[ CAS No. 13670-99-0 ] {[proInfo.proName]}

Name: 13670-99-0|1-(2,6-Difluorophenyl)ethanone|97%
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Quality Control of [ 13670-99-0 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 13670-99-0 ]

CAS No. :	13670-99-0	MDL No. :	MFCD00000328
Formula :	C₈H₆F₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VGIIILXIQLXVLC-UHFFFAOYSA-N
M.W :	156.13	Pubchem ID :	83643
Synonyms :

Calculated chemistry of [ 13670-99-0 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.55
TPSA :	17.07 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	1.81
Log Po/w (WLOGP) :	3.01
Log Po/w (MLOGP) :	2.63
Log Po/w (SILICOS-IT) :	2.99
Consensus Log Po/w :	2.42

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.29
Solubility :	0.808 mg/ml ; 0.00518 mol/l
Class :	Soluble
Log S (Ali) :	-1.79
Solubility :	2.54 mg/ml ; 0.0163 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.28
Solubility :	0.0825 mg/ml ; 0.000528 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.07

Safety of [ 13670-99-0 ]

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 [ 13670-99-0 ]

* 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 [ 13670-99-0 ]
Downstream synthetic route of [ 13670-99-0 ]

[ 13670-99-0 ] Synthesis Path-Upstream 1~12

1
[ 13670-99-0 ]
[ 341-23-1 ]

Reference： [1] European Journal of Medicinal Chemistry, 2014, vol. 87, p. 386 - 397

2
[ 18063-02-0 ]
[ 105-53-3 ]
[ 13670-99-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With triethylamine; magnesium chloride In ethyl acetate at 20℃; for 1 h; Stage #2: at 0 - 20℃; for 3.25 h;	Magnesium chloride (1.65 g, 17.3 mmol) was added to a solution of diethyl malonate (1.24 g, 7.7 mmol) in ethyl acetate (20 mL) and the slurry was stirred at ambient temperature for 30 minutes. Triethylamine (2.35 mL, 16.7 mmol) was added and the slurry was stirred for another 30 minutes. The slurry was cooled to 0 °C and a solution of 2,6-difluorobenzoyl chloride (1.0 g, 5.6 mmol) in ethyl acetate (5 mL) was added dropwise over 15 minutes maintaining the internal temperature below 5 °C. At the end of the addition the reaction was allowed to warm to ambient temperature and stirred for approximately 3 hours. The slurry was then treated with IN hydrochloric acid (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was separated, dried over MgS0₄, and filtered. The filtrate was concentrated under reduced pressure yielding a colorless oil (1.97 g) containing the intermediate. The oil was dissolved in acetonitrile (25 mL) and water (2 mL) was added. The solution was transferred to a pressure reactor and sealed. The intermediate solution was stirred and heated to 150 °C for 1 hour. The reaction mixture was cooled to ambient temperature and the residual pressure released. HPLC wtpercent analysis of the solution indicated a 2,6-difluroacetophenone yield of 874 mg (100 percent).

Reference： [1] Patent: WO2013/85686, 2013, A1, . Location in patent: Page/Page column 22

3
[ 6148-64-7 ]
[ 18063-02-0 ]
[ 13670-99-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: With triethylamine; magnesium chloride In tetrahydrofuran; ethyl acetate at 0 - 50℃; Stage #2: at 0 - 20℃; for 19.9167 h;	EXAMPLE 5 Preparation of 2,6-Difluoroacetophenone Using Ethyl Malonate, Potassium Salt Ethyl malonate, potassium salt (13.4 g, 77 mmol), magnesium chloride (16.5 g, 173 mmol), ethyl acetate (40 mL) and tetrahydrofuran (60 mL) were combined and stirred for 30 minutes at ambient temperature. The reaction mixture was cooled to 0 °C and triethylamine (23.5 mL, 167 mmol) was added. The reaction slurry was heated to 50 °C and held for 1 hour, then cooled back to 0 °C. A solution of 2,6-difluorobenzoyl chloride (10.0 g, 56 mmol) in ethyl acetate (25 mL) was added slowly to the slurry over 55 min maintaining the internal temperature below 2 °C. At the end of the addition the reaction was allowed to warm to ambient temperature and stirred for 19 hours. The reaction was cooled to 0 °C and treated with IN hydrochloric acid (200 mL). The clear biphasic mixture was allowed to return to ambient temperature and additional ethyl acetate (100 mL) was added. The phases allowed to separate and the organic phase was dried over MgS0₄, filtered and the filtrate concentrated under reduced pressure, yielding a yellow oil residue (15.46 g) containing the intermediate. The oil was dissolved in acetonitrile (100 mL) and water (5 mL) and transferred to a pressure reactor with a condenser and backpressure regulator. The reaction mixture was sealed in the pressure reactor, stirred and heated to 150 °C for 1 hour. The reaction was cooled to ambient temperature and the residual pressure was released. HPLC wtpercent analysis of the reaction solution indicated a 2,6-difluoroacetophenone yield of 8.60 g (99 percent).

Reference： [1] Patent: WO2013/85686, 2013, A1, . Location in patent: Page/Page column 23

4
[ 1897-52-5 ]
[ 676-58-4 ]
[ 13670-99-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: at 20℃; for 20 h; Inert atmosphere Stage #2: With sulfuric acid In tetrahydrofuran; 5,5-dimethyl-1,3-cyclohexadiene; water at 50℃;	4.5 g of 2,6-difluorobenzonitrile and 45.3 g of xylene were added to a 200 mL four-necked flask under nitrogen atmosphere at room temperature and stirred, then 21.7 g of a methylmagnesium chloride solution (3.0 M THF solution) was added at room temperature Was added dropwise over 1 hour. The resulting mixture was stirred at room temperature for 19 hours,Was added dropwise to 31.5 g of a 20percent sulfuric acid aqueous solution.The obtained mixture was heated to 50 ° C. and liquid separation was carried out,9.1 g of water was added to the organic layer, and the mixture was separated at 50 ° C.The obtained organic layer was analyzed by a high performance liquid chromatograph internal standard method, and 4.8 g of 2,6-difluoroacetophenone was confirmed to be contained (yield 95percent)

Reference： [1] Patent: JP2016/169165, 2016, A, . Location in patent: Paragraph 0021

5
[ 1897-52-5 ]
[ 13670-99-0 ]

Reference： [1] Patent: US4638067, 1987, A,
[2] Patent: US4438271, 1984, A,

6
[ 75-36-5 ]
[ 133117-48-3 ]
[ 13670-99-0 ]

Reference： [1] Tetrahedron, 1993, vol. 49, # 47, p. 10843 - 10854

7
[ 1897-52-5 ]
[ 917-54-4 ]
[ 13670-99-0 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 6, p. 1509 - 1520

8
[ 87327-65-9 ]
[ 13670-99-0 ]

Reference： [1] Green Chemistry, 2017, vol. 19, # 2, p. 474 - 480

9
[ 372-18-9 ]
[ 13670-99-0 ]

Reference： [1] Tetrahedron, 1993, vol. 49, # 47, p. 10843 - 10854

10
[ 108-24-7 ]
[ 18611-72-8 ]
[ 13670-99-0 ]

Reference： [1] Patent: WO2004/24738, 2004, A1, . Location in patent: Page/Page column 15

11
[ 87327-65-9 ]
[ 13670-99-0 ]

Reference： [1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 14, p. 2730 - 2732

12
[ 372-18-9 ]
[ 75-36-5 ]
[ 13670-99-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1968, vol. 11, # 4, p. 814 - 819

[ 13670-99-0 ] Synthesis Path-Downstream 1~88

1
[ 372-18-9 ]
[ 75-36-5 ]
[ 13670-99-0 ]

Reference： [1]Journal of Medicinal Chemistry,1968,vol. 11,p. 814 - 819

2
[ 1121-60-4 ]
[ 13670-99-0 ]
(E)-1-(2,6-Difluoro-phenyl)-3-pyridin-2-yl-propenone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2855 - 2863

3
[ 1897-52-5 ]
[ 917-54-4 ]
[ 13670-99-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

4
[ 13670-99-0 ]
[ 91188-91-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; nitric acid; at -40 - 0℃; for 1.5h;	2', 6'-Difluoro-3'-nitro-acetophenone, which has the structural formula first prepared as follows. To conc. H2SO4 (3 mL) and conc. HNO3 (3 mL) at -40C was added 2, 6-difluoroacetophenone (500 mg, 3.20 MMOL). The mixture was allowed to slowly warm to 0 C over 90 minutes, then dumped onto crushed ice and extracted with CH2CI2. The organic layer was separated, washed with water and sat. aq. NAHCO3, dried over NA2SO4, and concentrated to give 640 mg (100%) of yellow oil, which was used without further purification. H NMR : 8 8. 20 (1H, ddd, J = 5. 6,8. 3, 9. 3 HZ), 7.12 (1H, ddd, J = 1. 8,8. 3,9. 3 HZ), 2.65 (3H, t, J = 1. 6 HZ). 2-Bromo-2', 6'-difluoro-3'-nitro-acetophenone, which has the structural formula was made with a procedure from King et AL., J. Org. Chem, 29, 3459-3461 (1964). To a solution of 2', 6'-difluoro-3'-nitro-acetophenone (3.91 g, 19.4 MMOL) in EtOAc (25 mL) was added copper (II) bromide (8.70 g, 38.9 MMOL). The resultant mixture was heated at reflux for 3 hours, allowed to cool, and the solid was filtered off and rinsed with ether. The filtrate was passed through a pad of silica gel and concentrated in vacuo to provide 5.37 g (99% yield) of a yellow solid, which was used without any further purification. 1H NMR: 8 8. 27 (1 H, ddd, J = 5.6, 8.4, 9.3 Hz), 7.17 (1H, ddd, J = 1.8, 8.4, 9.3 Hz), 4.34 (2H, t, J = 0. 8 HZ). The title compound was made as follows. To a mixture of 4-isothiocyanato- BENZENESULFONAMIDE (557 mg, 2.60 MMOL), cyanamide (131 mg, 3.12 MMOL), and MECN (3 mL) was added a solution of potassium t-butoxide (321 mg, 2.86 MMOL) in t-butanol (3 mL). After a half-hour, 2-bromo-2', 6 -DIFLUORO-3 -NITRO-ACETOPHENONE (800 mg, 2.86 MMOL) was added. After one hour, water (20 mL) was added, allowed to stir for half hour, then acidified to pH=6 with 1 N HCI. The resultant solid was filtered, washed with water and ether (2 x 3mL), recrystallized from methanol, and dried under vacuum to furnish a yellow powder in 43% yield. 1H NMR (DMSO-D6) : 8 11.08 (1 H, s), 8.25 (2H, bs), 7.62 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9. 0 HZ), 7.33 (2H, dd, J = 8. 1,8. 8 HZ), 7.09 (2H, s). ESIMS (M+H ) : 456. Anal. calcd. for C16H11F2NSO5S2 * 0. 6 MEOH : C, 42.01 ; H, 2.85 ; N, 14.75 ; S, 13.51. Found: C, 41.73 ; H, 2.57 ; N, 14,48 ; S, 13.45.
	With sulfuric acid; nitric acid;	2,6-Difluoro-3-nitroacetophenone To 100 ml of concentrated sulfuric acid at 0 was added 17.0 g (109 mmol) of the <strong>[13670-99-0]2,6-difluoroacetophenone</strong> slowly over 20 minutes keeping the temperature at 0-10 C. To this solution, at -5 C., was added a mixture of 20 ml concentrated sulfuric acid and 6.5 ml of 70% nitric acid premixed at 0 C. before the addition. The nitrating agent was added at a sufficient rate to keep the reaction temperature at 5 C. The reaction was then stirred for 20 minutes and poured over ice. The mixture was extracted with dichloromethane two times. The dichloromethane was dried and concentrated to an oil which was purified by column chromatography to give 14.8 g of 2,6-difluoro-3-nitroacetophenone as a pale yellow oil: IR (liquid film) 1715, 1620, 1590, 1540, 1350 cm-1.
	With sulfuric acid; nitric acid; at -40℃; for 2h;	Step 1: (0665) To a -40 C. mixture of concentrated H2SO4 (100 mL) and fuming HNO3 (100 mL) was added <strong>[13670-99-0]<strong>[13670-99-0]1-(2,6-difluorophenyl)ethanon</strong>e</strong> (20 g, 128 mmol) dropwise. The resulting mixture was stirred at -40 C. for 2 h then poured slowly onto ice. That mixture was diluted with DCM and the phases were separated. The aqueous layer was neutralized with sat. aq. NaHCO3 and then extracted with DCM. All organic portions were combined, dried over MgSO4, filtered, and concentrated to give 1-(2,6-difluoro-3-nitrophenyl)ethanone (26.3 g, 131 mmol, >theoretical) that was used without further purification.

Reference： [1]Patent: WO2004/72070,2004,A1 .Location in patent: Page 61-62
[2]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520
[3]Patent: US4638067,1987,A
[4]Patent: US2015/307465,2015,A1 .Location in patent: Paragraph 0665

5
[ 13670-99-0 ]
[ 56159-89-8 ]

Yield	Reaction Conditions	Operation in experiment
~ 100%		Reference Example 94 2-bromo-<strong>[13670-99-0]<strong>[13670-99-0]1-(2,6-difluorophenyl)ethanon</strong>e</strong>; To a solution of <strong>[13670-99-0]<strong>[13670-99-0]1-(2,6-difluorophenyl)ethanon</strong>e</strong> (10.0 g) in diethyl ether (50 mL) was added anhydrous aluminum chloride (86 mg) and the mixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at 10-15 C. After stirring at room temperature for 2 hr, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 15.2 g, about 100%). 1H-NMR (CDCl3) delta: 4.37 (2H, s), 6.97-7.04 (2H, m), 7.43-7.53 (1H, m).
95%		2-Bromo-<strong>[13670-99-0]1-(2,6-difluoro-phenyl)-ethanone</strong>: To a stirred solution of <strong>[13670-99-0]1-(2,6-difluoro-phenyl)-ethanone</strong> (1.0 g, 6.4 mmol) in diethyl ether (14 mL), was added anhydrous aluminium chloride (0.009 g, 0.064 mmol) at rt. After 5 min the reaction mixture was cooled to 0 C., and bromine (0.33 mL, 6.4 mmol) was added dropwise. Stirring was continued for 2 h at rt (monitoring by TLC; ethyl acetate/hexane=1:9; Rf ?0.6), at which point the reaction mixture was poured onto crushed ice and extracted with EtOAc (3×20 mL). The organic layer was washed with aqueous sodium thiosulphate (20 mL) and brine (10 mL), dried, and concentrated under reduce pressure to give 2-bromo-<strong>[13670-99-0]1-(2,6-difluoro-phenyl)-ethanone</strong> (1.3 g, 95%) as yellow oil which was sufficiently pure for the next step.
78%	With bromine; copper(ll) bromide; In ethyl acetate; for 2.25h;Heating / reflux;	[0114] To a mechanically stirring solution of <strong>[13670-99-0]2',6'-difluoroacetophenone</strong> (100.0 g, 640.0 mmol; Melford Laboratories, Ltd.) in ethyl acetate (1300 ml) was added freshly milled copper(II) bromide (300 g, 1.35 mol) and bromine (1.6 ml, 32 mmol). The mixture was heated at reflux for 2.25 hours and allowed to cool to room temperature. The resultant green mixture was filtered and the solids rinsed with ethyl acetate (4×100 ml). The filtrate was concentrated with a rotary evaporator at <40 C. under reduced pressure, diluted with methyl t-butyl ether (MTBE; 650 ml), filtered through a pad of silica gel (230-400 k; 9.5 cm diam.×4 cm. ht.), and solids rinsed with MTBE (5×200 ml). Concentration of the filtrate gave a pale green oil, which was purified by fractional vacuum distillation to give 117 g of pale yellow oil, bp 88-97 C. (2.0 mm Hg) in 78% yield. The results matched that previously described in PCT Patent Publication WO99/21845 (in Example C(79)) and was used without any further purification or characterization. [0115] 1H NMR: delta 7.48 (ddd, 1H, J=6.3, 8.5, 14.8 Hz), 7.01 (ddd, 2H, J=4.6, 5.8, 16.6 Hz), 4.37 (t, 2H, J=0.7 Hz).

78%	With bromine; copper(ll) bromide; In ethyl acetate; for 2.25h;Heating / reflux;	First 4-isothiocyanato-benzenesulfonyl fluoride, which has the structural formula was prepared. According to a method from MCKEE et AL., J. Am. Chem. Soc. , 48 (1946), 2506-2507, sulfanilyl fluoride (6.00 g, 34.3 MMOL, from Sigma-Aldrich Chemical--discontinued ; see Krazer Helv. Chim. Acta. 43, 1513-1519 (1960) ) was dissolved in water (60 mL) containing 38% HCI (14.4 mL). Thiophosgene (2.7 mL, 36.0 MMOL) was added in one portion. The resultant mixture was stirred rapidly for a half hour, then diluted with water (200 mL). The resultant white precipitate was filtered off, washed with water, and dried under high vacuum to obtain 7.28 G (99%) of white powder, which was used without further purification. 1HNMR (DMSO-D6) : 8 8. 03 (2H, d, J = 9. 3 HZ), 7.44 (2H, d, J = 9. 3 HZ). FABMS: (M-H+) : 216. 2-Bromo-2', 6'-difluoroacetophenone, which has the structural formula was prepared as follows. To a mechanically stirring solution of 2', 6'-difluoroacetophenone (100.0 G, 640.0 mmol ; Melford Laboratories, Ltd. ) in ethyl acetate (1300 mL) were added freshly milled copper (II) bromide (300 G, 1.35 mol) and bromine (1.6 mL, 32 MMOL). The mixture was heated at reflux for 2.25 hours and allowed to cool to ambient temperature. The resultant green mixture was filtered and the solids rinsed with ethyl acetate (4x100 mL). The filtrate was concentrated with a rotary evaporator under reduced pressure, diluted with methyl t-butyl ether (MTBE; 650 mL), filtered through a pad of silica gel (230-400 ; 9.5 cm diam. X4 cm. ht. ), and solids rinsed with MTBE (5x200 mL). Concentration of the filtrate gave a pale green oil, which was purified by fractional vacuum distillation to give 117 g of pale yellow oil, bp 88-97C (2.0 mm Hg) in 78% yield. Matched that previously described in World Patent APPLICATION W099/21845 (in Example C (79) ) and was used without any further purification or characterization. 1H NMR: 8 7.48 (1H, ddd, J = 6.3, 8.5, 14.8 Hz), 7.01 (2H, ddd, J = 4.6, 5.8, 16.6 Hz), 4.37 (2H, t, J = 0. 7 HZ). 4- [4-AMINO-5- (2, 6-DIFLUORO-BENZOYL)-THIAZOL-2-YLAMINO]-BENZENESULFONYL FLUORIDE, which has the structural formula was then made as follows. To 4-isothiocyanato-benzenesulfonyl fluoride (4.00 G, 18.4 MMOL) and cyanamide (851 mg, 20.3 MMOL) in CH3CN (20 mL), in a vessel placed in a cold-water bath, was added 1,8- diazabicyclo [5.4. 0] undec-7-ene (DBU; 3.0 mL, 20 MMOL). After 15 minutes, a solution of 2- bromo-2', 6'-difluoro-acetophenone (4.54 g, 19.3 mmol ; from Example A (1)) in CH3CN (1 mL) and DBU (3.0 mL, 20. 3 MMOL) were sequentially added. The mixture was stirred at ambient temperature for a half-hour, then partitioned between CH2C12 and water, and acidified to pH=4 with 1 N HCI. The organic layer was separated, washed with brine, and dried over NA2SO4. The solvent was evaporated to give a hard foam, which was purified via column chromatography with 1: 1 ethyl acetate (EtOAc) and hexane (hex) as eluant to afford 6.2 G (82% yield) of a yellow powder. 1H NMR (DMSO-D6) : 8 11.50 (1 H, s), 8.35 (2H, bm), 8.10 (2H, d, J = 9.0 Hz), 7.96 (2H, d, J = 9. 0 HZ), 7.58 (1H, m), 7.24 (2H, dd, J = 7. 8,8. 2 HZ). Anal. calcd. for C16H10F2N3O3S2No.0. 1 EtOAc: C, 46.65 ; H, 2.58 ; N, 9.95 ; S, 15.19. Found: C, 46.65 ; H, 2 : 55 ; N, 9.80 ; S, 15.02. The title compound was prepared as follows. A mixture of 4- [4-AMINO-5- (2, 6-DIFLUORO- benzoyl)-thiazol-2-ylamino]-benzenesulfonyl fluoride (200 mg, 0.484 MMOL), piperazine (125 mg, 1.45 MMOL), CH3CN (2 mL), and 4- (N, N-dimethylamino)-pyridine (DMAP; 5 mg) was refluxed for 2 hours. The solvent was removed under reduced pressure, the residue was taken up into MeOH (2 mL), then precipitated with water, filtered, and washed with water. Further purification with column chromatography gave 91 mg (43% yield) of a yellow powder. 1H NMR (DMSO-D6) : 8 8.22 (2H, bs), 7.83 (2H, d, J = 8.7 Hz), 7.68 (2H, d, J = 8.7 Hz), 7.56 (1H, m), 7.22 (2H, dd, J = 7. 8,8. 2 HZ). HRESIMS : calcd. for C2OH2OF2N503S2 (M+H+) : 480.0976. Found: 480.0988. Anal. CALCD. for C2OHI9F2NS03S2 0. 7 MeOH : C, 49.53 ; H, 4.38 ; N, 13.95 ; S, 12.78. Found: C, 49.51 ; H, 4.39 ; N, 13.84 ; S, 12.93.
78%	With bromine; copper(I) bromide; In ethyl acetate; for 2.25h;Heating / reflux;	To a mechanically stirring solution of 2', 6'-difluoroacetophenone (100. 0 g, 640. 0 mmol ; Melford Laboratories, Ltd.) in ethyl acetate (1300 ML) was added freshly milled copper (II) bromide (300 g, 1. 35 mol) and bromine (1. 6 ML, 32 MMOL). The mixture was heated at reflux for 2. 25 hours and allowed to cool to room temperature. The resultant green mixture was filtered and the solids rinsed with ethyl acetate (4X100 ML). The filtrate was concentrated with a rotary evaporator at <40 C under reduced pressure, diluted with methyl t-butyl ether (MTBE ; 650 MI), filtered through a pad of silica gel (230-400 L ; 9. 5 cm DIAM. 4 cm. ht.), and solids rinsed with MTBE (5X200 ML). Concentration of the filtrate gave a pale green oil, which was purified by fractional vacuum distillation to give 117 g of pale yellow oil, bp 88-97 C (2. 0 mm Hg) in 78% yield. Matched that previously described in World Patent Application W099/21845 (in Example C (79)) and was used without any further purification or characterization. 1H NMR : 87. 48 (ddd, 1H, J=6. 3, 8. 5, 14. 8 Hz), 7. 01 (ddd, 2H, J=4. 6, 5. 8, 16. 6 Hz), 4. 37 (t, 2H, J=0. 7 Hz)
78%	With bromine; copper(ll) bromide; In ethyl acetate; for 2.25h;Heating / reflux;	To a mechanically stirring solution of <strong>[13670-99-0]2',6'-difluoroacetophenone</strong> (100.0 g, 640.0 mmol; Melford Laboratories, Ltd.) in ethyl acetate (1300 mL) was added freshly milled copper(II) bromide (300 g, 1.35 mol) and bromine (1.6 mL, 32 mmol). The mixture was heated at reflux for 2.25 hours and allowed to cool to ambient temperature. The resultant green mixture was filtered and the solids rinsed with ethyl acetate (4100 mL). The filtrate was concentrated with a rotary evaporator at <40 C. under reduced pressure, diluted with methyl t-butyl ether (MTBE; 650 mL), filtered through a pad of silica gel (230-400 ; 9.5 cm diam.4 cm. ht.), and the solids rinsed with MTBE (5*200 mL). Concentration of the filtrate gave a pale green oil, which was purified by fractional vacuum distillation to give 117 g (78% yield) of 2-bromo-<strong>[13670-99-0]2',6'-difluoroacetophenone</strong> as a pale yellow oil, bp 88-97 C. (2.0 mm Hg). The compound matched that previously described in World Patent Application WO99/21845 and was typically used without any further purification or characterization. 1H NMR(CDCl3): 7.48 (ddd, 1H, J=6.3, 8.5, 14.8 Hz), 7.01 (ddd, 2H, J=4.6, 5.8, 16.6 Hz), 4.37 (t, 2H, J=0.7 Hz).
78%	With bromine; copper(I) bromide; In ethyl acetate; for 2.25h;Heating / reflux;	To a mechanically stirring solution of 2', 6'-difluoroacetophenone (100.0 g, 640.0 mmol ; Melford Laboratories, Ltd. ) in ethyl acetate (1300 mL) was added freshly milled copper [(II)] bromide (300 g, 1.35 mol) and bromine (1.6 mL, 32 mmol). The mixture was heated at reflux for 2.25 hours and allowed to cool to ambient temperature. The resultant green mixture was filtered and the solids rinsed with ethyl acetate [(4X100] mL). The filtrate was concentrated with a rotary evaporator at [&LT;40C] under reduced pressure, diluted with methyl t-butyl ether (MTBE ; 650 mL), filtered through a pad of silica gel [(230-400] [U] ; 9.5 cm diam. [X4] cm. ht. ), and the solids rinsed with MTBE (Sx200 mL). Concentration of the filtrate gave a pale green oil, which was purified by fractional vacuum distillation to give 117 g (78% yield) of 2-bromo-2', 6'-difluoroacetophenone as a pale yellow oil, bp [88-97C] (2.0 mm Hg). The compound matched that previously described in World Patent Application [W099/21845] and was typically used without any further purification or characterization. 1H NMR [(CDC13)] : [8] 7.48 (ddd, 1H, J=6.3, 8.5, 14.8 Hz), 7.01 (ddd, 2H, J=4.6, 5.8, 16.6 Hz), 4.37 (t, 2H, J=0.7 Hz).
	With bromine;aluminium chloride; In chloroform;	a) 40.6 g of <strong>[13670-99-0]2,6-difluoroacetophenone</strong> are placed in 120 ml of chloroform, and 0.1 g of aluminium chloride is added. Then, at 0 C., 37 g of bromine in 240 ml of chloroform are added dropwise and stirring is carried out at 0 C. for 1 h. The reaction mixture is then heated to room temperature and is concentrated using a rotary evaporator. The residue is distilled over a Vigreux column. In this way 2-bromo-1-(2,6-difluorophenyl)-ethanone having a boiling point of 101-11 C. at 9 mbar is obtained.

Reference： [1]Patent: US2007/60623,2007,A1 .Location in patent: Page/Page column 35
[2]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1093 - 1102
[3]Patent: EP1215208,2002,A2 .Location in patent: Example C(79)
[4]Patent: US2013/90333,2013,A1 .Location in patent: Paragraph 0194
[5]Patent: US2003/225147,2003,A1 .Location in patent: Page 14
[6]Patent: WO2004/72070,2004,A1 .Location in patent: Page 34-36
[7]Patent: WO2004/74283,2004,A1 .Location in patent: Page 34
[8]Patent: US2005/38078,2005,A1 .Location in patent: Page/Page column 23
[9]Patent: WO2004/14904,2004,A1 .Location in patent: Page 39-40
[10]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602
[11]Synlett,2002,p. 1544 - 1546
[12]Patent: US2003/36544,2003,A1

6
[ 13670-99-0 ]
[ 109-77-3 ]
2-[1-(2,6-difluorophenyl)ethylidene]-malononitrile [ No CAS ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 11311 - 11319

7
[ 6007-26-7 ]
[ 13670-99-0 ]
[ 936231-56-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1445 - 1448

8
[ 13670-99-0 ]
[ 936231-72-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1445 - 1448

9
[ 13670-99-0 ]
[ 936231-36-6 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1445 - 1448

10
[ 13670-99-0 ]
5-(2,6-difluoro-phenyl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1445 - 1448

11
[ 13670-99-0 ]
2-amino-4-(2,6-difluorophenyl)-3-thiophenecarbonitrile [ No CAS ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 11311 - 11319

12
[ 13670-99-0 ]
1-[3-(2,6-difluoro-phenyl)-5-phenyl-4,5-dihydro-pyrazol-1-yl]-ethanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2041 - 2045

13
[ 13670-99-0 ]
N-[5-(2,6-difluoro-benzoyl)-1H-pyridin-2-ylidene]-3-(2,6-difluoro-phenyl)-3-oxo-propionamidine [ No CAS ]

Reference： [1]Synlett,2002,p. 1544 - 1546

14
[ 13670-99-0 ]
[2-amino-6-(2,6-difluoro-benzoyl)-imidazo[1,2-a]pyridin-3-yl]-(2,6-difluoro-phenyl)-methanone [ No CAS ]

Reference： [1]Synlett,2002,p. 1544 - 1546

15
[ 13670-99-0 ]
1-(5-chloro-pyridin-2-yl)-3-[3-(2,6-difluoro-phenyl)-3-oxo-propyl]-thiourea [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 265 - 268

16
[ 13670-99-0 ]
1-(5-bromo-pyridin-2-yl)-3-[3-(2,6-difluoro-phenyl)-3-oxo-propyl]-thiourea [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 265 - 268

17
[ 372-18-9 ]
[ 13670-99-0 ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 10843 - 10854

18
[ 13670-99-0 ]
[ 40017-77-4 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

19
[ 13670-99-0 ]
[ 40017-76-3 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

20
[ 13670-99-0 ]
[ 40017-80-9 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

21
[ 13670-99-0 ]
[ 40017-98-9 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

22
[ 13670-99-0 ]
[ 40017-78-5 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

23
[ 13670-99-0 ]
[ 40017-79-6 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

24
[ 13670-99-0 ]
[ 40017-97-8 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

25
[ 13670-99-0 ]
[ 40017-96-7 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

26
[ 13670-99-0 ]
[ 75473-30-2 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

27
[ 13670-99-0 ]
[ 40017-81-0 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

28
[ 13670-99-0 ]
[ 40018-02-8 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

29
[ 13670-99-0 ]
[ 40017-75-2 ]

Reference： [1]Archiv der Pharmazie,1980,vol. 313,p. 587 - 602

30
[ 13670-99-0 ]
(3S,8aR)-3-(2,6-Difluoro-phenyl)-octahydro-indolizine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2855 - 2863

31
[ 13670-99-0 ]
(3S,8aS)-3-(2,6-Difluoro-phenyl)-octahydro-indolizine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2855 - 2863

32
[ 13670-99-0 ]
[ 91189-02-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

33
[ 13670-99-0 ]
[ 91189-01-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

34
[ 13670-99-0 ]
[ 91188-93-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

35
[ 13670-99-0 ]
[ 91189-00-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

36
[ 13670-99-0 ]
[ 91188-92-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

37
[ 13670-99-0 ]
[ 91188-88-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

38
[ 13670-99-0 ]
[ 91188-98-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

39
[ 13670-99-0 ]
[ 91188-96-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

40
[ 13670-99-0 ]
[ 91189-03-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

41
[ 13670-99-0 ]
[ 91188-61-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

42
[ 13670-99-0 ]
[ 115173-35-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1509 - 1520

43
[ 420-04-2 ]
[ 13670-99-0 ]
[ 23861-85-0 ]
{4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,6-difluoro-phenyl)-methanone [ No CAS ]

Reference： [1]Patent: EP1215208,2002,A2 .Location in patent: Example C(80)

44
[ 13670-99-0 ]
[ 154258-88-5 ]

Yield	Reaction Conditions	Operation in experiment
		Production Example 208 3-(2,6-Difluorophenyl)-1H-pyrazole 5.62 g of the title compound (yellow solid) was obtained from 5.0 g of 2', 6'-difluoroacetophenone by the same method as in Production Example 3.1H-NMR (CDCl3) delta: 6.83(dd, J=4.4, 2.0Hz, 1H), 6.99-7.08(m, 2H), 7.28(dddd, J=8.0, 8.0, 6.0, 6.0Hz, 1H), 7.71(d, J=2.0Hz, 1H)

Reference： [1]Patent: EP1382603,2004,A1 .Location in patent: Page 117; 118
[2]Journal of the American Chemical Society,2016,vol. 138,p. 1486 - 1489

45
[ 13670-99-0 ]
[ 57260-71-6 ]
[ 846031-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride; potassium carbonate; In acetonitrile; at 100℃; for 24h;	[0740] A first intermediate compound, 4-(2-Acetyl-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, was produced as follows: To acetonitrile (100 mL) was added boc-piperazine (28.63 g, 0.153 mol), <strong>[13670-99-0]2,6-difluoroacetophenone</strong> (24 g, 0.154 mol), potassium carbonate (53 g, 0.384 mol) and potassium fluoride (8.93 g, 0.154 mol) followed by heating to 100 C. for 24 hours. Concentration of the solution in vacuo gave a mixture of solids which were isolated by filtration. The first intermediate compound was obtained by recrystallization from ethyl acetate, mp 88 C.

Reference： [1]Patent: US2005/43309,2005,A1 .Location in patent: Page/Page column 38

46
[ 13670-99-0 ]
[ 57848-46-1 ]
[ 676131-79-6 ]

Reference： [1]Patent: WO2004/31176,2004,A2 .Location in patent: Page/Page column 106

47
[ 108-24-7 ]
[ 18611-72-8 ]
[ 13670-99-0 ]

Reference： [1]Patent: WO2004/24738,2004,A1 .Location in patent: Page/Page column 15

48
[ 5292-43-3 ]
[ 13670-99-0 ]
[ 478163-14-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step A: Preparation of tert-Butyl 4-(2,6-difluorophenyl)-4-oxobutyrate To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at -60 C. under argon. After stifling for 10 minutes at -60 C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1) to provide the title compound. 1H NMR (270 MHz, CDCl3): 1.4 (s, 9H); 2.8 (t, 2H); 3.2 (t, 2H); 6.9-7.0 (m, 2H); 7.4 (m, 1H).
	With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium hexamethyldisilazane; In tetrahydrofuran; ethyl acetate;	Step A Preparation of tert-Butyl 4-(2,6-difluorophenyl)-4-oxobutyrate: To a stirred solution of 2,6-Difluoroacetophenone (5 g, 32 mmol) in dry THF (40 ml) and DMPU (8 ml) was added a solution of lithium bis(trimethylsilyl)amide (1.0M, 45 ml) at -60 C. under argon. After stirring for 10 minutes at -60 C., tert-Butyl bromoacetate (6.99 g, 35.8 mmol) was added rapidly. The reaction mixture was stirred for an additional 10 minutes and then warmed to room temperature for 4 hours. The crude mixture was taken in EtOAc and washed with water and brine. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate, 2:1) to provide the title compound. 1NMR (270 MHz, CDCl3): 1.4 (s, 9H); 2.8 (t, 2H); 3.2 (t, 2H); 6.9-7.0 (m, 2H); 7.4 (m, 1H).

Reference： [1]Patent: US9133073,2015,B2 .Location in patent: Page/Page column 81
[2]Patent: US2003/149107,2003,A1

49
[ 13670-99-0 ]
[ 794464-16-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With selenium(IV) oxide; In 1,4-dioxane; water; for 20h;Reflux;	1043] A mixture of selenium dioxide (111 g, 1000 mmol) in dioxane/ H2O (500 mL/20 mL) at 55 C. was stirred for 30 min and then added <strong>[13670-99-0]<strong>[13670-99-0]1-(2,6-difluorophenyl)ethanon</strong>e</strong> (156 g, 1000 mmol). The mixture was refluxed for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation collecting the fractions between 90-94 C., under roughly 1 mm mercury, to afford the title compound as yellow oil (98.5 g, 58%). 1H NMR (500 MHz, DMSO-d6): delta 9.48 (t, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H); MS (ESI): [M+H]+ 171.
	With sodium bicarbonate; bromine; sodium sulfate; In dichloromethane; water; dimethyl sulfoxide;	a) 5 g of <strong>[13670-99-0]2,6-difluoroacetophenone</strong> are placed in 13.6 ml of DMSO, and 2.7 ml of bromine (8.8M in water) are added dropwise, the reaction temperature rising from room temperature to 40 C. When the addition of bromine is complete, the mixture is heated at 80 C. for 30 min. After cooling to room temperature, the reaction mixture is poured into 100 ml of dichloromethane; with stirring, sodium sulfate and solid sodium hydrogen carbonate are added to the solution, filtration is carried out and the reaction mixture is concentrated using a rotary evaporator. The crude product is subjected to flash chromatography with dichloromethane. In this way (2,6-difluorophenyl)-oxoacetaldehyde is obtained in the form of a colourless viscous oil.
98.5 g	With selenium(IV) oxide; In 1,4-dioxane; water; at 55℃; for 20.5h;Reflux;	A mixture of selenium dioxide (111 g, 1000 mmol) in 1,4-dioxanelH2O (500 mLI2O mL) at 55 C was stilTed for 30 mm and then added 1 -(2,6-difluorophenyl)ethanone (156 g, 1000 mmol). The mixturewas refluxed for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation collecting the fractions between 90-94 C, under vacuum (-1 mm mercury), to afford the title compound as yellow oil(98.5 g). ?H NMR (500 MHz, DMSO-d6): 9.48 (t, J = 2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.3 3-7.29 (m, 2H); MS (ESI): [M+H] 171.

98.5 g		A mixture of selenium dioxide (111 g, 1000 mmol) in 1 ,4-dioxane/H20 (500 mL/20 mL) at 55 C was stirred for 30 min and then added l-(2,6-difluorophenyl)ethanone (156 g, 1000 mmol). The mixture was refluxed for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation collecting the fractions between 90-94 C, under vacuum (~1 mm mercury), to afford the title compound as yellow oil (98.5 g). H NMR (500 MHz, DMSO-<): delta 9.48 (t, / = 2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H); MS (ESI): [M+H]+ 171.
98.5 g	With selenium(IV) oxide; In 1,4-dioxane; water; at 55℃; for 20h;Reflux;	A mixture of selenium dioxide (111 g, 1000 mmol) in 1,4-dioxane/H2O (500 mL/20 mL) at 55 C was stirred for 30 min and then added <strong>[13670-99-0]<strong>[13670-99-0]1-(2,6-difluorophenyl)ethanon</strong>e</strong> (156 g, 1000 mmol). The mixture was refluxed for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation collecting the fractions between 90-94 C, under vacuum (~1 mm mercury), to afford the title compound as yellow oil (98.5 g).1H NMR (500 MHz, DMSO-d6): delta 9.48 (t, J = 2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H); MS (ESI): [M+H]+ 171.
98.5 g	With selenium(IV) oxide; water; In 1,4-dioxane; for 20h;Reflux;	A mixture of selenium dioxide (111 g, 1000 mmol) in 1,4-dioxane/H2O (500 mL/20 mL) at 55 C was stirred for 30 min and then added <strong>[13670-99-0]<strong>[13670-99-0]1-(2,6-difluorophenyl)ethanon</strong>e</strong> (156 g, 1000 mmol). The mixture was refluxed for 20 h. The reaction was cooled to RT and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation collecting the fractions between 90- 94 C, under vacuum (~1 mm mercury), to afford the title compound as yellow oil (98.5 g).1H NMR (500 MHz, DMSO-d6): delta 9.48 (t, J = 2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H); MS (ESI): [M+H]+ 171.

Reference： [1]Patent: US2015/126491,2015,A1 .Location in patent: Paragraph 1042; 1043
[2]Patent: US2003/36544,2003,A1
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 1418 - 1430
[4]Patent: WO2016/177760,2016,A1 .Location in patent: Page/Page column 36
[5]Patent: WO2016/177710,2016,A1 .Location in patent: Page/Page column 38; 39
[6]Patent: WO2016/177686,2016,A1 .Location in patent: Page/Page column 52
[7]Patent: WO2018/83105,2018,A1 .Location in patent: Page/Page column 100-101

50
[ 383-63-1 ]
[ 13670-99-0 ]
4,4,4-trifluoro-1-[2,6-(difluoro)phenyl]-butane-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate;	Step 1: Preparation of 4,4,4-trifluoro-1-[2,6-(difluoro)phenyl]-butane-1,3-dione) Ethyl trifluoroacetate (1.33 g, 9.3 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (2.11 g, 9.8 mmol) followed by <strong>[13670-99-0]2',6'-difluoroacetophenone</strong> (1.32 g, 8.5 mmol). The reaction was stirred at room temperature overnight (15.8 hours), then poured into a separatory funnel and washed with 3N HCl (20 mL), brine (20 mL), dried over MgSO4, and concentrated in vacuo to give the diketone as a white solid (1.68 g, mp 40-44 C., 79%). 1 H NMR (CDCl3) 300 MHz 14.0 (br s, 1H), 7.49 (m, 1H), 7.02 (m, 2H), 6.36 (s, 1H); 19 F NMF (CDCl3) 300 MHz: -76.78 (s), -109.77(s) M+H 253.
	With sodium methylate;	Step 1 Preparation of 4,4,4-trifluoro-1-[2,6(difluoro)phenyl]butane-1,3-dione) Ethyl trifluoroacetate (1.33 g, 9.3 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (2.11 g, 9.8 mmol) followed by <strong>[13670-99-0]2',6'-difluoroacetophenone</strong> (1.32 g, 8.5 mmol). The reaction was stirred at room temperature overnight (15.8 hours), then poured into a separatory funnel and washed with 3N HCl (20 mL), brine (20 mL), dried over MgSO4, and concentrated in vacuo to give the diketone as a white solid (1.68 g, mp 40-44 C., 79%). 1 H NMR (CDCl3) 300 MHz 14.0 (br s, 1H), 7.49 (m, 1H), 7.02 (m, 2H), 6.36 (s, 1H); 19 F NMR (CDCl3) 300 MHz: -76.78 (s), -109.77(s) M+H 253.

Reference： [1]Patent: US5466823,1995,A
[2]Patent: US5521207,1996,A
[3]Dalton Transactions,2010,vol. 39,p. 9000 - 9007
[4]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3406 - 3413

51
[ 7521-41-7 ]
[ 13670-99-0 ]
2-(2',6'-Difluorophenyl)-1,8-naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium hydroxide; In methanol;	Example 3 2-(2',6'-Difluorophenyl)-1,8-naphthyridine 2-Aminonicotinaldehyde (2.44 g, 20 mmol) and <strong>[13670-99-0]2,6-difluoroacetophenone</strong> (3.28 g, 21 mmol) are dissolved in 20 ml of MeOH. The mixture is treated dropwise with 3 ml of 40% KOH and, after the exothermic reaction has subsided, it is poured onto water and the residue which is deposited is filtered off with suction. 3.8 g (79% yield) of the desired product are obtained. M.p. 100-103 C.

Reference： [1]Patent: US5723413,1998,A

52
[ 13670-99-0 ]
[ 302-01-2 ]
[ 662146-05-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 150℃; for 0.0833333h;Microwave irradiation;	Stepl) Synthesis of 4-fluoro-3-methyl-lH-indazole; EPO <DP n="43"/>2', 6' -Difluoroacetophenone (0.468 g, 3 mmol) was dissolved in anhydrous hydrazine (2 ml), followed by irradiating microwaves thereon with stirring at 1500C for 5 min. The addition of water (0.5 ml) at 00C terminated the reaction. Afterwards, the reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The residue was re-crystallized in dichloromethane to give the title compound (Yield 85%) .IH-NMR (300MHz, CDCl3) d 7.37-7.32 (m, 2H) , 6.91 (m, IH) , 2.79(s, 3H) .

Reference： [1]Patent: WO2006/109933,2006,A1 .Location in patent: Page/Page column 41-42

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE G 7-Acetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 2,6-Difluoroacetophenone To 64.19 g (455 mmol) of the 2,6-difluorobenzonitrile in 300 ml of diethyl ester was added in one hour at -78 C., 650 ml of 1.6M methyl lithium (2.0 eq). The mixture was stirred at -78 C. for 2.5 hours, and then treated with 250 ml of 6N hydrochloric acid. The reaction was brought to 5 C. and allowed to attain room temperature overnight. The layers were separated, then the water layer washed with dichloromethane. The ether and dichloromethane layers were combined, dried, and concentrated to an oil which was purified by column chromatography on silica gel to give 61 g of 2,6-difluoroacetophenone as a light yellow liquid: IR (liquid film) 1709, 1622 cm-1.

54
[ 1897-52-5 ]
[ 13670-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methyllithium;	2,6-Difluoroacetophenone To 64.19 g (455 mmol) of the 2,6-difluorobenzonitrile in 300 ml of diethyl ester was added in one hour at -78 C., 650 ml of 1.6 M methyl lithium (2.0 eq). The mixture was stirred at -78 C. for 2.5 hours, and then treated with 250 ml of 6 N hydrochloric acid. The reaction was brought to 5 C. and allowed to attain room temperature overnight. The layers were separated, then the water layer washed with dichloromethane. The ether and dichloromethane layers were combined, dried, and concentrated to an oil which was purified by column chromatography on silica gel to give 61 g of 2,6-difluoroacetophenone as a light yellow liquid: IR (liquid film) 1709, 1622 cm-1.
	With methylmagnesium bromide; In ice-water; diethyl ether;	(A) Preparation of 2,6-Difluoroacetophenone 2,6-Difluorobenzonitrile (20.0 g, 0.14 mol) is dissolved in anhydrous diethyl ether (30 ml) and methyl magnesium bromide (154 ml of a 2.8 M solution, 0.43 mol) is added. The whole is warmed to reflux (35 C.) overnight (16 hrs.). Then the reaction mixture is quenched in ice-water (150 ml). The resultant mixture is heated to 75 C. for 3 hours and cooled. Pure product is then extracted from the mixture using methylene chloride (17.2 g, 76.7%).

Reference： [1]Patent: US4638067,1987,A
[2]Patent: US4438271,1984,A

55
[ 13670-99-0 ]
[ 87327-65-9 ]

Yield	Reaction Conditions	Operation in experiment
85.5%	With sodium hydroxide; sodium tetrahydroborate; In water;	(B) Preparation of 2,6-Difluoro-alpha-methylbenzyl alcohol 2,6-Difluoroacetophenone of (A) (17.2 g, 0.11 mol) is dissolved in isopropyl alcohol (50 ml) and NaBH4 (2.0 g, 0.055 mol) is added. The resultant mixture is warmed to 60 C. for about 14 hours. A solution of NaOH (4.9 g, 0.12 mol) in water (20 ml) is then added. After 1 hour at 60 C., this reaction mixture is cooled and acidified with dilute HCl. Extraction with methylene chloride provided pure title product (14.9 g, 85.5%).

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 9150 - 9160
[2]Patent: US4438271,1984,A
[3]Catalysis Communications,2010,vol. 11,p. 1049 - 1053
[4]Green Chemistry,2017,vol. 19,p. 474 - 480

56
[ 75-18-3 ]
[ 13670-99-0 ]
dimethyl-2,6-difluorophenacylsulfonium bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.9 g (38%)	With bromine; In tetrahydrofuran; diethyl ether; dichloromethane;	a. 2,6-Difluorophenylglyoxylohydroxamyl bromide A solution of bromine (4.1 ml, 80 mmoles) in dichloromethane (6 ml) was added dropwise to a solution of <strong>[13670-99-0]2,6-difluoroacetophenone</strong> (12.4 g, 80 mmoles) in anhydrous diethyl ether (100 ml). the reaction solution was evaporated and the resulting liquid was dissolved in tetrahydrofuran (150 ml) and methyl sulfide (9 ml, 120 mmoles) was added. The mixture was allowed to stand at room temperature for 6 days (approximately 144 hours). The crystals were filtered to yield 8.9 g (38%) of dimethyl-2,6-difluorophenacylsulfonium bromide.

Reference： [1]Patent: US4514410,1985,A

57
[ 921846-38-0 ]
[ 64-17-5 ]
[ 13670-99-0 ]
7-(2-fluoro-6-ethoxy-phenyl)-N₄-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium hydroxide; at 100℃; for 18h;	A mixture of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde 11 (100 mg, 0.60 mmole), <strong>[13670-99-0]2',6'-difluoroacetophenone</strong> (V, 200 mg, 1.23 mmole), potassium hydroxide pellet (100 mg, 1.79 mmole) and ethanol (4 mL) in a sealed tube was heated in a 100 C. oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography (Isco 120 g, NH4OH/MeOH/CH2Cl2) to give 81 mg (46% yield) of 7-(2-Fluoro-6-ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine (VII, R1=CH3, B=F, D=CH2CH3) as a light brown solid; LRMS for C16H16FN5O (M+H)+ at m/z=314. 1H NMR (DMSO-d6, 300 MHz) delta 8.37 (d, 1H), 8.20 (broad s, 1H), 7.40 (q, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 6.90 (t, 1H), 6.47 (broad s, 2H), 4.05 (q, 2.97 (d, 3H), 1.18 (t, 3H).

Reference： [1]Patent: US2007/21445,2007,A1 .Location in patent: Page/Page column 5

58
[ 13670-99-0 ]
[ 105-56-6 ]
[ 928324-38-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 10 - 20℃; for 12h;	Reference Example 95 ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate; To a solution of ethyl cyanoacetate (7.24 g) and diisopropylethylamine (19.9 g) in tetrahydrofuran (30 mL) was added dropwise a solution of 2-bromo-<strong>[13670-99-0]<strong>[13670-99-0]1-(2,6-difluorophenyl)ethanon</strong>e</strong> (15.16 g) in tetrahydrofuran (15 mL) at 10-15 C. The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1?3:2) to give the title compound as a pale-green oil (yield 13.8 g, 81%). 1H-NMR (CDCl3) delta: 1.35 (3H, t, J=7.1 Hz), 3.44-3.53 (1H, m), 3.63-3.72 (1H, m), 4.13-4.18 (1H, m), 4.31 (2H, q, J=7.1 Hz), 6.95-7.05 (2H, m), 7.44-7.54 (1H, m).

Reference： [1]Patent: US2007/60623,2007,A1 .Location in patent: Page/Page column 35

59
[ 13670-99-0 ]
[ 1122-91-4 ]
[ 405061-26-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol; water;	Step 1 23.40 g of <strong>[13670-99-0]2,6-difluoroacetophenone</strong> (0.15 mol), 27.75 g of 4-bromobenzaldehyde (0.15 mol), 60 ml of methanol and 150 ml of water are initially charged in a three-necked flask. At room temperature, 45 ml of aqueous sodium hydroxide solution (10% strength solution in water) are added dropwise, and the mixture is then stirred at room temperature overnight. The reaction mixture is cooled to 5 C. and the precipitate is filtered off and washed with 100 ml of cold methanol/water (1:3). This gives 44.77 g (92% of theory) of (2E)-3-(4-bromophenyl)-1-(2,6-difluorophenyl)-2-propen-1-one of melting point 71 C. HPLC: log P (pH 2.3)=3.98 (98% pure). 1H-NMR spectrum (D6-DMSO): delta=7.25-7.35 (3H, m), 7.54 (1H, d), 7.62-7.72 (3H, m), 7.76 (2H, d) ppm.
	With sodium hydroxide; In methanol; water;	Step 1 23.40 g of <strong>[13670-99-0]2,6-difluoroacetophenone</strong> (0.15 mol), 27.75 g of 4-bromobenzaldehyde (0.15 mol), 60 ml of methanol and 150 ml of water are initially charged in a three-necked flask. At room temperature, 45 ml of aqueous sodium hydroxide solution (10% strength solution in water) are added dropwise, and the mixture is then stirred at room temperature overnight. The reaction mixture is cooled to 5 C. and the precipitate is filtered off and washed with 100 ml of cold methanol/water (1:3). This gives 44.77 g (92% of theory) of (2E)-3-(4-bromophenyl)-1-(2,6-difluorophenyl)-2-propen-1-one of melting point 71 C. HPLC: log P (pH 2.3)=3.98 (98% pure). 1H-NMR spectrum (D6-DMSO): delta=7.25-7.35 (3H, m), 7.54 (1H, d), 7.62-7.72 (3H, m), 7.76 (2H, d) ppm.

Reference： [1]Patent: US2004/54194,2004,A1
[2]Patent: US2004/97740,2004,A1

60
[ 131296-74-7 ]
[ 13670-99-0 ]
OsH₃(P(C₃H₇)3)2(C₈H₆FO) [ No CAS ]

Reference： [1]Organometallics,2001,vol. 20,p. 442 - 452

61
[ 13670-99-0 ]
[ 662146-05-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrazine; at 150℃; for 0.0833333h;Microwave irradiation;	2',6'-Difluoroacetophenone (0.468 g, 3 mmol) was dissolved in anhydrous hydrazine (2 ml), followed by irradiating microwaves thereon with stirring at 150 C. for 5 min. The addition of water (0.5 ml) at 0 C. terminated the reaction. Afterwards, the reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The residue was re-crystallized in dichloromethane to give the title compound (Yield 85%).1H-NMR(300 MHz, CDCl3) d 7.377.32(m,2H),6.91(m,1H), 2.79(s,3H).

Reference： [1]Patent: US2008/194661,2008,A1 .Location in patent: Page/Page column 15

62
[ 13670-99-0 ]
[ 10040-98-9 ]
3-(2,6-difluorophenyl)-3-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-1-one [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2009,vol. 44,p. 4654 - 4660

63
[ 13670-99-0 ]
[ 105-56-6 ]
[ 1036520-34-9 ]

Yield	Reaction Conditions	Operation in experiment
	With morpholine; sulfur; In ethanol; at 60℃; for 72.4h;	Step 1 : Ethyl cyanoacetate (6.8 m._) was added dropwise to a solution of 2',6'- difluoroacetophenone (10 g, 64 mmol) in ethanol (250 ml_). After 20 minutes at 6O0C, morpholine (19.6 mL) was added and 5 minutes later sulphur (4.1 g). Heating was carried on during 72 hours then filtered through a pad of silica and the solvent removed under reduced pressure. The crude was purified over silica (pentane / ethyl acetate 95/5). An oily compound (13.5 g) containing ethylcyanoactate was recovered; MS: 284.0 (M+1)
		Ethyl cyanoacetate (6.8 mL) was added dropwise to a solution of <strong>[13670-99-0]2',6'-difluoroacetophenone</strong> (10 g, 64 mmol) in ethanol (250 mL). After 20 minutes at 60 C., morpholine (19.6 mL) was added and 5 minutes later sulphur (4.1 g). Heating was carried on during 72 hours then filtered through a pad of silica and the solvent removed under reduced pressure. The crude was purified over silica (pentane/ethyl acetate 95/5). An oily compound (13.5 g) containing ethylcyanoactate was recovered; MS: 284.0 (M+1)

Reference： [1]Patent: WO2009/124636,2009,A1 .Location in patent: Page/Page column 50
[2]Patent: US2011/34505,2011,A1 .Location in patent: Page/Page column 16

64
[ 13670-99-0 ]
[ 1190765-91-3 ]

Reference： [1]Patent: US2011/34505,2011,A1

65
[ 13670-99-0 ]
[ 1190768-32-1 ]

Reference： [1]Patent: US2011/34505,2011,A1

66
[ 13670-99-0 ]
[ 1190768-33-2 ]

Reference： [1]Patent: US2011/34505,2011,A1

67
[ 13670-99-0 ]
[ 1279103-40-0 ]