Name: 167683-93-4|2-Fluoro-4-methoxyphenol|95%
Brand: Ambeed
SKU: A322191
Price: 5.0 USD
Availability: InStock
Rating: 93 (22 reviews)

1
[ 75-03-6 ]
[ 167683-93-4 ]
[ 1026793-94-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetone at 60℃; for 5h;
	With potassium carbonate

Reference： [1]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]
[2]Sahlberg, Christer; Noreen, Rolf; Engelhardt, Per; Hoegberg, Marita; Kangasmetsae, Jussi; Vrang, Lotta; Zhang, Hong [Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 12, p. 1511 - 1516]

2
[ 181305-63-5 ]
[ 167683-93-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With ammonium hydroxide In methanol for 1h; Ambient temperature;

Reference： [1]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]

3
[ 358-23-6 ]
[ 167683-93-4 ]
[ 550998-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In dichloromethane at 0 - 20℃;
	With pyridine In dichloromethane at 0℃; for 0.5h;

Reference： [1]Edsall Jr., Richard J; Harris, Heather A; Manas, Eric S; Mewshaw, Richard E [Bioorganic and medicinal chemistry, 2003, vol. 11, # 16, p. 3457 - 3474]
[2]Mewshaw, Richard E.; Edsall Jr., Richard J.; Yang, Cuijian; Manas, Eric S.; Xu, Zhang B.; Henderson, Ruth A.; Keith Jr., James C.; Harris, Heather A. [Journal of Medicinal Chemistry, 2005, vol. 48, # 12, p. 3953 - 3979]

4
[ 2105-94-4 ]
[ 124-41-4 ]
[ 167683-93-4 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(I) bromide In methanol; N,N-dimethyl-formamide Heating;

Reference： [1]Edsall Jr., Richard J; Harris, Heather A; Manas, Eric S; Mewshaw, Richard E [Bioorganic and medicinal chemistry, 2003, vol. 11, # 16, p. 3457 - 3474]

5
[ 74457-86-6 ]
[ 167683-93-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 1-(2-fluoro-4-methoxyphenyl)-1-ethanone With magnesium sulfate; 3-chloro-benzenecarboperoxoic acid In chloroform at 20℃; for 120h; Stage #2: With ammonium hydroxide In methanol; acetonitrile at 20℃; for 3h; Further stages.;
	Multi-step reaction with 2 steps 1: mCPBA, MgSO₄ / CHCl₃ / 12 h / Ambient temperature 2: 94 percent / aq. NH₃ / methanol / 1 h / Ambient temperature

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]
[2]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]

6
[ 76513-69-4 ]
[ 167683-93-4 ]
[ 438497-28-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1.5h;

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

7
[ 4175-78-4 ]
[ 167683-93-4 ]
[ 936247-37-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1961 - 1965

8
[ 167683-93-4 ]
[ 936247-43-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: K₂CO₃ / dimethylformamide / 120 - 140 °C 2: Et₃N; CuI / Pd(PPh₃)2Cl₂ / tetrahydrofuran / 75 °C

Reference： [1]Clark, Richard F.; Zhang, Tianyuan; Wang, Xiaojun; Wang, Rongqi; Zhang, Xiaolin; Camp, Heidi S.; Beutel, Bruce A.; Sham, Hing L.; Gu, Yu Gui [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1961 - 1965]

9
[ 167683-93-4 ]
C₁₅H₁₃FN₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: K₂CO₃ / dimethylformamide / 120 - 140 °C 2: Et₃N; CuI / Pd(PPh₃)2Cl₂ / tetrahydrofuran / 75 °C 3: BBr₃ / CH₂Cl₂ / -78 - 20 °C

Reference： [1]Clark, Richard F.; Zhang, Tianyuan; Wang, Xiaojun; Wang, Rongqi; Zhang, Xiaolin; Camp, Heidi S.; Beutel, Bruce A.; Sham, Hing L.; Gu, Yu Gui [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1961 - 1965]

10
[ 167683-93-4 ]
C₁₉H₂₁FN₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: K₂CO₃ / dimethylformamide / 120 - 140 °C 2: Et₃N; CuI / Pd(PPh₃)2Cl₂ / tetrahydrofuran / 75 °C 3: BBr₃ / CH₂Cl₂ / -78 - 20 °C 4: DEAD; PPh₃ / tetrahydrofuran / 20 °C

Reference： [1]Clark, Richard F.; Zhang, Tianyuan; Wang, Xiaojun; Wang, Rongqi; Zhang, Xiaolin; Camp, Heidi S.; Beutel, Bruce A.; Sham, Hing L.; Gu, Yu Gui [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1961 - 1965]

11
[ 167683-93-4 ]
[ 550998-24-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine / CH₂Cl₂ / 0.5 h / 0 °C 2: 58 percent / aq. Na₂CO₃; Pd[P(Ph)3]4 / 1,2-dimethoxy-ethane / 85 °C

Reference： [1]Mewshaw, Richard E.; Edsall Jr., Richard J.; Yang, Cuijian; Manas, Eric S.; Xu, Zhang B.; Henderson, Ruth A.; Keith Jr., James C.; Harris, Heather A. [Journal of Medicinal Chemistry, 2005, vol. 48, # 12, p. 3953 - 3979]

12
[ 167683-93-4 ]
[ 550997-89-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / CH₂Cl₂ / 0.5 h / 0 °C 2: 58 percent / aq. Na₂CO₃; Pd[P(Ph)3]4 / 1,2-dimethoxy-ethane / 85 °C 3: 91 percent / BBr₃ / CH₂Cl₂ / 0 - 20 °C

Reference： [1]Mewshaw, Richard E.; Edsall Jr., Richard J.; Yang, Cuijian; Manas, Eric S.; Xu, Zhang B.; Henderson, Ruth A.; Keith Jr., James C.; Harris, Heather A. [Journal of Medicinal Chemistry, 2005, vol. 48, # 12, p. 3953 - 3979]

13
[ 167683-93-4 ]
1-chloro-6-(2-fluoro-4-hydroxyphenyl)-2-naphthol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: pyridine / CH₂Cl₂ / 0.5 h / 0 °C 2: 58 percent / aq. Na₂CO₃; Pd[P(Ph)3]4 / 1,2-dimethoxy-ethane / 85 °C 3: 91 percent / BBr₃ / CH₂Cl₂ / 0 - 20 °C 4: 50 percent / NCS / tetrahydrofuran / 3 h / Heating

Reference： [1]Mewshaw, Richard E.; Edsall Jr., Richard J.; Yang, Cuijian; Manas, Eric S.; Xu, Zhang B.; Henderson, Ruth A.; Keith Jr., James C.; Harris, Heather A. [Journal of Medicinal Chemistry, 2005, vol. 48, # 12, p. 3953 - 3979]

14
[ 167683-93-4 ]
[ 858946-69-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine / CH₂Cl₂ / 0.5 h / 0 °C 2: 0.60 g / aq. Na₂CO₃; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / dimethylformamide; CH₂Cl₂ / 2 h / 85 °C

Reference： [1]Mewshaw, Richard E.; Edsall Jr., Richard J.; Yang, Cuijian; Manas, Eric S.; Xu, Zhang B.; Henderson, Ruth A.; Keith Jr., James C.; Harris, Heather A. [Journal of Medicinal Chemistry, 2005, vol. 48, # 12, p. 3953 - 3979]

15
[ 167683-93-4 ]
3-(2-fluoro-4-hydroxy-phenyl)-7-hydroxy-naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / CH₂Cl₂ / 0.5 h / 0 °C 2: 0.60 g / aq. Na₂CO₃; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / dimethylformamide; CH₂Cl₂ / 2 h / 85 °C 3: 67 percent / C₅H₅N*HCl / 2 h / 190 °C

Reference： [1]Mewshaw, Richard E.; Edsall Jr., Richard J.; Yang, Cuijian; Manas, Eric S.; Xu, Zhang B.; Henderson, Ruth A.; Keith Jr., James C.; Harris, Heather A. [Journal of Medicinal Chemistry, 2005, vol. 48, # 12, p. 3953 - 3979]

16
[ 167683-93-4 ]
[ 634192-51-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine / CH₂Cl₂ / 0 - 20 °C 2: Na₂CO₃ / Pd(PPh₃)4 / 1,2-dimethoxy-ethane; H₂O / 95 °C

Reference： [1]Edsall Jr., Richard J; Harris, Heather A; Manas, Eric S; Mewshaw, Richard E [Bioorganic and medicinal chemistry, 2003, vol. 11, # 16, p. 3457 - 3474]

17
[ 167683-93-4 ]
2-fluoro-4-hydroxy-[1,1'-biphenyl] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / CH₂Cl₂ / 0 - 20 °C 2: Na₂CO₃ / Pd(PPh₃)4 / 1,2-dimethoxy-ethane; H₂O / 95 °C 3: 38 percent / pyridine hydrochloride / 190 °C

Reference： [1]Edsall Jr., Richard J; Harris, Heather A; Manas, Eric S; Mewshaw, Richard E [Bioorganic and medicinal chemistry, 2003, vol. 11, # 16, p. 3457 - 3474]

18
[ 167683-93-4 ]
[ 634192-52-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine / CH₂Cl₂ / 0 - 20 °C 2: Na₂CO₃ / Pd(PPh₃)4 / 1,2-dimethoxy-ethane; H₂O / 95 °C

Reference： [1]Edsall Jr., Richard J; Harris, Heather A; Manas, Eric S; Mewshaw, Richard E [Bioorganic and medicinal chemistry, 2003, vol. 11, # 16, p. 3457 - 3474]

19
[ 167683-93-4 ]
3'-chloro-2-fluoro-biphenyl-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / CH₂Cl₂ / 0 - 20 °C 2: Na₂CO₃ / Pd(PPh₃)4 / 1,2-dimethoxy-ethane; H₂O / 95 °C 3: 91 percent / pyridine hydrochloride / 190 °C

Reference： [1]Edsall Jr., Richard J; Harris, Heather A; Manas, Eric S; Mewshaw, Richard E [Bioorganic and medicinal chemistry, 2003, vol. 11, # 16, p. 3457 - 3474]

20
[ 167683-93-4 ]
[ 438497-29-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

21
[ 167683-93-4 ]
[ 438497-30-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

22
[ 167683-93-4 ]
[ 231621-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

23
[ 167683-93-4 ]
[ 231621-40-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

24
[ 167683-93-4 ]
[ 438497-15-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

25
[ 167683-93-4 ]
[ 438497-25-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 17 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KFAl₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h 13.1: 87 percent / tetrahydrofuran / 3 h / 0 °C 14.1: DIBAL / CH₂Cl₂ / 0.5 h / -78 °C 15.1: 88 percent / m-CPBA; 4A molecular sieves / CH₂Cl₂ / 0.17 h 16.1: 73 percent / TEA(HF)3 / acetonitrile / 1 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

26
[ 167683-93-4 ]
[ 438497-17-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

27
[ 167683-93-4 ]
endo-6,8-dimethoxy-11-hydroxy-2-thiophenyl-7H-1,2-dihydrofuro[2','3:4,5]furo[2,3-c]-xanthen-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 18 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KFAl₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h 13.1: 87 percent / tetrahydrofuran / 3 h / 0 °C 14.1: DIBAL / CH₂Cl₂ / 0.5 h / -78 °C 15.1: 88 percent / m-CPBA; 4A molecular sieves / CH₂Cl₂ / 0.17 h 16.1: 73 percent / TEA(HF)3 / acetonitrile / 1 h 17.1: 4A molecular sieves; Amberlyst 15 resin / acetonitrile / 2 h / Heating

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

28
[ 167683-93-4 ]
exo-6,8-dimethoxy-11-hydroxy-2-thiophenyl-7H-1,2-dihydrofuro[2','3:4,5]furo[2,3-c]-xanthen-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 18 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KFAl₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h 13.1: 87 percent / tetrahydrofuran / 3 h / 0 °C 14.1: DIBAL / CH₂Cl₂ / 0.5 h / -78 °C 15.1: 88 percent / m-CPBA; 4A molecular sieves / CH₂Cl₂ / 0.17 h 16.1: 73 percent / TEA(HF)3 / acetonitrile / 1 h 17.1: 4A molecular sieves; Amberlyst 15 resin / acetonitrile / 2 h / Heating

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

29
[ 167683-93-4 ]
[ 438497-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

30
[ 167683-93-4 ]
[ 438497-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 12 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

31
[ 167683-93-4 ]
2,4-dihydroxy-6,6'-dimethoxy-2'-fluoro-3-methoxycarbonyl-3'-pivaloyl-benzophenone-N-(2-methylethyl)ketimine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

32
[ 167683-93-4 ]
[ 438497-19-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

33
[ 167683-93-4 ]
3,5-bis-(<i>tert</i>-butyl-dimethyl-silanyloxy)-1,8-dimethoxy-9-oxo-9<i>H</i>-xanthene-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

34
[ 167683-93-4 ]
[ 438497-21-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 13 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

35
[ 167683-93-4 ]
[ 438497-24-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 16 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h 13.1: 87 percent / tetrahydrofuran / 3 h / 0 °C 14.1: DIBAL / CH₂Cl₂ / 0.5 h / -78 °C 15.1: 88 percent / m-CPBA; 4A molecular sieves / CH₂Cl₂ / 0.17 h

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

36
[ 167683-93-4 ]
[ 438497-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 15 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h 13.1: 87 percent / tetrahydrofuran / 3 h / 0 °C 14.1: DIBAL / CH₂Cl₂ / 0.5 h / -78 °C

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

37
[ 167683-93-4 ]
[ 438497-22-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 14 steps 1.1: 89 percent / DIPEA / CH₂Cl₂ / 1.5 h / 0 - 20 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C 2.2: 2 h 3.1: 73 percent / H₂SO₄ / methanol / 1 h 4.1: 93 percent / pyridine / CH₂Cl₂ / 2 h 5.1: SbCl₅ / CH₂Cl₂ / 0.67 h 5.2: 95 percent / CH₂Cl₂ / 2 h / 20 °C 6.1: K₂CO₃; KF*Al₂O₃; 18-crown-6 / acetonitrile / 7 h / Heating 6.2: 75 percent / H₂O / acetonitrile; methanol / 1 h / Heating 7.1: imidazole / CH₂Cl₂; acetonitrile / 1 h 8.1: 1.77 g / 49percent aq. HF / acetonitrile / 0.5 h 9.1: 92 percent / diisopopylethylamine / CH₂Cl₂ / 0 - 20 °C 10.1: 92 percent / tetrahydrofuran / 1 h / -82 °C 11.1: DIBAL / CH₂Cl₂ / 0.25 h / -78 °C 12.1: NMO / acetonitrile; CH₂Cl₂ / 0.33 h 12.2: TPAP / 2 h 13.1: 87 percent / tetrahydrofuran / 3 h / 0 °C

Reference： [1]Udwary, Daniel W.; Casillas, Linda K.; Townsend, Craig A. [Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5294 - 5303]

38
[ 167683-93-4 ]
[ 1027198-33-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: K₂CO₃ 2: BuLi
	Multi-step reaction with 2 steps 1: K₂CO₃ / acetone / 5 h / 60 °C 2: 1.) BuLi / 1.) hexane, THF, -65 degC, 0.5 h, 2.) hexane, THF, from -65 deg C to RT

Reference： [1]Sahlberg, Christer; Noreen, Rolf; Engelhardt, Per; Hoegberg, Marita; Kangasmetsae, Jussi; Vrang, Lotta; Zhang, Hong [Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 12, p. 1511 - 1516]
[2]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]

39
[ 167683-93-4 ]
[(1S,2S)-2-(3-Ethoxy-2-fluoro-6-methoxy-phenyl)-cyclopropyl]-carbamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: K₂CO₃ 2: BuLi 4: CuI, Pd(OAc)2 / 90 °C 5: aq. NaOH 6: diphenylphosphoryl azide, Et₃N / toluene / 120 °C

Reference： [1]Sahlberg, Christer; Noreen, Rolf; Engelhardt, Per; Hoegberg, Marita; Kangasmetsae, Jussi; Vrang, Lotta; Zhang, Hong [Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 12, p. 1511 - 1516]

40
[ 167683-93-4 ]
1-(5-Bromo-pyridin-2-yl)-3-[(1S,2S)-2-(3-ethoxy-2-fluoro-6-methoxy-phenyl)-cyclopropyl]-urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: K₂CO₃ 2: BuLi 4: CuI, Pd(OAc)2 / 90 °C 5: aq. NaOH 6: diphenylphosphoryl azide, Et₃N / toluene / 120 °C

Reference： [1]Sahlberg, Christer; Noreen, Rolf; Engelhardt, Per; Hoegberg, Marita; Kangasmetsae, Jussi; Vrang, Lotta; Zhang, Hong [Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 12, p. 1511 - 1516]

41
[ 167683-93-4 ]
[ 1025884-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: K₂CO₃ / acetone / 5 h / 60 °C 2: 1.) BuLi / 1.) hexane, THF, -65 degC, 0.5 h, 2.) hexane, THF, from -65 deg C to RT 3: 1.) NaOH, 2.) 4N aq. HCl / 1.) H₂O, methanol, -3 deg C, 15 min 4: LiAlH₄ / tetrahydrofuran / 2 h / Heating

Reference： [1]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]

42
[ 167683-93-4 ]
[ 1026500-31-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: K₂CO₃ / acetone / 5 h / 60 °C 2: 1.) BuLi / 1.) hexane, THF, -65 degC, 0.5 h, 2.) hexane, THF, from -65 deg C to RT 3: 1.) NaOH, 2.) 4N aq. HCl / 1.) H₂O, methanol, -3 deg C, 15 min

Reference： [1]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]

43
[ 167683-93-4 ]
[ 181305-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: K₂CO₃ / acetone / 5 h / 60 °C 2: 1.) BuLi / 1.) hexane, THF, -65 degC, 0.5 h, 2.) hexane, THF, from -65 deg C to RT 3: 1.) NaOH, 2.) 4N aq. HCl / 1.) H₂O, methanol, -3 deg C, 15 min 4: LiAlH₄ / tetrahydrofuran / 2 h / Heating 5: acetonitrile / Ambient temperature

Reference： [1]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]

44
[ 600-00-0 ]
[ 167683-93-4 ]
[ 672931-52-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 90℃;	90 Reference Example 90 ; Ethyl 2-(2-fluoro-4-methoxyphenoxy)-2-methylpropionate [] To a solution of 2-fluoro-4-methoxyphenol (5.29 g) and ethyl 2-bromo-2-methylpropionate (8.7 g) in N,N-dimethylformamide (30 ml) was added potassium carbonate (10.3 g) and the mixture was stirred at 90°C overnight. The reaction solution was poured into water and twice extracted with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane : ethyl acetate = 15 : 1) to obtain an objective product (5.86 g) as an oily matter.1H-NMR (CDCl3) δ 1.31 (3H, t), 1.53 (6H, s), 3.75 (3H, s), 4.24 (2H, q), 6.54 (1H, ddd), 6.63 (1H, dd), 6.98 (1H, t).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1535915, 2005, A1 Location in patent: Page/Page column 103

45
NH₃ (aq) [ No CAS ]
[ 74457-86-6 ]
[ 167683-93-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	In methanol	50 N-(cis)-(3-Ethoxy-2-fluoro-6-methoxyphenyl)-cyclopropyl-N'-(5-bromopyrid-2-yl)-urea A solution of the 1-acetyl-2-fluoro-4-methoxybenzene (5.3 g, 0.029 mol) in 100 mL of MeOH and 20 mL of 25% NH3 (aq) was stirred for 1 hr. at RT. The mixture was then concentrated in vacuo, diluted with water, extracted with EtOAc, dried over Na2 SO4 and concentrated in vacuo to give 2-fluoro-4-methoxyphenol as an oil (3.85 g, 94%).

Reference： [1]Current Patent Assignee: MEDIVIR AB - US5849769, 1998, A

46
[ 610-71-9 ]
[ 167683-93-4 ]
[ 1335218-39-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1 : A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5- dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then charged, followed by 2- methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added in portions. The mixture was heated to 90 C for 4 hours. The mixture was cooled to 35 C and water (15 L) was added. After 15 minutes of stirring the phases were separated and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the aqueous phase, followed by 6 M HC1 (5.6 L) keeping the internal temperature below 30 C. The layers were separated and the organics were dried over magnesium sulfate. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtAOc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. Drying provided 2560 g of 5-bromo-2-(2-fluoro-4- methoxyphenoxy)benzoic acid as a cream colored solid.
		A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5- dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then charged, followed by 2- methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added in portions. The mixture was heated to 90 C for 4 hours. The mixture was cooled to 35 C and water (15 L) was added. After 15 minutes of stirring the phases were sping and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the rich aqueous phase, followed by 6 M HCl (5.6 L) keeping the internal temperature below 30 C. The layers were separated and the organic layers were dried over magnesium sulfate, filtered through a pad of celite and concentration to provide a solid that was re-slurried in 915 mL of EtOAc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. The resulting solids were dired to provide 2560 g of 5-bromo-2-(2-fluoro- 4-methoxyphenoxy)benzoic acid as a cream colored solid.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 9796 - 9810
[2]Patent: WO2011/115928,2011,A1 .Location in patent: Page/Page column 58
[3]Patent: WO2012/109165,2012,A1 .Location in patent: Page/Page column 57

47
[ 167683-93-4 ]
[ 1335219-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

48
[ 167683-93-4 ]
[ 1335219-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

49
[ 167683-93-4 ]
[ 1335219-05-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C 9.1: boron tribromide; triethylamine / dichloromethane / 2 h

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

50
[ 167683-93-4 ]
[ 1335219-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C 9.1: boron tribromide; triethylamine / dichloromethane / 2 h 10.1: lithium hexamethyldisilazane / chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) / tetrahydrofuran / 0.33 h / 20 °C / Sealed vial

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

51
[ 167683-93-4 ]
[ 1335215-37-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C 9.1: boron tribromide; triethylamine / dichloromethane / 2 h 10.1: lithium hexamethyldisilazane / chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) / tetrahydrofuran / 0.33 h / 20 °C / Sealed vial 11.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

52
[ 167683-93-4 ]
[ 1335215-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C 9.1: boron tribromide; triethylamine / dichloromethane / 2 h 10.1: potassium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 1 h / 85 °C / Inert atmosphere; Sealed vial 11.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

53
[ 167683-93-4 ]
[ 1335219-46-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C 9.1: boron tribromide; triethylamine / dichloromethane / 2 h 10.1: potassium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 1 h / 85 °C / Inert atmosphere; Sealed vial

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

54
[ 167683-93-4 ]
[ 1335218-40-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate; copper (I) trifloromethanesulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Industry scale 1.2: 30 °C 2.1: trifluoroacetic acid; trifluoroacetic anhydride; boron trifluoride diethyl etherate / 4 h / Industry scale 2.2: 1 h
	Multi-step reaction with 2 steps 1: caesium carbonate; copper(I) trifluoromethanesulfonate toluene adduct (1/1) / toluene; ethyl acetate / 3.17 h / 20 - 95 °C 2: polyphosphoric acid / 2 h / 125 °C
	Multi-step reaction with 2 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/109165, 2012, A1
[2]Epstein, Oleg; Bryan, Marian C.; Cheng, Alan C.; Derakhchan, Katayoun; Dineen, Thomas A.; Hickman, Dean; Hua, Zihao; Human, Jason B.; Kreiman, Charles; Marx, Isaac E.; Weiss, Matthew M.; Wahl, Robert C.; Wen, Paul H.; Whittington, Douglas A.; Wood, Stephen; Zheng, Xiao Mei; Fremeau, Robert T.; White, Ryan D.; Patel, Vinod F. [Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 9796 - 9810]
[3]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

55
[ 167683-93-4 ]
[ 1335219-47-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C 9.1: caesium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

56
[ 167683-93-4 ]
[ 1335215-39-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.5 h / 85 °C / Inert atmosphere 8.1: boron tribromide / dichloromethane / 47 h / 0 - 20 °C 9.1: caesium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C 10.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

57
[ 167683-93-4 ]
[ 1335215-47-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: lithium hexamethyldisilazane / chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-t-butylether / tetrahydrofuran / 3 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

58
[ 167683-93-4 ]
[ 1335217-37-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: lithium hexamethyldisilazane / chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-t-butylether / tetrahydrofuran / 3 h / 0 - 20 °C 8.1: boron tribromide / dichloromethane / 3 h / 20 °C 8.2: 4 h / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

59
[ 167683-93-4 ]
[ 1335215-49-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate 7.1: potassium carbonate / PdCl₂(Cy₂PC₆H₄NMe₂)2 / 1,4-dioxane / 0.5 h / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

60
[ 167683-93-4 ]
[ 1335218-55-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate; copper (I) trifloromethanesulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Industry scale 1.2: 30 °C 2.1: trifluoroacetic acid; trifluoroacetic anhydride; boron trifluoride diethyl etherate / 4 h / Industry scale 2.2: 1 h 3.1: trimethylsilylazide; potassium <i>tert</i>-butylate / dimethyl sulfoxide; tetrahydrofuran / 1.08 h 3.2: 0 - 20 °C / Cooling with ice
	Multi-step reaction with 3 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/109165, 2012, A1
[2]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

61
[ 167683-93-4 ]
[ 1335218-56-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

62
[ 167683-93-4 ]
[ 1335219-41-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

63
[ 167683-93-4 ]
[ 1335219-79-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

64
[ 167683-93-4 ]
[ 1335219-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: trimethylsulphonium iodide; potassium <i>tert</i>-butylate / tetrahydrofuran; dimethyl sulfoxide / 0.25 h / 20 °C 3.2: 0.08 h / 0 - 20 °C 4.1: lithium tert-butoxide / tetrahydrofuran / 11.5 h / 20 °C 5.1: trimethylaluminum / 1,2-dichloro-ethane; toluene / 1.17 h / 20 - 70 °C 6.1: carbon dioxide / methanol; 2,2'-iminobis[ethanol] / 40 °C / 75007.5 Torr / Resolution of racemate

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

65
[ 167683-93-4 ]
[ 1335216-11-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: tetrahydrofuran / -78 °C / Inert atmosphere 4.1: trifluoroacetic acid / acetic acid / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

66
[ 167683-93-4 ]
[ 1335218-57-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate / copper (I) trifluoromethane sulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Reflux; Industry scale 1.2: 30 °C 2.1: boron trifluoride diethyl etherate; trifluoroacetic acid; trifluoroacetic anhydride / 5 h / 0 - 20 °C / Reflux 3.1: tetrahydrofuran / -78 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AMGEN INC - WO2011/115928, 2011, A1

67
[ 167683-93-4 ]
[ 1393343-83-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: caesium carbonate; copper (I) trifloromethanesulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Industry scale 1.2: 30 °C 2.1: trifluoroacetic acid; trifluoroacetic anhydride; boron trifluoride diethyl etherate / 4 h / Industry scale 2.2: 1 h 3.1: trimethylsilylazide; potassium <i>tert</i>-butylate / dimethyl sulfoxide; tetrahydrofuran / 1.08 h 3.2: 0 - 20 °C / Cooling with ice 4.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / water; tetrahydrofuran / 1.5 h 5.1: trimethylaluminum / toluene / 1 h / 90 °C 5.2: 20 °C 6.1: boron tribromide / dichloromethane / 1 h / Cooling with ice

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/109165, 2012, A1

68
[ 167683-93-4 ]
[ 1393343-75-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: caesium carbonate; copper (I) trifloromethanesulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Industry scale 1.2: 30 °C 2.1: trifluoroacetic acid; trifluoroacetic anhydride; boron trifluoride diethyl etherate / 4 h / Industry scale 2.2: 1 h 3.1: trimethylsilylazide; potassium <i>tert</i>-butylate / dimethyl sulfoxide; tetrahydrofuran / 1.08 h 3.2: 0 - 20 °C / Cooling with ice 4.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / water; tetrahydrofuran / 1.5 h 5.1: trimethylaluminum / toluene / 1 h / 90 °C 5.2: 20 °C 6.1: boron tribromide / dichloromethane / 1 h / Cooling with ice 7.1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 100 °C 8.1: potassium phosphate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.75 h / 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/109165, 2012, A1

69
[ 167683-93-4 ]
[ 1393343-77-5 ]
[ 1393343-76-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: caesium carbonate; copper (I) trifloromethanesulfonate toluene complex / ethyl acetate; toluene / 4 h / 90 °C / Industry scale 1.2: 30 °C 2.1: trifluoroacetic acid; trifluoroacetic anhydride; boron trifluoride diethyl etherate / 4 h / Industry scale 2.2: 1 h 3.1: trimethylsilylazide; potassium <i>tert</i>-butylate / dimethyl sulfoxide; tetrahydrofuran / 1.08 h 3.2: 0 - 20 °C / Cooling with ice 4.1: tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide / water; tetrahydrofuran / 1.5 h 5.1: trimethylaluminum / toluene / 1 h / 90 °C 5.2: 20 °C 6.1: boron tribromide / dichloromethane / 1 h / Cooling with ice 7.1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 100 °C 8.1: potassium phosphate / bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / 1,4-dioxane; water / 0.75 h / 90 °C / Inert atmosphere 9.1: diethylamine; methanol / Resolution of racemate

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/109165, 2012, A1

70
[ 1402595-17-8 ]
[ 167683-93-4 ]
[ 1402593-38-7 ]

Yield	Reaction Conditions	Operation in experiment
14%	With pyrrolidine-2-phosphonic acid phenyl monoester; caesium carbonate; copper(l) chloride In 1,4-dioxane at 120℃; for 2h; Microwave irradiation;	6-2 Preparation of N-cyclopropyl-4-{6-(2-fluoro-4-methoxyphenoxy)- -[(3,3,3-trifluoropropyl)amino]imidazo[1,2-a]pyridin-3-yl}-2-methylbenzamideA m i x t u r e c o m p r i s i n g 5 0 . 5 m g ( 1 05 p m o I ) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-a]pyridin-3-yl}-N-cycloprop yl-2-methylbenzamide which was prepared according to intermediate example 6-1, 74.6 mg 2-fluoro-4-methoxyphenol 171 mg caesium carbonate, 4.77 mg (RS)-phenyl hydrogen pyrrolidin-2-ylphosphonate, 4.2 mg copper(l)chloride and 1 ml_ 1,4-dioxane was heated at 120°C using microwave irradiation for 2 hours. The mixture war poured into water and extracted with a mixture of ethyl acetate and methanol. The organic layer was dried over sodium sulfate. After filtration and removal of the solvent the residue war purified by chromatography to give 7.0 mg (14%) of the title compound: m/z (ES+) 543 [MH+]; required MW = 542.2.1H-NMR (DMSO-d6): δ= 0.49 (2H), 0.65 (2H), 2.29 (3H), 2.62 (2H), 2.80 (1H), 3.47 (2H), 3.72 (3H), 6.12 (1H), 6.54 (1H), 6.73 (1H), 7.00 (1H), 7.20 (1H), 7.29-7.36 (3H), 7.43 (1H), 7.59 (1H), 8.28 (1H) ppm.

Reference： [1]Current Patent Assignee: BAYER AG - WO2012/136531, 2012, A1 Location in patent: Page/Page column 98

71
[ 705280-36-0 ]
[ 167683-93-4 ]
[ 1421365-72-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In 1,4-dioxane; mineral oil at 15 - 20℃;

Reference： [1]Guerrero, Miguel; Urbano, Mariangela; Schaeffer, Marie-Therese; Brown, Steven; Rosen, Hugh; Roberts, Edward [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 614 - 619]

72
[ 50-00-0 ]
[ 167683-93-4 ]
[ 1417996-86-1 ]

Yield	Reaction Conditions	Operation in experiment
15%	With triethylamine; magnesium chloride In acetonitrile for 8h; Inert atmosphere; Reflux;

Reference： [1]Hu, Jun Jacob; Wong, Nai-Kei; Gu, Qiangshuai; Bai, Xiaoyu; Ye, Sen; Yang, Dan [Organic Letters, 2014, vol. 16, # 13, p. 3544 - 3547]

73
[ 167683-93-4 ]
[ 1615214-13-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: magnesium chloride; triethylamine / acetonitrile / 8 h / Inert atmosphere; Reflux 2: potassium carbonate / tetrahydrofuran / 10 h / Inert atmosphere; Reflux

Reference： [1]Hu, Jun Jacob; Wong, Nai-Kei; Gu, Qiangshuai; Bai, Xiaoyu; Ye, Sen; Yang, Dan [Organic Letters, 2014, vol. 16, # 13, p. 3544 - 3547]

74
[ 167683-93-4 ]
C₃₁H₄₁FN₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: magnesium chloride; triethylamine / acetonitrile / 8 h / Inert atmosphere; Reflux 2.1: potassium carbonate / tetrahydrofuran / 10 h / Inert atmosphere; Reflux 3.1: trifluoroacetic acid / 1,2-dichloro-ethane / 4 h / Inert atmosphere; Reflux 3.2: 2 h / 20 °C / Inert atmosphere

Reference： [1]Hu, Jun Jacob; Wong, Nai-Kei; Gu, Qiangshuai; Bai, Xiaoyu; Ye, Sen; Yang, Dan [Organic Letters, 2014, vol. 16, # 13, p. 3544 - 3547]

75
[ 167683-93-4 ]
[ 1615224-39-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: magnesium chloride; triethylamine / acetonitrile / 8 h / Inert atmosphere; Reflux 2.1: potassium carbonate / tetrahydrofuran / 10 h / Inert atmosphere; Reflux 3.1: trifluoroacetic acid / 1,2-dichloro-ethane / 4 h / Inert atmosphere; Reflux 3.2: 2 h / 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 8 h / 20 °C / Inert atmosphere

Reference： [1]Hu, Jun Jacob; Wong, Nai-Kei; Gu, Qiangshuai; Bai, Xiaoyu; Ye, Sen; Yang, Dan [Organic Letters, 2014, vol. 16, # 13, p. 3544 - 3547]

76
[ 167683-93-4 ]
[ 1615224-42-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: magnesium chloride; triethylamine / acetonitrile / 8 h / Inert atmosphere; Reflux 2.1: potassium carbonate / tetrahydrofuran / 10 h / Inert atmosphere; Reflux 3.1: trifluoroacetic acid / 1,2-dichloro-ethane / 4 h / Inert atmosphere; Reflux 3.2: 2 h / 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 8 h / 20 °C / Inert atmosphere 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol / 8 h / Inert atmosphere; Reflux

Reference： [1]Hu, Jun Jacob; Wong, Nai-Kei; Gu, Qiangshuai; Bai, Xiaoyu; Ye, Sen; Yang, Dan [Organic Letters, 2014, vol. 16, # 13, p. 3544 - 3547]

77
[ 167683-93-4 ]
[ 1615224-45-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: magnesium chloride; triethylamine / acetonitrile / 8 h / Inert atmosphere; Reflux 2.1: potassium carbonate / tetrahydrofuran / 10 h / Inert atmosphere; Reflux 3.1: trifluoroacetic acid / 1,2-dichloro-ethane / 4 h / Inert atmosphere; Reflux 3.2: 2 h / 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 8 h / 20 °C / Inert atmosphere 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / ethanol / 8 h / Inert atmosphere; Reflux 6.1: sodium hypochlorite / aq. phosphate buffer; N,N-dimethyl-formamide / 0.5 h / pH 7.4

Reference： [1]Hu, Jun Jacob; Wong, Nai-Kei; Gu, Qiangshuai; Bai, Xiaoyu; Ye, Sen; Yang, Dan [Organic Letters, 2014, vol. 16, # 13, p. 3544 - 3547]

78
[ 1621060-74-9 ]
[ 167683-93-4 ]
C₂₂H₁₆Cl₂FNO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 2.5h;	Example 11 Preparation of 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid (18) General procedure: Example 11 Preparation of 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid (18) [embedded image] A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (794.5 mg, 3.49 mmol) in dichloromethane (7.3 mL) was added drop-wise to a mixture of methyl 4-aminobenzoate (528.0 mg, 3.49 mmol), pyridine (847.6 -L, 10.48 mmol) and dichloromethane (11.0 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 1.5 hours. To the reaction, water (10 mL) was added. The solid was isolated by filtration, washed with water (210 mL) and hexane (210 mL) to yield methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (955 mg, 80%) as a light pink solid. ESI-MS m/z calc. 341.00. found 342.2 (M+1)+. Retention time: 1.75 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) - 10.90 (s, 1H), 8.03 (d, J=6.7 Hz, 1H), 8.02-7.95 (m, 2H), 7.93 (d, J=9.4 Hz, 1H), 7.88-7.76 (m, 2H), 3.84 (s, 3H) ppm.A mixture of methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (34.21 mg, 0.1 mmol), 4-chloro-2-methoxyphenol (12.16 -l, 0.1 mmol), potassium carbonate 13.82 mg, 0.1 mmol) and N-methylpyrrolidinone (1 mL) were heated at 80° C. for 2.5 hours. Methanol (100 -L) and sodium hydroxide (3M, 100 -L, 0.3 mmol) were added and the reaction was stirred at 50° C. for 2 hours. An additional 100 -L of MeOH and 100 -L of 3M NaOH were added and the reactions were heated for another hour. The reaction mixture was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid (18) (11.78 mg, 25%). ESI-MS m/z calc. 464.99. found 466.3 (M+1)+. Retention time: 2.20 minutes (3 minutes run). The following compounds were prepared using a procedure similar to the one described above for compound 18 from the following alcohols.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2014/221435, 2014, A1 Location in patent: Paragraph 0622-0625

79
[ 1621060-62-5 ]
[ 167683-93-4 ]
C₂₁H₁₅Cl₂FN₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 1.5h;	Example 2 Preparation of 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (51) General procedure: Example 2 Preparation of 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (51) [embedded image] A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (4.35 g, 19.13 mmol) in dichloromethane (40 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (2.91 g, 19.13 mmol), pyridine (4.64 mL, 57.39 mmol) and dichloromethane (60 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 2 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The two layers were separated. The aqueous layer was extracted with dichloromethane (3200 mL). The combined organic layer was washed with water (1150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration using hexane to yield methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (5.33 g, 81%) as a cream color solid. 1H NMR (400 MHz, DMSO-d6) - 11.11 (s, 1H), 8.94 (d, J=2.5 Hz, 1H), 8.36 (dd, J=8.6, 2.5 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.95 (d, J=9.6 Hz, 1H), 3.87 (s, 3H) ppm. ESI-MS m/z calc. 342.00. found 343.1 (M+1)+. Retention time: 1.72 minutes (3 minutes run).Methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (50 mg, 0.14 mmol), 4-fluoro-2-methoxy-phenol (18.27 -L, 0.16 mmol) and K2CO3 (60.41 mg, 0.44 mmol) were combined in DMF (0.5 mL) and heated at 70° C. for 1.5 hours to form methyl 5-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxylate. Aqueous NaOH (145.7 -L of 3 M, 0.44 mmol) was then added and heating continued for 30 min. HPLC purification (1-99% CH3CN/5 mM HCl) provided 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid (51) (35.28 mg, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6) - 13.05 (s, 1H), 10.96 (s, 1H), 8.93 (d, J=2.4 Hz, 1H), 8.30 (dd, J=8.7, 2.5 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.97 (s, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.12 (dd, J=10.7, 2.9 Hz, 1H), 6.91 (s, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 3.75 (s, 3H) ppm. ESI-MS m/z calc. 450.02. found 451.1 (M+1)+. Retention time: 1.61 minutes (3 minutes run). The following compounds were prepared using a procedure similar to the one described above for compound 51 from the following alcohols.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2014/221435, 2014, A1 Location in patent: Paragraph 0582-0585

80
[ 167683-93-4 ]
sodium 2-fluoro-4-methoxyphenolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium hydroxide In methanol Inert atmosphere; Schlenk technique;

Reference： [1]Serrano-Plana, Joan; Garcia-Bosch, Isaac; Miyake, Ryosuke; Costas, Miquel; Company, Anna [Angewandte Chemie - International Edition, 2014, vol. 53, # 36, p. 9608 - 9612][Angew. Chem., 2014, vol. 53-126, # 36, p. 9762 - 9766,5][Angewandte Chemie, 2014, vol. 53-126, # 36, p. 9762 - 9766,5]

81
[ 167683-93-4 ]
[ 3934-97-2 ]
C₇H₇FO₃ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 9608 - 9612,5
Angew. Chem.,2014,vol. 53-126,p. 9762 - 9766,5
Angewandte Chemie,2014,vol. 53-126,p. 9762 - 9766,5

82
[ 109384-19-2 ]
[ 167683-93-4 ]
tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 0 - 65℃;	14 [0164] A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g, 12.03 mmol) in THF (33.4 mL) at room temperature was treated with 2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine (3.16 g, 12.03 mmol). The reaction mixture was cooled to 0° C. and DEAD (40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 65° C. for 5 h, then at room temperature overnight. Flash silica gel chromatography using a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 85%) as a light yellow oil. ESI-MS m/z [M+Na]+ 348.2
85%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 0 - 65℃; for 6h;	13 A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g, 12.03 mmol) in THF (33.4 mL) at room temperature was treated with 2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine (3.16 g, 12.03 mmol). The reaction mixture was cooled to 0 °C and DEAD (40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 65 °C for 5 h, then at room temperature overnight. Flash silica gel chromatography using a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 85%) as a light yellow oil. ESI-MS mlz [M+Na]+ 348.2.
85%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 0 - 65℃; for 5h;	12 j0147j A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g, 12.03 mmol) in THF (33.4 mL) at room temperature was treated with 2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine (3.16 g, 12.03 mmol). The reaction mixture was cooled to 0 °C and DEAD (40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 65 °C for 5 h, then at room temperature overnight. Flash silica gel chromatography using a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine- 1 -carboxylate (2.78 g, 85%) as a light yellow oil. ESI-MS mlz [M+Na]+ 348.2.

Reference： [1]Current Patent Assignee: ENERSYS; TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2015/175602, 2015, A1 Location in patent: Paragraph 0164
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/123505, 2015, A1 Location in patent: Paragraph 0144
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2015/123533, 2015, A1 Location in patent: Paragraph 0147

83
2-(2-fluoro-4-methoxyphenoxy)pyridine [ No CAS ]
[ 167683-93-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 2-(2-fluoro-4-methoxyphenoxy)pyridine With methyl trifluoromethanesulfonate In toluene at 100℃; for 2h; Inert atmosphere; Stage #2: With sodium ethanolate for 1h; Reflux; Inert atmosphere;	4.3 A mixture of 219 mg (1.0 mmol) of 2- (2-fluoro-4-methoxyphenoxy) pyridine was dissolved in 30 mL of toluene,200 μL (1.75 mmol) of methyl trifluoromethanesulfonate was added under argon, and the mixture was stirred at 100 ° C for 2 hours.The reaction solution was cooled to room temperature and toluene was removed under reduced pressure,The resulting residue was added with 18 mL of freshly prepared sodium ethoxide solution (0.69 g (30.0 mmol) of metal sodium in 18 mL of absolute ethanol) under nitrogen atmosphere,Then heated to reflux,The reaction was stirred for 1 hour,The obtained reaction solution was distilled off the solvent, and then 30 mL of water was added,And extracted with ethyl acetate (20 ml x 3)The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure.Column chromatography (eluent ratio:Petroleum ether to ethyl acetate in a volume ratio of 20: 1)Collecting the eluate containing the product,The solvent was distilled off to give 106.5 mg of 2-fluoro-4-methoxyphenol (77% yield by gas chromatography).

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN104844399, 2016, B Location in patent: Paragraph 0064; 0065; 0068

84
[ 762-42-5 ]
[ 167683-93-4 ]
C₁₃H₁₃FO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 25℃; for 2h;	General procedure for the synthesis of olefin diesters General procedure: To a mixture of phenol (1 eq) and Et3N (2 eq) in DCM, was added DMAD (1.1 eq). The reaction mixture was stirred at 25°C for 2h. The mixture was diluted with water (200 ml_) and extracted with DCM (2 x 200 ml_), the organic layers were separated and dried over Na2S04 and filtered. The solvent was concentrated under reduced pressured. Product was purified by column chromatography.

Reference： [1]Current Patent Assignee: UNIVERSITY OF DUNDEE - WO2017/221002, 2017, A1 Location in patent: Page/Page column 132-133; 156

85
[ 1126-79-0 ]
[ 167683-93-4 ]
C₁₇H₁₈O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With iodosodilactone at 90℃; for 18h; Sealed tube;

Reference： [1]Yu, Congjun; Patureau, Frederic W. [Angewandte Chemie - International Edition, 2019, vol. 58, # 51, p. 18530 - 18534][Angew. Chem., 2019, # 58, p. 18701 - 18705,5]

86
[ 1746-13-0 ]
[ 167683-93-4 ]
C₁₆H₁₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With iodosodilactone at 90℃; for 18h; Sealed tube;

Reference： [1]Yu, Congjun; Patureau, Frederic W. [Angewandte Chemie - International Edition, 2019, vol. 58, # 51, p. 18530 - 18534][Angew. Chem., 2019, # 58, p. 18701 - 18705,5]

87
[ 167683-93-4 ]
[ 622-86-6 ]
C₁₅H₁₃ClO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With iodosodilactone at 90℃; for 18h; Sealed tube;

Reference： [1]Yu, Congjun; Patureau, Frederic W. [Angewandte Chemie - International Edition, 2019, vol. 58, # 51, p. 18530 - 18534][Angew. Chem., 2019, # 58, p. 18701 - 18705,5]

88
[ 167683-93-4 ]
[ 150-78-7 ]
C₁₅H₁₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With iodosodilactone at 90℃; for 18h; Sealed tube;

Reference： [1]Yu, Congjun; Patureau, Frederic W. [Angewandte Chemie - International Edition, 2019, vol. 58, # 51, p. 18530 - 18534][Angew. Chem., 2019, # 58, p. 18701 - 18705,5]

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CAS No. :	167683-93-4	MDL No. :	MFCD00070796
Formula :	C₇H₇FO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FCJHBXCQIOVMEM-UHFFFAOYSA-N
M.W :	142.13	Pubchem ID :	2774557
Synonyms :

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319	Packing Group:	N/A
GHS Pictogram:

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H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 167683-93-4 ] {[proInfo.proName]}

Quality Control of [ 167683-93-4 ]

Related Doc. of [ 167683-93-4 ]

Product Details of [ 167683-93-4 ]

Safety of [ 167683-93-4 ]

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[ 167683-93-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 167683-93-4 ]

Fluorinated Building Blocks

Aryls

Ethers

Precautionary Statements-General

Prevention

Response

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Health hazards

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[ CAS No. 167683-93-4 ] {[proInfo.proName]}

Quality Control of [ 167683-93-4 ]

Related Doc. of [ 167683-93-4 ]

Product Details of [ 167683-93-4 ]

Safety of [ 167683-93-4 ]

Application In Synthesis of [ 167683-93-4 ]

[ 167683-93-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 167683-93-4 ]

Fluorinated Building Blocks

Aryls

Ethers

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 167683-93-4 ]