873697-78-0|1-(2-Fluoro-3-nitrophenyl)ethanone| Ambeed

Structure of 2'-Fluoro-3'-nitroacetophenone
CAS No.: 873697-78-0

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Quality Control of [ 873697-78-0 ] Purity: 98% SDS Specification

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Product Details of [ 873697-78-0 ]

CAS No. :	873697-78-0
Formula :	C₈H₆FNO₃
M.W :	183.14
SMILES Code :	CC(C1=CC=CC([N+]([O-])=O)=C1F)=O
MDL No. :	MFCD13194361
InChI Key :	FMRFQXVFOFXBLH-UHFFFAOYSA-N
Pubchem ID :	21561870

Safety of [ 873697-78-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 873697-78-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	45.42
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	62.89 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.94
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.54
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.36
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.02
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.43
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.26

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.16
Solubility	1.28 mg/ml ; 0.007 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.47
Solubility	0.621 mg/ml ; 0.00339 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.39
Solubility	0.741 mg/ml ; 0.00405 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.32 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.78

Application In Synthesis of [ 873697-78-0 ]

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

Upstream synthesis route of [ 873697-78-0 ]
Downstream synthetic route of [ 873697-78-0 ]

[ 873697-78-0 ] Synthesis Path-Upstream 1~2

1
[ 58534-94-4 ]
[ 97674-02-7 ]
[ 873697-78-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 90℃; for 4 h;	The dichlorobis (triphenylphosphine) palladium (II) (1.6g, 2.28mmol, 0.05equiv) was added to the two dioxanyl (100 mL) of 1-bromo-2-fluoro-3-nitrobenzene (10.0g, 45.6mmol, 1equiv) and tri-n-butyl (1-ethoxy-vinyl) stannane (15.4 mL, 45.6mmol, 1equiv) solution.The resulting cloudy solution was heated 4 hours at 90 , during which the formation of a dark brown solution.In TLC (30percent MTBE / heptane) to confirm complete conversion, the reaction was cooled to room temperature.Was added KF (100mL) and ethyl acetate (100 mL), saturated solution, and the biphasic mixture stirred for 1 hour and filtered through celite, washed with ethyl acetate.The organic layer was separated over Na₂SO₄Sulfate, filtered, and evaporated to give a brown oil of the crude enol ether form.The crude product was dissolved in THF (50mL) and added 2NHCl (50mL).The reaction was stirred at room temperature for 1.5 hours.The reaction was then saturated with NaCl, and extracted with MTBE (2x150mL).Washed with brine (1x300mL) and the organic layer was washed over Na₂SO₄Sulfate, filtered, and evaporated to give the crude material was eluted through silica gel column chromatography crude material was purified with 0-40percent ethyl acetate / heptane gradient solutions.Compound under reduced pressure, the product-containing fractions evaporated to give a yellow oil of 1- (2-fluoro-3-nitrophenyl) ethanone (7.1g, 86percent yield)
82%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 10 - 95℃; for 4 h; Inert atmosphere; Large scale	Pd(dppf)C12 (0.13 kg, 0.19 mol) was added to a solution of 1-bromo-2-fluoro-3-nitrobenzene (0.827 kg, 3.6 mol) and tributyl(1-ethoxyvinyl)tin (1.36 kg, 3.6 mol) in 1,4-dioxane (8.27 kg) at 10-30°C under N2. The solution was heated to 85-95°C and thetemperature was maintained at 85-95°C for 4 h under N2. The mixture was cooled to 10- 30°C, then ethyl acetate (8.27 L) and saturated aqueous KF solution (4 L) were added.The mixture was stirred for 1 h, then the solution was filtered through a pad of celite and washed with ethyl acetate (2 L). The organic layer was separated and dried over Na2SO4,then concentrated. The resulting crude material was combined with two similar batches, then treated with THF (12.5 L) and 2N HC1 (12.5 L). The mixture was stirred at 10-25°C for 3 h, then extracted with ethyl acetate (3 x 20 L). The organic phase was separated and washed with saturated aqueous NaHCO3 solution (10 L) and brine (10 L), then the solvent was concentrated. The crude residue was purified by chromatography (silica, 100-200mesh, 4percent EtOAc in petroleum ether) to give the title compound (1.70 kg, 82percent). oH (400MHz, CDC13) 8.21-8.13 (m, 2H), 7.42-7.38 (m, 1H), 2.71-2.69 (d, J5.2 Hz, 3H).

References: [1] Patent: CN105228983, 2016, A, . Location in patent: Paragraph 0697; 0698; 0699.
[2] Patent: WO2017/89453, 2017, A1, . Location in patent: Page/Page column 44; 45.

2
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[ 873697-78-0 ]

References: [1] Patent: US2006/14761, 2006, A1, . Location in patent: Page/Page column 36.
[2] Patent: WO2007/75377, 2007, A2, . Location in patent: Page/Page column 65.
[3] Patent: US2009/192168, 2009, A1, . Location in patent: Page/Page column 23.
[4] Patent: WO2007/70626, 2007, A2, . Location in patent: Page/Page column 52-53.
[5] Patent: WO2007/70683, 2007, A2, . Location in patent: Page/Page column 95.
[6] Patent: WO2007/78839, 2007, A2, . Location in patent: Page/Page column 53.

[ 873697-78-0 ] Synthesis Path-Downstream 1~35

1
[ 873697-78-0 ]
[ 873697-79-1 ]

Yield	Reaction Conditions	Operation in experiment
79%		Example 6; Step 3; To a mixture of 0.1 to 0.15 eq of (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole in toluene (1-1.5 M) and toluene (a volume about 10 times that of the oxazaborole in toluene) under N2 at 20 C. was added 1.05 eq of Et2NPh-BH3. To this reaction mixture was added dropwise 1.0 eq 6C in toluene (about 0.4 M) over 1.5 hours. The reaction mixture was then stirred for additional 1 hour at RT. To the reaction mixture was added about 1.9 volumes of MeOH, followed by about 3.4 volumes of 1N HCl. The mixture was stirred for 20 min. To the reaction mixture was added about 7.8 volumes of ether and about 7.8 volumes of brine. The organic layer was separated, dried and concentrated to a residue. The residue was purified by chromatography over silica gel to afford 6D (79%).
79%		EXAMPLE 6; Step 3 To a mixture of 0.1 to 0.15 eq of (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole in toluene (1-1.5 M) and toluene (a volume about 10 times that of the oxazaborole in toluene) under N2 at 20 C. was added 1.05 eq of Et2NPh-BH3. To this reaction mixture was added dropwise 1.0 eq 6C in toluene (about 0.4 M) over 1.5 hours. The reaction mixture was then stirred for additional 1 hour at RT. To the reaction mixture was added about 1.9 volumes of MeOH, followed by about 3.4 volumes of 1N HCl. The mixture was stirred for 20 min. To the reaction mixture was added about 7.8 volumes of ether and about 7.8 volumes of brine. The organic layer was separated, dried and concentrated to a residue. The residue was purified by chromatography over silica gel to afford 6D (79%).
79%	With borane N,N-diethylaniline complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; In toluene; at 20℃; for 2.5h;	To a mixture of 0.1 to 0.15 eq of (S)-l-methyl-3,3-diphenyl- hexahydropyrrolo[l,2-c][l,3,2]oxazaborole in toluene (1 -1.5 M) and toluene (a volume about 10 times that of the oxazaborole in toluene) under N2 at 200C was added 1.05 eq of Et2NPh-BH3. To this reaction mixture was added dropwise 1.0 eq 6C in toluene (about 0.4 M) over 1.5 hours. The reaction mixture was then stirred for additional 1 hour at RT. To the reaction mixture was added about 1.9 volumes of MeOH, followed by about 3.4 volumes of IN HCl. The mixture was stirred for 20 min. To the reaction mixture was added about 7.8 volumes ofether and about 7.8 volumes of brine. The organic layer was separated, dried and concentrated to a residue. The residue was purified by chromatography over silica gel to afford 6D (79%).

79%		To a mixture of 0.1 to 0.15 eq of (S)-l-methyl-3,3-diphenyl- hexahydropyrrolo[l,2-c][l,3,2]oxazaborole in toluene (1 -1.5 M) and toluene (a volume about 10 times that of the oxazaborole in toluene) under N2 at 200C was added 1.05 eq of Et2NPh- BH3. To this reaction mixture was added dropwise 1.0 eq 6C in toluene (about 0.4 M) over 1.5 hours. The reaction mixture was then stirred for additional 1 hour at RT. To the reaction mixture was added about 1.9 volumes of MeOH, followed by about 3.4 volumes of IN HCl. The mixture was stirred for 20 min. To the reaction mixture was added about 7.8 volumes ofether and about 7.8 volumes of brine. The organic layer was separated, dried and concentrated to a residue. The residue was purified by chromatography over silica gel to afford 6D (79%).
79%		Example 6 Step 3. To a mixture of 0.1 to 0.15 eq of (S)-I -methyl-3,3-diphenyl- hexahydropyrrolo[l,2-c][l,3,2]oxazaborole in toluene (1 -1.5 M) and toluene (a volume about 10 times that of the oxazaborole in toluene) under N2 at 200C was added 1.05 eq of Et2NPh-BH3. To this reaction mixture was added dropwise 1.0 eq 6C in toluene (about 0.4 M) over 1.5 hours. The reaction mixture was then stirred for additional 1 hour at RT. To the reaction mixture was added about 1.9 volumes of MeOH, followed by about 3.4 volumes of IN HCl. The mixture was stirred for 20 min. To the reaction mixture was added about 7.8 volumes of ether and about 7.8 volumes of brine. The organic layer was separated, dried and concentrated to a residue. The residue was purified by chromatography over silica gel to afford 6D (79%).

References: [1]Patent: US2006/14761,2006,A1 .Location in patent: Page/Page column 36.
[2]Patent: US2009/192168,2009,A1 .Location in patent: Page/Page column 23.
[3]Patent: WO2007/70626,2007,A2 .Location in patent: Page/Page column 53.
[4]Patent: WO2007/70683,2007,A2 .Location in patent: Page/Page column 95-96.
[5]Patent: WO2007/78839,2007,A2 .Location in patent: Page/Page column 54.

2
[ 943769-01-5 ]
[ 873697-78-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 6; Steps 1 and 2; PdCl2(PPh3)2 (0.05 eq) was added to a mixture of 1.0 eq of 6A, 1.0 eq of tributyl(1-ethoxyvinyl)-tin in dioxane (about 0.4 M) under N2. The mixture was heated at 95 C. for 4 hours under N2. A mixture of 1:1 v/v EtOAc/(1 M KF) solution was added to the reaction mixture and the mixture was stirred for 1 hour. The precipitate was filtered off. The organic layer was dried and concentrated to give 6B that was used without further purification. To a mixture of 6B in THF (0.8 M relative to 6A) was added about 2.3 volumes of 2N HCl and the mixture was stirred at RT for 1 h. Saturated NaHCO3 was added to the reaction mixture. The reaction mixture was concentrated to remove THF and to the resultant mixture was added a volume of ether about 3 times that of the volume of the reaction mixture. The organic layer was dried and concentrated to a residue. The residue was purified over silica gel to obtain 6C (87% in 2 steps).
		PdCl2(PPh3)2 (0.05 eq) was added to a mixture of 1.0 eq of 6A, 1.0 eq of tributyl(l-ethoxyvinyl)-tin in dioxane (about 0.4 M) under N2. The mixture was heated at 950C for 4 hours under N2. A mixture of 1:1 v/v EtOAc/ (IM KF) solution was added to the reaction mixture and the mixture was stirred for 1 hour. The precipitate was filtered off. The organic layer was dried and concentrated to give SR that was used without further purification.[0196] To a mixture of 6B in THF (0.8 M relative to 6A) was added about 2.3 volumes of 2N HCl and the mixture was stirred at RT for 1 h. Saturated NaHCO3 was added to the reaction mixture. The reaction mixture was concentrated to remove THF and to the resultant mixture was added a volume of ether about 3 times that of the volume of the reaction mixture. The organic layer was dried and concentrated to a residue. The residue was purified over silica gel to obtain 6C (87% in 2 steps).
	With hydrogenchloride; water; In tetrahydrofuran; at 20℃; for 1h;	To a mixture of 6B in THF (0.8 M relative to 6A) was added about 2.3 volumes of 2N HCl and the mixture was stirred at RT for 1 h. Saturated NaHCO3 was added to the reaction mixture. The reaction mixture was concentrated to remove THF and to the resultant mixture was added a volume of ether about 3 times that of the volume of the reaction mixture. The organic layer was dried and concentrated to a residue. The residue was purified over silica gel to obtain 6C (87% in 2 steps).

		To a mixture of 6B in THF (0.8 M relative to 6A) was added about 2.3 volumes of2N HCl and the mixture was stirred at RT for 1 h. Saturated NaHCO3 was added to the reaction <n="54"/>09367-0149mixture. The reaction mixture was concentrated to remove THF and to the resultant mixture was added a volume of ether about 3 times that of the volume of the reaction mixture. The organic layer was dried and concentrated to a residue. The residue was purified over silica gel to obtain 6C (87% in 2 steps).
		To a mixture of 6B in THF (0.8 M relative to 6A) was added about 2.3 volumes of 2N HCl and the mixture was stirred at RT for 1 h. Saturated NaHCO3 was added to the reaction mixture. The reaction mixture was concentrated to remove THF and to the resultant mixture was added a volume of ether about 3 times that of the volume of the reaction mixture. The organic layer was dried and concentrated to a residue. The residue was purified over silica gel to obtain 6C (87% in 2 steps).
		Example 6 Step 2. To a mixture of 6B in THF (0.8 M relative to 6A) was added about 2.3 volumes of2N HCl and the mixture was stirred at RT for 1 h. Saturated NaHCO3 was added to the reaction mixture. The reaction mixture was concentrated to remove THF and to the resultant mixture was added a volume of ether about 3 times that of the volume of the reaction mixture. The organic layer was dried and concentrated to a residue. The residue was purified over silica gel to obtain 6C (87% in 2 steps).

References: [1]Patent: US2006/14761,2006,A1 .Location in patent: Page/Page column 36.
[2]Patent: WO2007/75377,2007,A2 .Location in patent: Page/Page column 65.
[3]Patent: US2009/192168,2009,A1 .Location in patent: Page/Page column 23.
[4]Patent: WO2007/70626,2007,A2 .Location in patent: Page/Page column 52-53.
[5]Patent: WO2007/70683,2007,A2 .Location in patent: Page/Page column 95.
[6]Patent: WO2007/78839,2007,A2 .Location in patent: Page/Page column 53.

Yield	Reaction Conditions	Operation in experiment
		Examples of specific compounds which we have found particularly useful in our invention include: ... 4'-bromo-3'-nitroacetophenone 4'-fluoro-3',5'-dinitroacetophenone 4'-chloro-3',5'-dinitroacetophenone 4'-bromo-3',5'-dinitroacetophenone 2'-fluoro-3'-nitroacetophenone 2'-chloro-3'-nitroacetophenone 2'-bromo-3'-nitroacetophenone 2'-fluoro-3',5'-dinitroacetophenone ...

4
[ 873697-78-0 ]
C₈H₈FNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With borane Nu,Nu-diethylaniline complex; (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; In toluene; at 20℃; for 2.5h;	To a mixture of 0.1 to 0.15 eq of (S)-l-methyl-3,3-diphenyl- hexahydropyrrolo[l,2-c][l,3,2]oxazaborole in toluene (1 -1.5 M) and toluene (a volume about 10 times that of the oxazaborole in toluene) under N2 at 200C was added 1.05 eq of Et2NPh-BH3. To this reaction mixture was added dropwise 1.0 eq 6C in toluene (about 0.4 M) over 1.5 hours. The reaction mixture was then stirred for additional 1 hour at RT. To the reaction mixture was added about 1.9 volumes of MeOH, followed by about 3.4 volumes of 1 N HCl. The mixture was stirred for 20 min. To the reaction mixture was added about 7.8 volumes ofether and about 7.8 volumes of brine. The organic layer was separated, dried and concentrated to a residue. The residue was purified by chromatography over silica gel to afford 6D (79%).

References: [1]Patent: WO2007/75377,2007,A2 .Location in patent: Page/Page column 66.

5
[ 58534-94-4 ]
[ 97674-02-7 ]
[ 873697-78-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 90℃; for 4h;	The dichlorobis (triphenylphosphine) palladium (II) (1.6g, 2.28mmol, 0.05equiv) was added to the two dioxanyl (100 mL) of 1-bromo-2-fluoro-3-nitrobenzene (10.0g, 45.6mmol, 1equiv) and tri-n-butyl (1-ethoxy-vinyl) stannane (15.4 mL, 45.6mmol, 1equiv) solution.The resulting cloudy solution was heated 4 hours at 90 , during which the formation of a dark brown solution.In TLC (30% MTBE / heptane) to confirm complete conversion, the reaction was cooled to room temperature.Was added KF (100mL) and ethyl acetate (100 mL), saturated solution, and the biphasic mixture stirred for 1 hour and filtered through celite, washed with ethyl acetate.The organic layer was separated over Na2SO4Sulfate, filtered, and evaporated to give a brown oil of the crude enol ether form.The crude product was dissolved in THF (50mL) and added 2NHCl (50mL).The reaction was stirred at room temperature for 1.5 hours.The reaction was then saturated with NaCl, and extracted with MTBE (2x150mL).Washed with brine (1x300mL) and the organic layer was washed over Na2SO4Sulfate, filtered, and evaporated to give the crude material was eluted through silica gel column chromatography crude material was purified with 0-40% ethyl acetate / heptane gradient solutions.Compound under reduced pressure, the product-containing fractions evaporated to give a yellow oil of 1- (2-fluoro-3-nitrophenyl) ethanone (7.1g, 86% yield)
82%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 10 - 95℃; for 4h;Inert atmosphere; Large scale;	Pd(dppf)C12 (0.13 kg, 0.19 mol) was added to a solution of 1-bromo-2-fluoro-3-nitrobenzene (0.827 kg, 3.6 mol) and tributyl(1-ethoxyvinyl)tin (1.36 kg, 3.6 mol) in 1,4-dioxane (8.27 kg) at 10-30C under N2. The solution was heated to 85-95C and thetemperature was maintained at 85-95C for 4 h under N2. The mixture was cooled to 10- 30C, then ethyl acetate (8.27 L) and saturated aqueous KF solution (4 L) were added.The mixture was stirred for 1 h, then the solution was filtered through a pad of celite and washed with ethyl acetate (2 L). The organic layer was separated and dried over Na2SO4,then concentrated. The resulting crude material was combined with two similar batches, then treated with THF (12.5 L) and 2N HC1 (12.5 L). The mixture was stirred at 10-25C for 3 h, then extracted with ethyl acetate (3 x 20 L). The organic phase was separated and washed with saturated aqueous NaHCO3 solution (10 L) and brine (10 L), then the solvent was concentrated. The crude residue was purified by chromatography (silica, 100-200mesh, 4% EtOAc in petroleum ether) to give the title compound (1.70 kg, 82%). oH (400MHz, CDC13) 8.21-8.13 (m, 2H), 7.42-7.38 (m, 1H), 2.71-2.69 (d, J5.2 Hz, 3H).

References: [1]Patent: CN105228983,2016,A .Location in patent: Paragraph 0697; 0698; 0699.
[2]Patent: WO2017/89453,2017,A1 .Location in patent: Page/Page column 44; 45.

6
[ 873697-78-0 ]
N-[3-[2-tert-butyl-5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl]-2-fluorophenyl]pyrrolidine-1-sulfonamide [ No CAS ]

References: [1]Patent: CN105228983,2016,A .
[2]Patent: CN105228983,2016,A .

7
[ 873697-78-0 ]
N-[3-[2-tert-butyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)thiazol-4-yl]-2-fluorophenyl]pyrrolidine-1-sulfonamide [ No CAS ]

References: [1]Patent: CN105228983,2016,A .
[2]Patent: CN105228983,2016,A .

8
[ 873697-78-0 ]
N-[3-(5-bromo-2-tert-butylthiazol-4-yl)-2-fluorophenyl]pyrrolidine-1-sulfonamide [ No CAS ]

References: [1]Patent: CN105228983,2016,A .

9
[ 873697-78-0 ]
[ 1336804-14-8 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(ll) bromide; In chloroform; ethyl acetate; for 24h;Reflux;	By mechanical stirring (33.9g, 152mmol, 1.9equiv) was suspended / dissolved bromide, copper (II) in ethyl acetate (75mL) in.Was then added in CHCl3Form (75mL) solution of 1- (2-fluoro-3-nitrophenyl) ethanone (14.4g, 80.0mmol, 1equiv), and the reaction was heated to reflux for 24 hours.The reaction was cooled to room temperature and filtered through a silica gel short blocks, washed with ethyl acetate.The filtrate was evaporated, leaving crude 2-bromo-1- (2-fluoro-3-nitrophenyl) ethanone, it is dissolved in dimethyl acetamide (150 mL) and 2,2-dimethyl thioamide propane (10.3g, 88.0mmol, 1 equiv) in.The reaction was stirred at room temperature for 1.5 hours.The reaction was heated to 60 2 hours, cooled to room temperature, and washed with water (300mL) was diluted.(2x200mL) and the mixture extracted with 15% MTBE in heptane.The combined organic layers were washed with brine, in Na2SO4Dried, filtered and evaporated.Using 0-15% ethyl acetate in heptane eluting crude material was purified by silica gel column chromatography.The component containing the product was evaporated to give an off-white solid of 2- (t-butyl) -4- (2-fluoro-3-nitrophenyl) thiazole (15.6g, 70% yield in two steps )

References: [1]Patent: CN105228983,2016,A .Location in patent: Paragraph 0698; 0700.

10
[ 873697-78-0 ]
2-(tert-butyl)-4-(2-fluoro-3-nitrophenyl)thiazole [ No CAS ]

References: [1]Patent: CN105228983,2016,A .

11
[ 873697-78-0 ]
5-bromo-2-(t-butyl)-4-(2-fluoro-3-nitrophenyl)thiazole [ No CAS ]

References: [1]Patent: CN105228983,2016,A .

12
[ 873697-78-0 ]
3-(5-bromo-2-(t-butyl) thiazol-4-yl)-2-fluoroaniline [ No CAS ]

References: [1]Patent: CN105228983,2016,A .

13
[ 873697-78-0 ]
N-(3-(2-(t-butyl)-5-(2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-4yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide [ No CAS ]

References: [1]Patent: CN105228983,2016,A .
[2]Patent: CN105228983,2016,A .

14
[ 873697-78-0 ]
N-(3-(2-(t-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-thiazole-yl)-2-fluorophenyl)pyrrolidine-1-sulfonamide [ No CAS ]

References: [1]Patent: CN105228983,2016,A .

15
[ 873697-78-0 ]
[ 196929-78-9 ]
(R)-(NE)-2-methyl-N-[1-(2-fluoro-3-nitrophenyl)ethylidene]propane-2-sulfinamide [ No CAS ]