[ CAS No. 59255-94-6 ] {[proInfo.proName]}

Name: 59255-94-6|2-Bromo-3-fluoronitrobenzene|95%
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Quality Control of [ 59255-94-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 59255-94-6 ]

CAS No. :	59255-94-6	MDL No. :	MFCD07782080
Formula :	C₆H₃BrFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ICIVWQQTOYDXDM-UHFFFAOYSA-N
M.W :	220.00	Pubchem ID :	18373474
Synonyms :

Calculated chemistry of [ 59255-94-6 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	42.92
TPSA :	45.82 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.51
Log Po/w (XLOGP3) :	2.54
Log Po/w (WLOGP) :	2.92
Log Po/w (MLOGP) :	2.06
Log Po/w (SILICOS-IT) :	0.81
Consensus Log Po/w :	1.97

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.14
Solubility :	0.159 mg/ml ; 0.000721 mol/l
Class :	Soluble
Log S (Ali) :	-3.15
Solubility :	0.156 mg/ml ; 0.000709 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.92
Solubility :	0.266 mg/ml ; 0.00121 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.94

Safety of [ 59255-94-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 59255-94-6 ]

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

Upstream synthesis route of [ 59255-94-6 ]
Downstream synthetic route of [ 59255-94-6 ]

[ 59255-94-6 ] Synthesis Path-Upstream 1~6

1
[ 17809-36-8 ]
[ 59255-94-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; hydrogen bromide; acetic acid; copper(I) bromide; sodium nitrite In water at 20℃; for 7 h;	Under mechanical stirring, 94.0 g of water and 102.2 g of concentrated sulfuric acid were slowly added to a 500 mL glass reaction bottle.19.5 g of acetic acid, 19.5 g of 1-fluoro-2-amino-3-nitrobenzene,Concentrated hydrobromic acid 63.2 g (48percent aqueous solution of hydrogen bromide) and cuprous bromide 9.0 g.A solution of 11.2 g of sodium nitrite and 22.4 g of water was added dropwise at room temperature, and the mixture was dripped in about 5 hours.Stirring was continued for 2 hours at room temperature. It was diluted with 130.8 g of water and extracted with 39.0 g of dichloromethane.The oil layer was washed with water 39.0 g, and the solvent was concentrated.get1-fluoro-2-bromo-3-nitrobenzene 23.4 g, yield 85percent.

Reference： [1] Patent: CN108002976, 2018, A, . Location in patent: Paragraph 0045; 0047; 0048; 0049; 0058; 0067
[2] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1976, vol. 30, p. 141 - 149

2
[ 402-67-5 ]
[ 59255-94-6 ]

Reference： [1] Organic Letters, 2009, vol. 11, # 2, p. 421 - 423
[2] Journal of Organic Chemistry, 2009, vol. 74, # 21, p. 8309 - 8313
[3] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3416 - 3437

3
[ 399-31-5 ]
[ 59255-94-6 ]

Reference： [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1976, vol. 30, p. 141 - 149

4
[ 342-52-9 ]
[ 59255-94-6 ]

Reference： [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1976, vol. 30, p. 141 - 149

5
[ 59255-94-6 ]
[ 7772-99-8 ]
[ 21397-08-0 ]

Reference： [1] Patent: US6500863, 2002, B1,

6
[ 59255-94-6 ]
[ 111721-75-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen; nickel In methanol at 20℃; for 5 h; Autoclave	22.0 g of 1-fluoro-2-bromo-3-nitrobenzene was added to a 500 mL stainless steel autoclave.220.0 g of methanol and 2.2 g of Raney nickel catalyst. Stir vigorously for 5 hours at room temperature and 1 MPa hydrogen pressure.The catalyst was filtered off, and the mother liquid was concentrated to give a solvent to give 1-fluoro-2-bromo-3-aminobenzene (18.6 g, yield 98percent).
70%	With sodium tetrahydroborate; nickel dichloride In methanol at 0℃; for 0.0833333 h;	To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH₃OH (50 mL) was added NiCl₂(2.2 g 10 mmol) and NaBH₄(0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL.x.3). The organic layers were dried over anhydrous Na₂SO₄and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70percent). ¹H NMR (400 MHz, CDCl₃) δ 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).
70%	With sodium tetrahydroborate In methanol; water	2-Bromo-3-fluoroaniline To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH₃OH (50 mL) was added NiCl₂ (2.2 g 10 mmol) and NaBH₄ (0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3). The organic layers were dried over anhydrous Na₂SO₄ and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70percent). ¹H NMR (400 MHz, CDCl₃) .box. 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).

70%

With sodium tetrahydroborate; nickel dichloride In methanol at 0℃; for 0.0833333 h;

To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH₃OH (50 mL) was added NiCl₂ (2.2 g 10 mmol) and NaBH₄ (0.50 g 14 mmol) at 0° C.
After the addition, the mixture was stirred for 5 min.
Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3).
The organic layers were dried over anhydrous Na₂SO₄ and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70percent).
¹H NMR (400 MHz, CDCl₃) 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).

Reference： [1] Patent: CN108002976, 2018, A, . Location in patent: Paragraph 0045; 0047; 0050; 0051; 0060; 0069
[2] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3416 - 3437
[3] Patent: US2007/244159, 2007, A1, . Location in patent: Page/Page column 121
[4] Patent: US2011/98311, 2011, A1,
[5] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 1674

[ 59255-94-6 ] Synthesis Path-Downstream 1~76

1
[ 17809-36-8 ]
[ 59255-94-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; hydrogen bromide; acetic acid; copper(I) bromide; sodium nitrite; In water; at 20℃; for 7h;	Under mechanical stirring, 94.0 g of water and 102.2 g of concentrated sulfuric acid were slowly added to a 500 mL glass reaction bottle.19.5 g of acetic acid, 19.5 g of 1-fluoro-2-amino-3-nitrobenzene,Concentrated hydrobromic acid 63.2 g (48% aqueous solution of hydrogen bromide) and cuprous bromide 9.0 g.A solution of 11.2 g of sodium nitrite and 22.4 g of water was added dropwise at room temperature, and the mixture was dripped in about 5 hours.Stirring was continued for 2 hours at room temperature. It was diluted with 130.8 g of water and extracted with 39.0 g of dichloromethane.The oil layer was washed with water 39.0 g, and the solvent was concentrated.get1-fluoro-2-bromo-3-nitrobenzene 23.4 g, yield 85%.

Reference： [1]Patent: CN108002976,2018,A .Location in patent: Paragraph 0045; 0047; 0048; 0049; 0058; 0067
[2]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1976,vol. 30,p. 141 - 149

3
[ 399-31-5 ]
[ 59255-94-6 ]

Reference： [1]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1976,vol. 30,p. 141 - 149

4
[ 342-52-9 ]
[ 59255-94-6 ]

Reference： [1]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1976,vol. 30,p. 141 - 149

5
NaHCO₃ (aq) [ No CAS ]
[ 59255-94-6 ]
[ 7772-99-8 ]
[ 21397-08-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	In ethanol;	b 2-chloro-3-fluoroaniline To the solution of <strong>[59255-94-6]2-bromo-3-fluoronitrobenzene</strong> (100 mg, 0.46 mmol) in ethanol (5 ml), Tin (II) chloride (520 mg, 2.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The NaHCO3 (aq) was added to pH=7. Then was extracted with ethyl acetate (3x). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give desired product (80 mg, 93%). EI-MS m/z 191 (M+).

Reference： [1]Patent: US6500863,2002,B1

6
5-chloro-1,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline [ No CAS ]
[ 59255-94-6 ]
(+/-)-5-chloro-1,2,3,4-tetrahydro-3β-hydroxy-2,2,4α,8-tetramethyl-6-(6-fluoro-2-nitrophenyl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With barium dihydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 16 - 24h;	General Method 12: Palladium-catalyzed cross-coupling of an aryl halide and an aryl boronic acid. In a sealed tube or Schlenck flask, a mixture of an aryl bromide (1 equiv); an aryl boronic acid or aryl pinacol boronate (1.0-1.2 equiv), tetrakis(triphenylphosphine)palladium(0) (10 mol%), and barium hydroxide (2 equiv) is flushed with nitrogen. A 90% dioxane/water solution is added to form a 0.1 M solution, and the mixture is heated at 100 C for 16-24 h. The mixture is distributed between ethyl acetate and saturated ammonium chloride, and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and concentrated. Flash chromatography (ethyl acetate:hexanes) affords the product.; This compound was prepared according to General Method 12 from (+/-)-5-chloro4523,4-tetrahydro-3B-hydroxy-2,2,4a,8-tetramethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (EXAMPLE 63) and 3-fluoro-2-bromonitrobenzene to afford compound 262. XH NMR (500 MHz, CDC13) 8 7.81 (m, 1H), 7.52 (dd, J=8.2, 5.3 Hz, 1H), 7.43 (td, J=8.2, 1.0 Hz, 0.5H),7.42 (td, J=8.2, 1.0 Hz, 0.5H), 6.83 (s, 0.5H), 6.82 (s, 0.5H), 3.68 (s, 1H), 3.61 (m, 1H), 3.12 (dq, J=4.6, 7.0 Hz, 0.5H), 3.10 (dq, J=4.8, 7.0 Hz, 0.5H), 2.14 (s, 3H), 1.92 (d, J=8.2 Hz, 0.5H), 1.89 (d, J=8.2 Hz, 0.5H), 1.54 (d, J=7.0 Hz, 1.5H), 1.53 (d, J=7.0 Hz, 1.5H), 1.38 (s, 3H), 1.26 (s, 1.5H), 1.24 (s, 1.5H).

Reference： [1]Patent: WO2006/19716,2006,A1 .Location in patent: Page/Page column 163; 164

7
[ 59255-94-6 ]
[ 111721-75-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen; nickel; In methanol; at 20℃; under 7500.75 Torr; for 5h;Autoclave;	22.0 g of <strong>[59255-94-6]1-fluoro-2-bromo-3-nitrobenzene</strong> was added to a 500 mL stainless steel autoclave.220.0 g of methanol and 2.2 g of Raney nickel catalyst. Stir vigorously for 5 hours at room temperature and 1 MPa hydrogen pressure.The catalyst was filtered off, and the mother liquid was concentrated to give a solvent to give 1-fluoro-2-bromo-3-aminobenzene (18.6 g, yield 98%).
70%	With sodium tetrahydroborate; nickel dichloride; In methanol; at 0℃; for 0.0833333h;	To a solution of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (1.0 g, 5.0 mmol) in CH3OH (50 mL) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0 C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) delta 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).
70%	With sodium tetrahydroborate;nickel dichloride; In methanol; water;	2-Bromo-3-fluoroaniline To a solution of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (1.0 g, 5.0 mmol) in CH3OH (50 mL) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0 C. After the addition, the mixture was stirred for 5 min Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).

70%

With sodium tetrahydroborate; nickel dichloride; In methanol; at 0℃; for 0.0833333h;

To a solution of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (1.0 g, 5.0 mmol) in CH3OH (50 mL) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0 C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H).

Reference： [1]Patent: CN108002976,2018,A .Location in patent: Paragraph 0045; 0047; 0050; 0051; 0060; 0069
[2]Journal of Organic Chemistry,2011,vol. 76,p. 3416 - 3437
[3]Patent: US2007/244159,2007,A1 .Location in patent: Page/Page column 121
[4]Patent: US2011/98311,2011,A1
[5]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 1674

8
[ 402-67-5 ]
[ 59255-94-6 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 421 - 423
[2]Journal of Organic Chemistry,2011,vol. 76,p. 3416 - 3437

9
[ 59255-94-6 ]
[ 1826-67-1 ]
[ 1000339-62-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at -78 - 20℃;	Description for D140; 7-Bromo-6-fluoro-1H-indole (D140); To a solution of 2-bromo-3-fluoro-1 -nitrobenzene (13 g) in anhydrous THF (80 mL) was added 1 M vinylmagnesium bromide in THF (178 mL) dropwise at -78 0C slowly. Then the mixture was allowed to warm to RT and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated NH4CI solution, the organic phase was separated by extraction with EtOAc (3 * 200 mL). Purification by column chromatography afforded of 7-bromo-6-fluoro-1H-indole (D140) (3 g) as a brown oil.
		Description for D140; 7-Bromo-6-fluoro-1H-indole (D140); To a solution of <strong>[59255-94-6]2-bromo-3-fluoro-1-nitrobenzene</strong> (13 g) in anhydrous THF (80 mL) was added 1 M vinylmagnesium bromide in THF (178 mL) dropwise at -78 C. slowly. Then the mixture was allowed to warm to RT and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated NH4Cl solution, the organic phase was separated by extraction with EtOAc (3×200 mL). Purification by column chromatography afforded of 7-bromo-6-fluoro-1H-indole (D140) (3 g) as a brown oil.

Reference： [1]Patent: WO2009/153307,2009,A1 .Location in patent: Page/Page column 112
[2]Patent: US2010/29729,2010,A1 .Location in patent: Page/Page column 54

10
[ 59255-94-6 ]
2-tert-butyl-4-fluoro-1H-indol-5-amine [ No CAS ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

11
[ 59255-94-6 ]
[ 952664-87-8 ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

12
[ 59255-94-6 ]
[ 952664-88-9 ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

13
[ 59255-94-6 ]
[ 952664-89-0 ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

14
[ 59255-94-6 ]
[ 952664-90-3 ]

Reference： [1]Patent: US2011/98311,2011,A1
[2]Patent: US2015/231142,2015,A1

15
[ 59255-94-6 ]
[ 765-30-0 ]
[ 1338482-91-9 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 60℃; for 96h;Inert atmosphere;	A mixture of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (2.0 g, 9.1 mmol), cyclopropanamine (1.26 mL, 18.2 mmol) in THF (10 mL) under N2 was heated at 60 C. for 4 days. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using hexane-EtOAc (8.5:1.5) as eluent to give N-cyclopropyl-2-fluoro-6-nitroaniline.

Reference： [1]Patent: US2011/245257,2011,A1 .Location in patent: Page/Page column 50

16
[ 59255-94-6 ]
[ 1338482-92-0 ]

Reference： [1]Patent: US2011/245257,2011,A1

17
[ 59255-94-6 ]
[ 1338482-94-2 ]

Reference： [1]Patent: US2011/245257,2011,A1

18
[ 59255-94-6 ]
[ 1338482-93-1 ]

Reference： [1]Patent: US2011/245257,2011,A1

19
[ 59255-94-6 ]
[ 1384984-18-2 ]

Reference： [1]Patent: US2012/184742,2012,A1
[2]Patent: US2012/184564,2012,A1
[3]Patent: WO2012/177707,2012,A1
[4]Patent: WO2014/14845,2014,A1
[5]Patent: WO2014/15105,2014,A1
[6]Patent: US2012/184512,2012,A1

20
[ 59255-94-6 ]
[ 1384984-25-1 ]

21
[ 59255-94-6 ]
[ 1384984-26-2 ]

22
[ 59255-94-6 ]
[ 1384984-27-3 ]

23
[ 59255-94-6 ]
[ 1384984-28-4 ]

24
[ 59255-94-6 ]
[ 1384984-29-5 ]

25
[ 59255-94-6 ]
[ 1384984-17-1 ]

26
[ 59255-94-6 ]
[ 1384984-19-3 ]

Reference： [1]Patent: US2012/184742,2012,A1
[2]Patent: US2012/184564,2012,A1
[3]Patent: WO2014/15105,2014,A1

27
[ 1191-99-7 ]
[ 59255-94-6 ]
[ 1384984-22-8 ]
[ 1384984-23-9 ]

Yield	Reaction Conditions	Operation in experiment
96%; 4%	With N-ethyl-N,N-diisopropylamine;di-mu-bromobis(tri-tert-butylphosphino)dipalladium(I); In 1,4-dioxane; for 2h;Reflux;	<strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N-diisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri-tert-butylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). The reaction mixture was allowed to cool; the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. The semi-solid oil was dissolved in CH2Cl2, eluted through a plug of silica with CH2Cl2, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 min); 1H NMR (300 MHz, CDCl3) delta 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.43 (td, J=8.2, 5.2 Hz, 1H), 7.32 (ddd, J=9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J=4.9, 2.4 Hz, 1H), 5.80 (t, J=10.9 Hz, 1H), 5.06 (q, J=2.4 Hz, 1H), 3.18-3.07 (m, 1H), 2.94-2.82 (m, 1H) ppm. The minor product was 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 210 (11.95 min). 1H NMR (300 MHz, CDCl3) delta 7.47 (d, J=8.0 Hz, 1H), 7.43-7.34 (m, 1H), 7.30-7.23 (m, 1H), 6.21-6.15 (m, 1H), 6.11-6.06 (m, 1H), 5.97-5.91 (m, 1H), 4.89-4.73 (m, 2H) ppm.
	With N-ethyl-N,N-diisopropylamine;di-mu-bromobis(tri-tert-butylphosphino)dipalladium(I); In 1,4-dioxane; for 2h;Reflux;	Example 2.aPreparation of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) and 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) <strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N-diisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri-tert-butylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). The reaction mixture was allowed to cool; the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. The semi-solid oil was dissolved in CH2Cl2, eluted through a plug of silica with CH2Cl2, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 min); 1H NMR (300 MHz, CDCl3) delta 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.43 (td, J=8.2, 5.2 Hz, 1H), 7.32 (ddd, J=9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J=4.9, 2.4 Hz, 1H), 5.80 (t, J=10.9 Hz, 1H), 5.06 (q, J=2.4 Hz, 1H), 3.18-3.07 (m, 1H), 2.94-2.82 (m, 1H) ppm. The minor product was 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 210 (11.95 min). 1H NMR (300 MHz, CDCl3) delta 7.47 (d, J=8.0 Hz, 1H), 7.43-7.34 (m, 1H), 7.30-7.23 (m, 1H), 6.21-6.15 (m, 1H), 6.11-6.06 (m, 1H), 5.97-5.91 (m, 1H), 4.89-4.73 (m, 2H) ppm.
	With N-ethyl-N,N-diisopropylamine;di-mu-bromobis(tri-tert-butylphosphino)dipalladium(I); In 1,4-dioxane; for 2h;Reflux;	<strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N-diisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri-tert-butylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). It was allowed to cool, the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. This was dissolved in CH2Cl2, eluted through a plug of silica with CH2Cl2, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 min); 1H NMR (300 MHz, CDCl3) delta 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.43 (td, J=8.2, 5.2 Hz, 1H), 7.32 (ddd, J=9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J=4.9, 2.4 Hz, 1H), 5.80 (t, J=10.9 Hz, 1H), 5.06 (q, J=2.4 Hz, 1H), 3.18-3.07 (m, 1H), 2.94-2.82 (m, 1H) ppm. The minor product was 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 210 (11.95 min). 1H NMR (300 MHz, CDCl3) delta 7.47 (d, J=8.0 Hz, 1H), 7.43-7.34 (m, 1H), 7.30-7.23 (m, 1H), 6.21-6.15 (m, 1H), 6.11-6.06 (m, 1H), 5.97-5.91 (m, 1H), 4.89-4.73 (m, 2H) ppm.

	With N-ethyl-N,N-diisopropylamine;[PdP(t-Bu)3Br]2; In 1,4-dioxane; for 2h;Reflux;	Preparation 1[00259] Preparation of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) and 2-(2- fluoro-6-nitro- henyl)-2,5-dihydrofuran (15B).14 2 15A 15B[00260] 2-Bromo-1 -fluoro-3-nitro-benzene (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1 ,4-dioxane (981 .5 mL, Sigma-Aldrich 360481 ), and 2,3-dihydrofuran (2) (341 .1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N- diisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri- tert-butylphosphine)palladium(l) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). It was allowed to cool, the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. This was dissolved in CH2CI2, eluted through a plug of silica with CH2CI2, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291 .3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (C18 column eluting with 10-90% CH3CN / water gradient over 5 minutes with formic acid modifier) M+1 : 210.23 (3.13 min); 1 H NMR (300 MHz, CDCI3) delta 7.54 (dt, J = 8.0, 1 .2 Hz, 1 H), 7.43 (td, J = 8.2, 5.2 Hz, 1 H), 7.32 (ddd, J = 9.7, 8.3, 1 .3 Hz, 1 H), 6.33 (dd, J = 4.9, 2.4 Hz, 1 H), 5.80 (t, J = 10.9 Hz, 1 H), 5.06 (q, J = 2.4 Hz, 1 H), 3.18 - 3.07 (m, 1 H), 2.94 - 2.82 (m, 1 H) ppm. The minor product was 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30 m x 250 Mm x 0.25 Mm column heating at 60C for 2 min to 300C over 15 min with a 1 mL/min flow rate) M+1 : 210 (1 1 .95 min). 1 H NMR (300 MHz, CDCI3) delta 7.47 (d, J = 8.0 Hz, 1 H), 7.43 - 7.34 (m, 1 H), 7.30 - 7.23 (m, 1 H), 6.21 - 6.15 (m, 1 H), 6.1 1 - 6.06 (m, 1 H), 5.97 - 5.91 (m, 1 H), 4.89 - 4.73 (m, 2H) ppm.
	With di-mu-bromobis(tri-tert-butylphosphino)dipalladium(I); N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; for 2h;Reflux;	1001641 Example 121001651 Preparation of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (iSA) and 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B).<strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1 ,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,Ndiisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri-tertbutylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). It was allowed to cool, the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. This was dissolved in CH2C12, eluted through a plug of silica with CH2C12, and concentrated in vacuo giving a mixture of iSA and 1SB as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro- phenyl)-2,3-dihydrofuran (iSA) (96%): LCMS (C18 column eluting with 10-90% CH3CN / water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 mm); ?H NMR (300 MHz, CDC13) 67.54 (dt, J 8.0, 1.2 Hz, 1H), 7.43 (td, J 8.2, 5.2 Hz, 1H), 7.32 (ddd, J 9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J =4.9,2.4Hz, 1H), 5.80 (t, J = 10.9 Hz, 1H), 5.06(q, J =2.4 Hz, 1 H), 3.18 -3.07 (m, 1 H), 2.94 -2.82 (m, 1 H) ppm. The minor product was 2-(2- fluoro-6-nitro-phenyl)-2,5-dihydrofuran (1SB) (4%): GCMS (Agilent HP-5M5 30 m x 250 Jim X 0.25 jim column heating at 60C for 2 mm to 3 00C over 15 mm with a 1 mL/min flow rate) M+1: 210 (11.95 mm). ?H NMR (300 MHz, CDC13) 67.47 (d, J 8.0 Hz, 1H), 7.43- 7.34 (m, 1H), 7.30 -7.23 (m, 1H), 6.21 -6.15 (m, 1H), 6.11 - 6.06(m, 1H), 5.97-5.91 (m, 1H), 4.89 -4.73 (m, 2H)ppm
	With di-mu-bromobis(tri-tert-butylphosphino)dipalladium(I); N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; for 2h;Reflux;	<strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N-diisopropylethylamine (155.4 mL, 892.3 mrnol, Sigma-Aldrich550043) and bromo(tri-tert-butylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting aryibromide). It was allowed to cool, the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. This was dissolved in CH2C12, eluted through aplug of silica with CH2C12, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (Cl 8 column eluting with 10-90% CH3CN / water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 mm); ?H NMR (300 MHz,CDC13) 7.54 (dt, J = 8.0, 1.2 Hz, 1H), 7.43 (td, J = 8.2, 5.2 Hz, 1H), 7.32 (ddd, J =9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J = 4.9, 2.4 Hz, 1H), 5.80 (t, J = 10.9 Hz, 1H), 5.06 (q, J= 2.4 Hz, 1H), 3.18 -3.07 (m, 1H), 2.94-2.82 (m, 1H) ppm. The minor product was2-(2-fluoro-6-nitro-phenyl)-2,5 -dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30m x 250 jim x 0.25 jim column heating at 60C for 2 mm to 300C over 15 mm with a1 mL/min flow rate) M+1: 210 (11.95 mm). ?H NMR (300 MHz, CDC13) oe 7.47 (d, J =8.0 Hz, 1H), 7.43 -7.34 (m, 1H), 7.30-7.23 (m, ill), 6.21 -6.15 (m, 1H), 6.11 -6.06 (m, 1H), 5.97 - 5.91 (m, 1H), 4.89 -4.73 (m, 2H) ppm.

Reference： [1]Patent: US2012/184564,2012,A1 .Location in patent: Page/Page column 14-16
[2]Patent: US2012/184742,2012,A1 .Location in patent: Page/Page column 27
[3]Patent: US2012/184512,2012,A1 .Location in patent: Page/Page column 19
[4]Patent: WO2012/177707,2012,A1 .Location in patent: Page/Page column 39-40
[5]Expert Opinion on Therapeutic Patents,2013,vol. 23,p. 1233 - 1237
[6]Patent: WO2014/14845,2014,A1 .Location in patent: Paragraph 00164; 00165; 00166
[7]Patent: WO2014/15105,2014,A1 .Location in patent: Paragraph 00164; 00165; 00166

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[ 1384984-24-0 ]

Yield	Reaction Conditions	Operation in experiment
84%		Placed 5% palladium on carbon (37.3 g, 50% wet, 8.76 mmol, Aldrich 330116) in a Parr bottle under nitrogen, followed by MeOH (70 mL, JT-Baker909333). Added the crude mixture of 2-(2-fluoro-6-nitro-phcnyl)-2,3 -dihydrofuranand 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15A&15B) (186.6 g, 892.1 mmol) dissolved in MeOH (117 mL), followed by NEt3 (124.3 mL, 892.1 mmol, Sigma- Aldrich 471283). Placed the vessel on a Parr shaker and saturated with H2. After adding 45 psi H2, the reaction mixture was shaken until consumption of the startingmaterial was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through CeliteTM and rinsed with EtOAc. The filtrate was concentrated on a rotary evaporator giving a brown oil, which was dissolved in Et20 and washed with water (2x). The ether phase was extracted with aqueous 1 N HC1 (5 x 250 mL), which was washed with Et20 (3x) and then basifiedwith aqueous 6 N NaOH to pH 12-14. The basic aqueous phase was extracted with CH2C12(4x), and the combined organic extract washed with saturated aqueous NH4C1, dried over MgSO4, and filtered through a pad of silica eluting with CH2C12 to 25% EtOAc / hexane. The desired filtrate was concentrated under reduced pressure giving 16 as a light brown oil (121.8 g, 84% GCMS plus NMR purity). GCMS (Agilent HP-5MS 30 mx 250 jim x 0.25 jim column heating at 60C for 2 mm to 300C over 15mm with a I mL/min flow rate) M+1: 182.0 (11.44 mm). LCMS (Cl 8 column elutingwith 10-90% CH3CN / water gradient over 5 minutes with formic acid modifier) M+1:182.10 (2.61 mm). ?H NMR (300 MHz, CDC13) oe 6.97 (td, J = 8.1, 6.3 Hz, 1H), 6.436.35 (m, 2H), 5.21 -5.13 (m, 1H), 4.54 (s, 2H), 4.16 -4.07 (m, 1H), 3.90 - 3.81 (m,1H), 2.23 - 2.00 (m, 4H) ppm. Additional crops were obtained as follows: the combined ether phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The oil was vacuum distilled (ca. 15 torr) collecting the distillate at 101 - 108C. To a stirring solution of the distilled oil in EtOH (1 volume) at 2C was slowly added 5 M HC1 (1 eq) in iPrOH.The resulting suspension was brought to room temperature, diluted with EtOAc (3 volumes, vol/vol), and stirred for 2 hrs. The white solid was collected by filtration, washed with EtOAc, and dried under reduced pressure giving a second crop of product as the HC1 salt. The mother liquor was concentrated to a slurry, diluted with EtOAc and the solid collected by filtration, washed with EtOAc, and dried in vacuo giving the HC1 salt as a third crop of the product. LCMS (C18 column eluting with 10-90%CH3CN / water gradient over 5 minutes with fonnic acid modifier) M+1: 182.10 (2.58mi. 1H NMR (300 MHz, CDC13) 10.73 (br.s, 3H), 7.66 (d, J = 8.1 Hz, 1H), 7.33(td, J = 8.2, 5.9 Hz, 1H), 7.13 -7.05 (m, 1H), 5.26 (dd, J = 9.0, 6.5 Hz, 1H), 4.38 -4.28 (m, 1H), 4.00 - 3.91 (m, 1H), 2.59 - 2.46 (m, 1H), 2.30 - 1.95 (m, 3H) ppm. The overall yield from the three crops was 76%.
		Example 2.aPreparation of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) and 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) <strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N-diisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri-tert-butylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). The reaction mixture was allowed to cool; the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. The semi-solid oil was dissolved in CH2Cl2, eluted through a plug of silica with CH2Cl2, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 min); 1H NMR (300 MHz, CDCl3) delta 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.43 (td, J=8.2, 5.2 Hz, 1H), 7.32 (ddd, J=9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J=4.9, 2.4 Hz, 1H), 5.80 (t, J=10.9 Hz, 1H), 5.06 (q, J=2.4 Hz, 1H), 3.18-3.07 (m, 1H), 2.94-2.82 (m, 1H) ppm. The minor product was 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 210 (11.95 min). 1H NMR (300 MHz, CDCl3) delta 7.47 (d, J=8.0 Hz, 1H), 7.43-7.34 (m, 1H), 7.30-7.23 (m, 1H), 6.21-6.15 (m, 1H), 6.11-6.06 (m, 1H), 5.97-5.91 (m, 1H), 4.89-4.73 (m, 2H) ppm._Example 2.bPreparation of 3-fluoro-2-tetrahydrofuran-2-yl-aniline (16) 5% Palladium on carbon (37.3 g, 50% wet, 8.76 mmol, Aldrich 330116) was placed in a Parr bottle under nitrogen, followed by MeOH (70 mL, JT-Baker 909333). The crude mixture of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran and 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15A & 15B) (186.6 g, 892.1 mmol) dissolved in MeOH (117 mL) was added to the Parr bottle, followed by NEt3 (124.3 mL, 892.1 mmol, Sigma-Aldrich 471283). The bottle was placed on a Parr shaker and saturated with H2. After adding 45 psi H2, the reaction mixture was shaken until consumption of the starting material was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite and rinsed with EtOAc. The filtrate was concentrated on a rotary evaporator giving brown oil, which was dissolved in Et2O and washed with water (2×). The ether phase was extracted with aqueous 1 N HCl (5×250 mL), which was washed with Et2O (3×) and then basified with aqueous 6 N NaOH to pH 12-14. The basic aqueous phase was extracted with dichloromethane (CH2Cl2, 4×), and the combined organic extract was washed with saturated aqueous NH4Cl, dried over MgSO4, and filtered through a pad of silica eluting with CH2Cl2 to 25% EtOAc/hexane. The desired filtrate was concentrated under reduced pressure giving 16 as a light brown oil (121.8 g, 84% GCMS plus NMR purity). GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 182.0 (11.44 min). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.61 min). 1H NMR (300 MHz, CDCl3) delta 6.97 (td, J=8.1, 6.3 Hz, 1H), 6.43-6.35 (m, 2H), 5.21-5.13 (m, 1H), 4.54 (s, 2H), 4.16-4.07 (m, 1H), 3.90-3.81 (m, 1H), 2.23-2.00 (m, 4H) ppm. Additional crops were obtained as follows: the combined ether phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The oil was vacuum distilled (ca. 15 torr) collecting the distillate at 101-108 C. To a stirring solution of the distilled oil in EtOH (1 volume) at 2 C. was slowly added 5 M HCl (1 eq) in iPrOH. The resulting suspension was brought to room temperature, diluted with EtOAc (3 volumes, vol/vol), and stirred for 2 hrs. A white solid was collected by filtration, washed with EtOAc, and dried under reduced pressure giving a second crop of product as the HCl salt. The mother liquor was concentrated to a slurry, diluted with EtOAc and the solid collected by filtration, washed with EtOAc, and dried in vacuo giving the HCl salt as a third crop of the product. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.58 min). 1H NMR (300 MHz, CDCl3) delta 10.73 (br.s, 3H), 7.66 (d, J=8.1 Hz, 1H), 7.33 (td, J=8.2, 5.9 Hz, 1H), 7.13-7.05 (m, 1H), 5.26 (dd, J=9.0, 6.5 Hz, 1H), 4.38-4.28 (m, 1H), 4.00-3.91 (m, 1H), 2.59-2.46 (m, 1H), 2.30...
		<strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N-diisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri-tert-butylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). It was allowed to cool, the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. This was dissolved in CH2Cl2, eluted through a plug of silica with CH2Cl2, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 min); 1H NMR (300 MHz, CDCl3) delta 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.43 (td, J=8.2, 5.2 Hz, 1H), 7.32 (ddd, J=9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J=4.9, 2.4 Hz, 1H), 5.80 (t, J=10.9 Hz, 1H), 5.06 (q, J=2.4 Hz, 1H), 3.18-3.07 (m, 1H), 2.94-2.82 (m, 1H) ppm. The minor product was 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 210 (11.95 min). 1H NMR (300 MHz, CDCl3) delta 7.47 (d, J=8.0 Hz, 1H), 7.43-7.34 (m, 1H), 7.30-7.23 (m, 1H), 6.21-6.15 (m, 1H), 6.11-6.06 (m, 1H), 5.97-5.91 (m, 1H), 4.89-4.73 (m, 2H) ppm. Placed 5% palladium on carbon (37.3 g, 50% wet, 8.76 mmol, Aldrich 330116) in a Parr bottle under nitrogen, followed by MeOH (70 mL, JT-Baker 909333). Added the crude mixture of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran and 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15A&15B) (186.6 g, 892.1 mmol) dissolved in MeOH (117 mL), followed by NEt3 (124.3 mL, 892.1 mmol, Sigma-Aldrich 471283). Placed the vessel on a Parr shaker and saturated with H2. After adding 45 psi H2, the reaction mixture was shaken until consumption of the starting material was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite and rinsed with EtOAc. The filtrate was concentrated on a rotary evaporator giving a brown oil, which was dissolved in Et2O and washed with water (2×). The ether phase was extracted with aqueous 1 N HCl (5×250 mL), which was washed with Et2O (3×) and then basified with aqueous 6 N NaOH to pH 12-14. The basic aqueous phase was extracted with CH2Cl2(4×), and the combined organic extract washed with saturated aqueous NH4Cl, dried over MgSO4, and filtered through a pad of silica eluting with CH2Cl2 to 25% EtOAc/hexane. The desired filtrate was concentrated under reduced pressure giving 16 as a light brown oil (121.8 g, 84% GCMS plus NMR purity). GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 182.0 (11.44 min). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.61 min). 1H NMR (300 MHz, CDCl3) delta 6.97 (td, J=8A, 6.3 Hz, 1H), 6.43-6.35 (m, 2H), 5.21-5.13 (m, 1H), 4.54 (s, 2H), 4.16-4.07 (m, 1H), 3.90-3.81 (m, 1H), 2.23-2.00 (m, 4H) ppm. Additional crops were obtained as follows: the combined ether phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The oil was vacuum distilled (ca. 15 torr) collecting the distillate at 101-108 C. To a stirring solution of the distilled oil in EtOH (1 volume) at 2 C. was slowly added 5 M HCl (1 eq) in iPrOH. The resulting suspension was brought to room temperature, diluted with EtOAc (3 volumes, vol/vol), and stirred for 2 hrs. The white solid was collected by filtration, washed with EtOAc, and dried under reduced pressure giving a second crop of product as the HCl salt. The mother liquor was concentrated to a slurry, diluted with EtOAc and the solid collected by filtration, washed with EtOAc, and dried in vacuo giving the HCl salt as a third crop of the product. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.58 min). 1H NMR (300 MHz, CDCl3) delta 10.73 (br.s, 3H), 7.66 (d, J8.1 Hz, 1H), 7.33 (td, J8.2, 5.9 Hz, 1H), 7.13-7.05 (m, 1H), 5.26 (dd, J=9.0, 6.5 Hz, 1H), 4.38-4.28 (m, 1H), 4.00-3.91 (m, 1H), 2.59-2.46 (m, 1H), 2.30-1.95 (m, 3H) ppm. The overall yield from the three crops was 76%.

		<strong>[59255-94-6]2-Bromo-1-fluoro-3-nitro-benzene</strong> (14) (200.3 g, 98%, 892.3 mmol, Bosche F6657), 1,4-dioxane (981.5 mL, Sigma-Aldrich 360481), and 2,3-dihydrofuran (2) (341.1 mL, 99%, 4.462 mol, Aldrich 200018) were charged in a reaction flask, followed by N,N-diisopropylethylamine (155.4 mL, 892.3 mmol, Sigma-Aldrich 550043) and bromo(tri-tert-butylphosphine)palladium(I) dimer (6.936 g, 8.923 mmol, Johnson Matthey C4099). The mixture was stirred at reflux for 2 hrs (HPLC showed 98% consumption of starting arylbromide). The reaction mixture was allowed to cool; the precipitate was removed by filtration, rinsed with EtOAc, and the filtrate concentrated in vacuo to a dark reddish brown semi-solid oil. The semi-solid oil was dissolved in CH2Cl2, eluted through a plug of silica with CH2Cl2, and concentrated in vacuo giving a mixture of 15A and 15B as a dark amber oil (291.3 g). The crude product was carried forward without further purification. The major product was 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran (15A) (96%): LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 210.23 (3.13 min); 1H NMR (300 MHz, CDCl3) delta 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.43 (td, J=8.2, 5.2 Hz, 1H), 7.32 (ddd, J=9.7, 8.3, 1.3 Hz, 1H), 6.33 (dd, J=4.9, 2.4 Hz, 1H), 5.80 (t, J=10.9 Hz, 1H), 5.06 (q, J=2.4 Hz, 1H), 3.18-3.07 (m, 1H), 2.94-2.82 (m, 1H) ppm. The minor product was 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15B) (4%): GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 210 (11.95 min). 1H NMR (300 MHz, CDCl3) delta 7.47 (d, J=8.0 Hz, 1H), 7.43-7.34 (m, 1H), 7.30-7.23 (m, 1H), 6.21-6.15 (m, 1H), 6.11-6.06 (m, 1H), 5.97-5.91 (m, 1H), 4.89-4.73 (m, 2H) ppm.5% Palladium on carbon (37.3 g, 50% wet, 8.76 mmol, Aldrich 330116) was placed in a Parr bottle under nitrogen, followed by MeOH (70 mL, JT-Baker 909333). The crude mixture of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran and 2-(2-fluoro-6-nitro-phenyl)-2,5-dihydrofuran (15A&15B) (186.6 g, 892.1 mmol) dissolved in MeOH (117 mL) was added to the Parr bottle, followed by NEt3 (124.3 mL, 892.1 mmol, Sigma-Aldrich 471283). The bottle was placed on a Parr shaker and saturated with H2. After adding 45 psi H2, the reaction mixture was shaken until consumption of the starting material was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite and rinsed with EtOAc. The filtrate was concentrated on a rotary evaporator giving brown oil, which was dissolved in Et2O and washed with water (2×). The ether phase was extracted with aqueous 1 N HCl (5×250 mL), which was washed with Et2O (3×) and then basified with aqueous 6 N NaOH to pH 12-14. The basic aqueous phase was extracted with dichloromethane (CH2Cl2, 4×), and the combined organic extract was washed with saturated aqueous NH4Cl, dried over MgSO4, and filtered through a pad of silica eluting with CH2Cl2 to 25% EtOAc/hexane. The desired filtrate was concentrated under reduced pressure giving 16 as a light brown oil (121.8 g, 84% GCMS plus NMR purity). GCMS (Agilent HP-5MS 30 m×250 mum×0.25 mum column heating at 60 C. for 2 min to 300 C. over 15 min with a 1 mL/min flow rate) M+1: 182.0 (11.44 min). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.61 min). 1H NMR (300 MHz, CDCl3) delta 6.97 (td, J=8.1, 6.3 Hz, 1H), 6.43-6.35 (m, 2H), 5.21-5.13 (m, 1H), 4.54 (s, 2H), 4.16-4.07 (m, 1H), 3.90-3.81 (m, 1H), 2.23-2.00 (m, 4H) ppm. Additional crops were obtained as follows: the combined ether phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The oil was vacuum distilled (ca. 15 ton) collecting the distillate at 101-108 C. To a stirring solution of the distilled oil in EtOH (1 volume) at 2 C. was slowly added 5 M HCl (1 eq) in iPrOH. The resulting suspension was brought to room temperature, diluted with EtOAc (3 volumes, vol/vol), and stirred for 2 hrs. A white solid was collected by filtration, washed with EtOAc, and dried under reduced pressure giving a second crop of product as the HCl salt. The mother liquor was concentrated to a slurry, diluted with EtOAc and the solid collected by filtration, washed with EtOAc, and dried in vacuo giving the HCl salt as a third crop of the product. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 182.10 (2.58 min). 1H NMR (300 MHz, CDCl3) delta 10.73 (br.s, 3H), 7.66 (d, J=8.1 Hz, 1H), 7.33 (td, J=8.2, 5.9 Hz, 1H), 7.13-7.05 (m, 1H), 5.26 (dd, J=9.0, 6.5 Hz, 1H), 4.38-4.28 (m, 1H), 4.00-3.91 (m, 1H), 2.59-2.46 (m, 1H), 2.30-1.95 (m, 3H) ppm. The overall yield from the three crops was 76%.
		Preparation 2[00262] Pre aration of 3-fluoro-2-tetrahydrofuran-2-yl-aniline (16).15A 15B 16[00263] Placed 5% palladium on carbon (37.3 g, 50% wet, 8.76 mmol, Aldrich 3301 16) in a Parr bottle under nitrogen, followed by MeOH (70 ml_, JT-Baker 909333). Added the crude mixture of 2-(2-fluoro-6-nitro-phenyl)-2,3-dihydrofuran and 2-(2-fluoro- 6-nitro-phenyl)-2,5-dihydrofuran (15A&15B) (186.6 g, 892.1 mmol) dissolved in MeOH (1 17 ml_), followed by NEt3 (124.3 ml_, 892.1 mmol, Sigma-Aldrich 471283). Placed the vessel on a Parr shaker and saturated with H2. After adding 45 psi H2, the reaction mixture was shaken until consumption of the starting material was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite and rinsed with EtOAc. The filtrate was concentrated on a rotary evaporator giving a brown oil, which was dissolved in Et20 and washed with water (2x). The ether phase was extracted with aqueous 1 N HCI (5 x 250 ml_), which was washed with Et20 (3x) and then basified with aqueous 6 N NaOH to pH 12-14. The basic aqueous phase was extracted with CH2CI2 (4x), and the combined organic extract washed with saturated aqueous NH CI, dried over MgSO4, and filtered through a pad of silica eluting with CH2CI2 to 25% EtOAc / hexane. The desired filtrate was concentrated under reduced pressure giving 16 as a light brown oil (121.8 g, 84% GCMS plus NMR purity). GCMS (Agilent HP-5MS 30 m x 250 Mm x 0.25 Mm column heating at 60C for 2 min to 300C over 15 min with a 1 mL/min flow rate) M+1 : 182.0 (1 1 .44 min). LCMS (C18 column eluting with 10-90% CH3CN / water gradient over 5 minutes with formic acid modifier) M+1 : 182.10 (2.61 min). 1 H NMR (300 MHz, CDCI3) 5 6.97 (td, J = 8.1 , 6.3 Hz, 1 H), 6.43 - 6.35 (m, 2H), 5.21 - 5.13 (m, 1 H), 4.54 (s, 2H), 4.16 - 4.07 (m, 1 H),3.90 - 3.81 (m, 1 H), 2.23 - 2.00 (m, 4H) ppm. Additional crops were obtained as follows: the combined ether phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The oil was vacuum distilled (ca. 15 torr) collecting the distillate at 101 - 108C. To a stirring solution of the distilled oil in EtOH (1 volume) at 2C was slowly added 5 M HCI (1 eq) in /PrOH. The resulting suspension was brought to room temperature, diluted with EtOAc (3 volumes, vol/vol), and stirred for 2 hrs. The white solid was collected by filtration, washed with EtOAc, and dried under reduced pressure giving a second crop of product as the HCI salt. The mother liquor was concentrated to a slurry, diluted with EtOAc and the solid collected by filtration, washed with EtOAc, and dried in vacuo giving the HCI salt as a third crop of the product. LCMS (C18 column eluting with 10-90% CH3CN / water gradient over 5 minutes with formic acid modifier) M+1 : 182.10 (2.58 min). 1 H NMR (300 MHz, CDCI3) delta 10.73 (br.s, 3H), 7.66 (d, J = 8.1 Hz, 1 H), 7.33 (td, J = 8.2, 5.9 Hz, 1 H), 7.13 - 7.05 (m, 1 H), 5.26 (dd, J = 9.0, 6.5 Hz, 1 H), 4.38 - 4.28 (m, 1 H), 4.00 -3.91 (m, 1 H), 2.59 - 2.46 (m, 1 H), 2.30 - 1 .95 (m, 3H) ppm. The overall yield from the three crops was 76%.

Reference： [1]Patent: WO2014/15105,2014,A1 .Location in patent: Paragraph 00167; 00168; 00169
[2]Patent: US2012/184742,2012,A1 .Location in patent: Page/Page column 27-28
[3]Patent: US2012/184512,2012,A1 .Location in patent: Page/Page column 19; 20
[4]Patent: US2012/184564,2012,A1 .Location in patent: Page/Page column 14-16
[5]Patent: WO2012/177707,2012,A1 .Location in patent: Page/Page column 40-41
[6]Expert Opinion on Therapeutic Patents,2013,vol. 23,p. 1233 - 1237

29
[ 59255-94-6 ]
(R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate disodium salt [ No CAS ]

Reference： [1]Patent: WO2014/14845,2014,A1
[2]Patent: WO2014/15105,2014,A1
[3]Patent: WO2014/15105,2014,A1
[4]Patent: WO2014/15105,2014,A1
[5]Patent: US2012/184512,2012,A1
[6]Patent: US2012/184512,2012,A1

30
[ 59255-94-6 ]
[ 1384984-30-8 ]

Reference： [1]Patent: WO2014/14845,2014,A1
[2]Patent: WO2014/15105,2014,A1
[3]Patent: WO2014/15105,2014,A1
[4]Patent: US2012/184512,2012,A1

31
[ 59255-94-6 ]
1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea methanesulfonic acid salt [ No CAS ]

Reference： [1]Patent: WO2014/14845,2014,A1
[2]Patent: US2012/184512,2012,A1

32
[ 59255-94-6 ]
[ 1386857-51-7 ]

Reference： [1]Patent: US2012/184564,2012,A1
[2]Patent: WO2014/14845,2014,A1
[3]Patent: WO2014/15105,2014,A1
[4]Patent: US2012/184512,2012,A1

33
[ 59255-94-6 ]
[ 1416702-57-2 ]

Reference： [1]Patent: WO2012/177707,2012,A1

34
[ 59255-94-6 ]
[ 1416702-58-3 ]

Reference： [1]Patent: WO2012/177707,2012,A1

35
[ 59255-94-6 ]
[ 1416702-59-4 ]

Reference： [1]Patent: WO2012/177707,2012,A1

36
[ 59255-94-6 ]
[ 1416702-60-7 ]

Reference： [1]Patent: WO2012/177707,2012,A1

37
[ 59255-94-6 ]
[ 1416702-61-8 ]

Reference： [1]Patent: WO2012/177707,2012,A1

38
[ 59255-94-6 ]
[ 1416702-62-9 ]

Reference： [1]Patent: WO2012/177707,2012,A1

39
[ 59255-94-6 ]
C₁₀H₁₂FNO [ No CAS ]

Reference： [1]Expert Opinion on Therapeutic Patents,2013,vol. 23,p. 1233 - 1237

40
[ 59255-94-6 ]
C₁₀H₁₁BrFNO [ No CAS ]

Reference： [1]Expert Opinion on Therapeutic Patents,2013,vol. 23,p. 1233 - 1237

41
[ 59255-94-6 ]
4,5-difluoro-9H-carbazole [ No CAS ]

Reference： [1]Patent: US2013/303524,2013,A1

42
[ 59255-94-6 ]
4,5-difluoro-9-(oxiran-2-ylmethyl)-9H-carbazole [ No CAS ]

Reference： [1]Patent: US2013/303524,2013,A1

43
[ 59255-94-6 ]
[ 1993-03-9 ]
2,2'-difluoro-6-nitro-1,1'-biphenyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 16h;Inert atmosphere;	Preparation 50 2,2'-Difluoro-6-nitro-1,1'-biphenyl To a solution of <strong>[59255-94-6]2-bromo-3-fluoronitrobenzene</strong> (1.500 g, 6.8 mmol), 2-fluorophenylboronic acid (1.145 g, 8.2 mmol), N,N-dimethylformamide (50 mL), and 2.0 M aqueous potassium carbonate (10 mL) under argon was added tetrakis(triphenylphosphine)palladium (0) (0.394 g, 0.3 mmol). The mixture was stirred at 110 C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% methylene chloride/hexanes) to afford a pale yellow solid (0.780 g, 49%). 1H NMR (300 MHz, CDCl3) delta 7.86 (dt, 1H, J=7.8, 1.2 Hz), 7.56 (td, 1H, J=8.1, 5.7 Hz), 7.52-7.40 (m, 2H), 7.35-7.15 (m, 3H).

Reference： [1]Patent: US2013/303524,2013,A1 .Location in patent: Paragraph 0337-0338

44
[ 59255-94-6 ]
[ 1384984-24-0 ]

Reference： [1]Patent: WO2014/14845,2014,A1

45
[ 59255-94-6 ]
C₂₆H₃₃FN₆O₅ [ No CAS ]

Reference： [1]Patent: WO2014/15105,2014,A1

46
[ 59255-94-6 ]
C₃₈H₄₂FN₆O₈P [ No CAS ]

Reference： [1]Patent: WO2014/15105,2014,A1

47
[ 59255-94-6 ]
1-ethyl-3-[N₁,N₃-di-Boc-6-fluoro-5-[2-(1-hydroxy-1-methylethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea [ No CAS ]

Reference： [1]Patent: WO2014/15105,2014,A1

48
[ 59255-94-6 ]
1-ethyl-3-[N,N'-di-Boc-6-fluoro-5-[2-(1-hydroxy-1-methylethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]ureadibenzyl phosphate [ No CAS ]

Reference： [1]Patent: WO2014/15105,2014,A1

49
[ 59255-94-6 ]
(R)-2(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl dihydrogenphosphate monohydrate [ No CAS ]

Reference： [1]Patent: WO2014/15105,2014,A1
[2]Patent: WO2014/15105,2014,A1
[3]Patent: WO2014/15105,2014,A1

50
[ 59255-94-6 ]
[ 1384984-31-9 ]

Reference： [1]Patent: WO2014/15105,2014,A1
[2]Patent: WO2014/15105,2014,A1
[3]Patent: WO2014/15105,2014,A1

51
[ 59255-94-6 ]
1-(5-fluoro-9H-carbazol-3-yl)-ethanone [ No CAS ]

Reference： [1]Patent: WO2014/153043,2014,A1

52
[ 59255-94-6 ]
1-(5-fluoro-9-propyl-9H-carbazol-3-yl)-ethanone [ No CAS ]

Reference： [1]Patent: WO2014/153043,2014,A1

53
[ 59255-94-6 ]
3-acetylphenylboronic acid [ No CAS ]
1-(6'-fluoro-2'-nitrobiphenyl-3-yl)-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 1h;Microwave irradiation;	A biphasic mixture of 2-bromo-l-fluoro-3 -nitrobenzene (500 mg, 2.27 mmol), 3-acetylphenyl- boronic acid (447 mg, 2.727 mmol), dichloro(l, -/?(diphenylphosphino)ferrocene) palladium(II) (166 mg, 0.227 mmol) and aqueous potassium carbonate (2 M, 2.3 mL, 4.54 mmol) in 1,4-dioxane (12 mL) was heated at 120 C for 1 h under microwave irradiation. The mixture was evaporated and the residue was diluted with water (20 mL). The aqueous phase was extracted with dichloromethane (3 x 25 mL) and the combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with hexane:ethyl acetate (10: 1) to give the title compound (492 mg, 1.90 mmol, 84%) as a yellow powder. LCMS: 99%, Rt 1.591, ESMS m/z 260 (M+H)+.

Reference： [1]Patent: WO2014/153043,2014,A1 .Location in patent: Paragraph 0117

54
[ 59255-94-6 ]
[ 97674-02-7 ]
2-(1-ethoxyvinyl)-1-fluoro-3-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With dichlorobis(triphenylphosphine)palladium[II]; In 1,4-dioxane; at 95℃; for 4.5h;Inert atmosphere;	Example 91a 2-(1-ethoxyvinyl)-1-fluoro-3-nitrobenzene A mixture of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (1.364 g, 6.20 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.435 g, 0.620 mmol) was degassed and flushed with nitrogen. 1,4-Dioxane (15.5 mL) and tributyl(1-ethoxyvinyl)tin (2.51 mL, 7.44 mmol) were added sequentially under nitrogen. The resulting mixture was heated at 95 C. for 4.5 hours and then cooled to ambient temperature. A solution of potassium fluoride (1.4 g in 12 mL water) was added followed by the addition of ethyl acetate. The mixture was stirred overnight and was then filtered through diatomaceous earth, rinsing with 500 mL of ethyl acetate. The filtrate was washed with water and brine, dried (anhydrous MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2 to 20% ethyl acetate in hexanes) to provide the title compound (0.91 g, 70%).

Reference： [1]Patent: US2014/275079,2014,A1 .Location in patent: Paragraph 0524

55
[ 1221239-08-2 ]
[ 59255-94-6 ]
4-(2-fluoro-6-nitrophenyl)-indan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation;	Step 1. A mixture of 2-bromo-l-fluoro-3 -nitrobenzene (610 mg, 2.77 mmol), 4-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-indan-l-one (Preparation 7-1 , 858 mg, 3.33 mmol), potassium carbonate (2M aq. solution, 2.8 mL, 5.6 mmol) and 1,1'- 6w(diphenylphosphino)ferrocene palladium(II) dichloride (101 mg, 0.14 mmol) in 1 ,4- dioxane (12 mL) was irradiated at 100 C in a microwave reactor for 1 h. The mixture was partitioned between water (15 mL) and ethyl acetate (30 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were washed with brine (15 mL), dried over magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography eluting with -hexane: ethyl acetate (10: 1 - 1 : 1) to give the title compound (447 mg, 1.65 mmol, 59%) as a yellow solid. LCMS: 100%, t 1.548 min, ESMS m/z 272 (M+H)+.
59%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Microwave irradiation;	A mixture of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (610 mg, 2.77 mmol), 4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yI)-indan-1-one (Preparation 7-1, 858 mg, 3.33 mmol), potassium carbonate (2M aq. solution, 2.8 mL, 5.6 mmol) and 1,1?- bis(diphenylphosphino)ferrocene palladium(11) dichloride (101 mg, 0.14 mmol) in 1,4-dioxane (12 mL) was irradiated at 100 C in a microwave reactor for 1 h. The mixture was partitioned between water (15 mL) and ethyl acetate (30 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were washed with brine (15 mL), dried over magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography eluting with n-hexane:ethyl acetate (10:1-1:1) to give the title compound (447 mg, 1.65 mmol, 59%) as a yellow solid. LCMS: 100%, Rt 1.548 mm, ESMS mlz 272 (M+H).
59%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation;	1001291 Step 1. A mixture of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (610 mg, 2.77 mmol),(4,4,5 ,5-tetramethyl-[ 1,3 ,2]dioxaborolan-2-yl)-indan- 1-one (Preparation 7-1, 858 mg, 3.33 mmol), potassium carbonate (2M aq. solution, 2.8 mL, 5.6 mmol) and 1,1?- bis(diphenylphosphino)ferrocene pal ladium(II) dichloride (101 mg, 0.14 mmol) in 1 ,4-dioxane (12 mL) was irradiated at 100 C in a microwave reactor for I h. The mixture was partitioned between water (15 mL) and ethyl acetate (30 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were washed with brine (15 mL), dried over magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography eluting with n-hexane:ethyl acetate (10:1-1:1) to give the title compound (447 mg, 1.65 mmol, 59%) as a yellow solid. LCMS: 100%, Rt 1.548 mm, ESMS m/z 272 (M+Hj.

Reference： [1]Patent: WO2015/20553,2015,A1 .Location in patent: Paragraph 00144
[2]Patent: WO2015/50472,2015,A1 .Location in patent: Page/Page column 00131; 00132
[3]Patent: WO2015/50471,2015,A1 .Location in patent: Paragraph 00128; 00129

56
[ 59255-94-6 ]
[ 157665-53-7 ]
tert-butyl-3-fluoro-4-[(2-fluoro-6-nitrophenyl)amino]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
320 mg	With palladium diacetate; caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 3h;	To a well stirred mixture of <strong>[59255-94-6]2-bromo-1-fluoro-3-nitrobenzene</strong> (300 mg, 1.363 mmol) in 1,4- dioxane (10 mL) were added tert-butyl 4-amino-3-fluorobenzoate (287 mg, 1.3636 mmol),acetate (31 mg, 0.136 mmol), XPhos (94 mg, 0.1036 mmol) and cesium carbonate (666 mg,2.045 mmol). The reaction mixture was heated at 100 C for 3 h. The reaction mixture diluted with ethyl acetate (20 mL) and filtered through celite pad. The filtrate was concentrated under reduced pressure and residue thus obtained was purified by silica gel column chromatography to afford 320 mg of the title product as yellow oil. ?H NMR (300 MHz,CDC13) oe 1.58 (s, 9H), 6.84-6.89 (m, 1H), 7.10-7.13 (m, 1H), 7.41 (t, J= 10.2 Hz, 1H), 7.69-7.74 (m, 2H), 8.00 (d, J 8.1 Hz, 1H), 8.45 (s, 1H).

Reference： [1]Patent: WO2015/52675,2015,A1 .Location in patent: Page/Page column 43

57
[ 59255-94-6 ]
4-[3-(2-chloro-6-cyclopropylbenzoyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]-3-fluorobenzoic acid [ No CAS ]

Reference： [1]Patent: WO2015/52675,2015,A1

58
[ 59255-94-6 ]
tert-butyl-4-[3-(2-chloro-6-cyclopropylbenzoyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]-3-fluorobenzoate [ No CAS ]

Reference： [1]Patent: WO2015/52675,2015,A1

59
[ 59255-94-6 ]
tert-butyl-3-fluoro-4-(7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate [ No CAS ]

Reference： [1]Patent: WO2015/52675,2015,A1

60
[ 110-91-8 ]
[ 59255-94-6 ]
C₁₀H₁₁FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In neat (no solvent); at 120℃; for 2h;	A solution of commercially available <strong>[59255-94-6]2-bromo-3-fluoronitrobenzene</strong> (1.78 g, 8.09 mmol) and morpholine (2.12 mL, 24.3 mmol) was heated for 2 h at 120 C using a Biotage Initiator microwave. The mixture was dissolved in dichloromethane (50 mL) and water (20 mL). The organic phase was separated, dried over Na2S04, filtered and the solvents were removed under reduced pressure. The residue was purified by chromatography on HP-Sil SNAP cartridges using a Biotage Isolera system employing an ethyl acetate/n-heptane gradient (5/95->40/60) to afford the title compound as a bright orange oil (1.39 g, 76 %).H-NMR (400 MHz, CDCI3): delta = 3.13-3.17 (m, 4H), 3.76-3.80 (m, 4H), 7.15-7.22 (m, 1 H), 7.23-7.28 (m, 1 H), 7.43 (dt, 1 H)
76%	at 120℃; for 2h;	(0685) Step A (0686) A solution of commercially available <strong>[59255-94-6]2-bromo-3-fluoronitrobenzene</strong> (1.78 g, 8.09 mmol) and morpholine (2.12 mL, 24.3 mmol) was heated for 2 h at 120 C. using a Biotage Initiator microwave. The mixture was dissolved in dichloromethane (50 mL) and water (20 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed under reduced pressure. The residue was purified by chromatography on HP-Sil SNAP cartridges using a Biotage Isolera system employing an ethyl acetate/n-heptane gradient (5/95->40160) to afford the title compound as a bright orange oil (1.39 g, 76%). (0687) 1H-NMR (400 MHz, CDCl3): delta=3.13-3.17 (m, 4H), 3.76-3.80 (m, 4H), 7.15-7.22 (m, 1H), 7.23-7.28 (m, 1H), 7.43 (dt, 1H).

Reference： [1]Patent: WO2015/110263,2015,A1 .Location in patent: Page/Page column 146; 147
[2]Patent: US2017/2005,2017,A1 .Location in patent: Paragraph 0684; 0685; 0686; 0687

61
[ 59255-94-6 ]
C₁₀H₁₃FN₂O [ No CAS ]

Reference： [1]Patent: WO2015/110263,2015,A1
[2]Patent: US2017/2005,2017,A1

62
[ 59255-94-6 ]
C₁₈H₁₁ClFNO₂ [ No CAS ]