaction Conditions	Operation in experiment
88%		Referential Example 34: 6-(t-Butyl-diphenylsilyloxy)-1-(2,5-difluorophenyl)-1-hexanol A tetrahydrofuran (30 ml) solution of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (0.956 ml, 8.46 mmol) was stirred at -78C. To the reaction mixture was added a hexane solution (6.46 ml, 10.2 mmol) of n-butyl lithium.. The reaction mixture was added to a tetrahydrofuran (20 ml) solution of 6-(t-butyldiphenylsilyloxy)hexanal (2.50 g, 7.05 mmol) at -78C and the mixture was stirred at the same temperature for 30 minutes.. After the temperature of the reaction mixture was elevated to room temperature, diethyl ether was added thereto.. The mixture was washed with a saturated aqueous solution of ammonium chloride and the organic layer was dried over anhydrous sodium sulfate.. After filtration, the filtrate was concentrated under reduced pressure.. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=9:1 elude was concentrated under reduced pressure, whereby the title compound (2.92 g, 4.65 mmol, 88%) was obtained as a colorless oil.1H-NMR (400MHz, CDCl3) delta: 1.04(9H,m), 1.21-1.90(8H,m), 3.64(2H,t,J=6.3Hz), 4.96(1H,t,J=6.5Hz), 6.86-7.01(2H,m), 7.13-7.20(1H,m), 7.32-7.45(6H,m), 7.62-7.70(4H,m).

Reference： [1]Patent: EP1466898,2004,A1 .Location in patent: Page 135

11
[ 558466-08-3 ]
[ 399-94-0 ]
[ 558466-09-4 ]

Yield	Reaction Conditions	Operation in experiment
37%	With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 0.5h;	Referential Example 30: 1-(2,5-Difluorophenyl)-5-(methylsulfonyl)-1-pentanol A tetrahydrofuran (5 ml) solution of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (0.151 ml, 1.34 mmol) was stirred at -78C. To the resulting mixture was added a hexane solution (0.843 ml, 1.34 mmol) of n-butyl lithium.. The reaction mixture was added to a tetrahydrofuran (5 ml) solution of 5-(methylsulfonyl)pentanal (183 mg, 1.11 mmol) at -78C and at the same temperature, stirring was conducted for 30 minutes.. After elevating the temperature of the reaction mixture to room temperature, diethyl ether was added thereto.. The resulting mixture was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium bicarbonate.. The organic layer was then dried over anhydrous sodium sulfate.. After filtration, the filtrate was concentrated under reduced pressure.. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=1:2 elude was concentrated under reduced pressure, whereby the title compound (116 mg, 0.42 mmol, 37%) was obtained as a colorless oil.1H-NMR (400MHz, CDCl3) delta: 1.49-1.69(2H,m), 1.71-1.97(4H,m), 2.89(3H,s), 3.01(2H,t,J=8.1Hz), 5.02(1H,t,J=6.2Hz), 6.88-7.01(2H,m), 7.16-7.22(1H,m). MS m/z: 296 (M++NH4).

Reference： [1]Patent: EP1466898,2004,A1 .Location in patent: Page 119

12
[ 399-94-0 ]
[ 147974-19-4 ]
[ 558466-14-1 ]

Yield	Reaction Conditions	Operation in experiment
90%		Referential Example 35: 7-(t-Butyldiphenylsilyloxy)-1-(2,5-difluorophenyl)-1-heptanol A tetrahydrofuran (40 ml) solution of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (1.21 ml, 10.7 mmol) was stirred at -78C, followed by the addition of a hexane solution (8.50 ml, 13.4 mmol) of n-butyl lithium.. The reaction mixture was added to a tetrahydrofuran (20 ml) solution of 7-(t-butyldiphenylsilyloxy)heptanal (3.28 g, 8.90 mmol) at -78C and the mixture was stirred at the same temperature for 30 minutes.. After the temperature of the reaction mixture was elevated to room temperature, diethyl ether was added thereto.. The mixture was washed with a saturated aqueous solution of ammonium chloride.. The organic layer was then dried over anhydrous sodium sulfate.. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=9:1 elude was concentrated under reduced pressure, whereby the title compound (3.88 g, 8.04 mmol, 90%) was obtained as a colorless oil.1H-NMR (400MHz, CDCl3) delta: 1.04(9H,m), 1.21-1.92(10H,m), 3.64(2H,t,J=6.5Hz), 4.97(1H,t,J=6.5Hz), 6.86-7.00(2H,m), 7.13-7.20(1H,m), 7.33-7.44(6H,m), 7.62-7.70(4H,m).

Reference： [1]Patent: EP1466898,2004,A1 .Location in patent: Page 137

13
[ 399-94-0 ]
[ 135270-08-5 ]
[ 241479-69-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		8(i) (2R)-2',5'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone 6.50 g (yield 98%) of the title compound were obtained as an oil according to the reaction and treatment described in Example 7(i) above using 7.04 g (36.5 mmol) of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> and 6.0 g (25 mmol) of 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine [prepared as described in Chem. Pharm. Bull., 41, 1035-1042 (1993)]. 1H-Nuclear magnetic resonance spectrum (400 MHz, CDCl3) delta ppm: 1.43 [(3/2)H, doublet of doublets, J=6, 1 Hz]; 1.48 [(3/2)H, doublet of doublets, J=7, 1 Hz]; 1.50-1.89 (6H, multiplet); 3.36 [(1/2)H, doublet of triplets, J=12, 4 Hz]; 3.53 [(1/2)H, doublet of triplets, J=12, 4 Hz]; 3.73 [(1/2)H, doublet of triplets, J=12, 4 Hz]; 3.90 [(1/2)H, doublet of triplets, J=11, 4 Hz]; 4.66 [(1/2)H, triplet, J=4 Hz]; 4.75 [(1/2)H, triplet, J=4 Hz]; 4.87 [(1/2)H, quartet of doublets, J=7, 1 Hz]; 5.12 [(1/2)H, quartet of doublets. J=7, 2 Hz); 7.08-7.15 (1H, multiplet); 7.17-7.25 (1H, multiplet); 7.50-7.54 (1H, multiplet). IR spectrum numax (CHCl3) cm-11: 1698, 1491, 1417, 1257. Mass spectrum m/z (FAB); 271 (M++1).
81%	With iodine; magnesium; In tetrahydrofuran;	a) Preparation of (2R)-2',5'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (20.0 g, 0.178 mol) in THF (250ml) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65 C. To this mixture was added additional <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55 C. over 45min. The resulting mixture was stirred at 55 C. for 30min. then at r.t. for 1 hr. The mixture was cooled down to -5 C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol) in THF (150ml) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5 C. and saturated NH4Cl aq. (100ml) was added carefully. The whole was diluted with H2O (600ml) and extracted with EtOAc (400 ml+200 ml2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1~5:1) to give (2R)-2',5'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81%) as pale yellow syrup. Physical form: colorless oil; FAB-MS: m/z 271(M+H)+; 1H-NMR(CDCl3): 1.42~1.90(9H,m),3.32~3.40(1H1/2,m),3.69~3.77(1H1/2,m), 3.86~3.94 (1H1/2,m),4.66(1H1/2,t,J=3.6Hz),4.75(1H'1/2, t,J=3.6Hz), 4.87(1H1/2,q,J=6.6Hz), 5.11(1H*1/2,q,J=6.9Hz),7.08~7.25(2H,m),7.49~7.55(1H,m).
81%	With iodine; magnesium; In tetrahydrofuran;	a) Preparation of (2R)-2',5'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (20.0 g, 0.178 mol) in THF (250 ml) was vigorously stirred. The color of iodine was disappeared and the inner temperature rose up to 65 C. To this mixture was added additional <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55 C. over 45 min. The resulting mixture was stirred at 55 C. for 30 min. then at r.t. for 1 hr. The mixture was cooled down to -5 C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol) in THF (150 ml) dropwise over 40 min. And the resulting mixture was stirred at r.t. for 4 hrs. The reaction mixture was cooled down to 5 C. and saturated NH4Cl aq. (100 ml) was added carefully. The whole was diluted with H2O (600 ml) and extracted with EtOAc (400 ml+200 ml2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane:EtOAc=10:1~5:1) to give (2R)-2',5'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81%) as pale yellow syrup. Physical form: colorless oil; FAB-MS: m/z 271(M+H)+; 1H-NMR(CDCl3) delta1.42~1.90(9H,m),3.32~3.40(1H1/2,m),3.69~3.77(1H1/2,m),3.86~3.94(1H1/2,m), 4.66(1H1/2,t,J=3.6 Hz),4.75(1H1/2,t,J=3.6 Hz),4.87(1H1/2,q,J=6.6 Hz), 5.11(1H1/2,q,J=6.9 Hz),7.08~7.25(2H,m),7.49~7.55(1 H,m).

Reference： [1]Patent: US6337403,2002,B1
[2]Journal of Fluorine Chemistry,2006,vol. 127,p. 643 - 650
[3]Patent: US6300353,2001,B1
[4]Patent: US6300353,2001,B1

14
[ 399-94-0 ]
[ 68-12-2 ]
[ 934987-26-5 ]

Yield	Reaction Conditions	Operation in experiment
79.4%		To a 500 mL dry three-necked flask was added <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (C7-1a) (22 g, 114 mmol) and dry THF (200 mL) and cooled to -70 C. Lithium diisopropylamide (2M, 68.4 mL) was slowly added dropwise to the reaction mixture. After the reaction mixture was stirred at the same temperature for 45 minutes, DMF (17.8 mL, 228 mmol) was added. The reaction solution was stirred at the same temperature for two hours and then raised to 0 C. Saturated ammonium chloride (200 mL) was added to the reaction mixture. The reaction was extracted with EtOAc (200 mL EtOAc). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate. The residue was purified on silica gel (petroleum ether: ethyl acetate = 100: 1), to give 2-bromo-3,6-difluorobenzaldehyde (C7-1b) (20g, 79.4% yield) as a pale yellow solid.
79.4%		A 500 mL dry three-necked flask was charged with <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> C5-1a (22 g, 114 mmol) and dry THF (200 mL), and cooled to -70 C. Lithium diisopropylamide (2M, 68.4 mL) was slowly added dropwise to the reaction solution.After the reaction solution was stirred at the same temperature for 45 minutes,DMF (17.8 mL, 228 mmol) was added. The reaction solution was stirred at the same temperature for two hours and then raised to 0 C. Saturated ammonium chloride (200 mL) was added to the reaction solution.The reaction was extracted with EtOAc (200 mL X 2).The combined organic phases were washed once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether: ethyl acetate = 100: 1) to give 2-bromo-3,6-difluorobenzaldehyde C5-1b(20 g, 79.4% yield) as a pale yellow solid.
60%		2-Bromo-3,6-difluorobenzaldehyde (C2.1) (0506) To a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (16 g, 83 mol) in 200 mL THF under N2 atmosphere at -78 C. was added LDA (54 mL, 108 mmol) dropwise. After stirring at -78 C. for 45 min, DMF (18.2 g, 249 mmol) was added. The mixture was stirred for another 2 h at -78 C. The reaction mixture was warmed up to 0 C., added 200 mL and sat. NH4Cl was added. The resulting mixture was extracted with EtOAc (200 mL×2). The combined organic layer was washed with brine (400 mL×1), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give crude product. The crude product was purified by column chromatography (silica, EtOAc/PE=1/30) to give the title compound (11 g, 60%) as a yellow solid. 1H NMR (500 MHz, CDCl3) delta ppm 7.57-7.34 (m, 2H), 10.20 (dd, 1H).

60%		To a solution of 2-bromo-1 ,4-difluorobenzene (100 g, 518 mmol) in anhydrous tetrahydrofuran (500 ml_) was added a solution of lithium diisopropylamide (61.1 g, 570 mmol) in anhydrous tetrahydrofuran (100 ml_) over 30 minutes at -78 C. The reaction mixture was then stirred at -78 C for 1 h, and A/,//-dimethylformamide (45.5 g, 622 mmol) was added to it. The reaction mixture was stirred at -78 C for 30 minutes, and then quenched by addition of saturated aqueous ammonium chloride (200 ml_). The mixture was allowed to warm to ambient temperature and extracted with ethyl acetate (500 ml_). The combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography, eluting with 5% of ethyl acetate in petroleum ether, provided the title compound as a colorless oil (69.0 g, 60% yield): 1H NMR (400MHz, CDCI3) d 10.35- 10.20 (m, 1 H), 7.27 (ddd, J = 9.2, 7.4, 4.4 Hz, 1 H), 7.08 (dt, J = 9.2, 4.0, Hz, 1 H).
58.2%		To a solution of A-2-1 (30.0 g, 155 mmol, 1 eq. ) in THF (300 mL) was added LDA (2 M, 116 mL, 1.5 eq.) at -78 C and stirred for 1 hour, then DMF (34.1 g, 466 mmol, 3 eq.) was added at -78C and stirred for 2 hours. The reaction mixture was quenched by addition saturated ammonium chloride (200 mL) at 0C, then diluted with water (300 mL) and extracted with ethyl acetate (1.00 L). The organic layer was washed by brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give A-2-2 (20.0 g, 90.5 mmol, yield = 58.2%) as yellow solid. 1H NMR (400 MHz, CDC13) delta = 10.34 (s, 1H), 7.37-7.34 (m, 1H), 7.17-7.34 (m, 1H)
2.72 g		Example 106A 2-Bromo-3,6-difluorobenzaldehyde 2-Bromo-1,4-difluorobenzene (5.00 g, 25.9 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to -78 C. Lithium diisopropyl amide (1.8 M in tetrahydrofuran, 15.8 mL, 28.5 mmol) was added. After stirring at -78 C. for 30 min, N,N-dimethylformamide (2.28 g, 31.1 mmol) was added. After stirring at -78 C. for an additional 15 min, acetic acid (6 mL) and water (100 mL) was added and the mixture was warmed to RT. After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate. Concentration in vacuo afforded the title compound (2.72 g, 42% of theory) in a purity of 90%. GC-MS (Method 2G): Rt=3.40 min, MS (ESIPos): m/z=221 [M+H]+
		2-Bromo-l,4-difluorobenzene (5.00 g, 25.9 mmol) was dissolved in tetrahydroiuran (100 mL) and cooled to -78 C. Lithium diisopropyl amide (1.8 M in tetrahydroiuran, 15.8 mL, 28.5 mmol) was added. After stirring at -78 C for 30 min, N,N-dimethylformamide (2.28 g, 31.1 mmol) was added. After stirring at -78 C for an additional 15 min, acetic acid (6 mL) and water (100 mL) was added and the mixture was warmed to RT. After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate. Concentration in vacuo afforded the title compound (2.72 g, 42% of theory) in a purity of 90%. GC-MS (Method 2G): Rt = 3.40 min, MS (ESIPos): m/z = 221 [M+H]+
		To a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (1 g, 5.18 mmol) in THF (25 mL) was added LDA solution (2 M in THF, 2.9 mL, 5.8 mmol) dropwise at -78 C. After stirring for 1 h at -78 C., DMF (0.441 mL, 6.03 mmol) was added dropwise and the resulting reaction mixture was stirred at -78 C. for additional 30 min. The reaction was quenched by sat. NH4Cl solution (40 mL) carefully and the mixture was extracted with EtOAc (80 mL*2). The combined organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 2-bromo-3,6-difluorobenzaldehyde as light brown solid (1.05 g, 92%, crude yield) which was used in next step without further purification.
		Description 14:; 2-Bromo-3,6-difluorobenzaldehyde (D14)To solution of diisopropylamine (13.29 mL, 93 mmol) in THF (300 mL) at -78 0C, was added n-butyllithium (34.2 mL of 2.5M in hexanes, 85 mmol), dropwise over 10 mins. The mixture was stirred at -78 0C for 15 mins and then 2-bromo-1 ,4-difluorobenzene (15 g, 78 mmol) in THF (100 mL) was added dropwise over 15 mins maintaining the temperature below -65 C. After stirring for 1 hr at -78 0C, N,N-dimethylformamide (6.62 mL, 85 mmol) was added via syringe. The mixture was stirred at -78 0C for 30 mins and then quenched with sat. NH4CI solution and the mixture was allowed to reach room temperature. The product was extracted into ether and the extracts were dried (Na2SO4) and evaporated. <n="24"/>Chromatography (silica, 0-100% dichloromethane in hexane) gave the title compound(D14) as a yellow solid (12.73 g)NMR (deltaH), (CDCI3): 7.16 (1 H, m), 7.35 (1 H, m), 10.32 (1 H, s).

Reference： [1]Patent: CN109942556,2019,A .Location in patent: Paragraph 0381-0385
[2]Patent: CN110563722,2019,A .Location in patent: Paragraph 0343-0347
[3]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0505; 0506
[4]Patent: WO2019/241533,2019,A1 .Location in patent: Page/Page column 68-69
[5]Patent: WO2019/23417,2019,A1 .Location in patent: Paragraph 0245; 0246
[6]Patent: US2015/126449,2015,A1 .Location in patent: Paragraph 0663 - 0665
[7]Patent: WO2015/67549,2015,A1 .Location in patent: Page/Page column 120
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[9]Patent: WO2008/107455,2008,A1 .Location in patent: Page/Page column 22-23

15
[ 399-94-0 ]
[ 1172623-95-8 ]
[ 1172623-96-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With isopropylmagnesium chloride; In tetrahydrofuran; toluene; at -20 - 25℃; for 2h;	Tert-butyl {1-[methoxy(methyl)amino]-1-oxopent-4-yn-2-yl}carbamate (5g; Formula V; Example 3, 4, or 5) in toluene (40 mL) was added to a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (4.9 mL) and isopropyl magnesium chloride (21 mL; 2 M in THF) intoluene (15 mL) at -20C to -10C. The reaction mixture was allowed to warm to 25C,and then the mixture was stirred for 2 hours. After the completion of the reaction, thereaction mixture was quenched with aqueous ammonium chloride (20%; 40 mL) to adjustthe pH to 4 to 5. The reaction mixture was stirred for 10 minutes at 20C to 25C, andthen allowed to settle. The layers were separated. The organic layer was washed with anaqueous sodium bicarbonate solution (5%; 25 mL) and then with a saturated sodium chloride solution (25 mL) at 20C to 25C. The organic layer was concentrated underreduced pressure at 50C to 55C to obtain a residue. IPA (15 mL) was added to the residue, and then the mixture was stirred at 55C to 60C for 30 minutes. Water (22.5 mL) was added to the reaction mixture at 50C to 60C. The reaction mixture was cooled to 20C to 25C, and then stirred for 15 minutes. The reaction mixture was filtered, and then dried under reduced pressure at 45C to 50C to obtain the title compound.Yield: 96%
83.5%		Under N2 protection, 2,5-difluorobromobenzene (15.05 g, 78 mmol) was dissolved in dry toluene (50 ml), cooledto -10C or lower in an ice salt bath, and a solution of isopropyl magnesium chloride/lithium chloride in tetrahydrofuran(66 ml, 1.3 mol/l) was added dropwise, followed by stirring at about -10C for 1 hour. 1D (10 g, 39 mmol) was dissolvedin dry tetrahydrofuran (100 ml), and added dropwise to the reaction solution while the temperature was maintained at-10C. When the addition was complete, the reaction was allowed to proceed at room temperature for 4 hours. Thetemperature was lowered to about -10C, and a saturated ammonium chloride solution (40 ml) was added dropwise,followed by stirring for 10 min. The pH was adjusted to 5 to 6 with a 3 mol/l hydrochloric acid solution, to allow settlingand partitioning. The aqueous phase was extracted with methyl t-butyl ether (50 ml32). The organic phases werecombined, washed with a saturated sodium chloride solution (30 ml32), dried by addition of anhydrous sodium sulfatethereto, filtered, concentrated, and separated by column chromatography (petroleum ether/ethyl acetate (v/v) = 50:1 to8:1), to obtain a light yellow solid 1E (10.1 g, yield 83.5%).MS m/z (ESI): 210.1 [M-99].
83.5%		Under nitrogen, 2,5-difluorobromobenzene (15.05 g, 78 mmol) was dissolved in dry toluene (50 mL), the ice salt bath was cooled below -10 C,A solution of isopropylmagnesium chloride / lithium chloride tetrahydrofuran (66 mL, 1.3 mol / L) was added dropwise and the mixture was stirred at about -10 C for 1 hour.A solution of 1D (10 g, 39 mmol) in dry tetrahydrofuran (100 mL) was added dropwise to the reaction solution, maintaining the temperature at -10 C, and the reaction was carried out at room temperature for 4 hours.The temperature was lowered to about -10 C, saturated ammonium chloride solution (40 mL) was added dropwise, stirred for 10 minutes, adjusted to pH 5 to 6 with 3 mol / L hydrochloric acid solution,The aqueous phase was extracted with methyl tertiary butyl ether (50 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered,Column chromatography (petroleum ether / ethyl acetate (v / v) = 50: 1-8: 1) gave a pale yellow solid 1E (10.1 g, yield 83.5%).

83.5%		Under nitrogen, 2,5-difluorobromobenzene (15.05 g, 78 mmol) was dissolved in dry toluene (50 mL)(66 mL, 1.3 mol / L), and the mixture was stirred at about -10 C for 1 hour, and the mixture was cooled to -10 C or lower and the isopropylmagnesium chloride / lithium chloride tetrahydrofuran solution (66 mL, 1.3 mol / L) was added dropwise.1D (10 g, 39 mmol) was dissolved in dry tetrahydrofuran (100 mL) and added dropwise to the above reaction solution. The temperature was maintained below -10 C and the reaction was carried out at room temperature for 4 hours. The temperature was reduced to below -10 C, saturated ammonium chloride solution (40 mL) was added dropwise, stirred for 10 minutes, adjusted to pH 5 to 6 with 3 mol / L hydrochloric acid solution, The organic phase was washed with saturated sodium chloride solution (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the column was separated by column chromatography. (Petroleum ether / ethyl acetate (nu / nu) = 50: 1 -8: 1) to give 1E as a pale yellow solid (10.1 g, yield 83.5%).
83.5%		Under nitrogen, 2,5-difluorobromobenzene (15.05 g, 78 mmol) was dissolved in dry toluene (50 mL)(66 mL, 1.3 mol / L) in an isopropylmagnesium chloride / lithium chloride solution was added dropwise to the temperature below -10 C, and the mixture was stirred at about -10 C for 1 hour. A solution of 1D (10 g, 39 mmol) in dry tetrahydrofuran (100 mL) was added dropwise to the reaction solution, maintaining the temperature at -10 C, and the reaction was carried out at room temperature for 4 hours. The temperature was reduced to about -10 C, and the saturated ammonium chloride solution (40 mL) was added dropwise. The mixture was stirred for 10 minutes. The pH was adjusted to 5 to 6 with 3 mol / L hydrochloric acid solution, (50 mL x 2). The organic phases were combined and washed with saturated sodium chloride solution (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (petroleum ether / Ethyl acetate (v / v) = 50: 1-8: 1),To give light yellow solid 1E (10.1 g, yield 83.5%).
83.5%		Under the protection of nitrogen, 2,5-difluorobromobenzene (15.05g, 78mmol) is dissolved in dry toluene (50 ml), lowering the temperature to ice salt bath -10 C following, dropwise adding isopropyl magnesium chloride/tetrahydrofuran solution of lithium chloride (66 ml, 1.3 mol/L), maintained at about -10 C stirring 1 hour. the1D (10g, 39mmol) dissolved in dry tetrahydrofuran (100 ml) in, is dropped is added to the reaction solution, maintaining the temperature -10 C, canada finishes, to react at room temperature for 4 hours. The temperature dropped to about -10 C, dropwise adding saturated ammonium chloride solution (40 ml), stirring 10 minutes, for 3 mol/L hydrochloric acid solution to adjust pH value to 5 - 6, layered, 3rd phase for methyl tert-butyl ether (50mL × 2) extraction, the combined organic phase, saturated sodium chloride solution (30mL × 2) washing, drying of the organic phase by adding anhydrous sodium sulfate, filtered, concentrated, column chromatography (petroleum ether/ethyl acetate=50:1 - 8:1 (v/v)), get the yellow solid1E(10.1g, 83.5% yield).
83.5%		Under nitrogen, 2,5-difluorobromobenzene (15.05 g, 78 mmol) was dissolved in dry toluene (50 mL), the ice salt bath was cooled below -10 C,A solution of isopropylmagnesium chloride / lithium chloride tetrahydrofuran (66 mL, 1.3 mol / L) was added dropwise, and the mixture was stirred at about -10 C for 1 hour,A solution of 1D (10 g, 39 mmol) in dry tetrahydrofuran (100 mL) was added dropwise and maintained at a temperature of -10 C. After completion of the reaction, the reaction was carried out at room temperature for 4 hours,The temperature was reduced to about -10 C, and the saturated ammonium chloride solution (40 mL) was added dropwise. The mixture was stirred for 10 minutes. The pH was adjusted to 5 to 6 with 3 mol / L hydrochloric acid solution, The organic phase was washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum Ether / ethyl acetate (v / v) = 50: 1 to 8: 1) to give 1E as a light yellow solid (10.1 g, yield 83.5%).
83.5%		Under nitrogen protection,A mixture of 2,5-difluorobromobenzene (15.05 g, 78 mmol)Was dissolved in dry toluene (50 mL)Ice bath cooling down to -10 below,A solution of isopropylmagnesium chloride / lithium chloride tetrahydrofuran (66 mL, 1.3 mol / L) was added dropwise,The mixture was stirred at about -10 C for 1 hour,A solution of 1D (10 g, 39 mmol) in dry tetrahydrofuran (100 mL) was added dropwise,Keep the temperature -10 ,Plus,The reaction was carried out at room temperature for 4 hours,The temperature dropped to about -10 ,A saturated solution of ammonium chloride (40 mL) was added dropwise,Stir for 10 minutes,With 3mol / L hydrochloric acid solution to adjust the pH 5 to 6,Static liquid separation,The aqueous phase was extracted with methyl tert-butyl ether (50 mL x 2)Combined organic phase,The organic phase was washed with saturated sodium chloride solution (30 mL x 2)Dried over anhydrous sodium sulfate,filter,concentrate,The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50: 1 to 8: 1)To give light yellow solid 1E (10.1 g, yield 83.5%).
83.5%		2,5-difluorobromobenzene (15.05g, 78mmol) was dissolved in dry toluene (50mL) under nitrogen, and the ice salt bath was cooled to below -10 C. Isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution was added dropwise. (66 mL, 1.3 mol/L), kept stirring at about -10 C for 1 hour.1D (10 g, 39 mmol) was dissolved in dry tetrahydrofuran (100 mL).Add dropwise to the above reaction solution, keep the temperature below -10 C, add,The reaction was carried out for 4 hours at room temperature. Lower the temperature below -10 C,Saturated ammonium chloride solution (40 mL) was added dropwise and stirred for 10 minutes.Adjust the pH to 5-6 with a 3 mol/L hydrochloric acid solution, and let stand for stratification.The aqueous phase was extracted with methyl tert-butyl ether (50 mL×2) and the organic phases were combined.Wash with a saturated sodium chloride solution (30 mL × 2), and dry over anhydrous sodium sulfate.Filtration, concentration, column chromatography (petroleum ether / ethyl acetate (v / v) = 50:1-8:1),A pale yellow solid 1E (10.1 g, yield 83.5%) was obtained.
65%		2,5-difluorobromobenzene (11.58 g, 60 mmol) was dissolved in 25 mL toluene and cooled to -10 C to 5 C. Thereto was added lithium bromide (2.61 g, 30 mmol), and a solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 33 ml, 66 mmol) was added dropwise over 1.5 hours, and stirred at low temperature for 1 hour. A solution of 2-(tert-butoxycarbonylamino)pent-4-ynylacyl-(N-methoxy-N-methyl)amine (7.68 g, 30 mmol) in 35 mL tetrahydrofuran was added dropwise to the reaction system over 1 hour, then slowly warmed to room temperature and stirred at room temperature for 1 hour. To a reaction solution was added 22 mL of 3N hydrochloric acid to quench the reaction. The organic phase was washed sequentially with water, saturated sodium bicarbonate solution and saturated brine, dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1) to give the product tert-butyl 1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-ylcarbamate (6.07 g). Yield: 65%. 1H-NMR (400 MHz, CDCl3): delta=7.56(1H, m), 7.26(1H, m), 7.15(1H, m), 5.68 (1H, d, J=7.6Hz), 5.24(1H, m), 2.91 (1H, m), 2.68 (1H, m), 1.99(1H, s), 1.45 (9H, s).
		Method A:To a nitrogen degassed, light brown solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (48.3 mL, 0.429 mol) in CH2Cl2 (500 mL) was added i-PrMgCl (2.0 M in THF, 205 mL, 0.41 mol) slowly while the internal temperature was maintained below -15 C. The resulting reaction mixture was aged for additional 30 min. In a separate 500-mL round bottom flask, the Weinreb amide 4 (50 g, 0.195 mol) was dissolved in CH2Cl2 (300 mL) and cooled to -15 C. The Weinreb amide solution was transferred to the above aryl Grignard solution via cannula over 1 h such that temperature was less than -15 C. The reaction mixture was allowed to warm to room temperature upon completion of addition and aged overnight. The reaction mixture was quenched into a 3-L round bottom flask containing 1.2 L of half-saturated aqueous NH4Cl via cannula. The pH of the solution was then adjusted to 7 with concentrated HCl. Upon separation of the layers, the organic layer was dried over MgSO4 in preparation for isolation.
		Method B:To a solution of <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (42.2 g, 0.218 mol) in toluene (85 mL) at -10 to -5 C. was added iPrMgCl/LiCl solution (1.0 M in THF, 240 mL, 0.24 mol) dropwise over 1.5 h. The reaction solution was then aged for 30 min at -10 to -5 C.In a separate vessel, Weinreb amide 4 (28 g, 0.109 mol) was dissolved in THF (112 mL), cooled to 15 C. and then charged to the above Grignard solution over about 30 min, while the internal temperature was maintained at -10 to -5 C. The reaction mixture was then warmed to 20 C. over 1 h, and aged for additional 1 h at 20 C. for complete reaction. The reaction mixture was quenched with an aqueous HCl solution (32.5 g of concentrated hydrochloric acid in 110 mL of water) at 0 to 10 C. over 30 min. The organic phase was washed with 10% NaCl solution (200 mL×2). The organic phase was solvent switched to iPrOH (final volume about 270 mL) and water (380 mL) was added over 1 h at 20 C. Solids were filtered and washed with 40% iPrOH in water (60 mL×2). The wet cake was dried under vacuum at 45 C.1H-NMR (500 MHz, CDCl3): delta 7.56 (m, 1H), 7.25 (m, 1H); 7.15 (m, 1H), 5.67 (d, J=7.3 Hz, 1H), 5.24 (m, 1H), 2.91 (m, 1H), 2.68 (m, 1H), 2.00 (t, J=2.43, 1H), 1.45 (s, 9H). 13C-NMR (125 MHz, CDCl3): delta 159.03 (dd, J=245.5, 1.8 Hz), 157.4 (d, J=248.0 Hz), 124.6 (dd, J=15.4, 6.2 Hz), 122.2 (dd, J=24.6, 9.8 Hz), 118.4 (dd, J=27.1, 8.0 Hz), 117.6 (DD, J=25.2, 3.7 Hz), 80.4, 78.4, 72.1, 57.9 (d, J=7.5 Hz), 28.5, 22.3.
		Step B: tert-Butyl [1 -(2 ,5-difluorophenyl)- I -oxopent-4-yn-2-yl]carbamateAn inerted vessel was charged dichioromethane (866 kg) and cooled to -20 to -10 C.Then iso-propylmagnesium chloride solution in THF (2M, 326.1 kg, 669 mol) was slowly addedfollowed by <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (120.1 kg, 622 mol). After 2h at this temperature, an additional charge of iso-propylmagnesium chloride in THF solution was slowly added (2M, 58.65 kg, 121 mol) and the reaction aged lh. Then, a drop-wise addition of a dichloromethane solution of tert-butyl (1 -[methoxy(methyl)amino]- 1 -oxopent-4-yn-2-yl)carbamate (70.8 kg, 276mol in 292 kg dichloromethane) was conducted over 2h at -20 to -20 C. The mixture was then warmed to room temperature and stirred for 1 Oh. The reaction was then slowly reverse quenched into aqueous ammonium chloride (175.6 kg in 1550 kg of water) at 5-10 C. The solution pH was then adjusted to 7 by adding 68 kg of con. HC1. The layers were then separated and the aqueous extracted with dicbloromethane (414 kg). The combined organics were then dried withNa2SO4, filtered, treated with activated carbon (10 kg), filtered, and concentrated to 71-141 L. A constant volume (71-141 L) vacuum distillation solvent switch to n-beptane was then performed to crystallize the product. The slurry was then cooled to 0 C and stirred 2h. The slurry was filtered and the cake washed with n-heptane, 2-propanol, and then water. The solids were dried under vacuum at 40-50 C overnight to give tert-butyl [l-(2,5-difluorophenyl)-l-oxopent-4-yn-2-yl]carbamate.
		Step B: tert-Butyl [1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate An inerted vessel was charged dichloromethane (866 kg) and cooled to -20 to -10 C. Then iso-propylmagnesium chloride solution in THF (2M, 326.1 kg, 669 mol) was slowly added followed by <strong>[399-94-0]1-bromo-2,5-difluorobenzene</strong> (120.1 kg, 622 mol). After 2 h at this temperature, an additional charge of iso-propylmagnesium chloride in THF solution was slowly added (2M, 58.65 kg, 121 mol) and the reaction aged 1 h. Then, a drop-wise addition of a dichloromethane solution of tert-butyl (1-[methoxy(methyl)amino]-1-oxopent-4-yn-2-yl)carbamate (70.8 kg, 276 mol in 292 kg dichloromethane) was conducted over 2 h at -20 to -20 C. The mixture was then warmed to room temperature and stirred for 10 h. The reaction was then slowly reverse quenched into aqueous ammonium chloride (175.6 kg in 1550 kg of water) at 5-10 C. The solution pH was then adjusted to ?7 by adding 68 kg of con. HCl. The layers were then separated and the aqueous extracted with dichloromethane (414 kg). The combined organics were then dried with Na2SO4, filtered, treated with activated carbon (10 kg), filtered, and concentrated to 71-141 L. A constant volume (71-141 L) vacuum distillation solvent switch to n-heptane was then performed to crystallize the product. The slurry was then cooled to 0 C. and stirred 2 h. The slurry was filtered and the cake washed with n-heptane, 2-propanol, and then water. The solids were dried under vacuum at 40-50 C. overnight to give tert-butyl [1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate.

Reference： [1]Patent: WO2017/81590,2017,A1 .Location in patent: Page/Page column 19; 20
[2]Organic Process Research and Development,2015,vol. 19,p. 1760 - 1768
[3]Patent: EP3159344,2017,A1 .Location in patent: Paragraph 0096; 0097; 0101
[4]Patent: TW2017/8221,2017,A .Location in patent: Page/Page column 33; 34; 35
[5]Patent: TW2017/8224,2017,A .Location in patent: Page/Page column 28; 30
[6]Patent: TW2017/8220,2017,A .Location in patent: Page/Page column 56; 57; 58; 59
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[8]Patent: TW2017/8223,2017,A .Location in patent: Page/Page column 38
[9]Patent: CN106632349,2017,A .Location in patent: Paragraph 0082; 0083; 0084; 0085; 0086
[10]Patent: CN105085530,2019,B .Location in patent: Paragraph 0166-0168
[11]Organic Letters,2014,vol. 16,p. 5422 - 5425
[12]Patent: EP3257857,2017,A1 .Location in patent: Paragraph 0084; 0089
[13]Patent: US2009/187028,2009,A1 .Location in patent: Page/Page column 7
[14]Patent: US2009/187028,2009,A1 .Location in patent: Page/Page column 7-8
[15]Patent: WO2013/3249,2013,A1 .Location in patent: Page/Page column 9
[16]Patent: US9181262,2015,B2 .Location in patent: Page/Page column 8; 9

16
[ 399-94-0 ]
[ 86953-79-9 ]
[ 1218935-58-0 ]

Yield	Reaction Conditions	Operation in experiment
72%		A solution of tert-butyl pyrrolidine- 1-carboxylate (20 g, 116.8 mmol) and (- )sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to -78 0C, and sec-BuLi (10OmL, 140 mmol, 1.4 M in cyclohexane) was introduced drop-wise via cannula, keeping the internal temperature under -70 0C. The resulting solution was stirred for 3 hours at -78 0C, followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, IM in Et2O) drop-wise with rapid stirring, keeping the internal temperature below -65 0C. The resulting light suspension was stirred at -78 0C for 30 minutes and then warmed to ambient temperature. The resulting mixture was charged with 2-bromo-l,4-difluorobenzene (14.5 mL, 128 mmol), followed by Pd(OAc)2 (1.31 g, 5.8mmol) and ^-Bu3P-HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, 10.5 mL Of NH4OH solution was added and the reaction was stirred for another hour. The resulting slurry was filtered through CELITE and washed with Et2O (1 L). The filtrate was washed with HCl (0.5 L, IM aq.) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtO Ac/hex anes to give product (R)-tert-butyl 2- (2,5-difluorophenyl)pyrrolidine- 1-carboxylate as yellow oil (23.9 g, 72% yield).
72%		Preparation A; Preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine; [00378] Step A: Preparation of (PQ-tert-butyl 2-(2.5-difluorophenv0pyrrolidine-l- carboxylate; A solution of tert-butylpyrrolidine-1-carboxylate (20 g, 116.8 mmol) and (-)sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to -78 0C, and sec-BuU (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduced dropwise via cannula, keeping the internal temperature under -70 0C. The resulting solution was stirred for 3 hours at -78 0C, followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, IM in Et2O) drop-wise with rapid stirring, keeping the internal temperature below -65 0C. The resulting light suspension was stirred at -78 0C for 30 minutes and then warmed to ambient temperature. The resulting mixture was charged with 2-bromo-l,4-difluorobenzene (14.5 mL, 128 mmol), followed by Pd(OAc)2 (1.31 g, 5.8 mmol) and J-Bu3P-HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, 10.5 mL Of NH4OH solution was added and the reaction was stirred for another hour. The resulting slurry was filtered through CELITE and washed with Et2O (1 L). The filtrate was washed with HCl (0.5 L, IM aq.) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate as yellow oil (23.9 g, 72% yield).
72%		Preparation A; (R)-2-(2,5-difluorophenyl)pyrrolidine; Step A: Preparation of (RVtert-butyl 2-(2.5-difluorophenyl)pyrrolidine-l- carboxylate.; A solution of tert-butyl pyrrolidine- 1-carboxylate (20 g, 116.8 mmol) and (-)- sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to -78 0C and sec-BuU (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduced drop-wise via cannula, keeping the internal temperature under -70 0C. The resulting solution was stirred for 3 hours at -78 0C, followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, IM in Et2O) drop-wise with rapid stirring, keeping the internal temperature below -65 0C. The resulting light suspension was stirred at -78 0C for 30 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 2-bromo-l,4-difluorobenzene (14.5 mL, 128 mmol), Pd(OAc)2 (1.31 g, 5.8 mmol) and J-Bu3P-HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (10.5 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite and the filter cake washed with Et2O (1 L). The filtrate was washed with a IM aqueous HCl solution (0.5 L) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tert-butyl 2-(2, 5 -difluorophenyl)pyrrolidine- 1-carboxylate as yellow oil (23.9 g, 72% yield).

Reference： [1]Patent: WO2010/33941,2010,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2010/48314,2010,A1 .Location in patent: Page/Page column 44-45
[3]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 68-69

17
[ 399-94-0 ]
[ 179737-33-8 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 327 - 340

18
[ 399-94-0 ]
[ 1218935-60-4 ]

Reference： [1]Patent: WO2011/6074,2011,A1

19
[ 399-94-0 ]
[ 1218935-59-1 ]

Reference： [1]Patent: WO2011/6074,2011,A1
[2]Patent: US2017/281632,2017,A1
[3]Patent: CN108101820,2018,A
[4]Patent: EP3533796,2019,A1

20
[ 399-94-0 ]
[ 31166-44-6 ]
[ 1353530-94-5 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium t-butanolate; ruphos;bis(dibenzylideneacetone)-palladium(0); In toluene; at 100℃; for 1h;Inert atmosphere;	Step 1 Preparation of Compound 132To a suspension of NaOt-Bu (3.73 g, 38.9 mmol), Pd(dba)2 (0.298 g, 0.518 mmol), RuPhos (0.484 g, 1.036 mmol) and 2-bromo-l,4-difluorobenzene (5 g, 25.9 mmol) in Toluene (50 ml) was added benzyl piperazine-l-carboxylate (6.00 ml, 31.1 mmol) at r.t. under N2.The mixture was stirred at 100C under N2 for 1 hr. The reaction mixture was diluted with H20 and AcOEt at r.t., then the resulting solid was filtered, rinsed with AcOEt and H2O.The filtrate was extracted with AcOEt x 2. The organic layers were combined and washed with brine. The organic layer was dried over MgS04, filt and cone. The crude product was added to a silica gel column and was eluted with AcOEt-Hexane. Collected fractions were evaporated. The residual oil was triturated with CH2C12-Hexane, then filtered, rinsed with Hexane to afford compound 132 (3.7 g, 43.0 %) as a white solid.1H-NMR (CDC13) delta: 7.40-7.29 (5H, m), 7.01-6.89 (1H, m), 6.66-6.56 (2H, m), 5.16 (2H, s), 3.67 (4H, t, J= 5.1 Hz), 3.11-2.97 (4H, m).

Reference： [1]Patent: WO2011/162409,2011,A1 .Location in patent: Page/Page column 450

21
[ 399-94-0 ]
[ 1394120-64-9 ]

Reference： [1]Patent: US2012/214762,2012,A1

22
[ 399-94-0 ]
[ 172921-32-3 ]

Reference： [1]Patent: WO2012/174342,2012,A1
[2]Patent: WO2013/12500,2013,A1
[3]Patent: CN109369412,2019,A

23
[ 399-94-0 ]
[ 85909-08-6 ]
[ 1443538-33-7 ]

Yield	Reaction Conditions	Operation in experiment
76 g		2.0 M Isopropyl magnesium chloride solution in THF (163mL, 324.3 mmol) was added to a solution of 2-bromo-l,4-difluorobenzene (62.5 g, 324.3 mmol) in THF (350mL) at -40C and stirring was continued at 5C for 1 h. tert- utyl 2- oxopyrrolidine-l-carboxylate(Step-l)(73 g, 392 mmol) in THF(150mL) was added dropwise to above reaction mixture at -40C and stirring was continued at 10C for 2 h. Reaction mixture was quenched with saturated NH4CI solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 76 g of the title compound.
76 g		2.0 M Isopropyl magnesium chloride solution in THF (163 mL, 324.3 mmol) was added to a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (62.5 g, 324.3 mmol) in THF (350 mL) at -40 C. and stirring was continued at 5 C. for 1 h. tert-Butyl 2-oxopyrrolidine-1-carboxylate (Step-1) (73 g, 392 mmol) in THF (150 mL) was added dropwise to above reaction mixture at -40 C. and stirring was continued at 10 C. for 2 h. Reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 76 g of the title compound.
76 g		2.0 M Isopropyl magnesium chloride solution in THF (163 mL, 324.3 mmol) was added to a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (62.5 g, 324.3 mmol) in THF (350 mL) at -40 C. and stirring was continued at 5 C. for 1 h. tert-Butyl 2-oxopyrrolidine-1-carboxylate (Step-1)(73 g, 392 mmol) in THF (150 mL) was added dropwise to above reaction mixture at -40 C. and stirring was continued at 10 C. for 2 h. Reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 76 g of the title compound.

76 g		Int-8: tert-butyl 5-(2,5-difluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate 2.0 M Isopropyl magnesium chloride solution in THF (163 mL, 324.3 mmol) was added to a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (62.5 g, 324.3 mmol) in THF (350 mL) at -40 C. and stifling was continued at 5 C. for 1 h. tert-Butyl 2-oxopyrrolidine-1-carboxylate (Step-1) (73 g, 392 mmol) in THF (150 mL) was added dropwise to above reaction mixture at -40 C. and stifling was continued at 10 C. for 2 h. Reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 76 g of the title compound.
		At -40C,Add 2.0 M isopropyl chloride to a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (186 g) in THF (1.0 L)Magnesium in THF (482 mL),And continue stirring at 5 C for 1 h.At -40C,A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (215.5 g) in THF (250 mL) was added dropwise to the above reaction mixture.And continue stirring at 10 C for 2 h.The reaction mixture was quenched with saturated ammonium chloride solution,Extract with ethyl acetate,Dry with anhydrous sodium sulfatefilter,And concentrate the filtrate under reduced pressure,The crude title compound was obtained (323.4 g),It is used directly in the next step without purification.
		To a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (186 g) in THF (1.0 L) was added 2.0M isopropylmagnesium chloride solution in THF (482 mL) at -40C, and continuously stirred at 5C for 1 h. To the above reaction mixture was added a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (215.5 g) in THF (250 mL) dropwise, and continuously stirred at 10C for 2h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to afford a crude product of the title compound (323.4 g), which was used in a next step without purification.

Reference： [1]Patent: WO2013/88256,2013,A1 .Location in patent: Page/Page column 59
[2]Patent: US2014/371217,2014,A1 .Location in patent: Paragraph 0565
[3]Patent: US2015/5280,2015,A1 .Location in patent: Paragraph 0540 - 0541
[4]Patent: US2015/368238,2015,A1 .Location in patent: Paragraph 0580; 0582
[5]Patent: CN108003161,2018,A .Location in patent: Paragraph 0349; 0350; 0355-0357
[6]Patent: EP3533796,2019,A1 .Location in patent: Paragraph 0074; 0077; 0078

24
[ 399-94-0 ]
[ 64214-66-0 ]
[ 1216260-42-2 ]

Yield	Reaction Conditions	Operation in experiment
39%		To a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (30.0 g, 155 mmol) in dry THF (155 mL) was added isopropylmagnesium chloride (2 M in THF, 93.0 mL, 187 mmol) at -78 C. The mixture was slowly warmed to 0 C., stirred for 1 hour at that temperature and then cooled to -78 C. again. After addition of a solution of 4-chloro-N-methoxy-N-methylbutanamide (28.3 g, 171 mmol) in THF (100 mL), the reaction mixture was allowed to warm to room temperature with stirring for 4 hours and quenched with saturated aq. NH4Cl. The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=7:1 to 6:1) to afford 4-chloro-1-(2,5-difluorophenyl)butan-1-one (13.3 g, 39%) as a pale yellow oil. 1H-NMR (CDCl3, Varian, 400 MHz): delta 2.22 (2H, quint, J=6.8 Hz), 3.16-3.20 (2H, m), 3.67 (2H, t, J=6.4 Hz), 7.11-7.17 (1H, m), 7.20-7.26 (1H, m), 7.55-7.59 (1H, m).
35 g		2-Bromo-l,4-difluorobenzene(53.6 g, 277.74 mmol) in THF cooled to -50C was added to isopropyl magnesium chloride (2M in THF)( 133mL, 266 mmol). The reaction mixture thus obtained was warmed to 0C and stirred for lh. The reaction mixture was cooled again to -50C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0C for lh. The reaction mixture was quenched with saturated aqueous NH4C1 solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. 1H NMR (300MHz, CDC13) delta ppm 7.6-7.53(lH, m), 7.26-7.09(2H, m), 3.7(2H, t) 3.22- 3.14(2H, m), 2.28-2.16(2H, m).
35 g		2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to -50 C. was added to isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0 C. and stirred for 1 h. The reaction mixture was cooled again to -50 C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0 C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. 1H NMR (300 MHz, CDCl3) delta ppm 7.6-7.53 (1H, m), 7.26-7.09 (2H, m), 3.7 (2H, t) 3.22-3.14 (2H, m), 2.28-2.16 (2H, m).

35 g		2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to -50 C. was added to isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0 C. and stirred for 1 h. The reaction mixture was cooled again to -50 C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0 C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. 1H NMR (300 MHz, CDCl3) delta ppm 7.6-7.53 (1H, m), 7.26-7.09 (2H, m), 3.7 (2H, t) 3.22-3.14 (2H, m), 2.28-2.16 (2H, m).
35 g		-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF (50 ml) was cooled to -50 C., to it was added isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0 C. and stirred for 1 h. The reaction mixture was cooled again to -50 C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added drop wise to this reaction mixture with stirring and the stifling was continued at 0 C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colorless liquid. 1H NMR (300 MHz, CDCl3) delta 7.60-7.53 (1H, m), 7.26-7.09 (2H, m), 3.70 (2H, t), 3.22-3.14 (2H, m), 2.28-2.16 (2H, m).
101 g		Isopropylmagnesium chloride in THF (2M, 604 mL) was added dropwise to <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> cooled to -50C.(244.7 g) in THF (1 L) solution.After dropping,Warm to 0C and stir for 1 h.The reaction mixture was again cooled to -50 C.Under stirringTo this reaction mixture was added dropwise a solution of 4-chloro-N-methoxy-N-methylbutanamide (100 g) in THF (200 mL).Gradually increase the temperature to 30 C and continue stirring at 30 C for 3 h.The reaction mixture was quenched with saturated aqueous ammonium chloride,Extract with ethyl acetate.The collected organic phase is washed with water,Then it was washed with saturated saline.Separation of the organic phase;Drying with anhydrous sodium sulfate,filter,And concentrate the filtrate under reduced pressureThe residue was purified by column chromatography on silica gel,The title compound (101 g) was obtained.
17.3 g		To a 500 ml three-necked flask, isopropylmagnesium chloride (2M in THF, 60 ml, 120 mmol) was added and the mixture was cooled to 0, and a solution of 2,5-difluorobromobenzene (19.3 g, 100 mmol) in tetrahydrofuran (150 ml) was added dropwise. After the completion of the dropwise addition, the reaction was carried out for 2 h at room temperature; then, the temperature was controlled to be lower than 20 C, and a solution of N-methoxy-N-methyl-4-chlorobutanamide (16.5 g, 100 mmol) in tetrahydrofuran (50 ml) was added dropwise. After the completion of the dropwise addition, the reaction was carried out for 16 hours at room temperature; 50 ml of an equivalent concentration of 2N hydrochloric acid was added dropwise to the reaction mixture, and the mixture was stirred for 30 minutes, and the aqueous phase was separated and extracted with ethyl acetate (100 ml) twice, and the organic phase was combined. It was washed with 50 ml of a saturated brine and dried over anhydrous sodium sulfate, and the organic solvent was removed to give 17.3 g of the compound of formula (A) as a light brown liquid.
101 g		A solution of isopropylmagnesium chloride in THF (2M, 604 mL) was added dropwise to a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (244.7 g) in THF (1 L) that had been cooled to -50C. After completion of the dropwise addition, the temperature was warmed to 0C while stirring for 1 h. The reaction mixture was cooled to -50C again. To the reaction mixture was added a solution of 4-chloro-N-methoxy-N-methylbutyramide (100 g) in THF (200 mL) dropwise under stirring, and gradually warmed to 30C and then continuously stirred at 30C for 3h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The collected organic phase was washed with water and then a saturated saline solution. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the title compound (101 g). 1H NMR (400 MHz, CDCl3) delta 7.59-7.55 (m, 1H), 7.26-7.20 (m, 1H), 7.17-7.11 (m, 1H), 3.68-3.65 (m, 2H), 3.20-3.16 (m, 2H), 2.25-2.19 (m, 2H). m/z=219[M+1]+.

Reference： [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0207; 0209; 0210
[2]Patent: WO2013/88256,2013,A1 .Location in patent: Page/Page column 57-58
[3]Patent: US2014/371217,2014,A1 .Location in patent: Paragraph 0553
[4]Patent: US2015/5280,2015,A1 .Location in patent: Paragraph 0517 - 0519
[5]Patent: US2015/368238,2015,A1 .Location in patent: Paragraph 0574; 0576
[6]Patent: CN108003161,2018,A .Location in patent: Paragraph 0324; 0325; 0329-0331
[7]Patent: CN108101820,2018,A .Location in patent: Paragraph 0033; 0050
[8]Patent: EP3533796,2019,A1 .Location in patent: Paragraph 0061; 0064; 0065

25
[ 399-94-0 ]
[ 6500-65-8 ]
[ 1353008-16-8 ]

Yield	Reaction Conditions	Operation in experiment
19%	at 20℃; Reflux;	6-(2,5-Difluorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 6-(2,5-Difluorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 24.63 g (129.5 mmol) of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one was reacted according to general specification 5-vPd with 25 g (129.5 mmol) of 1-bromo-2,5-fluorobenzene. It was stirred for 30 hours under reflux, overnight at room temperature and again for 3 hours under reflux. The residue was purified using Silica Gel 60 (solvent: hexane, hexane-ethyl acetate 95:5, 94:6, 93:7, 92:8, 90:10 and 80:20). 9.53 g (24% of theor.) of product was isolated. The intermediate fractions were purified again using Silica Gel 60 (solvent: hexane-ethyl acetate 95:5, 93:7 and 90:10). A further 7.55 g (19% of theor.) of product was obtained. 1H-NMR (300 MHz, chloroform-d1): δ=1.76-1.92 (m, 1H), 1.99-2.27 (m, 3H), 2.94 (dt, 1H), 3.15 (mc, 1H), 3.86 (s, 3H), 4.23 (dd, 1H), 6.76 (d, 1H), 6.84 (dd, 1H), 6.87-7.08 (m, 3H), 7.76 (d, 1H).

Reference： [1]Current Patent Assignee: BAYER AG - US2013/252890, 2013, A1 Location in patent: Paragraph 0291; 0292; 0293

26
[ 399-94-0 ]
[ 931-50-0 ]
1-cyclohexyl-2,5-difluorobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		General procedure: In a typical experiment a dry and argonflushed50-mL Schlenk tube, equipped with a magnetic stirring bar, was charged with therespective fluorinated bromobenzene derivative (0.5 mmol, 88 mg for monosubstituted, 97 mgfor disubstituted and 105 mg for trisubstituted derivatives) and 3 mol% of the respective catalystdissolved in 15 ml of THF ([FeCl2(dppe)]: 7.9 mg, [FeCl2(dppp)]: 8.1 mg, [NiCl2(dppm)]: 7.7mg, [NiCl2(dppe)]: 7.9 mg, [NiCl2(dppp)]: 8.1 mg, [PdCl2(dppm)]: 8.4 mg, [PdCl2(dppe)]: 8.6mg, [PdCl2(dppp)]: 8.8 mg). The solution was stirred for 5 min, then cyclohexyl magnesiumbromide or the respective LiCl or LiBr adduct (0.8 mmol, 4 ml of a 0.2M Grignard reagent) wasquickly added to the reaction mixture and vigorous stirring at room temperature was continuedfor 24 hours. After hydrolysis with diluted hydrochloric acid, the organic layer and ether extractsfrom the aqueous layer were combined, washed with water and saturated NaCl solution, driedover MgSO4 and filtrated through a pad of silica. Concentration under reduced pressure followedby column chromatography (hexane : diethyl ether, v/v 100 : 1) afforded the respective coupling products as light yellow oily compounds

Reference： [1]ARKIVOC,2013,vol. 2013,p. 200 - 216

27
[ 399-94-0 ]
[ 1613333-42-8 ]
[ 1613333-44-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation;	Example 3 3 -((2.5 -difluorophenyl)ethynyl)-5 -( 1 -(piperidin-4-yl)- 1 H-pyrazol-4-yl)- 1 H- pyrrolor2,3-b1pyridine Step 1) tert-butyl 4-(4-(3-((2.5-difluorophenyl ethvnyl -lH-pyrrolor2.3-b1pyridin-5-yl -lH- pyrazol- 1 -yPpiperidine- 1 -carboxylate To a microwave vial was added tert-butyl 4-(4-(3-ethynyl-lH-pyrrolo[2,3-b] pyridin-5-yl)-lH- pyrazol-l-yl)piperidine-l -carboxylate (0.1 g, 0.26 mmol), 2-bromo-l,4-difluorobenzene (58 mg, 0.26 mmol), Pd(PPh3)2Cl2 (9.0 mg, 0.013 mmol), Cul (2.0 mg, 0.013 mmol), Et3N (1 mL), and DMF (4 mL). The mixture was degassed and charged with nitrogen for three times. The vial was capped and then stirred and heated under microwave conditions at 120 C for 30 minutes. Then the mixture was cooled to rt, diluted with DCM (100 mL), and washed with brine (100 mL x 3). The separated organic phase was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a light yellow solid (0.14 g, 81%). MS (ESI, pos. ion) m/z: 504.2 (M+l); 'HNMR: (400 Hz, DMSO-i): delta 1.43 (s, 9H), 1.84 (m, 2H), 2.05 (m, 2H), 2.95 (s, 2H), 4.06 (m, 2H), 4.38 (m, IH), 7.31 (m, IH), 7.38 (m, IH), 7.62 (m, IH), 7.98 (d, J=2.8 Hz, IH), 8.02 (s, IH), 8.19 (d, J=1.8 Hz, IH), 8.41 (s, IH), 8.62 (d, J=1.8 Hz, IH), 12.26 (s, IH).
81%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; Sealed tube;	Adding compounds to the microwave tube in sequence4-(4-(3-ethynyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (0.1 g , 0.26mmol), <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (58mg, 0.26mmol), Pd(PPh3)2Cl2 (9.0mg, 0.013mmol), CuI (2.0mg, 0.013mmol),Et3N (1 mL) and DMF (4 mL). After the reaction liquid is exchanged for three times (nitrogen),The microwave tube was sealed, and then the reaction solution was stirred at 120 C for 30 minutes under microwave conditions.The reaction solution was cooled to room temperature, and the reaction mixture was diluted with DCM (100 mL).The mixture was washed with saline (100 mL x 3). The organic phase obtained by liquid separation is dried with anhydrous Na2SO4.Concentrated under reduced pressure, and the residue was applied to silica gel column chromatography(PE/EtOAc(v/v)=1/2)Purification to give the title compound as a pale yellow solid(0.14 g, 81%).

Reference： [1]Patent: WO2014/89280,2014,A1 .Location in patent: Page/Page column 55
[2]Patent: CN103833753,2017,B .Location in patent: Paragraph 0400; 0402; 0403

28
[ 399-94-0 ]
[ 886503-15-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 0.5 h / -78 - -20 °C / Inert atmosphere 2.1: tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 2.2: 20 °C 3.1: hydrogenchloride; water monomer / methanol / 6 h / 70 °C 4.1: sodium tetrahydridoborate / ethanol / 20 °C
	Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 1 h / -45 - 0 °C 1.2: 0.5 h / -15 - 20 °C 2.1: dichloromethane / 1 h / 20 °C 3.1: palladium on activated charcoal; hydrogen / methanol / 20 °C
	Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 3 h / 5 - 25 °C 1.2: 2 h / 5 - 25 °C 1.3: 70 °C 2.1: sodium tetrahydridoborate; methanol / 2 h / Cooling with ice

	Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 1.2: 1.5 h / 0 - 5 °C / Inert atmosphere 2.1: hydrogenchloride / toluene; water monomer / 65 °C 3.1: sodium hydroxide / toluene; water monomer / 15 - 20 °C / pH Ca_. 14 4.1: platinum on carbon; hydrogen / 15 - 20 °C
	Multi-step reaction with 3 steps 1: magnesium; lithium chloride; tetrahydrofuran / 20 °C 2: hydrogenchloride / water monomer; toluene / 65 °C 3: acetic acid; sodium tetrahydridoborate / dichloromethane / 1.5 h / 10 - 25 °C
	Multi-step reaction with 2 steps 1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 1 h / -78 °C 2: methanol; sodium tetrahydridoborate / water monomer / 16 h / 20 °C

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/140128, 2009, A2
[2]Current Patent Assignee: SHENZHEN TARGETRX INC - CN109456331, 2019, A
[3]Chen, Fei-Fei; Chen, Qi; Li, Bo-Bo; Xu, Jian-He; Zhang, Yu-Hui; Zheng, Gao-Wei; Zhou, Xin-Yi [Organic Letters, 2020, vol. 22, # 9, p. 3367 - 3372]
[4]Current Patent Assignee: JIANGSU PHARMSYN PHARMACEUTICAL TECH - CN111302997, 2020, A
[5]Lv, Xunlei; Chen, Liang; Pan, Jing; Meng, Xue; Bi, Siju; Liu, Weiyuan; Zhou, Ting; Lin, Kuaile; Ye, Deyong; Zhou, Weicheng [Chirality, 2021, vol. 33, # 12, p. 931 - 937]
[6]Bernhard, Laura M.; McLachlan, Jill; Gröger, Harald [Organic Process Research and Development, 2022, vol. 26, # 7, p. 2067 - 2074]

29
[ 399-94-0 ]
[ 1443623-92-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 5 - 25 °C 1.2: 2 h / 5 - 25 °C 2.1: hydrogenchloride / water; toluene / 65 °C
	Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / 5 - 250 °C 1.2: 2 h / 25 - 50 °C / Inert atmosphere 2.1: hydrogenchloride / water; toluene / 65 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / -78 - -20 °C / Inert atmosphere 2.1: tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 2.2: 20 °C 3.1: hydrogenchloride; water / methanol / 6 h / 70 °C

	Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -78 °C 1.2: 16 h / -78 - 20 °C 2.1: trifluoroacetic acid / neat liquid / 16 h
	Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 1.2: 1.5 h / 0 - 5 °C / Inert atmosphere 2.1: hydrogenchloride / toluene; water / 65 °C 3.1: sodium hydroxide / toluene; water / 15 - 20 °C / pH Ca_. 14
	Multi-step reaction with 2 steps 1: magnesium; lithium chloride; tetrahydrofuran / 20 °C 2: hydrogenchloride / water; toluene / 65 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2016/137654, 2016, A1
[2]Current Patent Assignee: ELI LILLY & CO - US2017/281632, 2017, A1
[3]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/140128, 2009, A2
[4]Lundrigan, Travis; Welsh, Erin N.; Hynes, Toren; Tien, Chieh-Hung; Adams, Matt R.; Roy, Kayelani R.; Robertson, Katherine N.; Speed, Alexander W. H. [Journal of the American Chemical Society, 2019, vol. 141, # 36, p. 14083 - 14088]
[5]Current Patent Assignee: JIANGSU PHARMSYN PHARMACEUTICAL TECH - CN111302997, 2020, A
[6]Lv, Xunlei; Chen, Liang; Pan, Jing; Meng, Xue; Bi, Siju; Liu, Weiyuan; Zhou, Ting; Lin, Kuaile; Ye, Deyong; Zhou, Weicheng [Chirality, 2021, vol. 33, # 12, p. 931 - 937]

30
[ 399-94-0 ]
[ 107-18-6 ]
2-(2,5-difluorophenyl)prop-2-en-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; 1-butyl-3-methylimidazolium Tetrafluoroborate; In dimethyl sulfoxide; at 115℃; for 15h;	The reaction flask were sequentially added Compound 8 (386mg, 2.0mmol), Pd (OAc)2(18mg,4mol)dppp(66mg,8mol)DMSO(2mL)[bmim][BF 4] (2mL), allyl alcohol (0.27mL, 4.0mmol) and NEt3(0.42mL, 3mmol). The reaction mixture was stirred at 115 C 15 hours. After the reaction system was cooled to room temperature and extracted with dichloromethane, dried and the solvent was evaporated. Mixture was purified by column chromatography to give compound 9.

Reference： [1]Chemistry - A European Journal,2015,vol. 21,p. 120 - 124
[2]Patent: CN104370939,2016,B .Location in patent: Paragraph 0062; 0063

31
[ 399-94-0 ]
[ 201230-82-2 ]
[ 611-24-5 ]
2-fluoro-10-methyldibenzo[b,f][1,4]oxazepin-11(10H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With palladium diacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene; catacxium A In dimethyl sulfoxide at 120℃; for 24h;

Reference： [1]Shen, Chaoren; Neumann, Helfried; Wu, Xiao-Feng [Green Chemistry, 2015, vol. 17, # 5, p. 2994 - 2999]

32
[ 399-94-0 ]
[ 95-92-1 ]
[ 1049131-01-2 ]

Yield	Reaction Conditions	Operation in experiment
62%		Reference Example-71 THF (25 mL) was added to metal magnesium (2.55 g, 105 mmol), and 2-bromo-1,4-difluoro benzene (19.70 g, 100 mmol) was slowly added thereto, whereby a Grignard reagent was prepared. The previously prepared Grignard reagent was added dropwise to the separately prepared solution of diethyl oxalate (15.34 g, 105 mmol) in THF (10 mL) at -40 C. or lower. After the dropping was completed, the reaction temperature was raised to 0 C., followed stirring for 1 hour. A saturated ammonium chloride aqueous solution and water (200 mL) were added to the reaction solution, and the resultant product was extracted with ethyl acetate (200 mL*2). After the organic layer was dried over magnesium sulfate and filtered, the solvent was distilled off under reduced pressure, and the resultant product was distilled under reduced pressure, whereby ethyl 2-(2,5-difluorophenyl)-2-oxoacetate (14.82 g, yield: 62%) was obtained as a colorless liquid. 1H-NMR (400 MHz, CDCl3): delta1.40 (t, J=7.0 Hz, 3H), 4.44 (q, J=7.0 Hz, 2H), 7.16 (ddd, J=9.3, 9.3 and 4.0 Hz, 1H), 7.34 (dddd, J=9.3, 9.2, 7.3 and 3.3 Hz, 1H), 7.60 (ddd, J=8.2, 5.3 and 3.3 Hz, 1H). 19F-NMR (376 MHz, CDCl3): delta-116.9 (d, J=7.8 Hz, 1F), -116.3 (d, J=7.8 Hz, 1F).
62%	With magnesium; In tetrahydrofuran; at -40 - 0℃; for 1h;	THF (25 mL) was added to Magnesium metal (2.55g, 105 mmol), and then <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (19.70g, 100mmol) was addedslowly to prepare a Grignard reagent. To separately prepared THF (10mL)solution of diethyl oxalate (15.34g, 105mmol), Grignard reagent preparedearlier was added dropwise at -40 below. After completion of the addition, it was stirred for 1 hour at thereaction temperature of 0 . saturated aqueous solution of ammonium chlorideand water (200 mL) were added to the reaction solution, and extracted with ethyl acetate (200mL ×2). The organic layer was dried over magnesium sulfate, filtered, and thesolvent was evaporatedunder reduced pressure, and by distillation under reducedpressure, colorless liquid of 2- (2,5-difluorophenyl) -2- oxo-ethyl acetate(14.82g, yield: 62%)

Reference： [1]Patent: US2016/24110,2016,A1 .Location in patent: Paragraph 1225; 1226
[2]Patent: JP2016/56157,2016,A .Location in patent: Paragraph 0156

33
[ 399-94-0 ]
[ 146447-18-9 ]

Reference： [1]Patent: US2016/24110,2016,A1
[2]Patent: JP2016/56157,2016,A
[3]Patent: JP2016/60742,2016,A

34
[ 399-94-0 ]
[ 201230-82-2 ]
[ 1889-71-0 ]
2-(4-chlorophenyl)-6-fluoro-3-phenyl-4H-chromen-4-one [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 466 - 479

35
[ 399-94-0 ]
[ 635-93-8 ]
2-chloro-7-fluoro-9H-xanthen-9-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With palladium diacetate; potassium carbonate; catacxium A; In N,N-dimethyl-formamide; at 120℃; for 12h;Schlenk technique; Inert atmosphere;	General procedure: To an oven-dried 25 mL Schlenk tube containing a stirring bar was added 4.5 mg Pd(OAc)2 (0.02 mmol), 15.7mg nBuPAd2 (0.44 mmol), 2-bromofluorobenzene (0.50 mmol), salicylaldehyde (0.50 mmol), potassium carbonate (1.0 mmol). The Schlenk tube was vacuumed and then purged with argon before DMF (2.0 mL) was injected using a syringe. Afterwards the Schlenk tube in the ice bath was degassed by evacuation and back fillingwith argon three times. The reaction mixture was then stirred for 12 h at 120 C. After the reaction was complete,the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3 x 10 mL) and dried withanhydrous Na2SO4. After filtration and addition of silica gel into the solution, the organic solvent was reduced evaporated. The crude product was purified by column chromatography using ethyl acetate/n-pentane.

Reference： [1]Synlett,2016,vol. 27,p. 1269 - 1273

36
[ 399-94-0 ]
[ 90-02-8 ]
[ 2839-49-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With palladium diacetate; potassium carbonate; catacxium A; In N,N-dimethyl-formamide; at 120℃; for 12h;Schlenk technique; Inert atmosphere;	General procedure: To an oven-dried 25 mL Schlenk tube containing a stirring bar was added 4.5 mg Pd(OAc)2 (0.02 mmol), 15.7mg nBuPAd2 (0.44 mmol), 2-bromofluorobenzene (0.50 mmol), salicylaldehyde (0.50 mmol), potassium carbonate (1.0 mmol). The Schlenk tube was vacuumed and then purged with argon before DMF (2.0 mL) was injected using a syringe. Afterwards the Schlenk tube in the ice bath was degassed by evacuation and back fillingwith argon three times. The reaction mixture was then stirred for 12 h at 120 C. After the reaction was complete,the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3 x 10 mL) and dried withanhydrous Na2SO4. After filtration and addition of silica gel into the solution, the organic solvent was reduced evaporated. The crude product was purified by column chromatography using ethyl acetate/n-pentane.

Reference： [1]Synlett,2016,vol. 27,p. 1269 - 1273

37
[ 399-94-0 ]
[ 85909-08-6 ]
4-(2,5-difluorophenyl)-4-oxobutylcarbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (5.81 mL, 51.8 mmol) in dry THF (50 mL) was added isopropylmagnesium chloride (2.0 M in THF, 31.1 mL, 62.2 mmol) at -78 C. The mixture was slowly warmed to 0 C., stirred for 1 hour at that temperature and then cooled to -78 C. again. After addition of a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (11.5 g, 62.2 mmol) in dry THF (20 mL) at -78 C., the reaction mixture was allowed to warm to room temperature with stirring for 2 hours and quenched with saturated aq. NH4Cl. The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford tert-butyl 4-(2,5-difluorophenyl)-4-oxobutylcarbamate (15.5 g, 100%) as a pale green oil, which was used for the next reaction without further purification.
65.3%		In a 3000 ml three-necked flask, a magnesium shavings (26.4 g, 1.1 mmol) and a solution of 2,5-difluorobromobenzene (2,5-difluorobromobenzene 200 g, 1.036mol) in tetrahydrofuran (1500 mL) were added dropwise. After completion, the whole temperature control (water bath) is reacted at 35-45 C; then, it is naturally cooled to 25 C, the ice water bath is cooled, and a solution of N-BOC pyrrolidone (150 g, 810 mmol) in tetrahydrofuran (300 ml) is added dropwise. After the addition is completed, the reaction is carried out for 2 h at room temperature; after the reaction of N-BOC-pyrrolidone is observed by TLC (RhoEpsilon/EpsilonAlpha = 2), the reaction is started with dilute hydrochloric acid (2N), and the pH is adjusted to 2-3; EA extraction, combined organic phase, washed with saturated brine, dried, evaporated to remove organic solvent, then added to the mixture of n-heptane 600ml, add 20g of activated carbon decolorization, heated reflux, hot filtered, solid precipitation, cooling to about 20 C, suction filtration The filter cake was washed with n-hexane and dried to give 158 g of the compound of formula (1) as a white solid (yield: 65.3%).
63.6%		2,5-Difluorobromobenzene (7.95 g, 41.4 mmol) was dissolved in anhydrous THF (50 mL).31.1 mL of an anhydrous THF solution of isopropylmagnesium chloride (31.1 mL, 62.2 mmol) was slowly added dropwise at -45 C, and the mixture was naturally warmed to 0 C for 1 h.Further, a solution of N-tert-butoxycarbonyl-2-pyrrolidone (11.5 g, 62.1 mmol) in anhydrous tetrahydrofuran (30 mL) was slowly added dropwise at -15 C.Stir at room temperature for 30 min. The reaction mixture was poured into 100 mL of a saturated aqueous solution of ammonium chloride and stirred for 10 min, and the mixture was separated, and the aqueous phase was extracted three times with 30 mL of ethyl acetate. Concentration by filtration and column chromatography gave 7.87 g of a colorless solid, Compound 1, yield: 63.6%.

		2-bromo-l,4-difluorobenzene (1.5 eq.) was dissolved in 4 volumes of THF (based on weight of tert-butyl2-oxopyrrolidine-l-carboxylate) and cooled to about 5 Celsius. A solution of 2.0 M iPrMgCl in THF (1.4 eq.) was added over 2 hours to the mixture while maintaining a reaction temperature below 25 Celsius. The solution was allowed to cool to about 5 Celsius and stirred for 1 hour (GC analysis confirmed Grignard formation). A solution of tert-butyl 2-oxopyrrolidine-l-carboxylate (1.0 eq.) in 1 volume of THF was added over about 30 min while maintaining a reaction temperature below 25 Celsius. The reaction was stirred at about 5Celsius for 90 min (tert-butyl 2-oxopyrrolidine-l-carboxylate was confirmed to be less than 0.5 area % by HPLC). The reaction was quenched with 5 volumes of 2M aqueous HC1 while maintaining a reaction temperature below 45 Celsius. The reaction was then transferred to a reparatory funnel adding 10 volumes of heptane and removing the aqueous layer. The organic layer was washed with 4 volumes of saturated aqueous NaCl followed by addition of 2x1 volume of saturated aqueous NaCl. The organic layer was solvent-switched to heptane (<1% wt THF confirmed by GC) at a distillation temperature of 35-55 Celsius and distillation pressure of 100-200 mm Hg for 2x4 volumes of heptane being added with a minimum distillation volume of about 7 volumes. The mixture wasthen diluted to 10 volumes with heptane while heating to about 55 Celsius yielded a denser solid with the mixture being allowed to cool to room temperature overnight. The slurry was cooled to less than 5 Celsius and filtered through polypropylene filter cloth. The wet cake was washed with 2x2 volumes of heptane. The solids were dried under vacuum at 55 Celsius until the weight was constant, yielding tert-butyl (4-(2,5-difluorophe-nyl)-4-oxobutyl)-carbamate as a white solid at about 75% to 85% theoretical yield.
		Step A-Preparation of tert-butyl (4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (1.5 eq.) was dissolved in 4 volumes of THF (based on weight of tert-butyl 2-oxopyrrolidine-1-carboxylate) and cooled to about 5 Celsius. A solution of 2.0 M iPrMgCl in THF (1.4 eq.) was added over 2 hours to the mixture while maintaining a reaction temperature below 250 Celsius. The solution was allowed to cool to about 5 Celsius and stirred for 1 hour (GC analysis confirmed Grignard formation). A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.0 eq.) in 1 volume of THF was added over about 30 min while maintaining a reaction temperature below 25 Celsius. The reaction was stirred at about 50 Celsius for 90 min (tert-butyl 2-oxopyrrolidine-1-carboxylate was confirmed to be less than 0.5 area % by HPLC). The reaction was quenched with 5 volumes of 2 M aqueous HCl while maintaining a reaction temperature below 45 Celsius. The reaction was then transferred to a separatory funnel adding 10 volumes of heptane and removing the aqueous layer. The organic layer was washed with 4 volumes of saturated aqueous NaCl followed by addition of 21 volume of saturated aqueous NaCl. The organic layer was solvent-switched to heptane (<1% wt THF confirmed by GC) at a distillation temperature of 35-55 Celsius and distillation pressure of 100-200 mm Hg for 24 volumes of heptane being added with a minimum distillation volume of about 7 volumes. The mixture was then diluted to 10 volumes with heptane while heating to about 55 Celsius yielded a denser solid with the mixture being allowed to cool to room temperature overnight. The slurry was cooled to less than 5 Celsius and filtered through polypropylene filter cloth. The wet cake was washed with 2*2 volumes of heptane. The solids were dried under vacuum at 55 Celsius until the weight was constant, yielding tert-butyl (4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate as a white solid at about 75% to 85% theoretical yield.

Reference： [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0175; 0177; 0178
[2]Patent: CN108101820,2018,A .Location in patent: Paragraph 0056
[3]Patent: CN109456331,2019,A .Location in patent: Paragraph 0137; 0139; 0140; 0141; 0142
[4]Patent: US2016/137654,2016,A1 .Location in patent: Paragraph 0242-0244
[5]Patent: US2017/281632,2017,A1 .Location in patent: Paragraph 0382; 0411
[6]Journal of the American Chemical Society,2019,vol. 141,p. 14083 - 14088

38
[ 399-94-0 ]
[ 228267-20-7 ]
tert-butyl N-[(2R)-2-[(tert-butyldimethylsilyl)oxy]-4-(2,5-difluorophenyl)-4-hydroxybutyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		To a solution of <strong>[399-94-0]2-bromo-1,4-difluorobenzene</strong> (3.97 mL, 35.4 mmol) in dry THF (118 mL) was added isopropylmagnesium chloride (2.0 M in THF, 21.2 mL, 42.5 mmol) at -78 C. The mixture was slowly warmed to 0 C. and stirred for 1 hour at that temperature and then cooled to -78 C. again. After the addition of a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate (13.4 g, 42.5 mmol) in dry THF (40 mL) at -78 C., the reaction mixture was allowed to warm to 0 C. with stirring for 1 hour. After addition of MeOH (118 mL) followed by NaBH4 (2.01 g, 53.1 mmol) at 0 C., the resulting mixture was stirred for 1 hour and then quenched with saturated aq. NH4Cl. The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=6:1) to afford tert-butyl (2R)-2-(tert-butyldimethylsilyloxy)-4-(2,5-difluorophenyl)-4-hydroxybutylcarbamate (10.2 g, 67%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz): delta 0.09-0.14 (6H, m), 0.91-0.93 (9H, m), 1.44 (9H, s), 1.73-1.93 (2H, m), 3.22-3.44 (2H, m), 3.66-3.83 (1H, m), 4.06-4.15 (1H, m), 4.81 (1H, s), 5.15-5.21 (1H, m), 6.87-6.97 (2H, m), 7.22-7.29 (1H, m).
		To a solution of 2-bromo-l,4-difluoro-benzene (3.01 g, 15.60 mmol, 1.20 Eq) in THF (15 mL) was added isopropyimagnesium chloride complex (2.27 g, 15.60 mmol, 1.20 Eq) at 0C dropwise under N2. The reaction was stirred at 15C for 1 hr to prepare (2, 5-difluorophenyl) magnesium bromide (23 mL). To a solution of tert-butyl (R)-4-((tert-butyldiniethyl.silyl)oxy)-2- oxopyrrolidine-l-carboxylate (4.10 g, 13.00 mmol, 1.00 Eq) in THF (50 mL) was added (2,5- difluorophenyl) magnesium bromide (23 mL) dropwise at ()C over 30 mins. The reaction mixture was stirred at 0C for 1 hr. Methanol (20 mL) was added to the mixture followed by NaBH4 (738 mg, 19.50 mmol, 1.50 Eq) at 0C. The mixture was stirred at 0C for 1 hr then poured into 10% aqueous NH4CI. The mixture was extracted with EtOAc (20 mL*2), the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The crude product was purified by medium pressure liquid chromatography (MPLC) to give tert-butyl ((2R)-2-((tert- butyldimethylsilyl)oxy)-4-(2,5-difluorophenyl)-4-hydroxybutyl)carbamate (2.22 g, 5.14 mmol, 39.6% yield). 1H-NMR (400 MHz, CDC13) delta ppm 7.17-7.15 (m, 1H), 6.86-6.79 (m, 2H), 5.11-5.06 (m, 1H), 4.70 (br.s, 1H), 4.02-3.98 (m, 1H), 3.69 (br.s, 0.5H), 3.46 (br.s, 0.5H), 3.33-3.14 (m, 2H), 1.80-1.69 (m. 2H), 1.35 (s. 9H), 0.84-0.82 (9H, m), 0.04-0.03 (6H, m).

Reference： [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0217; 0223; 0224
[2]Patent: WO2017/35354,2017,A1 .Location in patent: Page/Page column 68; 69

39
[ 399-94-0 ]
[ 1427382-15-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.75 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C / Inert atmosphere 2.1: methanol; tetrahydrofuran / 16.5 h / 60 °C 3.1: boron tribromide / dichloromethane / -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 1.2: 2 h / -78 °C 2.1: tetrahydrofuran; methanol / 12 h / 60 °C 3.1: boron tribromide / dichloromethane / 3 h / -40 - 0 °C
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.75 h / -70 °C 1.2: 2 h / -70 °C 2.1: tetrahydrofuran; methanol / 18 h / 60 °C 3.1: boron tribromide / dichloromethane / 18 h / -78 - 20 °C

	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.75 h / -70 °C 1.2: 2 h / -70 - 0 °C 2.1: sodium methylate / tetrahydrofuran / 18 h / 60 °C 3.1: boron tribromide / dichloromethane / 18 h / -78 - 20 °C
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.5 h / -78 °C 1.2: 0.5 h / -78 °C 2.1: sodium / 1.17 h 2.2: 20 h / Reflux 3.1: boron tribromide / dichloromethane / 18 h / -78 - 20 °C
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.75 h / -70 °C 1.2: 2 h / -70 °C 2.1: methanol / tetrahydrofuran / 18 h / 60 °C 3.1: boron tribromide / dichloromethane / 18 h / -78 - 30 °C
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h 1.2: 2 h / -78 °C 2.1: tetrahydrofuran / 12 h / 60 °C 3.1: boron tribromide / dichloromethane / 3 h / -40 - 0 °C
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 45 min / -70 °C 1.2: 2 h / -70 - 0 °C 2.1: tetrahydrofuran; methanol / 18 h / 60 °C 3.1: boron tribromide / dichloromethane / 18 h / -78 - 20 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2016/176882, 2016, A1
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/23417, 2019, A1
[3]Current Patent Assignee: SHANGHAI BLUERAY BIOPHARMA; SHANGHAI QINGYU PHARMACEUTICAL TECH - CN109942556, 2019, A
[4]Current Patent Assignee: SHANGHAI BLUERAY BIOPHARMA - CN110563722, 2019, A
[5]Current Patent Assignee: XENON PHARMACEUTICALS INC - WO2019/241533, 2019, A1
[6]Current Patent Assignee: SHANGHAI BLUERAY BIOPHARMA; BLUERAY THERAPEUTICS SHANGHAI; SHANGHAI BLUERAY BIOPHARMA CO LTD - EP4019521, 2022, A1
[7]Current Patent Assignee: BEIJING GUOHONG BIOMEDICAL TECH - WO2022/171139, 2022, A1
[8]Current Patent Assignee: SHANGHAI BLUERAY BIOPHARMA - WO2022/171166, 2022, A1

40
[ 399-94-0 ]
[ 1223404-90-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 5 - 25 °C 1.2: 2 h / 5 - 25 °C 2.1: hydrogenchloride / water; toluene / 65 °C 3.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole; diphenylsilane / tert-butyl methyl ether / 5 - 20 °C 3.2: 65 °C 4.1: triethylamine / ethanol; tetrahydrofuran / 40 - 50 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / 5 - 250 °C 1.2: 2 h / 25 - 50 °C / Inert atmosphere 2.1: hydrogenchloride / water; toluene / 65 °C / Inert atmosphere 3.1: chloro(1,5-cyclooctadiene)iridium(I) dimer; (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole; diphenylsilane / tert-butyl methyl ether / 10 - 50 °C / Inert atmosphere 4.1: triethylamine / ethanol / 20 - 65 °C / Inert atmosphere 5.1: triethylamine / tetrahydrofuran; ethanol / 40 - 50 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC - US2016/137654, 2016, A1
[2]Current Patent Assignee: ELI LILLY & CO - US2017/281632, 2017, A1

41
[ 399-94-0 ]
[ 241479-72-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: magnesium / tetrahydrofuran / 3.5 h / 20 - 45 °C / Large scale 2.1: tetrahydrofuran / 4.25 h / -20 - 20 °C / Large scale 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 20 - 35 °C / Large scale 3.2: 30 - 90 °C / Large scale 4.1: toluene-4-sulfonic acid / 16 h / 0 - 35 °C / Large scale
	Multi-step reaction with 4 steps 1.1: magnesium / tetrahydrofuran / 3.5 h / 20 - 45 °C / Large scale 2.1: tetrahydrofuran / 4.25 h / -20 - 20 °C / Large scale 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 20 - 35 °C / Large scale 3.2: 30 - 90 °C / Large scale 4.1: toluene-4-sulfonic acid / 16 h / 0 - 35 °C / Large scale
	Multi-step reaction with 4 steps 1.1: magnesium / tetrahydrofuran / 3.5 h / 20 - 45 °C / Large scale 2.1: tetrahydrofuran / 4.25 h / -20 - 20 °C / Large scale 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 20 - 35 °C / Large scale 3.2: 30 - 90 °C / Large scale 4.1: toluene-4-sulfonic acid / 16 h / 0 - 35 °C / Large scale

	Multi-step reaction with 4 steps 1.1: magnesium / tetrahydrofuran / 3.5 h / 20 - 45 °C / Large scale 2.1: tetrahydrofuran / 4.25 h / -20 - 20 °C / Large scale 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 20 - 35 °C / Large scale 3.2: 30 - 90 °C / Large scale 4.1: toluene-4-sulfonic acid / 16 h / 0 - 35 °C / Large scale
	Multi-step reaction with 4 steps 1.1: magnesium / tetrahydrofuran / 3.5 h / 20 - 45 °C / Large scale 2.1: tetrahydrofuran / 4.25 h / -20 - 20 °C / Large scale 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 20 - 35 °C / Large scale 3.2: 30 - 90 °C / Large scale 4.1: toluene-4-sulfonic acid / 16 h / 0 - 35 °C / Large scale

Reference： [1]Current Patent Assignee: NANTONG NUOTAI BIOLOGICAL PHARMACEUTICAL - CN105367556, 2016, A
[2]Current Patent Assignee: NANTONG NUOTAI BIOLOGICAL PHARMACEUTICAL - CN105367556, 2016, A
[3]Current Patent Assignee: NANTONG NUOTAI BIOLOGICAL PHARMACEUTICAL - CN105367556, 2016, A
[4]Current Patent Assignee: NANTONG NUOTAI BIOLOGICAL PHARMACEUTICAL - CN105367556, 2016, A
[5]Current Patent Assignee: NANTONG NUOTAI BIOLOGICAL PHARMACEUTICAL - CN105367556, 2016, A

42
[ 399-94-0 ]
[ 241479-73-2 ]

Reference： [1]Patent: CN105367556,2016,A
[2]Patent: CN105367556,2016,A
[3]Patent: CN105367556,2016,A
[4]Patent: CN105367556,2016,A
[5]Patent: CN105367556,2016,A

43
[ 399-94-0 ]
C₁₁H₁₅NO₄ [ No CAS ]
(S)-tert-butyl (1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.2%		Preparation of Grignard reagentUnder argon atmosphere, to 25g, 0.13mol <strong>[399-94-0]2,5-difluoro-bromobenzene</strong> is dissolved in 50ml of toluene, cooled -10 deg.] C, was added dropwise isopropylmagnesium chloride in 150ml 1.3M solution of lithium chloride, and the reaction temperature was maintained not more than -5 . Completion of the dropwise addition, stirred for 30 minutes incubation.Grignard reactionUnder an argon atmosphere, the (4S) -N-Boc-4- propargyl-5-oxazolidinyl 13.7g, 65mmol in 100ml of anhydrous tetrahydrofuran was dissolved alkanones, cooled to -20 deg.] C; prepared above was added dropwise Grignard reagent, and maintaining the reaction temperature did not exceed -10 . Completion of the dropwise addition, stirring for 2 to 3 hours incubation, the reaction is complete, dilute hydrochloric acid was added dropwise 1M 100ml quenched reaction was slowly warmed to room temperature and stirred for 30 minutes. Liquid separation, the aqueous layer was extracted once 50ml of toluene, the organic layers combined, washed with water,Dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give compound 23 as a white semi-solid substance (15.1 g of), a yield of 75.2%.

Reference： [1]Patent: CN105693555,2016,A .Location in patent: Paragraph 0117-0125

44
[ 208520-80-3 ]
[ 399-94-0 ]
(S)-tert-butyl (1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.0%		Dichloromethane (150 mL) was added to the reactor, cooled to -20 deg.] C, then was slowly added a solution of isopropylmagnesium chloride in tetrahydrofuran (2M, 55mL, 0.11mol), and then (was added 19.3 g of <strong>[399-94-0]2,5-difluoro-bromobenzene</strong> , 0.1 mol) dissolved in anhydrous tetrahydrofuran (100 mL), which was slowly added to the above methylene chloride solution and stirred at this temperature for 2 hours, added another solution of isopropylmagnesium chloride in tetrahydrofuran (2M, 11mL, 0.22mol ), the resulting mixed solution was continued for 1 hour.Compound 3 (28.2g, 0.11mol) in dichloromethane (100 mL) was slowly added to the reaction solution, the reaction temperature was maintained below 0 .After the dropwise addition, the reaction solution was stirred at room temperature for 13 hours.The resultant reaction solution was cooled to 0 deg.] C, Another 200mL of saturated ammonium chloride was added dropwise to the reaction mixture, maintaining the reaction temperature was not higher than 10 .The resulting mixture was added hydrochloric acid (10%) pH was adjusted to 6-7.Liquid separation, the aqueous phase was extracted twice with dichloromethane, per 150mL.The combined extracts were washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate for 3 hours.After filtration, the filtrate solvent was removed to give crude compound 4 (29.5g).A mixed solution of 200mL of methylene chloride-hexane (1:20) was added to the crude product, the resulting suspension was stirred for 12 hours, filtered to give pure compound 4 (27.5 g of, 89.0% yield)

Reference： [1]Patent: CN106316888,2017,A .Location in patent: Paragraph 0058; 0059; 0069; 0061; 0062; 0063; 0064-0069
[2]Organic Process Research and Development,2016,vol. 20,p. 2074 - 2079

45
[ 399-94-0 ]
[ 1204-55-3 ]
[ 397-59-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 10h;Inert atmosphere;	General procedure: To an oven-dried 25 mL ground mouth test tube equipped with a stir bar was added S-2-acetamidophenyl ethanethioate (0.5 mmol), 1-bromo-2-iodobenzene (0.6 mmol), Cs2CO3 (2.0 mmol), DMF (3 mL). The test tube was sealed with a sleeve rubber stopper and evacuated and refilled with argon for three cycles. The mixture was stirred 130 oC for 10 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), and extracted with ethyl acetate (20 mL) for three times. The combined organic layer was dried with anhydrous MgSO4, and condensed in vacuum on a rotary evaporator. The residual was purified on a silica gel chromatograph column by means of gradient elution (eluent: petroleum ether / ethyl acetate) to give the desired product.

Reference： [1]Synthetic Communications,2017,vol. 47,p. 710 - 715

46
[ 399-94-0 ]
sodium pyrimidine-4-carboxylate [ No CAS ]
4-(2,5-difluorophenyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl acetamide; at 160℃; for 24h;Molecular sieve; Inert atmosphere;	General procedure: To an 10 mL vial reaction vessel equipped with a magnetic stirring bar was added Pyrimidinecarboxylates (0.6 mmol, 1.0 eq), aryl- and heteroaryl-bromides (1.2 mmol, 2.0 eq), Pd(PPh3)4 (35 mg, 0.03 mmol, 5.0 mol %), Cu2O (42 mg, 0.3 mmol, 0.5 eq), 3A MS (200 mg) and DMA (4.0 mL). The mixture was stirred at 160 C for 24 h under N2. After the reaction was complete, the mixture was washed with brine and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate / petroleum ether = 1/5 - 1/2).

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2723 - 2726

47
[ 399-94-0 ]
[ 57260-71-6 ]
tert-butyl 4-(2,5-difluorophenyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 110℃; for 16h;	Step 1 : tert-Butyi 4-(2,5-difluorophenyl)piperazine-l-carboxylate (0991) [00346] To a solution of A19-1 (500 mg, 2.59 mmol, 1.0 eq), A19-1A (579 mg, 3.11 mmol, 1.2 eq), BINAP (161 mg, 0.259 mmol, 0.1 eq), f-BuONa (498 mg, 5. 18 mmol, 2.0 eq) and Pdi(dba)3 (119 mg, 0.130 mmol, 0.05 eq) in toluene (5 mL). The reaction mixture was stirred at 110 C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with DCM (30 mL * 3). The combined organic layers were dried over NaiSOzt, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether: ethyl acetate = 1 : 0 to 10: 1) to afford the title compound (400 mg, 52% yield) as a yellow solid. NMR (400MHz, COC -d) delta 7.01 - 6.90 (m, 1H), 6.66 - 6.56 (m, 2H), 3.65 - 3.53 (m, 4H), 3.07 - 2.93 (m, 4H), 1.48 (s, 9H).

Reference： [1]Patent: WO2017/58716,2017,A1 .Location in patent: Paragraph 00346

48
[ 399-94-0 ]
[ 1223405-08-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 3 h / 5 - 250 °C 1.2: 2 h / 25 - 50 °C / Inert atmosphere 2.1: hydrogenchloride / water; toluene / 65 °C / Inert atmosphere 3.1: chloro(1,5-cyclooctadiene)iridium(I) dimer; (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole; diphenylsilane / tert-butyl methyl ether / 10 - 50 °C / Inert atmosphere 4.1: triethylamine / ethanol / 20 - 65 °C / Inert atmosphere 5.1: triethylamine / tetrahydrofuran; ethanol / 40 - 50 °C / Inert atmosphere 6.1: zinc; hydrogenchloride / tetrahydrofuran; water / 5 - 30 °C / Inert atmosphere 7.1: potassium carbonate / water / 20 - 30 °C / Inert atmosphere 8.1: water; ethanol / 50 °C / Inert atmosphere 8.2: 30 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US2017/281632, 2017, A1

49
[ 399-94-0 ]
[ 1217630-38-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 3 h / 5 - 250 °C 1.2: 2 h / 25 - 50 °C / Inert atmosphere 2.1: hydrogenchloride / water monomer; toluene / 65 °C / Inert atmosphere 3.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole; diphenylsilane / tert-butyl methyl ether / 10 - 50 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 1 h / -78 °C 2: D-glucose; β-nicotinamide adenine dinucleotide phosphate, oxidized form; sodium hydroxide / aq. phosphate buffer; methanol / 24 h / 30 °C / pH 7 / Enzymatic reaction

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US2017/281632, 2017, A1
[2]Bernhard, Laura M.; McLachlan, Jill; Gröger, Harald [Organic Process Research and Development, 2022, vol. 26, # 7, p. 2067 - 2074]

50
[ 399-94-0 ]
[ 1226781-44-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 15 steps 1.1: n-butyllithium / diethyl ether; hexane / 0.17 h / -98 °C 1.2: 1 h / -98 °C 2.1: triethylsilane / dichloromethane / 0.08 h / -78 °C / Inert atmosphere 2.2: 1 h 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 4.1: triethylamine / dichloromethane / 0.67 h / 0 - 20 °C / Inert atmosphere 5.1: sulfuric acid / acetone; water / 0.5 h / 100 °C 6.1: sodium methylate / methanol / 0.5 h / 50 °C 7.1: Dess-Martin periodane / dichloromethane / 2 h / 20 °C 8.1: acetic acid; sodium acetate / acetone / 4 h / 20 °C 9.1: boron trifluoride diethyl etherate / dichloromethane / 1 h / 20 °C / Inert atmosphere 10.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C 11.1: ammonium acetate / methanol / 0.08 h / 20 °C 11.2: 20 °C 12.1: triethylamine / dichloromethane; water / 4 h / 20 °C 13.1: bis-[(trifluoroacetoxy)iodo]benzene / water; acetonitrile / 1 h / 20 °C 14.1: trifluoroacetic acid / 1 h / 0 - 20 °C 14.2: 5 h / 0 - 15 °C 15.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h
	Multi-step reaction with 16 steps 1.1: n-butyllithium / diethyl ether; hexane / 0.17 h / -98 °C 1.2: 1 h / -98 °C 2.1: triethylsilane / dichloromethane / 0.08 h / -78 °C / Inert atmosphere 2.2: 1 h 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 4.1: triethylamine / dichloromethane / 0.67 h / 0 - 20 °C / Inert atmosphere 5.1: sulfuric acid / acetone; water / 0.5 h / 100 °C 6.1: sodium methylate / methanol / 0.5 h / 50 °C 7.1: Dess-Martin periodane / dichloromethane / 2 h / 20 °C 8.1: acetic acid; sodium acetate / acetone / 4 h / 20 °C 9.1: boron trifluoride diethyl etherate / dichloromethane / 1 h / 20 °C / Inert atmosphere 10.1: Dess-Martin periodane / dichloromethane / 0.5 h / 20 °C 11.1: hydroxylamine hydrochloride / methanol / 0.08 h / 20 °C 11.2: 20 °C 12.1: lithium aluminium tetrahydride / tetrahydrofuran / -78 - 20 °C 13.1: triethylamine / dichloromethane; water / 4 h / 20 °C 14.1: bis-[(trifluoroacetoxy)iodo]benzene / water; acetonitrile / 1 h / 20 °C 15.1: trifluoroacetic acid / 1 h / 0 - 20 °C 15.2: 5 h / 0 - 15 °C 16.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - CN107793389, 2018, A
[2]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - CN107793389, 2018, A

51
[ 942194-06-1 ]
[ 399-94-0 ]
C₂₀H₃₀F₂O₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		Under anhydrous and anaerobic conditions, 2,5-difluorobromobenzene (28.7 g, 0.149 mol) was dissolved in 150 mL of anhydrous ether, cooled to -98C, and n-BuLi (62 mL, 99 mmol, 1.6 M in Hexane), after 10 min of reaction, drip into intermediate 12-1(15g, 0.05mol) of anhydrous ether solution, after completion of the addition, maintained at -98C, reacted for 1 hour, and TLC detection reaction was completed. The reaction was quenched with saturated aqueous NH 4 Cl (100 mL), returned to room temperature, and extracted 4 times with TBME (100 mL×4). The layers were dried over anhydrous sodium sulfate, and the organic solvent was evaporated to dryness in vacuo. Toluene (50 mL × 2) was azeotropically removed twice and rapidly prepared. The spectrum was isolated as a colorless oil 14-1 (20 g, 0.048 mmol). Yield: 97%.

Reference： [1]Patent: CN107793389,2018,A .Location in patent: Paragraph 0287; 0288; 0289; 0290

52
[ 5724-81-2 ]
[ 399-94-0 ]
[ 886503-15-7 ]

Yield	Reaction Conditions	Operation in experiment
93%		In a reaction flask equipped with a reflux tube, a constant pressure drop filter and a thermometer, nitrogen protection, followed by addition of magnesium chips (3.00 g, 125 mmol, 1.4 eq),20 mL of anhydrous tetrahydrofuran, 1-bromoethane (0.2 mL), about 2/5 of 2,5-difluorobromobenzene (20.00 g, 104 mmol, 1.2 eq, dissolved in 40 mL of anhydrous THF).Stirring to 45 C, stirring for 0.5 hours, start the reaction, continue to slowly add 2,5-difluorobromobenzene solution, after the addition, the reaction was kept for 2 hours.The temperature was lowered to 10 C, and 3,4-dihydro-2H-pyrrole (6.00 g, 87 mol, 1.0 eq) was added dropwise. After the addition, the reaction was stirred at 10 C for 16 hours.The mixture was cooled to room temperature, dissolved in aq.The solvent was evaporated under reduced pressure to give a yellow oil 14.82 g, that is 2- (2,5-difluorophenyl) pyrrolidine in 93% yield.

Reference： [1]Patent: CN108218754,2018,A .Location in patent: Paragraph 0041; 0047; 0052; 0057; 0062; 0063; 0067

53
[ 399-94-0 ]
[ 1056264-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium; diisopropylamine / tetrahydrofuran; hexanes / 1.67 h / -78 - -65 °C 1.2: 0.5 h / -78 °C 2.1: hydrazine / 1,2-dimethoxyethane / 144.08 h / Heating / reflux

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/107455, 2008, A1

54
[ 399-94-0 ]
[ 1066-54-2 ]
[ 1152046-98-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 3h;Inert atmosphere;	Compound SM (2g, 10.4mmol), CuI (120mg, 0.6mmol) and Pd(PPh3)2Cl2 (440mg,0.6 mmol) was added to a three-necked flask, and after N2 was replaced three times, DMF (20 ml) and trimethylethynyl silane(1.63 g,16.6 mmol) was replaced with N2, and finally triethylamine (1.68 g, 16.6 mmol) was added. After N2 was replaced, the mixture was stirred at 70 C for 3 hours.After complete reaction, the system was cooled to room temperature, filtered over celite, and the filtrate was diluted with water and extracted with ethyl acetate.The phases were washed successively with water, brine, and brine, dried over anhydrous sodium sulfatePurification by column chromatography gave ((2,5-difluorophenyl)ethynyl)trimethylsilane (2.1 g, yield 96%, brown oil).

Reference： [1]Patent: CN109293652,2019,A .Location in patent: Paragraph 0442-0446

55
[ 399-94-0 ]
[ 116465-48-6 ]

Reference： [1]Patent: CN109369412,2019,A

56
[ 399-94-0 ]
3N-tert-butoxycarbonyl-2-pyrrolidone-3,3,4,4-d4 [ No CAS ]
(4-(2,5-difluorophenyl)-4-oxobutyl-2,2,3,3-d4)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.6%		2,5-Difluorobromobenzene (500 mg, 2.6 mmol) was dissolved in 5 mL of THF.An isopropylmagnesium chloride anhydrous THF solution (1.56 mL, 3.12 mmol) was slowly added dropwise at -45 C.After the dropwise addition, the temperature was naturally raised to 0 C and stirred for 1 h.Further, a solution of Compound 17 (466 mg, 2.46 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise at -15 C, and stirred at room temperature for 30 min.The reaction solution was poured into 10 mL of a saturated ammonium chloride solution and stirred for 10 min.The mixture was separated and the aqueous phase was extracted three times with 10 mL of ethyl acetate.The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration by filtration, column chromatography (PE / EA, 0% ~ 10%) to give 367 mg of colorless solids as compound 18Yield: 46.6%.

Reference： [1]Patent: CN109456331,2019,A .Location in patent: Paragraph 0182; 0184; 0185; 0192; 0193

57
[ 399-94-0 ]
[ 1099646-61-3 ]
methyl (3S)-1-(2,5-difluorophenyl)pyrrolidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 18.0h;Inert atmosphere;	A mixture of (S)-mcthyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (1.00 g, 6.04 mmol), l-bromo-2,5-difluorobenzene [399-94-0] (1.02 mL, 9.06 mmol) and cesium carbonate (5.90 g, 18.1 mmol) in l,4-dioxane (50 mL) was purged with nitrogen for 15 min. XantPhos (349 mg, 0.60 mmol) and palladium acetate (136 mg, 0.60 mmol) were added and the resulting mixture was purged with nitrogen. The reaction mixture was stirred at l00C for 18 h. The reaction mixture was filtered through a pad of Celite. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS04, filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 80 g Grace, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to afford intermediate 1101 (780 mg, 54%) as a colorless oil.

Reference： [1]Patent: WO2019/106004,2019,A1 .Location in patent: Page/Page column 150-151

58
[ 399-94-0 ]
[ 37500-95-1 ]
C₄₆H₅₁BrN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 24h;Inert atmosphere;	(1) 2.79 g (10.0 mmol) of 3,6-di-tert-butylcarbazole was added to a 100 mL three-necked flask.6.52g (20.0mmol) of cesium carbonate, replaced with nitrogen three times to remove oxygen,0.78 g (4 mmol) of 2,5-difluorobromobenzene was injected under a nitrogen atmosphere.15 mL DMF ultra dry solvent, heated at 160 C for 24 h.After the TCL monitoring reaction is completed, the reaction system is cooled to room temperature.Extracted with 150 mL of ethyl acetate and 300 mL of saturated brine.Subsequently, the organic phase was washed three times with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate for 10 min, filtered and concentrated.The crude product was passed through a silica gel column (5×10 cm), and the pure product was isolated and dried in vacuo.The product 24-1 2.59 g was obtained with a yield of 91%.

Reference： [1]Patent: CN110256409,2019,A .Location in patent: Paragraph 0051-0054

59
[ 399-94-0 ]
[ 1218935-59-1 ]
(S)-(–)-2-(2,5-difluorophenyl)pyrrolidine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 14083 - 14088

60
[ 15226-74-1 ]
[ 399-94-0 ]
[ 95-55-6 ]
[ 3158-90-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With palladium diacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 150℃; for 16h;Sealed tube; Inert atmosphere;	General procedure: A sealed tube equipped with a magnetic stir bar was charged with the corresponding 1-bromo -2-fluoro (or chloro) benzene/ 1-fluoro-2-iodobenzene (1 mmol), amino phenol (1 mmol), Pd(OAc)2 (5 mol%), xantphos (5 mol%) and DBU (2.5 mmol). The tube was purged with argon. Then DMF (10 V) was added followed by the addition of Co2(CO)8 (0.25 mmol). The tube was closed with seal plug instantly. The reaction tube was placed in a pre heated oil bath at 150 0C for 16 h. On completion, the reaction mixture was cooled to room temperature, added water and ethyl acetate (1:1). Precipitated solid was filtered through a Celite bed. The bed was washed thoroughly with ethyl acetate. Organic layer was separated. Aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure and purified by flash column chromatography on silica gel (230-400 mesh) with ethyl acetate and petroleum ether as eluent to afford the corresponding dibenzoxazepinones.

Reference： [1]Synthetic Communications,2020,vol. 50,p. 348 - 360

61
[ 399-94-0 ]
[ 85909-08-6 ]
[ 1443623-92-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 2-bromo-1,4-difluorobenzene With isopropylmagnesium chloride lithium chloride In tetrahydrofuran at 5 - 25℃; for 3h; Stage #2: tert-butyl 2-oxopyrrolidine-1-carboxylate In tetrahydrofuran at 5 - 25℃; for 2h; Stage #3: With hydrogenchloride In water monomer; toluene at 70℃;
67%	Stage #1: 2-bromo-1,4-difluorobenzene With isopropylmagnesium chloride lithium chloride In tetrahydrofuran at -78℃; for 1h; Stage #2: tert-butyl 2-oxopyrrolidine-1-carboxylate In tetrahydrofuran Stage #3: With trifluoroacetic acid

Reference： [1]Chen, Fei-Fei; Chen, Qi; Li, Bo-Bo; Xu, Jian-He; Zhang, Yu-Hui; Zheng, Gao-Wei; Zhou, Xin-Yi [Organic Letters, 2020, vol. 22, # 9, p. 3367 - 3372]
[2]Bernhard, Laura M.; McLachlan, Jill; Gröger, Harald [Organic Process Research and Development, 2022, vol. 26, # 7, p. 2067 - 2074]

62
[ 90870-83-0 ]
[ 399-94-0 ]
4-(4-morpholine-yl)-7-(2,5-difluorophenyl)-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With caesium carbonate; copper(I) oxide In N,N-dimethyl acetamide at 200℃; for 1h; Sealed tube; Microwave irradiation;	General synthetic procedure for 2,7 or4,7-disubstituted pyrrolo[2,3-d]pyrimidines(2a-7d) General procedure: 4-(Mophinyl)-7H pyrrolo[2,3-d]pyrimidine (1a) (0.5 mmol),bromobenzene (0.75 mmol), Cs2CO3 (0.5 mmol), Cu2O (10 mol%), and DMA (5 ml) were added to 10 ml vial.25,26The vial was sealed with a crimp cap and placed in aBiotage initiator microwave cavity. After irradiation at 200C for 1 h and subsequent cooling, the reacted mixturewas diluted with saturated aqueous ammonium chloride.Products were extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, filtered,and concentrated. Products were purified by silica gel columnchromatography using a hexane: ethyl acetate = 2:1eluent. 4-(4-Morpholinyl)-7-phenyl-pyrrolo[2,3-d]pyrimidine(2a) was obtained with 78% yields as a pink solid. mp:141-142 C. 1H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 7.68-7.61 (m, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H),7.23 (d, J = 3.6 Hz, 1H), 6.61 (d, J = 3.6 Hz, 1H), 4.01-3.91(m, 4H), 3.88-3.81 (m, 4H). 13C NMR (75MHz, CDCl3) δ157.44, 151.81, 151.43, 137.87, 129.37, 126.94, 124.41,123.96, 104.06, 102.00, 66.80, 46.08. MS(m/z):280.33(M + 1).The following compounds (2b-7d) were prepared bygeneral synthetic procedure.

Reference： [1]Hong, Chang Sung; Park, Seung Yeong; Byeon, Jeong Seob; Yum, Eul Kgun [Bulletin of the Korean Chemical Society, 2021, vol. 42, # 12, p. 1641 - 1649]

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Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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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. 399-94-0 ] {[proInfo.proName]}

Quality Control of [ 399-94-0 ]

Related Doc. of [ 399-94-0 ]

Product Details of [ 399-94-0 ]

Calculated chemistry of [ 399-94-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 399-94-0 ]

Application In Synthesis of [ 399-94-0 ]

[ 399-94-0 ] Synthesis Path-Upstream 1~16

[ 399-94-0 ] Synthesis Path-Downstream 1~62

Pharmaceutical Intermediates of [ 399-94-0 ]

Isavuconazonium Sulfate Related Intermediates

Related Functional Groups of [ 399-94-0 ]

Fluorinated Building Blocks

Aryls

Bromides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 399-94-0 ]

Related Functional Groups of
[ 399-94-0 ]