Name: 256417-11-5|2,3-Difluoro-4-methoxybenzaldehyde|98%
Brand: Ambeed
SKU: A936413
Price: 5.0 USD
Availability: InStock
Rating: 91 (25 reviews)

1
[ 558-13-4 ]
[ 256417-11-5 ]
1-(2,2-Dibromo-vinyl)-2,3-difluoro-4-methoxy-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine In dichloromethane Ambient temperature;

Reference： [1]Parlow, John J.; Clark, Robert D. [Journal of Agricultural and Food Chemistry, 1994, vol. 42, # 11, p. 2600 - 2609]

2
[ 4885-02-3 ]
[ 134364-69-5 ]
[ 256417-11-5 ]
2-methoxy-3,4-difluorobenzaldehyde [ No CAS ]

Reference： [1]Journal of Fluorine Chemistry,2003,vol. 123,p. 101 - 108

3
[ 108683-61-0 ]
[ 256417-11-5 ]
(Z)-1-(3',4',5'-trimethoxyphenyl)-2-(2'',3''-difluoro-4''-methoxyphenyl)ethene [ No CAS ]
(E)-1-(3',4',5'-trimethoxyphenyl)-2-(2'',3''-difluoro-4''-methoxyphenyl)ethene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 36% 2: 34%	With potassium <i>tert</i>-butylate In methanol at -78 - 20℃;

Reference： [1]Lawrence, Nicholas J.; Hepworth, Lucy A.; Rennison, David; McGown, Alan T.; Hadfield, John A. [Journal of Fluorine Chemistry, 2003, vol. 123, # 1, p. 101 - 108]

4
[ 6418-38-8 ]
[ 256417-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 78 percent / K₂CO₃ / dimethylsulfoxide / 0.5 h / 20 °C 2.1: TiCl₄ / CH₂Cl₂ / 0.08 h / 0 °C 2.2: 71 percent / CH₂Cl₂ / 0.5 h / 20 °C
	Multi-step reaction with 5 steps 1.1: 1H-imidazole / 18 h / 20 °C 2.1: 2,2,6,6-tetramethyl-piperidine; n-butyllithium / tetrahydrofuran; hexane / 2 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C 3.1: borane-THF / tetrahydrofuran / 24 h / 0 - 20 °C / Inert atmosphere 3.2: 6 h / 60 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C 5.1: potassium carbonate / N,N-dimethyl-formamide; acetone / 5.5 h / 20 °C

Reference： [1]Lawrence, Nicholas J.; Hepworth, Lucy A.; Rennison, David; McGown, Alan T.; Hadfield, John A. [Journal of Fluorine Chemistry, 2003, vol. 123, # 1, p. 101 - 108]
[2]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

Yield	Reaction Conditions	Operation in experiment
		The following are prepared analogously: 4-Methoxy-2,3-difluorobenzaldehyde 4-Propoxy-2,3-difluorobenzaldehyde 4-Pentoxy-2,3-difluorobenzaldehyde 4-Heptoxy-2,3-difluorobenzaldehyde 4-Methyl-2,3-difluorobenzaldehyde 4-Ethyl-2,3-difluorobenzaldehyde 4-Propyl-2,3-difluorobenzaldehyde 4-Pentyl-2,3-difluorobenzaldehyde
		63.2 (2-{2,3-Difluoro-4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]phenyl}cyclopropyl)acetic acid Trifluoroacetate. Step 2: 2,3-Difluoro-4-methoxybenzaldehyde. The product of step 1 (6.64 grams) was dissolved in THF (150 mL) and was treated with N,N,N',N'-tetramethylethylenediamine (13.9 grams) and the mixture was cooled to -55° C. 1.6M nBuLi (40 mL) was added via syringe under nitrogen atmosphere. The mixture was stirred at -55° C. for 2.5 hours. The mixture was quenched with 4-formylmorpholine (6.9 grams). The mixture was stirred at -55° C. for 1 hour. The reaction mixture was warmed upto an ambient temperature and was quenched with water (2.0 mL). The mixture was concentrated in vacuo afforded an oily gum, which was acidified with 1N HCl. The mixture was extracted with ethyl acetate. The organic extract was washed with water, dried (Na2SO4) and concentrated to yield crude oil, which was purified with silica gel chromatography (Biotage Flash40M, 20%EA/Hexane) to afford 4.8 grams of the title compound as oil. 1H-NMR(CDCl3): 10.18(s, 1H),7.63(m, 1H), 6.82(m, 2H), 3.98(s, 3H).

6
[ 4394-85-8 ]
[ 134364-69-5 ]
[ 256417-11-5 ]

Yield	Reaction Conditions	Operation in experiment
		The product of step 1 (6.64 grams) was dissolved in THF (150 mL) and was treated with N,N,N',N'-tetramethylethylenediamine (13.9 grams) and the mixture was cooled to -55 C. 1.6M nBuLi (40 mL) was added via syringe under nitrogen atmosphere. The mixture was stirred at -55 C. for 2.5 hours. The mixture was quenched with 4-formylmorpholine (6.9 grams). The mixture was stirred at -55 C. for 1 hour. The reaction mixture was warmed upto an ambient temperature and was quenched with water (2.0 mL). The mixture was concentrated in vacuo afforded an oily gum, which was acidified with 1N HCl. The mixture was extracted with ethyl acetate. The organic extract was washed with water, dried (Na2SO4) and concentrated to yield crude oil, which was purified with silica gel chromatography (Biotage Flash40M, 20%EA/Hexane) to afford 4.8 grams of the title compound as oil. 1HNMR(CDCl3): 10.18(s, 1H),7.63(m, 1H), 6.82(m, 2H), 3.98(s, 3H).

Reference： [1]Patent: US2004/92538,2004,A1 .Location in patent: Page 58

7
[ 124931-12-0 ]
[ 256417-11-5 ]
[ 689258-07-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 2,3-difluoro-4-methoxy-benzaldehyde In tetrahydrofuran at 20℃; for 1h;	63.3 Diethyl (N-methoxy-N-methylcarbamoylmethyl)-phosphonate (4.8 g) was added to a suspension of 95% NaH (550 mg) in THF (40 mL) under nitrogen atmosphere. The mixture was stirred at an ambient temperature for 10 minutes, and was treated with the product of step 2 (3.44 grams). The mixture was stirred at room temperature for 1 hour and was quenched with water (10 mL). The mixture was concentrated in vacuoo afforded an oily residue. The residue was extracted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated to yield 3.2 grams of the title compound as white solid. 1HNMR(CDCl3): 7.72 (d, 1H), 7.22(m, 1H), 7.15(d, 1H), 6.75(m,1H), 3.92(s, 3H), 3.78(s, 3H), 3.3(s, 3H).

Reference： [1]Current Patent Assignee: PFIZER INC - US2004/92538, 2004, A1 Location in patent: Page 58

8
[ 31469-15-5 ]
[ 256417-11-5 ]
[ 1010801-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With boron trifluoride diethyl etherate In diethyl ether at 20℃; for 1h; Inert atmosphere;	152 Methyl 3-(2,3-difluoro-4-methoxyphenyl)-3-hydroxy-2,2-dimethylpropionate ester The compound of Example 151 (1.30 g) was dissolved in diethyl ether (70 mL) under an argon atmosphere, and dimethylketene methyltrimethylsilyl acetal (2.30 mL) and a boron trifluoride-diethyl ether complex (1.44 mL) were added thereto at room temperature, followed by stirring at room temperature for 1 hour. To the reaction liquid was added a 10% aqueous sodium hydroxide solution, followed by extraction with ethyl acetate, and the extracted layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (1.98 g) as a white powder. 1H-NMR (CDCl3, 400 MHz): δ 1.15 (3H, s), 1.16 (3H, d, J=2.4 Hz), 3.37 (1H, d, J=4.9 Hz), 3.75 (3H, s), 3.91 (3H, s), 5.20 (1H, d, J=4.9 Hz), 6.79 (1H, ddd, J=8,6, 7.9, 2.4 Hz), 7.13 (1H, ddd, J=8.6, 7.3, 2.4 Hz).

Reference： [1]Current Patent Assignee: KYORIN HOLDINGS, INC. - EP2168960, 2010, A1 Location in patent: Page/Page column 137

9
[ 676500-39-3 ]
[ 74-88-4 ]
[ 256417-11-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In N,N-dimethyl-formamide; acetone; at 20℃; for 5.5h;	The residue was dissolved in acetone (50 mL) and DMF (20 mL). Then, MeI (0.918 mL, 14.8 mmol)and K2CO3 (2.72 g, 19.7 mmol) were added. After stirringfor 5.5 h at room temperature, the reaction mixture was filtered through a padof celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane : EtOAc = 3 : 1) to give the title compound (1.30 g, 7.55mmol, 77%)as a white solid. 1H-NMR (400 MHz, CDCl3):? delta 4.00 (3H, s), 6.86 (1H, ddd, J = 9.2, 6.7, 1.8 Hz), 7.64 (1H, ddd, J = 9.2, 6.7, 1.8 Hz), 10.20(1H, s).
	With potassium carbonate; In tetrahydrofuran; acetone; at 20℃; for 5.5h;	2,3-Difluoro-4-methoxybenzaldehyde The compound of Example 150 (3.09 g) was dissolved in THF (50 mL) under an argon atmosphere, and tetrabutyl ammonium fluoride (1.0 mol/L THF solution, 12.8 mL) was added thereto, followed by stirring at room temperature for 20 minutes. To the reaction liquid was added 1.0 mol/L hydrochloric acid, followed by extraction with ethyl acetate, and the extracted layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in acetone (50 mL) and DMF (20 mL), and potassium carbonate (2.72 g) and iodomethane (0.918 mL) were added thereto, followed by stirring at room temperature for 5.5 hours. The insoluble materials were removed by filtration through Celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3: 1) to obtain the desired product (1.30 g) as a white powder. 1H-NMR (CDCl3, 400 MHz): delta 4.00 (3H, s), 6.86 (1H, ddd, J=9.2, 6.7, 1.8 Hz), 7.64 (1H, ddd, J=9.2, 7.3, 1.8 Hz), 10.20 (1H, s).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 375 - 381
[2]Patent: EP2168960,2010,A1 .Location in patent: Page/Page column 136

10
[ 4885-02-3 ]
[ 134364-69-5 ]
[ 256417-11-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2082 - 2085

11
[ 256417-11-5 ]
[ 676500-39-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2082 - 2085

12
[ 90965-06-3 ]
[ 256417-11-5 ]
[ 931108-29-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In methanol for 1.5h;	4.5. Syntheses of alkynes using the Ohira-Bestmann reaction: general procedure General procedure: Dimethyl-1-diazo-2-oxopropylphosphonate (280 mg, 1.44 mmol) was added to a suspension of the aldehyde (1.2 mmol) and K2CO3 (336 mg, 2.4 mmol) in MeOH (15 mL). Stirring was continued for 1.5 h. Then the reaction mixture was diluted with Et2O (25 mL), washed with an aq solution of NaHCO3 (10 mL, 5%) and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent in vacuo the desired alkyne was obtained.

Reference： [1]Location in patent: experimental part Akselsen, Øyvind W.; Odlo, Kristin; Cheng, Jing-Jy; MacCari, Giorgio; Botta, Maurizio; Hansen, Trond Vidar [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 234 - 242]

13
[ 256417-11-5 ]
[ 1355330-17-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / methanol / 1.5 h 2.1: ethylmagnesium chloride / tetrahydrofuran / 0.25 h / 50 °C / Inert atmosphere 2.2: 3 h / 50 °C / Inert atmosphere

Reference： [1]Akselsen, Øyvind W.; Odlo, Kristin; Cheng, Jing-Jy; MacCari, Giorgio; Botta, Maurizio; Hansen, Trond Vidar [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 234 - 242]

14
[ 749230-30-6 ]
[ 256417-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 2,2,6,6-tetramethyl-piperidine; n-butyllithium / tetrahydrofuran; hexane / 2 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 °C 2.1: borane-THF / tetrahydrofuran / 24 h / 0 - 20 °C / Inert atmosphere 2.2: 6 h / 60 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C 4.1: potassium carbonate / N,N-dimethyl-formamide; acetone / 5.5 h / 20 °C

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

15
[ 1010800-88-0 ]
[ 256417-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: borane-THF / tetrahydrofuran / 24 h / 0 - 20 °C / Inert atmosphere 1.2: 6 h / 60 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C 3.1: potassium carbonate / N,N-dimethyl-formamide; acetone / 5.5 h / 20 °C

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

16
[ 1010801-00-9 ]
[ 256417-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide; acetone / 5.5 h / 20 °C

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

17
[ 256417-11-5 ]
[ 1010801-02-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: boron trifluoride diethyl etherate / diethyl ether / 1 h / 20 °C / Inert atmosphere 2: triethylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 1 h / 20 °C

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

18
[ 256417-11-5 ]
[ 1010801-04-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: boron trifluoride diethyl etherate / diethyl ether / 1 h / 20 °C / Inert atmosphere 2: triethylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 1 h / 20 °C 3: hydrazine hydrate / ethanol / 6 h / Reflux 4: aluminum (III) chloride / dichloromethane / 26 h / Reflux

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

19
[ 256417-11-5 ]
[ 1010802-00-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: boron trifluoride diethyl etherate / diethyl ether / 1 h / 20 °C / Inert atmosphere 2: triethylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 1 h / 20 °C 3: hydrazine hydrate / ethanol / 6 h / Reflux 4: aluminum (III) chloride / dichloromethane / 26 h / Reflux 5: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / 60 °C / Inert atmosphere

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

20
[ 256417-11-5 ]
[ 1093857-65-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: boron trifluoride diethyl etherate / diethyl ether / 1 h / 20 °C / Inert atmosphere 2: triethylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 1 h / 20 °C 3: hydrazine hydrate / ethanol / 6 h / Reflux 4: aluminum (III) chloride / dichloromethane / 26 h / Reflux 5: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / 60 °C / Inert atmosphere

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

21
[ 256417-11-5 ]
[ 1093857-58-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: boron trifluoride diethyl etherate / diethyl ether / 1 h / 20 °C / Inert atmosphere 2: triethylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 1 h / 20 °C 3: hydrazine hydrate / ethanol / 6 h / Reflux 4: aluminum (III) chloride / dichloromethane / 26 h / Reflux 5: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / 60 °C / Inert atmosphere

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

22
[ 256417-11-5 ]
[ 1010801-03-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: boron trifluoride diethyl etherate / diethyl ether / 1 h / 20 °C / Inert atmosphere 2: triethylamine; sulfur trioxide pyridine complex / dimethyl sulfoxide / 1 h / 20 °C 3: hydrazine hydrate / ethanol / 6 h / Reflux

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

23
dimethylketene methyl tirimethylsilyl acetal [ No CAS ]
[ 256417-11-5 ]
[ 1010801-01-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With boron trifluoride diethyl etherate In diethyl ether at 20℃; for 1h; Inert atmosphere;	Methyl 3-(2,3-difluoro-4-methoxyphenyl)-3-hydroxy-2,2-dimethylpropanoate To a stirred solution of 31 (1.30 g, 7.55 mmol) in Et2O(70 mL) were added dimethylketenemethyl tirimethylsilyl acetal (2.30 mL, 11.3 mmol) and BF3-Et2O(1.44 mL, 11.7 mmol) under argon atmosphere. After stirring for 1 h at roomtemperature, The reaction was quenched with 10% NaOH aq. and the resulting mixture was extracted with EtOAc. The organic layer was washed with water followed by brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (n-hexane: EtOAc = 3 : 1) to give the title compound (1.98 g,7.22 mmol, 96%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 1.15(3H, s), 1.16 (3H, d, J = 2.4 Hz),3.37 (1H, d, J = 4.9 Hz), 3.75 (3H, s), 3.91 (3H, s), 5.20 (1H, d, J = 4.9 Hz), 6.79 (1H, ddd, J = 8.6, 7.9, 2.4 Hz), 7.13 (1H, ddd, J = 8.6, 7.9, 2.4 Hz).

Reference： [1]Ochiai, Koji; Takita, Satoshi; Kojima, Akihiko; Eiraku, Tomohiko; Iwase, Kazuhiko; Kishi, Tetsuya; Ohinata, Akira; Yageta, Yuichi; Yasue, Tokutaro; Adams, David R.; Kohno, Yasushi [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 375 - 381]

24
[ 579-74-8 ]
[ 256417-11-5 ]
(E)-3-(2,3-difluoro-4-methoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium hydroxide In methanol; water at 20℃;

Reference： [1]Abdel-Halim, Mohammad; Diesel, Britta; Kiemer, Alexandra K.; Abadi, Ashraf H.; Hartmann, Rolf W.; Engel, Matthias [Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6513 - 6530]

25
[ 256417-11-5 ]
1-(3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-3-(2-methoxyphenyl)-4,5-dihydro-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium hydroxide / methanol; water / 20 °C 2: N,N-dimethyl-formamide / 5 h / 85 °C / Inert atmosphere

Reference： [1]Abdel-Halim, Mohammad; Diesel, Britta; Kiemer, Alexandra K.; Abadi, Ashraf H.; Hartmann, Rolf W.; Engel, Matthias [Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6513 - 6530]

26
[ 256417-11-5 ]
4-(1-(3-chlorophenyl)-3-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-5-yl)-2,3-difluorophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium hydroxide / methanol; water / 20 °C 2: N,N-dimethyl-formamide / 5 h / 85 °C / Inert atmosphere 3: boron tribromide / dichloromethane / 21 h / -78 - 20 °C / Inert atmosphere

Reference： [1]Abdel-Halim, Mohammad; Diesel, Britta; Kiemer, Alexandra K.; Abadi, Ashraf H.; Hartmann, Rolf W.; Engel, Matthias [Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6513 - 6530]

27
[ 594-19-4 ]
[ 68-12-2 ]
[ 134364-69-5 ]
[ 256417-11-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of l,2-difluoro-3-methoxybenzene (3.0 g, 21 mmol) in anhydrous tetrahydrofuran (40 mL) at -70 C under nitrogen was added dropwise tert-butyllithium (19 mL, 25 mmol, 1.3 M in n-pentane). The mixture was stirred at this temperature for 30 minutes, then NN- dimethylformamide (6.1 g, 83 mmol) was added dropwise at -70 C. The reaction was stirred at - 70 C for another 2 hours. On completion, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-168 (4.0 g, crude) as a yellow solid. LCMS (B): tR=0.661 min., (ES+) m/z (M+H)+ =173.1.

Reference： [1]Patent: WO2016/100184,2016,A1 .Location in patent: Paragraph 00399-00400

28
[ 256417-11-5 ]
7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 40 °C 2.1: lithium hydroxide monohydrate; water / methanol / 40 °C 2.2: pH 3

Reference： [1]Current Patent Assignee: SIO GENE THERAPIES INC; FORUM PHARMACEUTICALS INC - WO2016/100184, 2016, A1

29
[ 2365-48-2 ]
[ 256417-11-5 ]
methyl 7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In N,N-dimethyl-formamide at 40℃;	68B methyl 7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylate (B-169) To a mixture of compound B-168 (4.0 g, 23 mmol) in N, N-dimethylformamide (60 mL) was added methyl 2-mercaptoacetate (2.5 g, 23 mmol) and potassium carbonate (3.9 g, 28 mmol). The mixture was stirred at 40 °C overnight. On completion, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-169 (4.0 g, 72% yield) as a white solid. LCMS (B): tR=0.869 min., (ES+) m/z (M+H)+ = 241.0.
11.7 g	With piperidine; pyridine at 100℃; for 4h;	2.2 Synthesis of Compound 112: (S)-(4-fluoro-2,6-dimethylphenyl)(7-fluoro-3-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)methanone In Step 2, Compound 78 (10 g) was converted Compound 79 using methyl 2- mercaptoacetate in piperidine/pyridine at 100 °C. The reaction was stirred for 4 hour prior to purification that yielded Compound 79 (11.7 g). In Step 3, Compound 79 (2 g) was converted to benzothiophene Compound 72 using SOCI2 in xylenes/pyridine. The reaction was heated to 120 °C and allowed to stir overnight. In Step 4, Compound 72 is subjected to n-butyl lithium and 2- bromo-5-fluoro-1,3-dimethylbenzene to afford Compound 73. In Step 5, Compound 73 is demethylated using BBr3 to afford Compound 74. In Step 6, Compound 74 is reacted with sodium hydride and benzyl bromide to afford Compound 75. In Step 7, Compound 75 is mixed with Compound 38 and cesium carbonate in DMSO to afford Compound 76. In Step 8, the benzyl protecting group of Compound 76 is removed by hydrogenation to afford Compound 112.

Reference： [1]Current Patent Assignee: SIO GENE THERAPIES INC; FORUM PHARMACEUTICALS INC - WO2016/100184, 2016, A1 Location in patent: Paragraph 00401-00402
[2]Current Patent Assignee: G1 THERAPEUTICS INC - WO2020/37251, 2020, A1 Location in patent: Page/Page column 148; 158-159

30
C₁₂H₁₅O₂S⁽¹⁺⁾*BF₄^(1-) [ No CAS ]
[ 256417-11-5 ]
5-((2R*,3R*)-3-(2,3-difluoro-4-methoxyphenyl)oxiran-2-yl)benzo[d][1,3]dioxole [ No CAS ]
5-((2R*,3S*)-3-(2,3-difluoro-4-methoxyphenyl)oxiran-2-yl)benzo[d][1,3]dioxole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50 % de	Stage #1: C₁₂H₁₅O₂S⁽¹⁺⁾*BF₄^(1-) With sodium hydride In diethyl ether; acetonitrile at 0℃; for 0.0833333h; Stage #2: 2,3-difluoro-4-methoxy-benzaldehyde In diethyl ether; acetonitrile at 0 - 23℃; Overall yield = 1.09 g; diastereoselective reaction;	Synthesis of 5-((2R,3R)-3-(2,3-difluoro-4-methoxyphenyl)oxiran-2-yl)benzo[d][1,3]dioxole (37) frombenzo[d][1,3]dioxol-5-ylmethanol and 2,3-difluoro-4-methoxybenzaldehyde as a mixture of inseparable diastereomer General procedure: A flame-dried round bottom flask (for 3 mmol: 50 mL flask, 5 mmol: 100 mL, 10 mmol: 250 mL) with a magnetic stirring bar was charged with the benzyl alcohol (1.1 equiv), tetrahydrothiophene (THT) (1.2 equiv), and acetonitrile (MeCN) ([1 M] with respect to (w.r.t.) the benzyl alcohol). Thereafter, tetrafluoroboric acid diethyl ether complex (HBF4·OEt2) (1.2 equiv) was added dropwise and the reaction was left to stir until full consumption of the alcohol was observed by TLC (1:1 hexanes (Hex)/ethyl acetate (EtOAc)) or for a 12 h period. The reaction was then cooled to 0 °C (water/ice bath), diluted with MeCN ([0.1 M] w.r.t. aldehyde) and sodium hydride (NaH) (4 equiv) was added in small portions. After stirring for 5 minutes the aldehyde (1 equiv.) was added dropwise or in small portions (solids). The reaction was left to stir until full consumption of the aldehyde was seen by TLC (4:1 Hex/EtOAc) or for a 12 h period. Then, the reaction was cooled to 0 C and water was added dropwise until no further gas evolution was observed. The mixture was concentrated in vacuo and the resultant residue was introduced into a separatory funnel with the assistance of water and EtOAc. The mixture was extracted three times with EtOAc and the combined organic fractions were dried over MgSO4 and concentrated in vacuo. The resultant material was purified by flash chromatography. Diastereoselectivity was determined by crude 1H NMR prior to purification unless otherwise noted
50 % de	Stage #1: C₁₂H₁₅O₂S⁽¹⁺⁾*BF₄^(1-) With sodium hydride In acetonitrile at 0℃; for 0.0833333h; Stage #2: 2,3-difluoro-4-methoxy-benzaldehyde In acetonitrile at 0 - 23℃; Overall yield = 1.09 g; diastereoselective reaction;

Reference： [1]Alfonzo, Edwin; Mendoza, Jesse W.L.; Beeler, Aaron B. [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2308 - 2312]
[2]Alfonzo, Edwin; Beeler, Aaron B.; Millimaci, Alexandra M. [Organic Letters, 2020]

31
[ 256417-11-5 ]
[ 847905-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: piperidine; pyridine / 4 h / 100 °C 2: thionyl chloride; pyridine / 5,5-dimethyl-1,3-cyclohexadiene / 120 °C

Reference： [1]Current Patent Assignee: G1 THERAPEUTICS INC - WO2020/37251, 2020, A1

32
[ 256417-11-5 ]
C₁₈H₁₃ClF₂O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: piperidine; pyridine / 4 h / 100 °C 2: thionyl chloride; pyridine / 5,5-dimethyl-1,3-cyclohexadiene / 120 °C 3: n-butyllithium

Reference： [1]Current Patent Assignee: G1 THERAPEUTICS INC - WO2020/37251, 2020, A1

33
[ 256417-11-5 ]
C₁₇H₁₁ClF₂O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: piperidine; pyridine / 4 h / 100 °C 2: thionyl chloride; pyridine / 5,5-dimethyl-1,3-cyclohexadiene / 120 °C 3: n-butyllithium 4: boron tribromide

Reference： [1]Current Patent Assignee: G1 THERAPEUTICS INC - WO2020/37251, 2020, A1

34
[ 256417-11-5 ]
C₂₄H₁₇ClF₂O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: piperidine; pyridine / 4 h / 100 °C 2: thionyl chloride; pyridine / 5,5-dimethyl-1,3-cyclohexadiene / 120 °C 3: n-butyllithium 4: boron tribromide 5: sodium hydride

Reference： [1]Current Patent Assignee: G1 THERAPEUTICS INC - WO2020/37251, 2020, A1

35
[ 256417-11-5 ]
C₃₇H₃₄F₃NO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: piperidine; pyridine / 4 h / 100 °C 2: thionyl chloride; pyridine / 5,5-dimethyl-1,3-cyclohexadiene / 120 °C 3: n-butyllithium 4: boron tribromide 5: sodium hydride 6: caesium carbonate

Reference： [1]Current Patent Assignee: G1 THERAPEUTICS INC - WO2020/37251, 2020, A1

36
[ 256417-11-5 ]
2,3-difluoro-4-methoxy-5-nitro-benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.01%	With sulfuric acid; nitric acid at -10℃; for 1.16667h;	19.1 Step 12,3-difluoro-4-methoxy-5-nitro-benzaldehyde (19B) 2, 3-difluoro-4-methoxy-benzaldehyde (19A) (3 g,17.43 mmol ) was dissolved in concentrated sulfuric acid (18 mL) and cooled to -10°C. Concentrated nitric acid (1.5 mL) in concentrated sulfur acid (3 mL) was added dropwise over 10 min. After an additional hour of stirring at below -10°C, the mixture was poured into crushed ice. the precipitate was collected by filtration and partitioned between dichloromethane (30 mL) and saturated sodium hydrogen carbonate (30 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound (19B) (3.1g, 82.01%) as a white solid. LC-MS (ESI): m/z =218.1 [M+H]+

Reference： [1]Current Patent Assignee: ALUMIS - WO2020/185755, 2020, A1 Location in patent: Paragraph 00383

37
[ 256417-11-5 ]
(2,3-difluoro-4-methoxy-5-nitro-phenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid; nitric acid / 1.17 h / -10 °C 2: sodium tetrahydroborate; methanol / 2 h / 0 °C