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[ CAS No. 123843-57-2 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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Chemical Structure| 123843-57-2

Chemical Structure| 123843-57-2

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Quality Control of [ 123843-57-2 ]

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Product Details of [ 123843-57-2 ]

CAS No. :	123843-57-2	MDL No. :	MFCD03094499
Formula :	C₇H₃F₂NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KEIYYIGMDPTAPL-UHFFFAOYSA-N
M.W :	155.10	Pubchem ID :	2778774
Synonyms :

Safety of [ 123843-57-2 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P332+P313-P362-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405	UN#:	3439
Hazard Statements:	H301+H311+H331-H315-H319	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 123843-57-2 ]

* 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 [ 123843-57-2 ]
Downstream synthetic route of [ 123843-57-2 ]

[ 123843-57-2 ] Synthesis Path-Upstream 1~5

1
[ 123843-66-3 ]
[ 123843-57-2 ]

Reference： [1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190

2
[ 93343-10-3 ]
[ 123843-57-2 ]

Reference： [1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190

3
[ 125369-57-5 ]
[ 123843-57-2 ]

Reference： [1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190

4
[ 123843-65-2 ]
[ 123843-57-2 ]

Reference： [1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190

5
[ 125369-56-4 ]
[ 123843-57-2 ]

Reference： [1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190

[ 123843-57-2 ] Synthesis Path-Downstream 1~79

1
[ 26311-45-5 ]
[ 123843-57-2 ]
4-cyano-3,5-difluorophenyl 4-pentylbenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

2
[ 1498-96-0 ]
[ 123843-57-2 ]
4-cyano-3,5-difluorophenyl 4-butoxybenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

3
[ 123843-57-2 ]
[ 123843-53-8 ]
4-cyano-3,5-difluorophenyl 2-fluoro-4-pentylbenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

4
[ 123843-57-2 ]
[ 123843-55-0 ]
4-cyano-3,5-difluorophenyl 2,6-difluoro-4-pentylbenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

5
[ 123843-57-2 ]
[ 123843-56-1 ]
4-cyano-3,5-difluorophenyl 4-butoxy-2,6-difluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

6
[ 123843-57-2 ]
[ 123843-54-9 ]
4-cyano-3,5-difluorophenyl 4-butoxy-2-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

7
[ 123843-57-2 ]
[ 123843-54-9 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

8
[ 123843-66-3 ]
[ 123843-57-2 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

9
[ 93343-10-3 ]
[ 123843-57-2 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

10
[ 123843-57-2 ]
4-cyanophenyl 4-butoxy-2-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

11
[ 123843-57-2 ]
4-cyano-3-fluorophenyl 4-butoxy-2-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

12
[ 123843-57-2 ]
4-cyano-3,5-difluorophenyl 4-butoxy-2-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

13
[ 123843-57-2 ]
4-cyanobiphenyl-4'-yl 4-butoxy-2-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

14
[ 123843-57-2 ]
4-cyano-3-fluorobiphenyl-4'-yl 4-butoxy-2-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

15
[ 123843-57-2 ]
4-cyano-3,5-difluorobiphenyl-4'-yl 4-butoxy-2-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

16
[ 125369-57-5 ]
[ 123843-57-2 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

17
[ 123843-65-2 ]
[ 123843-57-2 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

18
[ 125369-56-4 ]
[ 123843-57-2 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190

19
[ 63649-88-7 ]
[ 123843-57-2 ]
2,6-difluoro-4-[2-(2-naphthalenyloxy)-ethoxy]benzonitrile [ No CAS ]
2,6-difluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; water;	EXAMPLE 200 Preparation of 2,6-difluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester A stirred mixture of <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong> (3 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.842 g), stirred for 30 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (5.1 g). The mixture was heated at 60 C. overnight and evaporated to dryness. The residue was mixed with water and excess sodium hydroxide solution, the product was extracted twice with dichloromethane, and the organic layers were washed with water. The combined organic layers were dried (Na2 SO4), filtered, and evaporated. The crude material was purified by HPLC (dichloromethane-hexane 2:1) and crystallized from dichloromethane-hexane to provide 4.3 g of 2,6-difluoro-4-[2-(2-naphthalenyloxy) ethoxy]benzonitrile as a colorless solid, mp 148-149 C. Analysis Calculated for C19 H13 F2 NO2: C, 70.15; H, 4.03; N, 4.31; F, 11.68. Found: C, 69.99; H, 3.92; N, 4.19; F, 11.56.

Reference： [1]Patent: US5344843,1994,A

Yield	Reaction Conditions	Operation in experiment
		The 3,5-difluoro-4-cyanophenol can be obtained by nitrating 2,6-difluoroaniline, diazotizing the resulting 4-nitro-2,6-difluoroaniline, decomposing the diazonium salt in the presence of a cuprous cyanide to obtain 4-nitro-2,6-difluoro-1-cyanobenzene, reducing the product to obtain 4-cyano-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

21
[ 123843-57-2 ]
2,6-difluoro-4-hydroxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With water; sodium hydroxide; In water; at 80℃;	2,6-difluoro-4-hydroxy-benzonitrile (0.7 g, 4.51 mmol) was dissolved in 3 mL distilled water and a solution of NaOH (0.632 g, 15.8 mmol) in 3 mL of water was then added. Reaction mixture was then heated at 80C overnight. Heating was then stopped, and the reaction mixture was acidified by adding concentrated HC1, extracted with DCM and then extracted with Et20. Organic phase was dried overNa2SO4, and evaporated, to give 790 mg of 2,6-difluoro-4-hydroxy-benzoic acid as a white solid, leading to a 100 % yield.MS: [M-t-H] mlz = 174.?H NMR (DMSO-d6): oe (ppm) 6.46-6.53 (m, 2H) ; 10.95 (s, 1H) ; 13.21 (s, 1H).
94%	With sodium hydroxide; In water; for 96h;Reflux;	2,6-Difluoro-4-hydroxy-benzoic acid2,6-Difluoro-4-hydroxy-benzonitrile (1.5 g) is dissolved in 7 mL distilled water and a solution of 1,35 g of NaOH in 4 mL water is then added. Reaction mixture is then heated at reflux for 4 days. Heating is then stopped, and reaction mixture is acidified by adding concentrated HCl, and extracted with Et20. Organic phase is then extracted by saturated NaHCC"3 aq. This aqueous solution is then acidified by adding concentrated HCl, and then extracted by Et20. Organic phase is dried over Na2S04, and evaporated, to give 1.58 g of a white solid corresponding to the expected acid (94 %).MS [M-H]- m/z = 172.91H-NMR DMSO-d6) : delta (ppm) ; 6.49 (m, 2H) ; 10.96 (brs, 1H) ; 13.20 (brs, 1H)

Reference： [1]Patent: WO2017/42380,2017,A1 .Location in patent: Page/Page column 74; 75
[2]Patent: WO2015/189330,2015,A1 .Location in patent: Page/Page column 45
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211
[4]Molecular Crystals and Liquid Crystals,2008,vol. 487,p. 52 - 60

22
C₁₉H₁₈ClFO₃ [ No CAS ]
[ 123843-57-2 ]
[ 1227870-17-8 ]

Reference： [1]Molecular Crystals and Liquid Crystals,2009,vol. 502,p. 258 - 271

23
[ 58573-94-7 ]
[ 123843-57-2 ]
[ 1392007-35-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;	[Example 3][0193] In this example, an example of synthesizing 4-(4-n-heptylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (abbreviation: PPEP-7FCNF) represented by the structural formula (107) in Embodiment 1 will be described.[0194](Synthesis method of 4-(4-«-heptylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (abbreviation: PPEP-7FCNF))[0195] A synthetic scheme of PPEP-7FCNF (abbreviation) represented by the structural formula (107) is shown in (C-l) below.[0196] [0197] Into a 50-mL recovery flask were put 2.0 g (6.7 mmol) of 4-(4-«-heptylphenyl)benzoic acid, 1.0 g (6.4 mmol) of <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong>, 0.12 g (0.98 mmol) of 4-dimethylaminopyridine, and 6.7 mL of dichloromethane, and stirring was performed. To this mixture, 1.4 g (7.3 mmol) of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochroride (EDC) was added, and stirring was performed in the air at room temperature for 24 hours. After predetermined time passed, water was added to the obtained mixture to extract an aqueous layer of this mixture with dichloromethane. The obtained extracted solution and an organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then, the mixture was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a white solid. This solid was purified by silica gel column chromatography (developing solvent: toluene). The obtained fraction was concentrated to give a white solid. This solid was purified by high performance liquid chromatography (HPLC) (developing solvent: chloroform). The obtained fraction was concentrated to give 2.3 g of a white solid, which was a target substance, in a yield of 79 %.[0198] Further, 1.4 g of the obtained white solid was purified by distillation, whereby 1.2 g of a white solid, which was a target substance, was obtained in a yield of 86 %.[0199] This compound was identified by a nuclear magnetic resonance method (NMR) as 4-(4-rc-heptylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (PPEP-7FCNF) which was a target substance.[0200] The H NMR data of the obtained substance (PPEP-7FCNF) is as follows. 1HNMR (CDCI3, 300 MHz): delta (ppm) = 0.89 (t, 3H), 1.30-1.34 (m, 8H), 1.63-1.69 (m, 2H), 2.67 (t, 2H), 7.09 (d, 2H), 7.31 (d, 2H), 7.58 (d, 2H), 7.75 (d, 2H), 8.20 (d, 2H). FIGS. 10A to IOC are 1H NMR charts. Note that FIG. 10B is an enlarged chart showing the range of 6.5 ppm to 8.5 ppm in FIG. 10A. Note also that FIG. IOC is an enlarged chart showing the range of 0.0 ppm to 3.0 ppm in FIG. 10A.

Reference： [1]Patent: WO2012/105380,2012,A1 .Location in patent: Page/Page column 45-47

24
[ 123843-57-2 ]
4'-n-undecylbiphenyl-4-carboxylic acid [ No CAS ]
[ 1392007-48-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;	[Example 5][0208] In this example, an example of synthesizing 4-(4-«-undecylphenyl)benzoic acid4-cyano-3,5-difluorophenyl (abbreviation: PPEP-11FCNF) represented by the structural formula (111) in Embodiment 1 will be described.[0209] (Synthesis method of 4-(4-«-undecylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (abbreviation: PPEP-11FCNF))[0210] A synthetic scheme of PPEP-11FCNF (abbreviation) represented by the structural formula (111) is shown in (E-l) below.[0211][0212] Into a 50-mL recovery flask were put 2.0 g (5.7 mmol) of 4-(4-n-undecylphenyl)benzoic acid, 0.88 g (5.7 mmol) of <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong>, 0.11 g (0.90 mmol) of 4-(N,N-dimethyl)aminopyridine, and 5.7 mL of dichloromethane, and stirring was performed. To this mixture, 1.2 g (6.3 mmol) of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochroride (EDC) was added, and stirring was performed in the air at room temperature for 24 hours. After predetermined time passed, water was added to the obtained mixture to extract an aqueous layer of this mixture with dichloromethane. The obtained extracted solution and an organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then, the mixture was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a white solid. This solid was purified by silica gel column chromatography (developing solvent: toluene). The obtained fraction was concentrated to give a white solid. This solid was purified by high performance liquid column chromatography (HPLC) (developing solvent: chloroform). The obtained fraction was concentrated to give 1.7 g of a white solid, which was a target substance, in a yield of 61 %.[0213] This compound was identified by a nuclear magnetic resonance method (NMR) as 4-(4-«-undecylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (PPEP-11FCNF) which was a target substance.[0214] The 1H NMR data of the obtained substance (PPEP-11FCNF) is as follows. 1H NMR (CDC13, 300 MHz): delta (ppm) = 0.88 (t, 3H), 1.27-1.33 (m, 16H), 1.63-1.68 (m, 2H), 2.67 (t, 2H), 7.08 (d, 2H), 7.31 (d, 2H), 7.58 (d, 2H), 7.75 (d, 2H), 8.20 (d, 2H). FIGS. 12A to 12C are 1H NMR charts. Note that FIG. 12B is an enlarged chart showing the range of 7.0 ppm to 8.5 ppm in FIG. 12A. Note also that FIG. 12C is an enlarged chart showing the range of 0.0 ppm to 3.0 ppm in FIG. 12A.

Reference： [1]Patent: WO2012/105380,2012,A1 .Location in patent: Page/Page column 48-50

25
[ 59662-47-4 ]
[ 123843-57-2 ]
[ 1350640-48-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	[Example 2][0185] In this example, an example of synthesizing 4-(4-n-pentylphenyl)benzoic acid 4-cyano-3,5-difluorophenyI (abbreviation: PPEP-5FCNF) represented by the structural formula (105) in Embodiment 1 will be described.[0186](Synthesis method of 4-(4-n-pentylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (abbreviation: PPEP-5FCNF)) [0187] A synthetic scheme of PPEP-5FCNF (abbreviation) represented by the structural formula (105) is shown in (A-l) below.[0188] [0189] Into -mL recovery flask were put 2.3 g (8.6 mmol)4-(4-n-pentylphenyl)benzoic acid, 1.3 g (8.4 mmol) of <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong>, 0.16 g (1.3 mmol) of 4-dimethylaminopyridine, and 8.6 mL of dichloromethane, and stirring was performed. To this mixture, 1.8 g (9.4 mmol) of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochroride (EDC) was added, and stirring was performed in the air at room temperature for 18 hours. After predetermined time passed, water was added to the obtained mixture to extract an aqueous layer with dichloromethane. The obtained extracted solution and an organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then, the mixture was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a light brown solid. This solid was purified by silica gel column chromatography (developing solvent: toluene). The obtained fraction was concentrated to give a yellow solid. This solid was purified by high performance liquid chromatography (HPLC) (developing solvent: chloroform). The obtained fraction was concentrated to give 2.7 g of a white solid, which was a target substance, in a yield of 79 %.[0190] Further, 2.7 g of the obtained white solid was purified by distillation, whereby 2.5 g of a white solid, which was a target substance, was obtained in a yield of 93 %.[0191] This compound was identified by a nuclear magnetic resonance method (NMR) as 4-(4-«-pentylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (PPEP-5FCNF) which was a target substance.[0192] The lU NMR data of the obtained substance is as follows. 1H NMR (CDC13, 300 MHz): 5 (ppm) = 0.91 (t, 3H), 1.31-1.40 (m, 4H), 1.62-1.72 (m, 2H), 2.67 (t, 2H), 7.09 (d, 2H), 7.31 (d, 2H), 7.58 (d, 2H), 7.75 (d, 2H), 8.20 (d, 2H). FIGS. 9A to 9C are 1H NMR charts. Note that FIG. 9B is an enlarged chart showing the range of 6.5 ppm to 8.5 ppm in FIG. 9A. Note also that FIG. 9C is an enlarged chart showing the range of 0.0 ppm to 3.0 ppm in FIG. 9A.
79%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	Into a 50-mL flask, 2.3 g (8.6 mmol) of 4-(4-n-Pentylphenyl)benzoic acid, 1.3 g (8.4 mmol) of <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong>, 0.16 g (1.3 mmol) of 4-dimethylaminopyridine, and 8.6 mL of dichloromethane were put, and stirring was performed. To the mixture, 1.8 g (9.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) was added, and the resulting mixture was stirred at room temperature under the air atmosphere for 18 hours. After a predetermined time, water was added to the obtained mixture, and an aqueous layer was extracted with dichloromethane. The obtained extracted solution and an organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then, the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a light brown solid. This solid was purified by silica gel column chromatography (developing solvent: toluene). The resulting fraction was concentrated to give a white solid. This solid was purified by high performance liquid chromatography (HPLC) (developing solvent: chloroform). The obtained fractions obtained were concentrated to obtain 2.7 g of a white solid which was a target substance in 79% yield.Further, 2.7 g of the obtained white solid was purified by distillation, whereby 2.5 g of a white solid which was a target substance, was obtained in 93% yield.

Reference： [1]Patent: WO2012/105380,2012,A1 .Location in patent: Page/Page column 43-45
[2]Patent: JP5715876,2015,B2 .Location in patent: Paragraph 0244-0249

26
[ 88038-94-2 ]
[ 123843-57-2 ]
[ 1392007-24-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;	[Example 1] [0177] In this example, an example of synthesizing 4-(4-«-propylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (abbreviation: PPEP-3FCNF) represented by the structural formula (103) in Embodiment 1 will be described. [0178] (Synthesis method of 4-(4-«-propylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (abbreviation: PPEP-3FCNF))[0179] A synthetic scheme of PPEP-3FCNF (abbreviation) represented by structural formula (103) is shown in (B-1) below. [0180][0181] Into a 50-mL recovery flask were put 2.4 g (10 mmol) of 4-(4-n-propylphenyl)benzoic acid, 1.6 g (10 mmol) of <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong>, 0.18 g (1.5 mmol) of 4-dimethylaminopyridine, and 10 mL of dichloromethane, and stirring was performed. To this mixture, 2.2 g (11 mmol) of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochroride (EDC) was added, and stirring was performed in the air at room temperature for 24 hours. After predetermined time passed, water was added to the obtained mixture to extract an aqueous layer of this mixture with dichloromethane. The obtained extracted solution and an organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then, the mixture was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a yellow solid. This solid was purified by silica gel column chromatography (developing solvent: chloroform). The obtained fraction was concentrated to give a yellow solid. This solid was purified by high performance liquid chromatography (HPLC) (developing solvent: chloroform). The obtained fraction was concentrated to give 3.5 g of a white solid, which was a target substance, in a yield of 93 %.[0182] Further, 1.6 g of the obtained white solid was purified by distillation, whereby 1.5 g of a white solid, which was a target substance, was obtained in a yield of 94 %.[0183] This compound was identified by a nuclear magnetic resonance method (NMR) as 4-(4-n-propylphenyl)benzoic acid 4-cyano-3,5-difluorophenyl (PPEP-3FCNF) which was a target substance.[0184] The 1H NMR data of the obtained substance (PPEP-3FCNF) is as follows. 1H NMR (CDC13, 300 MHz): delta (ppm) = 0.96 (t, 3H), 1.62-1.74 (m, 2H), 2.64 (t, 2H), 7.07 (d, 2H), 7.29 (d, 2H), 7.56 (d, 2H), 7.73 (d, 2H), 8.18 (d, 2H). FIGS. 8A to 8C are 1H NMR charts. Note that FIG. 8B is an enlarged chart showing the range of 6.5 ppm to 8.5 ppm in FIG. 8A. Note also that FIG. 8C is an enlarged chart showing the range of 0.0 ppm to 3.0 ppm in FIG. 8A.

Reference： [1]Patent: WO2012/105380,2012,A1 .Location in patent: Page/Page column 42-43

27
[ 123843-57-2 ]
[ 1446948-27-1 ]

Reference： [1]Chemical Biology and Drug Design,2013,vol. 81,p. 198 - 207

28
[ 123843-57-2 ]
[ 1446947-96-1 ]

Reference： [1]Chemical Biology and Drug Design,2013,vol. 81,p. 198 - 207

29
[ 106-96-7 ]
[ 123843-57-2 ]
[ 1446948-11-3 ]

Reference： [1]Chemical Biology and Drug Design,2013,vol. 81,p. 198 - 207

30
[ 123843-57-2 ]
C₁₁H₁₃ClF₂O₄S [ No CAS ]

Reference： [1]Patent: WO2015/189330,2015,A1

31
[ 123843-57-2 ]
2,6-difluoro-4-hydroxybenzoic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2015/189330,2015,A1
[2]Patent: WO2017/42380,2017,A1
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

32
[ 123843-57-2 ]
3,5-difluoro-4-(hydroxymethyl)phenol [ No CAS ]

Reference： [1]Patent: WO2015/189330,2015,A1
[2]Patent: WO2017/42380,2017,A1
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

33
[ 123843-57-2 ]
[4-(3-chloropropoxy)-2,6-difluorophenyl]methanol [ No CAS ]

Reference： [1]Patent: WO2015/189330,2015,A1
[2]Patent: WO2017/42380,2017,A1
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

34
[ 123843-57-2 ]
2-[2-[2,6-difluoro-4-(3-chloropropoxy)benzyl]-3-(4-fluorophenyl)isothioureido]-N-(3,4-dimethoxyphenyl)-N-methylacetamide [ No CAS ]

Reference： [1]Patent: WO2015/189330,2015,A1
[2]Patent: WO2017/42380,2017,A1
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

35
3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propyl methanesulfonate [ No CAS ]
[ 123843-57-2 ]
2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;	(Step 2-7 Preparation of 2,6-difluoro-4-(3-(l-(5-(5-isobutyl-h2,4-oxadiazol-3-yl) pyrimidi -2-yl)piperidin-4-yl)propoxy)benzonitrile 2,6-Difluoro-4-hydroxybenzonitrile (6.6 g, 0.042 mol) was dissolved in N,N-dimethyl formamide (DMF, 0.3 L), and 3-(l -(5-(5-isobutyl-l ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propyl methane sulfonate synthesized in the above step 2-6 (15 g, 0.035 mol) and potassium carbonate ( 2C03, 14.7 g, 0.1 1 mol) were added to the reaction solution. The reaction solution was stirred at 60C for 18 hours, and then diluted with water, and extracted with EA. Moisture was removed from an organic layer with MgS04, and the organic layer was filtered and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain the desired form of the compound, 2,6-difluoro-4-(3-(l -(5-(5-isobutyl-l ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propox y)benzonitrile in a yield of 85%. NMR (600 MHz, CDC13) delta 8.88 (s, 2H), 6.44 (d, 2H, JHF=10.2Hz), 4.86 (d, 2H, J=13.2Hz), 3.95-3.93 (m, 2H), 3.89 (s, 3H), 2.94-2.89 (m, 2H), 2.79 (d, 2H, J=7.8Hz), 2.27-2.22 (m, 1H), 1.85-1.80 (m, 4H), 1.61-1.59 (m, 1H), 1.43-1.39 (m, 2H), 1.23-1.19 (m, 2H), 1.02 (d, 6H, J=7.2Hz); [M+l]+ = 516.3 m/z (ESI).

Reference： [1]Patent: WO2016/68453,2016,A1 .Location in patent: Page/Page column 28

36
[ 123843-57-2 ]
2,6-difluoro-N',4-dihydroxybenzene-1-carboximidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With hydroxylamine; In ethanol; water; for 3h;Reflux;	Step 6-1 ) Preparation of 2,6-difluoro-N4-dihydrobenzimidamide 2,6-Difluoro-4-hydroxybenzonitrile (3.0 g, 19.3 mmol) was dissolved in ethanol (12mL), and then a 50% aqueous hydroxyamine solution (NH2OH, 12.6 g, 193.0 mmol) was added to the reaction solution. The reaction solution was stirred under reflux for 3 hours, then concentrated under reduced pressure to remove the solvent, water was added thereto, and filtering was carried out, thereby obtaining the desired form of the compound, 2,6-difluoro-N',4-dihydrobenzimidamide in a yield of 75%. [M+l]+=189.0 m/z(ESI).

Reference： [1]Patent: WO2016/68453,2016,A1 .Location in patent: Page/Page column 36-37

37
[ 123843-57-2 ]
3,5-difluoro-4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenol [ No CAS ]

Reference： [1]Patent: WO2016/68453,2016,A1

38
[ 123843-57-2 ]
3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole [ No CAS ]

Reference： [1]Patent: WO2016/68453,2016,A1

39
[ 123843-57-2 ]
C₁₅H₁₁F₂NO₄ [ No CAS ]

Reference： [1]Journal of Agricultural and Food Chemistry,2016,vol. 64,p. 8986 - 8993

40
[ 105-36-2 ]
[ 123843-57-2 ]
C₉H₅F₂NO₃ [ No CAS ]

Reference： [1]Journal of Agricultural and Food Chemistry,2016,vol. 64,p. 8986 - 8993

41
[ 123843-57-2 ]
tert-butyl N-tert-butoxycarbonyl-N-[3-[4-[[(Z)-N-[2-(3,4-dimethoxy-N-methylanilino)-2-oxoethyl]-N’-(4-fluorophenyl)carbamimidoyl]sulfanylmethyl]-3,5-difluorophenoxy]propyl]carbamate [ No CAS ]

Reference： [1]Patent: WO2017/42380,2017,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

42
[ 123843-57-2 ]
tert-butyl N-tert-butoxycarbonyl-N-[3-[4-[[5-(3,4-dimethoxy-N-methylanilino)-1-(4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluorophenoxy]propyl]carbamate [ No CAS ]

Reference： [1]Patent: WO2017/42380,2017,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

43
[ 123843-57-2 ]
2-[[4-(3-aminopropoxy)-2,6-difluorophenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methylimidazol-4-amine [ No CAS ]

Reference： [1]Patent: WO2017/42380,2017,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

44
[ 123843-57-2 ]
diammonium 2-[3-[4-[[5-(3,4-dimethoxy-N-methylanilino)-1-(4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluorophenoxy]propyl-(2-sulfonatoethyl)amino]ethanesulfonate [ No CAS ]

Reference： [1]Patent: WO2017/42380,2017,A1

45
[ 123843-57-2 ]
[4-(3-bromopropoxy)-2,6-difluorophenyl]methanol [ No CAS ]

Reference： [1]Patent: WO2017/42380,2017,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

46
[ 123843-57-2 ]
tert-butyl N-tert-butoxycarbonyl-N-[3-[3,5-difluoro-4-(hydroxymethyl)phenoxy]propyl]carbamate [ No CAS ]

Reference： [1]Patent: WO2017/42380,2017,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

47
[ 123843-57-2 ]
tert-butyl N-tert-butoxycarbonyl-N-[3-[4-(chloromethyl)-3,5-difluorophenoxy]propyl]carbamate [ No CAS ]

Reference： [1]Patent: WO2017/42380,2017,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

48
[ 123843-57-2 ]
4-fluoro-N-methyl-6-(piperidin-4-ylmethoxy)-1H-indazol-3-amine [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

49
[ 123843-57-2 ]
6-(piperidin-4-ylmethoxy)-4-(pyrrolidin-1-yl)-1H-indazol-3-amine [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

50
[ 123843-57-2 ]
tert-butyl 4-[(3-amino-4-fluoro-1H-indazol-6-yl)oxy]methyl}piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

51
[ 123843-57-2 ]
tert-butyl 4-([4-fluoro-3-(methylamino)-1H-indazol-6-yl]oxy}methyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

52
[ 123843-57-2 ]
tert-butyl 4-[4-cyano-3-fluoro-5-(pyrrolidin-1-yl)phenoxymethyl]piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

53
[ 123843-57-2 ]
tert-butyl 4-([3-amino-4-(pyrrolidin-1-yl)-1H-indazol-6-yl]oxy}methyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

54
[ 123843-57-2 ]
2-azido-6-fluoro-4-hydroxybenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.5%	With sodium azide; In N,N-dimethyl-formamide; at 70℃;	1003551 <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong> (600 mg, 3.87 mmol) was dissolved in anhydrous DIvIF (6m1) and NaN3 (276.64 mg, 4.26 mmol) was added. The reaction was heated to 70C overnight. On consumption of starting material the reaction was quenched with water (1 5m1), pH was adjusted with 2M NaOH to pH 9, then the aqueous was extracted with EtOAc (3 x lQml). The combined organics were dried over Na2SO4, then purified by column chromatography using gradient of 0% EtOAc / Heptane-100% EtOAc). NMR shows product to be about 70% clean-used in next step without further purification. 507 mg (51.5%) of title compound was obtained as a cream solid. METCRI673 Generic 2 minutes M/Z (ES+) no ionisation, Retention time 1.21 mm.1H NMR (500 MHz, DMSO-d6) 6 11.57 (s, 1H), 6.67 (dd, J = 1.9, 0.8 Hz, 1H), 6.64 (dd, J =11.3, 2.0 Hz, 1H).

Reference： [1]Patent: WO2017/45751,2017,A1 .Location in patent: Paragraph 00355

55
[ 123843-57-2 ]
C₇H₅FN₂O [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

56
[ 123843-57-2 ]
2-bromo-6-fluoro-4-hydroxybenzonitrile [ No CAS ]

Reference： [1]Patent: WO2017/45751,2017,A1

57
[ 123843-57-2 ]
[ 123855-51-6 ]
tert-butyl 4-(4-cyano-3,5-difluorophenoxymethyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	1002261 <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong> (5 g, 32.24 mmol) and triphenyiphosphine (99%,17.08 g, 64.47 mmol) were added to a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (8.33 g, 38.68 mmol) in anhydrous THF (20 ml) under nitrogen. The reaction was then placed in an ice bath and cooled to 0C and DIAD (10.13 ml, 51.58 mmol) was added drop wise, the ice bath was then removed and reaction was stirred under room temperature overnight. [002271 The solvent was reduced under vacuo, the resulting yellow oil diluted with ethyl acetate, (30m1) and washed with water (2x30m1), dried over magnesium sulphate, filtered and conc. in vacuo. The product was purified by flash column chromatography, eluting product in 20% EtOAc I Heptane. This yielded 8g (63%) of the title compound as a white solid. METCR1673 Generic 2 minutes MJZ (ES+) 297, Retention time 1.51 mm.1H NIvIR (500 MHz, DMSO-d6) 7.10 (d, J = 10.4 Hz, 2H), 4.81- 4.73(m,OH),4.00(d,J=6.5Hz,2H),2.74(s,2H),1.94(ddd,J=14.9,l I .3,3.6Hz,1H),1 .72 (d, J = 11.2 Hz, 2H), 1.40 (s, 9H), 1.15 (ddt, J = 24.8, 12.6, 5.7 Hz, 4H).

Reference： [1]Patent: WO2017/45751,2017,A1 .Location in patent: Paragraph 00226; 00227

58
[ 123843-57-2 ]
2-(chloromethyl)-5-(3-chloropropoxy)-1,3-difluorobenzene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

59
[ 123843-57-2 ]
2-[[4-(3-chloropropoxy)-2,6-difluorophenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methylimidazol-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

60
[ 123843-57-2 ]
2-[[4-[3-(1-aza-4-azoniabicyclo[2.2.2]octan-4-yl)propoxy]-2,6-difluorophenyl]methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N-methylimidazol-4-amine formate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

61
[ 123843-57-2 ]
3-[4-[[5-(3,4-dimethoxy-N-methylanilino)-1-(4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluorophenoxy]propane-1-sulfonate ammonium [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

62
[ 123843-57-2 ]
2-[3-[4-[[5-(3,4-dimethoxy-N-methylanilino)-1-(4-fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluorophenoxy]propyl-(2-sulfonatoethyl)amino]ethanesulfonate diammonium [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4185 - 4211

63
[ 105-39-5 ]
[ 123843-57-2 ]
C₁₁H₉F₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; for 2h;Reflux;	General procedure: Intermediates 14 were prepared by following the knownprocedure [22, 29, 30]. The mixture of ethyl 2-chloroacetate(1 mmol), substituted phenols (1 mmol), and K2CO3(1.2 mmol) in acetonitrile was stirred in refluxing for 2 h(the course of the reactions was monitored by TLC)

Reference： [1]Monatshefte fur Chemie,2018,vol. 149,p. 611 - 623
[2]Chinese Journal of Chemistry,2018,vol. 36,p. 939 - 944

64
[ 123843-57-2 ]
C₉H₇F₂N₃O₂ [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2018,vol. 149,p. 611 - 623
[2]Chinese Journal of Chemistry,2018,vol. 36,p. 939 - 944

65
[ 123843-57-2 ]
4-[[5-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-1,3,4-oxadiazol-2-yl]methoxy]-2,6-difluorobenzonitrile [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2018,vol. 149,p. 611 - 623

66
[ 123843-57-2 ]
2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8797 - 8810
[2]Patent: US2018/312490,2018,A1

67
[ 123843-57-2 ]
(E)-N′-(2-cyano-3-fluoro-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformamideamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8797 - 8810
[2]Patent: US2018/312490,2018,A1

68
[ 123843-57-2 ]
N -(4-[5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]-amino}phenyl)-2-[4-(propan-2-yl)-1 H -1,2,3-triazol-1-yl]acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8797 - 8810
[2]Patent: US2018/312490,2018,A1
[3]Patent: US2018/312490,2018,A1

69
[ 123843-57-2 ]
[ 6482-24-2 ]
2,6-difluoro-4-(2-methoxyethoxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetonitrile; at 80 - 85℃;Inert atmosphere; Large scale;	1-bromo-2-methoxyethane (9.6 kg, 69.06 mol) was added in one portion to <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong> (8.6 kg, 55.45 mol) and potassium carbonate (23 kg, 166.43 mol) in CH3CN (70.9 kg). The resulting solution was stirred at 80-85 C. for 8-10 hours. The reaction mixture was cooled to 40-45 C. and filtered. The cake was washed with CH3CN (13.4 kg). The combined filtrate was concentrated under vacuum to 34-43 L. Process water (92.0 kg) was added and the mixture was concentrated under vacuum to 77-85 L. The suspension was filtered to afford 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (13.70 kg, 100%) as a damp solid. 1H NMR (400 MHz. DMSO-d6) delta 3.29 (3H, s), 3.65-3.67 (2H, t), 4.24-4.26 (2H, t), 7.11 (1H, s), 7.14 (1H, s)

Reference： [1]Patent: US2018/312490,2018,A1 .Location in patent: Paragraph 0241; 0333; 0340; 0341; 0342; 0343; 0362-0364
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 8797 - 8810

70
[ 123843-57-2 ]
tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate [ No CAS ]

Reference： [1]Patent: US2018/312490,2018,A1

71
[ 123843-57-2 ]
N₁-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine dihydrochloride [ No CAS ]

Reference： [1]Patent: US2018/312490,2018,A1

72
[ 123843-57-2 ]
N₁-(5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)benzene-1,4-diamine [ No CAS ]

Reference： [1]Patent: US2018/312490,2018,A1

73
[ 123843-57-2 ]
N-(4-[5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide tosylate [ No CAS ]

Reference： [1]Patent: US2018/312490,2018,A1
[2]Patent: US2018/312490,2018,A1

74
[ 957217-43-5 ]
[ 123843-57-2 ]
C₆₄H₃₈F₈N₆O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 8h;Inert atmosphere;	4) the product N, N'-di-n-hexyl-1,6,7,12-tetrachloro-3,4: 9,10-fluorenediimide (1.1 g) obtained in step (3), 3 , 5-difluoro-4-cyanophenol (2.0 g),K2CO3 (1.8 g) was added to a microreactor containing 16 mL of N-methylpyrrolidone, and reacted for 8 hours under the protection of nitrogen at a reaction temperature of 130 C; (5) The reaction mixture is poured into 100 mL of a 10% (volume ratio) hydrochloric acid aqueous solution with stirring and filtered, and washed with water until neutral;Use a mixed solution of dichloromethane and methanol as an eluent for purification with a silica gel column; the volume ratio of the dichloromethane and methanol solution is 9: 1; 6) In order to improve the purity of the product, the crude product obtained in step (5) is dissolved in dichloromethane,Recrystallization using methanol; the molar ratio of dichloromethane and methanol is 1: 6;Among them, dichloromethane is used as a soluble solvent and methanol as a poor solvent; the obtained product is a perylene imide compound CN-PDI; (7) The obtained product was comprehensively characterized, and the synthesized product was determined to be a perylene imide compound CN-PDI by mass spectrometry, ultraviolet, infrared, and XRD.

Reference： [1]Patent: CN110283173,2019,A .Location in patent: Paragraph 0042-0043; 0047-0051; 0055-0059; 0063-0066

75
[ 123843-57-2 ]
4-(difluoromethoxy)-2-fluoro-6-methoxybenzonitrile [ No CAS ]

Reference： [1]Patent: WO2019/243491,2019,A1

76
[ 123843-57-2 ]
6-(difluoromethoxy)-4-methoxybenzo[d]isoxazol-3-amine [ No CAS ]

Reference： [1]Patent: WO2019/243491,2019,A1

77
[ 123843-57-2 ]
N-(6-(difluoromethoxy)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide [ No CAS ]

Reference： [1]Patent: WO2019/243491,2019,A1

78
[ 65094-22-6 ]
[ 123843-57-2 ]
4-(difluoromethoxy)-2,6-difluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium hydroxide; In water; acetonitrile; at -20 - 20℃;	a) 4-(Difluoromethoxy)-2,6-difluorobenzonitrile I119 To a suspension of KOH (22.0 g, 392 mmol) in acetonitrile (30 ml.) and water (30 ml.) at -20 C was added <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong> (3.1 g, 20.0 mmol) portion-wise followed by diethyl (bromodifluoromethyl)phosphonate (10.0 g, 37.4 mmol) and the mixture was stirred at RT overnight. Water was added and the mixture was extracted with EtOAc (50 ml. x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (4.0 g, 97%) as a colorless oil. LCMS-C: Rt 2.1 1 min; m/z 205.9 [M+H]+.

Reference： [1]Patent: WO2019/243491,2019,A1 .Location in patent: Page/Page column 119

79
[ 75-03-6 ]
[ 123843-57-2 ]
[ 916483-58-4 ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2h;	1 Step ethyl iodide (14 g, 90.3 mmol) and potassium carbonate (12.46 g, 90.3 mmol) were added to a solution composed of A1 (7.0 g, 45.2 mmol), N,N-dimethylformamide (100 mL). The reaction mixture was stirred at 60°C for 2 hours and cooled to room temperature. After the reaction mixture was concentrated, a pale yellow solid product A3 (3.65 g, yield 44%) was obtained. 1HNMR: (400 MHz, CDCl3) δ ppm: 6.56 (d, J = 9.4 Hz, 1H), 4.10 (d, J = 7.0 Hz, 1H), 1.48 (t, J = 7.0 Hz, 2H). LC-MS: (ESI) m/z=184(M+H)+.

Reference： [1]Current Patent Assignee: WAYSHINE BIOPHARM HOLDING - EP3778589, 2021, A1 Location in patent: Paragraph 0199-0201

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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

Ghs Hazard Statements

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