19064-24-5|1,3-Difluoro-2-nitrobenzene| Ambeed

Structure of 19064-24-5

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 19064-24-5 ] Purity: 98% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 19064-24-5 ]

CAS No. :	19064-24-5
Formula :	C₆H₃F₂NO₂
M.W :	159.09
SMILES Code :	C1=CC=C(C(=C1F)[N+](=O)[O-])F
MDL No. :	MFCD00192035
InChI Key :	SSNCMIDZGFCTST-UHFFFAOYSA-N
Pubchem ID :	87922

Safety of [ 19064-24-5 ]

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

Computational Chemistry of [ 19064-24-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	35.18
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	45.82 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.13
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	1.95
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.71
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.	1.73
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	0.55
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.62

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.39
Solubility	0.644 mg/ml ; 0.00405 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.	-2.54
Solubility	0.462 mg/ml ; 0.0029 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	-2.33
Solubility	0.753 mg/ml ; 0.00473 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	No
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.	-5.89 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)	1.64

Application In Synthesis of [ 19064-24-5 ]

* 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.

Downstream synthetic route of [ 19064-24-5 ]

[ 19064-24-5 ] Synthesis Path-Downstream 1~35

1
[ 5509-65-9 ]
[ 19064-24-5 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium perborate; In acetic acid; at 80 - 90℃; for 1h;	Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80 C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10% THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52%). MS (ESI) m/z 160 ([M+H]+).
52%	With sodium perborate; In acetic acid; at 80 - 90℃; for 1h;	Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80 C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10% THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52%). MS (ESI) m/z 160 ([M+H]+).
	With sodium perborate; acetic acid; at 80 - 90℃; for 1h;	2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to a stirred suspension of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) at 80 C. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethylether and the combined organic layers were washed with a dilute solution of sodium bicarbonate, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (Hexane:THF, 9:1) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) which was used without further examination.

References: [1]Chemical Communications,2021,vol. 57,p. 7434 - 7437.
[2]Patent: US2005/222148,2005,A1 .Location in patent: Page/Page column 58.
[3]Patent: US2008/153873,2008,A1 .Location in patent: Page/Page column 20.
[4]Journal of Organic Chemistry,1992,vol. 57,p. 5577 - 5585.
[5]European Journal of Organic Chemistry,2006,p. 1109 - 1112.
[6]Patent: US2006/9509,2006,A1 .Location in patent: Page/Page column 8.

2
[ 19064-24-5 ]
[ 385-01-3 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 18.5h;	A solution of potassium TERT-BUTOXIDE (1.23 g, 11 mmol) in 25 mL of anhydrous DMSO was stirred at room temperature for 30 minutes and treated with 1, 3-difluoro-2-nitrobenzene (1.59 g, 10 mmol). After 18 hours, the mixture was diluted with 150 mL of 1 N aqueous sulfuric acid and extracted with three 50 mL portions of diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 50 mL of trifluoroacetic acid. After 30 minutes at room temperature, the mixture was concentrated in vacuo, treated with 50 mL of 1 N aqueous sodium hydroxide, and extracted with three 30 mL portions of diethyl ether. The aqueous layer was acidified with 1 N aqueous sulfuric acid and extracted with two 50 mL portions of dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.3 g of 3-fluoro-2-nitrophenol as orange oil (61% yield). An solution of 3-fluoro-2-nitrophenol (1.13 g, 7.2 mmol) and pyridine (0.65 mL, 8 mmol) in 15 mL of anhydrous dichloromethane was cooled in an ice bath and treated with a solution of triflic anhydride (1.33 mL, 7.9 mmol) in 3 mL of anhydrous dichloromethane. After 4 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with two 30 mL portions of saturated aqueous sodium bicarbonate, two 30 mL portions of 1 N aqueous sulfuric acid, and two 30 mL portions of water, dried over sodium sulfate, filtered, and concentrated in VACUA TAO give 2 g of the title product as a light brown oil (96% yield).
		To a mixture of potassium tert-butoxide (7.76 g) in dimethyl sulfoxide (150 ml) was added <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (10 g), and stirred at room temperature for 18 h. The reaction mixture was diluted with 1N hydrochloric acid, and extracted with 1,1'-oxydiethane. The combined organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in trifluoroacetic acid (100 ml), and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was diluted with 1N sodium hydroxide, washed with 1,1'-oxydiethane. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with 1,1'-oxydiethane. The combined organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give the title compound (7.59 g) as crude. The crude compound was used to next reaction without further purification.

References: [1]Patent: WO2005/30213,2005,A1 .Location in patent: Page/Page column 182-183.
[2]Magnetic Resonance in Chemistry,1996,vol. 34,p. 440 - 446.
[3]Journal of labelled compounds and radiopharmaceuticals,2006,vol. 49,p. 623 - 634.
[4]Patent: WO2011/106986,2011,A1 .
[5]ChemMedChem,2017,vol. 12,p. 1436 - 1448.
[6]Patent: US2010/94000,2010,A1 .Location in patent: Page/Page column 29.

3
[ 19064-24-5 ]
[ 107-19-7 ]
1-Fluoro-2-nitro-3-prop-2-ynyloxy-benzene [ No CAS ]

References: [1]Synlett,1998,p. 794 - 796.

4
[ 19064-24-5 ]
[ 22479-95-4 ]
[ 640296-13-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 4125 - 4128.

5
[ 19064-24-5 ]
[ 100-46-9 ]
3-(benzylamino)-2-nitrophenol [ No CAS ]

References: [1]Journal of Organic Chemistry,2004,vol. 69,p. 1097 - 1103.

6
[ 19064-24-5 ]
[ 27144-85-0 ]
[ 670234-43-2 ]

References: [1]Journal of Organic Chemistry,2004,vol. 69,p. 1097 - 1103.

7
[ 19064-24-5 ]
[ 135999-16-5 ]
[ 861885-66-7 ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 4056 - 4058.

8
[ 19064-24-5 ]
[ 124-41-4 ]
[ 641-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 0 - 20℃; for 15h;	To a 0 C solution of l,3-difluoro-2-nitrobenzene (100 g, 0.63 mol) in MeOH (1.3L) was slowly added a solution of MeONa (0.69 mol, in MeOH, freshly prepared from 15.9 g of sodium metal and 200 mL of MeOH). The resulting reaction was allowed to stir for about 15 hours at room temperature, then the reaction mixture was concentrated and diluted with EtOAc. The organic phase was washed sequentially with water and brine, dried over Na2S04, then filtered and concentrated in vacuo to provide l-fluoro-3-methoxy-2-nitrobenzene (98 g, yield: 91.4%), which was used without further purification. 1H-NMR (CDC13, 400 MHz) δ 7.38-7.44 (m, 1H), 6.72-6.88 (m, 2H), 3.95 (s, 3H).

References: [1]ChemMedChem,2017,vol. 12,p. 1436 - 1448.
[2]Journal of labelled compounds and radiopharmaceuticals,2006,vol. 49,p. 623 - 634.
[3]Patent: WO2011/106986,2011,A1 .Location in patent: Page/Page column 119.

9
[ 39513-24-1 ]
[ 19064-24-5 ]
[ 1001413-44-0 ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	Compound 44.1 (230 mg, 1.53 mmol) and 2,6-difluronitrobenzene (252 mg, 1.58 mmol) were dissolved in 8 ml dry DMF and 1.6 ml of 1 M potassium t-butoxide in THF was added. The reaction was stirred at room temperature overnight, then flooded with 50 ml EtOAC, rinsed with 2 x 25 ml saturated sodium bicarbonate, 25 ml brine, dried over sodium sulfate, filtered, and evaporated partially to dryness. The solid was resuspended in 5 ml dry THF and filtered to yield 58 mg of yellow solid. The remaining solution was purified by column chromatography using a 15.5 x 2.5 cm column and eluting with 95 : 5 DCM : methanol to yield an additional 43 mg of off-white solid. Both of these were combined to yield a total of 92 mg (0.318 mmol, 21%). ES (+) MS m/e = 290 (M+l).

References: [1]Patent: WO2008/5457,2008,A2 .Location in patent: Page/Page column 85.

10
[ 19064-24-5 ]
[ 53981-23-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; boron tribromide; In methanol; n-heptane; dichloromethane; water;	i 2-Amino-3-fluorophenol To a stirred solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (1100 mg, 6.9 mmol) in dry methanol (20 ml) was added a solution of sodium (180 mg, 7.8 mmol) in dry methanol (8 ml). The solution was stirred overnight. After concentration, water was added and the solution was extracted with ether, dried over MgSO4, filtered and concentrated to a yellow residue (870 mg.5.08 mmol). To the solution of the yellow residue in dichloromethane (10 ml) boron tribromide (1M in dichloromethane, 10 ml) was added and stirred at room temperature overnight. Water was then added and the solution stirred for further 60 min. The organic phase was separated and the water phase was extracted with ether. The combined organic phase were dried over MgSO4, filtered and concentrated in vacuo to give a brownish residue. The residue was taken up into ether and washed with 2M sodium hydroxide and water. The water and sodium hydroxide washings were combined and neutralised with 6M HCl and extracted with ether, dried over MgSO4 and evaporated to give a yellow residue which was purified by flash chromatography on silica gel with EtOAc:Heptane: 1:3 as eluant to give the product (720 mg, 4.6 mmol) which was directly suspended with palladium-charcoal (140 mg) in water-ethanol (30 ml).

References: [1]Journal of labelled compounds and radiopharmaceuticals,2006,vol. 49,p. 623 - 634.
[2]Patent: US2003/162772,2003,A1 .
[3]Patent: WO2011/106986,2011,A1 .
[4]ChemMedChem,2017,vol. 12,p. 1436 - 1448.

11
[ 19064-24-5 ]
[ 861885-69-0 ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 4056 - 4058.

12
[ 19064-24-5 ]
[ 861885-70-3 ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 4056 - 4058.

13
[ 19064-24-5 ]
[ 861885-68-9 ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 4056 - 4058.

14
[ 19064-24-5 ]
2,2':6',2'':6'',6-trioxytriphenylamine radical cation hexafluorophosphate [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 4056 - 4058.

15
[ 19064-24-5 ]
[ 781643-18-3 ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 4056 - 4058.

16
[ 110-91-8 ]
[ 19064-24-5 ]
[ 179900-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In DMF (N,N-dimethyl-formamide); for 18h;	To a 0.1 M DMF solution of 1, 3-difluoro-2-nitrobenzene was added Et3N (2 equivalents) followed by an amine (1 equivalent), e. g. morpholine. The mixture was stirred for 18 hours and then diluted with water and extracted with ethyl acetate. LC/MS M/Z 227.2 (MH+), RT2. 522 minutes. The combined organic layers were dried over MGS04, filtered, and concentrated. Ammonia was condensed into a pressure vessel containing the crude product. The pressure vessel was sealed and heated to 100 C (over 400 psi). After 72 hours, the pressure vessel was allowed to cool and the ammonia was evaporated to provide a reddish solid. The nitroamine was reduced as in Method 1 to provide the crude product which was used without FURTHERPURIFICATION. LC/MS M/Z194. 1 (MH+), RT1. 199 minutes.

References: [1]Patent: WO2004/18419,2004,A2 .Location in patent: Page 261-262.

17
[ 19064-24-5 ]
[ 108-59-8 ]
[ 866209-62-3 ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 24h;	To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+).
54%		Step 2: To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+).
54%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h;	To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+).

References: [1]Patent: US2005/222148,2005,A1 .Location in patent: Page/Page column 58-59.
[2]Patent: US2008/153873,2008,A1 .Location in patent: Page/Page column 20.
[3]Patent: US2007/72928,2007,A1 .Location in patent: Page/Page column 20.

18
[ 19064-24-5 ]
(3-fluoro-2-nitrophenyl)hydrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine; In water;	3-Fluoro-1,2-diaminobenzene is obtained as an oily amorphous product by hydrogenation of 3-fluoro-2-nitrophenyl hydrazine (prepared by reaction of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> with hydrazine hydrate) using hydrogen and 10% palladium on carbon catalyst in methanol at room temperature and atmospheric pressure.
	With hydrazine hydrate; In tetrahydrofuran; di-isopropyl ether;	a 3-Fluoro-2-nitro-phenylhydrazine A mixture of 0.01 M <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> and 0.01 M hydrazine hydrate (99% strength) in 30 ml of THF was stirred overnight at RT (exothermic reaction) and the residue was brought to crystallization after distilling off the solvent by treating with diisopropyl ether. Crystalline substance, m.p.: 93-95 C. MS (Cl+, M+H+): 172.1
	With hydrazine hydrate; In tetrahydrofuran; at 20℃;	INTERMEDIATE: (5-Fluoro-3-methyl-quinoxalin-2-yl)-hydrazine (lib). l,3-Difluoro-2- nitrobenzene (5 g) was dissolved in THF (180 mL) and treated with hydrazine hydrate (1.57 g) at ambient temperature overnight. The volatiles were removed in vacuo to afford (3-fluoro-2-nitro- phenyl)-hydrazine (3.0 g). 2.0 g of this material was dissolved in methanol (15 mL). 10% Palladium on charcoal (0.3 g) was added and the mixture was treated with hydrogen (1 bar) for 12h at ambient temperature. The catalyst was filtered off, and the filtrate was concentrated in vacuo to afford 3- fluoro-benzene-l,2-diamine (1.4 g). This material was dissolved in methanol, ethyl pyruvate (1.2 g) was added and the mixture was stirred at ambient temperature for 2h. The precipitated solid was filtered off to afford an approximate 1 :1 mixture of 5-fluoro-3 -methyl- lH-quinoxalin-2-one and 8- fluoro-3-methyl-lH-quinoxalin-2-one (1.6 g in total). 1.2 g of this mixture was refluxed in phosphoryl chloride (20 mL) for 2h. The volatiles were removed in vacuo. The residue was basified with aq NaHCOs and extracted with DCM. The organic layer was dried over Na2SO i, filtered, and concentrated in vacuo to afford an approximate 1 :1 mixture of 2-chloro-5-fluoro-3-methyl- quinoxaline and 3-chloro-5-fluoro-2-methyl-quinoxaline (1.1 g in total). This mixture was reacted with hydrazine hydrate (10 mL) at 110 C for 2h. The precipitated solid was filtered off to afford an approximate 1 :1 mixture of lib and its regioisomer (8-fluoro-3-methyl-quinoxalin-2-yl)-hydrazine (0.4 g in total). This mixture was applied in the next step.

With hydrazine hydrate; In tetrahydrofuran; at 20℃;

INTERMEDIATE (8-fluoro-3-methyl-quinoxalin-2-yl)-hydrazine (lie). l,3-Difluoro-2- nitrobenzene (5 g) was dissolved in THF (180 mL) and treated with hydrazine hydrate (1.57 g) at ambient temperature overnight. The volatiles were removed in vacuo to afford (3-fluoro-2-nitro- phenyl)-hydrazine (3 g). 2 g of this material was dissolved in methanol (15 mL). 10% Palladium on charcoal (0.3 g) was added and the mixture was treated with hydrogen (1 bar) for 12h at ambient temperature. The catalyst was filtered off, and the filtrate was concentrated in vacuo to afford 3-fluoro-benzene-l,2-diamine (1.4 g). This material was dissolved in methanol, ethyl pyruvate (1.2 g) was added and the mixture was stirred at ambient temperature for 2h. The precipitated solid was filtered off to afford an approximate 1:1 mixture of 5-fluoro-3-methyl-lH- quinoxalin-2-one and 8-fluoro-3-methyl-lH-quinoxalin-2-one (1.6 g in total). 1.2g of this mixture was refluxed in phosphoryl chloride (20 rriL) for 2h. The volatiles were removed in vacuo. The residue was basified with aq NaHCC>3 and extracted with DCM. The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford an approximate 1:1 mixture of 2-chloro-5- fluoro-3-methyl-quinoxaline and 3-chloro-5-fluoro-2-methyl-quinoxaline (1.1 g in total). This mixture was reacted with hydrazine hydrate (10 rriL) at 110 C for 2h. The precipitated solid was filtered off to afford an approximate 1:1 mixture of lie and its regioisomer (5-fiuoro-3-methyl- quinoxalin-2-yl)-hydrazine (0.4 g in total). This mixture was applied in the next step.

References: [1]Patent: US2004/6119,2004,A1 .Location in patent: Page/Page column 11.
[2]Patent: US2002/132842,2002,A1 .
[3]Patent: WO2013/34755,2013,A1 .Location in patent: Page/Page column 17.
[4]Patent: WO2013/34758,2013,A1 .Location in patent: Page/Page column 16.

19
[ 19064-24-5 ]
[ 862271-02-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of NaH (60% dispersion in mineral oil, 4.0 g, 100 mmol) in THF (200 mL) was added dropwise 4-methoxybenzyl alcohol (12 mL, 96.2 mmol) with stirring at 0 C. The mixture was stirred at room temperature for 15 min and <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (15.26 g, 100 mmol, Aldrich) was then added. The resulting red solution was heated to 65 C. with stirring and the progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in MeOH, evaporated onto SiO2 and eluted through a SiO2 plug with 25% EtOAc/hexane. Evaporation of the solvent under reduced pressure gave the crude product as a yellow amorphous solid, which was used in the next step without additional purification. MS (ESI, neg. ion.) m/z: 274.1 [M-1].

References: [1]Patent: US2005/176726,2005,A1 .Location in patent: Page/Page column 31.

20
[ 19064-24-5 ]
[ 884-35-5 ]
[ 866082-30-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h;	To a solution of methylsyringate (1.0 g; 4.72 mmol) in DMF (50 mL) were added Cs2CO3 (1.85 g; 5.66 mmol) and 2,6-difluoronitrobezene (0.5 mL; 4.72 mmol). The reaction mixture was heated to 80 C. for 16 h. The mixture was cooled and poured into water, then extracted with EtOAc (3×). The organic layers were combined and washed with water (1×) then brine (1×). The organic phase was dried (MgSO4), filtered and concentrated in vacuo giving 1.64 g (99%) of 1-1 which was used in the next reaction without further purification.
99%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	Preparation of Intermediate 1-5; Step l; [0051] To a solution of methylsyringate (1.Og; 4.72 mmol) in DMF (50 niL) were added Cs2CO3 (1.85 g; 5.66 mmol) and 2,6-difluoronitrobezene (0.5 niL; 4.72 mmol). The reaction mixture was heated to 80 0C for 16 h. The mixture was cooled and poured into water, then extracted with EtOAc (3X). The organic layers were combined and washed with water (IX) then brine (IX). The organic phase was dried (MgSO4), filtered and concentrated in vacuo giving 1.64 g (99%) of 1-1 which was used in the next reaction without further purification.

References: [1]Patent: US2005/222203,2005,A1 .Location in patent: Page/Page column 8-9.
[2]Patent: WO2007/1249,2007,A1 .Location in patent: Page/Page column 25-26.

21
C₁₄H₁₈O₃ [ No CAS ]
[ 19064-24-5 ]
C₂₀H₂₀FNO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h;	To a solution of phenol 7-3 (0.39 g; 1.66 mmol) in DMF (16 mL) were added <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.18 mL; 1.66 mmol) and Cs2CO3 (541 mg; 1.66 mmol). The reaction mixture was heated to 80 C. for 16 h. The mixture was cooled, diluted with EtOAc (100 mL) and washed with water (1×50 mL) and brine (1×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and the crude residue was purified by FCC (silica gel; elution with 5:1 hexanes:EtOAc) giving 210 mg of 7-4 (34%).
34%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	[0082] To a solution of phenol 7-3 (0.39 g; 1.66 mmol) in DMF (16 mL) were added <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.18 mL; 1.66 mmol) and Cs2CO3 (541 mg; 1.66 mmol). The reaction mixture was heated to 80 C for 16 h. The mixture was cooled, diluted with EtOAc (100 mL) and washed with water (1 X 50 mL) and brine (1 X 50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and the crude residue was purified by FCC (silica gel; elution with 5:1 hexanes:EtOAc) giving 210 mg of 7-4 (34%).

References: [1]Patent: US2005/222203,2005,A1 .Location in patent: Page/Page column 13-14.
[2]Patent: WO2007/1249,2007,A1 .Location in patent: Page/Page column 38; 39.

22
[ 866082-60-2 ]
[ 19064-24-5 ]
[ 866082-62-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h;	To a solution of 8-2 (123 mg; 0.522 mmol) in DMF (5 mL) were added <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (55 μL; 0.522 mmol) and Cs2CO3 (170 mg; 0.522 mmol). The reaction mixture was heated to 80 IC for 16 h. The mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3×). The organic phases were combined and washed with water (1×) and brine (1×). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC (silica gel, elution with 3:1 EtOAc:hexanes) giving 91 mg (47% for 2 steps) of 8-3.

References: [1]Patent: US2005/222203,2005,A1 .Location in patent: Page/Page column 15-16.
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 352 - 355.

23
[ 866082-79-3 ]
[ 19064-24-5 ]
[ 866082-80-6 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 18h;	A mixture of 18-2 (0.24 g, 0.9 mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.24 g, 1.5 mmol), and K2CO3 (0.28 g, 2 mmol) was stirred at 80 C. in 10 ml DMF for 18 hours. The mixture was then filtered and concentrated in vacuo to yield 18-3 (0.27 g, 0.67 mmol, 74%) as an oil which was used without further purification
74%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;Product distribution / selectivity;	[00163] A mixture of 18-2 (0.24g, 0.9mtnol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.24g, 1.5mmol), and K2CO3 (0.28g, 2mmol) was stirred at 80C in 10ml DMF for 18 hours. The mixture was then filtered and concentrated in vacuo to yield 18-3 (0.27g, 0.67mmol, 74%) as an oil which was used without further purification.
70%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 5h;	A solution of 11-4 (0.32 g, 1.2 mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.23 g, 1.4 mmol), and Cs2CO3 (0.86 g, 2.6 mmol) in 10 ml DMF was stirred at 60 C. for 5 hours. The mixture was cooled to room temp, filtered and concentrated in vacuo. The residue was chromatagraphed on a silica gel column, eluting with 5% MeOH/DCM to yield 11-5 as an oil (0.34 g, 0.84 mmol, 70%).

70%

With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5h;Product distribution / selectivity;

Step 5; [00111] A solution of 11-4 (0.32g, 1.2mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (0.23g, 1.4mmo), and Cs2CO3 (0.86g, 2.6mrnol) in 10ml DMF was stirred at 6O0C for 5 hours. The mixture was cooled to room temp, filtered and concentrated in vacuo. EPO <DP n="56"/>The residue was chromatagraphed on a silica gel column, eluting with 5% MeOH/DCM to yield 11-5 as an oil (0.34g, 0.84mmol, 70%).

References: [1]Patent: US2005/222203,2005,A1 .Location in patent: Page/Page column 34-35.
[2]Patent: WO2007/1249,2007,A1 .Location in patent: Page/Page column 79; 80.
[3]Patent: US2005/222203,2005,A1 .Location in patent: Page/Page column 19; 21.
[4]Patent: WO2007/1249,2007,A1 .Location in patent: Page/Page column 52; 53-54.
[5]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 352 - 355.

24
C₂₀H₁₉NO₆ [ No CAS ]
[ 19064-24-5 ]
[ 866083-12-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h;	17-2 (187 mg; 0.407 mmol) was debenzylated by hydrogenation in MeOH in the presence of a catalytic amount of 10% Pd/C (1 small scoop) under 1 atm of H2 (g) (balloon) for 3 d. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude phenol was taken up in DMF (4 mL) and 2,6 difluoronitrobenzene (43 μL; 0.407 mmol) and Cs2CO3 (133 mg; 0.407 mmol) were added. The mixture was heated to 80 C. for 16 h. After cooling to room temperature the mixture was filtered through a pad of Celite, concentrated in vacuo and the crude residue was purified by FCC (silica gel; elution with 3:1 hexanes:EtOAc) to afford 139 mg (67% for 2 steps) of 17-3.

References: [1]Patent: US2005/222203,2005,A1 .Location in patent: Page/Page column 31; 33.
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 352 - 355.

25
[ 19064-24-5 ]
[ 874279-84-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium azide; In dimethyl sulfoxide; at 20℃; for 18h;	Preparation of 1-Azido-3-fluoro-2-nitrobenzene To a stirred solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2.0 g, 12.6 mmol) in DMSO (6.0 mL) at room temperature, was added sodium azide (0.82 g; 12.6 mmol). After 18 hours the solution was poured into 200 mL of ice-cold water. The precipitate, 1-azido-3-fluoro-2-nitrobenzene, was collected and dried under vacuum (2.26 g; 99%); 1H NMR (CDCl3, 400 MHz) δ 7.00 (t, J=8.8 Hz, 1H); 7.07 (d, J=8.35 Hz, 1H); 7.47 (dt, J=8.35, 5.68 Hz, 1H). MS (ES) m/z 182.1
98%	With sodium azide; In dimethyl sulfoxide;	To a solution of 1 ,3-difluoro-2-nitrobenzene (4.80 g, 30.2 mmol) in DMSO (35 mL) was added sodium azide (2.26 g, 34.7 mmol). After stirring overnight, the reaction was diluted with EtOAc (150 mL), washed with water (2 X 150 mL), dried over Na2S04, filtered and concentrated to give the title compound (5.40 g, 98%) as a pale yellow solid. 1H NMR (CDCI3) δ 6.99-7.1 1 (m, 2 H), 7.46-7.52 (m, 1 H).
96%	With sodium azide; In dimethyl sulfoxide; for 2h;	A solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (10 g, 63 mMol) in DMSO (70 mL) was treated with sodium azide (4.5 g, 69 mMol) and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (500 mL), washed (water, 3500 mL; brine, 100 mL), dried (MgSO4) and evaporated under reduced pressure to leave the product as a tan oil that crystallized on standing (11 g, 96%). A solution of 1-(2-hydroxyethyl)piperazine (5.7 g, 43 mMol) in THF (40 mL) under nitrogen was cooled in an ice bath and treated with sodium hydride (60% mineral oil dispersion, 1.7 g, 43 mMol) portion wise over 15 mins. The mixture stirred an additional hour and was then cooled to -78 C. A solution of 2-azido-6-fluoronitrobenzene (6.0 g, 33 mMol) in THF (40 mL) was added to the reaction mixture drop wise over 15 mins. The mixture stirred an additional 2 h while warming to 20 C. then diluted with 1N HCl (50 mL) and water (500 mL). The mixture was washed with ethyl acetate (2500 mL) and the combined organic layers were further extracted with 1 N HCl (2100 mL) and water (200 mL). All aqueous layers were combined, neutralized (solid sodium carbonate) and extracted with chloroform (3200 mL). The extract was dried (MgSO4) and evaporated to leave the product as an oil (7.1 g, 24 mMol, 74%). It was dissolved in DCM (100 mL), treated with di-(t-butyl)dicarbonate and stirred for 30 mins. Aminomethylpolystyrene (1% DVB, 3.2 mMol/g, 7.5 g, 24 mMol) was added and stirring continued for 1 h. The resin was filtered, washed (DCM, 2*25 mL) and the combined organic washes were evaporated under reduced pressure to leave the product as a brown gum (9.4 g, 100%). LC/MS (method A); Rt=1.11 mins, purity=85%, [M+H]+=393.

References: [1]Patent: US2010/120779,2010,A1 .Location in patent: Page/Page column 17.
[2]Patent: WO2018/69863,2018,A1 .Location in patent: Page/Page column 244.
[3]Patent: US2006/111355,2006,A1 .Location in patent: Page/Page column 21.
[4]MedChemComm,2017,vol. 8,p. 1965 - 1969.
[5]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 6617 - 6640.
[6]European Journal of Organic Chemistry,2014,vol. 2014,p. 6451 - 6466.

26
[ 19064-24-5 ]
[ 57260-71-6 ]
[ 915135-20-5 ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 0.5h;	To a solution of piperazine-1-carboxylic acid tert-butyl ester (0.204 g, 1.1 mmol) in 1 mL dimethylsulfoxide was added potassium carbonate (0.303 g, 2.2 mmol) followed by 1,3-difluoro-2-nitro-benzene (0.159 g, 1 mmol). The solution was stirred 30 minutes at room temperature, and was then diluted with 50 mL ethyl ether. The organic phase was washed three times with 50 mL water and once with 50 mL brine, dried over sodium sulfated, and concentrated in vacuo to give 0.314 g (0.965 mmol, 96.5%) of 4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. MS: 226 (M-BOC+H)+.
83%	With potassium carbonate; In dimethyl sulfoxide; at 40℃; for 2.5h;	To a 1L flask equipped with mechanical stirrer, <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (16.5 g, 104 mmol) was added and flask was filled with DMSO (170 mL). Then, dried K2CO3 (31.6 g, 229 mmol) and N-BOC-piperazine (21.2 g, 114 mmol) were added. The reaction mixture was heated to 40 C and stirred for 2.5h at this temperature. The reaction was poured into water (400 mL) and diluted with DCM (500 mL). Phases were separated and the organic phase was washed with water (2 x 150 mL), brine (100 mL), dried under MgSO4 and the solvent was removed in vacuo. The solid residue was dissolved in MeOH (120 mL) then water (15 mL) was added dropwise and the whole mixture was cooled to 5 C, and stored at this temperature for 2h. After this time, solid product A-2A (21.9 g) was filtered and washed with the mixture of MeOH:water (10:1, 20 mL). The filtrate was reduced to the half of its volume and stored at 5 C for 16h. Additional portion of compound A-2A (6.3 g) was filtered and combined with previously obtained solid. As a result, product A-2A was obtained as the yellow solid (28.2 g, 83% yield) with 95 % of purity, according to UPLCMS analysis (Method A).
68%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 18h;	Example 10 4-(3-Fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester: To a solution of 1,3-difluoro-2-nitro-benzene (10 g, 62.9 mmol), ethyldiisopropylamine (27 mL, 157 mmol), in anhydrous DMSO (40 mL) was added piperazine-1-carboxylic acid tert-butyl ester (13.3 g, 69.1 mmol) and the solution stirred at room temperature, under nitrogen, for 18 h. The reaction was transferred to a separatory funnel with ethyl acetate (100 mL) and washed with distilled water (100 mL3). The aqueous washings were combined and extracted with ethyl acetate (100 mL2). The organic extracts were combined, washed with 1M aqueous citric acid solution (150 mL*2), saturated aqueous sodium bicarbonate solution (150 mL), brine (150 mL), decolorizing carbon and filtered. The filtrate was dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give a black liquid which solidified upon standing to give a dark yellow tinted crystalline solid (18.5 g). This material was adsorbed onto silica and purified by column chromatography, eluding with a solution of 33% ethyl acetate in hexane to afford an orange crystalline solid (13.9 g, 68%). Mass Spectrum (+ESI): 226 [M+H-Boc]+

References: [1]Patent: US2007/15744,2007,A1 .Location in patent: Page/Page column 42.
[2]Patent: EP3530651,2019,A1 .Location in patent: Paragraph 0073-0074.
[3]Patent: US2006/264631,2006,A1 .Location in patent: Page/Page column 26; 37-38.
[4]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2512 - 2515.

27
[ 67-56-1 ]
[ 19064-24-5 ]
[ 641-49-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium hydroxide; for 3h;Heating / reflux;	To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5 g, 32 mmol) in methanol (50 mL) was added potassium hydroxide (1.8 g, 32.5 mmol), and the mixture was heated to reflux for 3 hr. Water was added, and the mixture was extracted with dichloromethane. The organic layer was separated, dried, filtered, and evaporated to yield 5.1 g (95%) of 1-fluoro-3-methoxy-2-nitrobenzene, 1e. MS m/z (MH+) 172.
		EXAMPLE 18; (2R,3R,4S,5R,6E)-3,4,5-trihydroxy-2-methoxy-N-[(3R)-6-methoxy-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-8,8-dimethylnon-6-enamide; Step 1: Preparation of 1-fluoro-3-methoxy-2-nitrobenzene (52); 252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 100 mL three-necked flask containing 10 mL of THF and 0.255 mL of MeOH. The mixture is stirred at room temperature for 1 hour, and a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> 47 (1.0 g, 6.29 mmol) in 10 mL of THF is added. The reaction medium is left at room temperature for 16 hours. 10 mL of EtOAc are added and the resulting mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. 0.93 g of product 52 is obtained (cream-coloured solid).1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.95 (s, 3H); 7.15 (broad t, J=8.0 Hz, 1H); 7.21 (broad d, J=8.0 Hz, 1H); 7.65 (dt, J=6.0 and 8.0 Hz, 1H).

References: [1]Patent: US2006/135763,2006,A1 .Location in patent: Page/Page column 32-33.
[2]Patent: US2009/93459,2009,A1 .Location in patent: Page/Page column 29.

28
[ 19064-24-5 ]
[ 920284-79-3 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a suspension of sodium hydride (1.522 g, 38.06 mmol) in anhydrous DMF (150 mL) at room temperature was added benzyl alcohol (3.44 mL, 33.3 mmol) dropwise over 10 minutes, and stirring was continued for another 10 minutes. 2,6-Difluoronitrobenzene (5.046 g, 31.72 mmol) was added to the reaction mixture in one portion. The reaction mixture was stirred for an hour, and 100 mL water and 100 mL ethyl acetate were added. The layers were separated, and the aqueous layer was extracted with 75 mL ethyl acetate. The combined organic layers werre washed with 100 mL water and 100 mL brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (6% to 35% ethyl acetate in hexanes) to give 6.818 g (27.6 mmol, 87%) of 1-benzyloxy-3-fluoro-2-nitro-benzene as a yellow oil. MS: 248 (M+H)+. Also prepared in a similar manner using (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester in place of benzyl alcohol was [2-(3-Fluoro-2-nitro-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: 215 (M-BOC+H)+.

References: [1]Patent: US2007/15744,2007,A1 .Location in patent: Page/Page column 45.

29
[ 19064-24-5 ]
[ 34137-14-9 ]
[ 866082-35-1 ]

Yield	Reaction Conditions	Operation in experiment
96 - 100%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Product distribution / selectivity;	Preparation of Intermediate 2-5; Step 1; [0056] Following the general procedure described for step 1 in example 1, 4- hydroxy-3,5-dimethyl-benzoic acid methyl ester (1.0 g, 5.55 mmol) was reacted with 2,6-difluronitrobenzene giving 1.70 g (96%) of crude 2-1 which was used in the next step without purification.; Example 14; Step 1; [00137] Following the procedure described for step 3 in example 8, 4-hydroxy- 3,5-dimethylbenzoic acid methyl ester (708 mg; 3.93 mmol) was reacted with 2,6- EPO <DP n="67"/>difluoronitrobenzene giving, after purification by FCC (silica gel; elution with 1 : 1 hexanes:EtOac), 1.3 g (100%) of 14-1.

References: [1]Patent: WO2007/1249,2007,A1 .Location in patent: Page/Page column 25; 27; 64-65.

30
C₁₅H₁₉NO₄ [ No CAS ]
[ 19064-24-5 ]
C₂₁H₂₁FN₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	Step 3; [0089] To a solution of 8-2 (123 mg; 0.522 mmol) in DMF (5 mL) were added 2,6-difluoroitrobenzene (55 μL; 0.522 mmol) and Cs2CO3 (170 mg; 0.522 mmol). The reaction mixture was heated to 80 0C for 16 h. The mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3X). The organic phases were combined and washed with water (IX) and brine (IX). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC (silica gel, elution with 3 : 1 EtOAc-hexanes) giving 91 mg (47% for 2 steps) of 8-3.

References: [1]Patent: WO2007/1249,2007,A1 .Location in patent: Page/Page column 42; 43.

31
[ 19064-24-5 ]
[ 108-59-8 ]
[ 872141-24-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h;	To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry dimethylformamide (DMF -50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with dilute aqueous HCl and extracted with diethyl ether, dried (MgSO4), and concentrated in vacuo. Crystallization from hexane/ethylacetate (95/5), gave 2-(3-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (4.6 g, 54%).
54%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h;	Step 1 To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) of dimethyl (3-fluoro-2-nitrophenyl)malonate. MS (ESI) m/z 272 [M+H]+). Step 1:; To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5.0 g, 31.44 mmol) in dry N,N-dimethylformamide (50 mL) was added potassium carbonate (4.41 g, 32 mmol) and dimethylmalonate (3.6 mL, 31.44 mmol). The reaction mixture was heated to 65 C. and stirred for 24 hours. After cooling to room temperature, the mixture was neutralized with a dilute aqueous solution of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crystallization from 5% ethyl acetate/hexane gave 4.6 g (54%) of 2-(6-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester. MS (ESI) m/z 272 [M+H]+).
52%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 24h;	dimethyl 2-(3-fluoro-2-nitrophenyl)malonate; 1,3-Difluoro-2-nitrobenzene (2.83 g, 17.79 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (2.49 g, 18.02 mmol) was added to the mixture followed by dimethyl malonate (2.033 ml, 17.79 mmol). Mixture was warmed to 65 C. and held for 24 hours. Mixture was cooled to room temperature. Reaction was quenched with 1N hydrochloric acid. Material was extracted three times with diethyl ether and the aqueous phase was discarded. Material was washed twice with water and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Residue was crystallized with hexanes. Solids were filtered off and washed with hexanes. Title compound was obtained as yellow crystals in 52% yield. MS (M-H)-=270.1.

21%

With potassium carbonate; In N,N-dimethyl-formamide; at 65℃;

Step 1: dimethyl 2-(3-fluoro-2-nitro-phenyl)-malonate 5.40 g (38.3 mmol) potassium carbonate and 4.50 mL (38.0 mmol) dimethylmalonate were added successively to 6.00 g (37.7 mmol) <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> in 60 mL DMF and the mixture was stirred overnight at 65 C. Then the reaction mixture was cooled to RT and slowly poured onto 75 mL of 1N aqueous hydrochloric acid solution. The aqueous phase was extracted several times with EtOAc. The combined organic phases were washed with water and saturated sodium chloride solution, dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was stirred with n-hexane, suction filtered and dried. Yield: 2.18 g (21% of theoretical) ESI-MS: m/z=272 (M+H)+

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1861 - 1873.
[2]Patent: US2006/9509,2006,A1 .Location in patent: Page/Page column 9.
[3]Patent: US2007/72897,2007,A1 .Location in patent: Page/Page column 64; 68.
[4]Patent: US2007/259851,2007,A1 .Location in patent: Page/Page column 114.
[5]Patent: US2011/59954,2011,A1 .Location in patent: Page/Page column 94.

32
[ 19064-24-5 ]
[ 62-53-3 ]
[ 930791-49-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Step 1 To a solution of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2.0 g, 6.28 mmol) and aniline (d 1.022, 1.15 mL, 12.6 mmol) in dry N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (1.40 g, 12.5 mmol) in portions. After 16 hours at room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane (250 mL). The combined organic layers were washed with water (150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford crude 3-fluoro-2-nitro-N-phenylaniline (1.15 g, 78%), which was used in the next step without further purification.
73%		Step 1: (3-Fluoro-2-nitrophenyl)phenylamine Sodium tertbutoxide (1.2 g, 12.58 mmol) was added portionwise to a stirred solution of <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (1 g, 6.29 mmol) and phenylamine (1.15 mL, 12.58 mmol) in a hydrous DMF (5 mL) under a nitrogen atmosphere at RT and stirring was continued for 20 h. The mixture was poured into an aqueous solution of NH4Cl and extracted with EtOAc (150 mL). The organic layer was washed with brine, then dried and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-15% EtOAc in cyclohexane) affording (3-Fluoro-2-nitrophenyl)phenylamine as a red solid (1.06 g, 73%). LCMS: RT 3.80 min.
	With potassium fluoride; In dimethyl sulfoxide; at 95℃; for 15h;	(1) Add aniline (3.3mL, 36.2mmol), <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (3mL, 30mmol) and anhydrous potassium fluoride (1.8g, 30mmol) to 9mL of dimethyl sulfoxide and stir After the dissolution is complete, react at 95C for 15 hours; after the reaction is complete, cool the system to room temperature, then add 30mL of distilled water to the reaction system, stir until a large amount of red precipitate appears, filter the precipitate and wash with 30ml (10ml×3 times) distilled water 3 times The filtered solid is dried in a drying box to obtain intermediate product A;

References: [1]Patent: US2007/72897,2007,A1 .Location in patent: Page/Page column 86.
[2]Patent: US2012/202785,2012,A1 .Location in patent: Page/Page column 122.
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 5703 - 5711.
[4]Patent: CN112010904,2020,A .Location in patent: Paragraph 0047; 0050-0051; 0055-0056; 0060-0061.

33
[ 372-19-0 ]
[ 19064-24-5 ]
[ 500302-19-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In dimethyl sulfoxide; at 20℃;	Example 121 4-fluoro-1-(3-fluorophenyl)-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (5 g, 31.4 mmol), potassium tert-butoxide (3.5 g, 31.3 mmol), and 3-fluoroaniline (3.47 g, 31.3 mmol) in anhydrous dimethylsulfoxide (20 mL) was stirred at room temperature. Upon completion, the reaction was partitioned between saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified on silica gel to give (3-fluoro-2-nitro-phenyl)-(3-fluoro-phenyl)-amine that was directly in the next step.

References: [1]Patent: US2007/72897,2007,A1 .Location in patent: Page/Page column 87.

34
[ 107-59-5 ]
[ 19064-24-5 ]
[ 288580-60-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - 10℃; for 3h;	A mixture of potassium ferf-butoxide (12.3 g, 111.0 mmol) in NMP (100 ml) was cooled to -20 0C under N2. A mixture of 2, 6-difluoronitrobenzene (5.0 g, 31.43 mmol) and te/t-butylchloroacetate (7.6 ml, 53.11 mmol) in NMP (100 ml) was added slowly at -10 0C to -20 0C over 1.5 hrs. After 1.5 hrs the reaction was quenched by pouring into 2M HCI (120 ml) and ice, then heptane (300 ml) was added. The mixture was stirred for 10 minutes, separated and the aqueous extracted with heptane (2 x 400 ml). The organic layer was washed with brine twice, dried (MgSO4), filtered and washed with heptane. The solution was concentrated in vacuo and the residue purified by column chromatography (3-4% EtOAc/Heptane) to provide the title compound as an orange oil (4.34 g, 53 % yield). <n="22"/>1H NMR (300 MHz, CDCI3) δ: 7.06 (2H, d, J=8.7Hz), 3.59 (2H, s), 1.48 (9H, s).
53%	With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - 20℃; for 1.5h;Inert atmosphere;	A mixture of potassium fe/t-butoxide (12.3 g, 111.0 mmol) in NMP (100 ml) was cooled to -20 0C under N2. A mixture of 2, 6-difluoronitrobenzene (5.0 g, 31.43 mmol) and tert- butylchloroacetate (7.6 ml, 53.11 mmol) in NMP (100 ml) was added slowly at -10 0C to - 20 0C over 1.5 hours. After 1.5 hours the reaction was quenched by pouring into 2M HCI (120 ml) and ice, then heptane (300 ml) was added. The mixture was stirred for 10 minutes, separated and the aqueous extracted with heptane (2 x 400 ml). The organic layer was washed with brine (x2), dried (MgSO4), filtered and washed with heptane. The solution was concentrated in vacuo and the residue purified by column chromatography (3-4% EtOAc/Heptane) to provide the title compound as an orange oil (4.34 g, 53 % yield). 1H NMR (300 MHz, CDCI3) δ: 7.06 (2H, d, J=8.7Hz), 3.59 (2H, s), 1.48 (9H, s).
		A mixture of potassium terf-butoxide (248g) in NMP (2000ml) was cooled under nitrogen to -200C. A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (100g) and tert- butylchloroacetate (16Og) in NMP (2000ml) was added slowly at -100C to -20C EPO <DP n="62"/>over 1.5 hours. After 30 minutes, a further portion of potassium ferf-butoxide (88g) was added. The reaction mass was quenched into 1600ml of 2M HCI and 1kg crushed ice, then 2000ml hexane was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2 x 1500ml). The combined hexane layers were washed with saturated brine (2 x 1000ml), then dried over anhydrous sodium sulphate, then filtered and washed with 200ml hexane. The solution was then evaporated to give the title compound as a brown liquid (152g).

	With potassium tert-butylate; In N,N-dimethyl-formamide; at -35℃; for 2.5h;Inert atmosphere;	Stage 1 - tert-Butyl (3,5-difluoro-4-nitrophenyl)acetate A solution of difluoronitrobenzene (24.96 g, 157 mmol) and ter t-butyl chloroacetate (38.0 mL, 267 mmol) in anhydrous DMF (200 mL) was added dropwise over one hour to a cold (-35 C) suspension of potassium ert-butoxide (61.61 g, 549 mmol) in anhydrous DMF (200 mL) under nitrogen. The reaction mixture was stirred at -35 C for 1.5 hours, quenched with 2N HC1 (240 mL) and extracted with heptanes (4x200 mL). The combined organic extracts were washed with water (3x200 mL), brine (200 mL), dried (MgSC ), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (10 % EtOAc in heptanes) afforded a yellow oil (37.64 g). Another two batches (10.00 g and 23.54 g of difluoronitrobenzene) afforded 14.30 g and 31.39 g of product respectively. XH NMR's of all three batches showed a mixture of desired compound and small amounts of unidentified impurities. The 3 batches were combined and used in the next stage without further purification. NMR (300 MHz, CDC13) 7.05 (2H, d, J=8.5 Hz), 3.56 (2H, s), 1.46 (9H, s).
37.64 g	With potassium tert-butylate; In N,N-dimethyl-formamide; at -35℃; for 2.5h;Inert atmosphere;	A solution of difluoronitrobenzene (24.96 g, 157 mmol) and tert-butyl chloroacetate (38.0 mL, 267 mmol) in anhydrous DMF (200 mL) was added dropwise over one hour to a cold (- 35 C) suspension of potassium tert-butoxide (61.61 g, 549 mmol) in anhydrous DMF (200 mL) under nitrogen. The reaction mixture was stirred at -35 C for 1.5 hours, quenched with 2N HC1 (240 mL) and extracted with heptanes (4x200 mL). The combined organic extracts were washed with water (3x200 mL), brine (200 mL), dried (MgS04), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (10 % EtOAc in heptanes) afforded a yellow oil (37.64 g). Another two batches (10.00 g and 23.54 g of difluoronitrobenzene) afforded 14.30 g and 31.39 g of product respectively. 1H MR's of all three batches showed a mixture of desired compound and small amounts of unidentified impurities. The 3 batches were combined and used in the next stage without further purification.1H NMR (300 MHz, CDC13) 7.05 (2H, d, J=8.5 Hz), 3.56 (2H, s), 1.46 (9H, s).
		A mixture of potassium te/f-butoxide (248g) in NMP (2000ml) was cooled under nitrogen to -200C. A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (100g) and te/f-butylchloroacetate (16Og) in NMP (2000ml) was added slowly at -100C to -20C over 1.5 hours. After 30 minutes, a further portion of potassium te/f-butoxide (88g) was added. The reaction mass was quenched into 1600ml of 2M HCI and 1 kg crushed ice, then 2000ml hexane was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2 x 1500ml). The combined hexane layers were washed with saturated brine (2 x 1000ml), then dried over anhydrous sodium sulphate, then filtered and washed with 200ml hexane. The solution was then evaporated to give the title compound as a brown liquid (152g).
	With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - -10℃; for 2h;	A mixture of potassium te/f-butoxide (248g) in N-methyl-2-pyrrolidinone (2000ml) was cooled under nitrogen to -200C. A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (10Og) and tert- butylchloroacetate (16Og) in N-methyl-2-pyrrolidinone (2000ml) was added slowly at -100C to -20C over 1.5 hours. After 30 minutes, a further portion of potassium te/f-butoxide (88g) was added. The reaction mass was quenched into 1600ml of 2M HCI and 1 kg crushed ice, then 2000ml hexane was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2 x 1500ml). The combined hexane layers were washed with saturated brine (2 x 1000ml), then dried over anhydrous sodium sulphate, then filtered and washed with 200ml hexane. The solution was then evaporated to give the title compound as a brown liquid (152g).
	With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at -20 - -10℃; for 0.833333h;	Description 1. t-Butyl 3,5-difluoro-4-nitrophenylacetate (D1); A mixture of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2.5g), t-butyl chloroacetate (3.8ml) and N-methyl pyrrolidone (50ml) was added over 20min at -100C to -200C to a solution of potassium t- butoxide (4.2g) in N-methyl pyrrolidone (50ml). After 30min more at the same temperature the reaction was poured onto a mixture of ice and 2M hydrochloric acid and then extracted twice with hexane. Drying, evaporation and chromatography (2Og silica, 1 :1 hexane:dichloromethane) gave the title compound as a yellow oil, 1.3g.
37.64 g	With potassium tert-butylate; In N,N-dimethyl-formamide; at -35℃; for 2.5h;Inert atmosphere;	A solution of difluoronitrobenzene (24.96 g, 157 mmol) and tert-butyl chloroacetate (38.0 mL, 267 mmol) in anhydrous DMF (200 mL) was added dropwise over one hour to a cold (-35 C) suspension of potassium ferZ-butoxide (61.61 g, 549 mmol) in anhydrous DMF (200 mL) under nitrogen. The reaction mixture was stirred at -35 C for 1.5 hours, quenched with 2N HC1 (240 mL) and extracted with heptanes (4x200 mL). The combined organic extracts were washed with water (3x200 mL), brine (200 mL), dried (MgSC^), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (10 % EtOAc in heptanes) afforded a yellow oil (37.64 g). Another two batches (10.00 g and 23.54 g of difluoronitrobenzene) afforded 14.30 g and 31.39 g of product respectively. H NMR's of all three batches showed a mixture of desired compound and small amounts of unidentified impurities. The 3 batches were combined and used in the next stage without further purification. (0142) NMR (300 MHz, CDCb) 7.05 (2H, d, J=8.5 Hz), 3.56 (2H, s), 1.46 (9H, s).

References: [1]Patent: WO2009/60160,2009,A1 .Location in patent: Page/Page column 20-21.
[2]Patent: WO2009/106844,2009,A1 .Location in patent: Page/Page column 27.
[3]Patent: WO2007/36715,2007,A2 .Location in patent: Page/Page column 59-60.
[4]Patent: WO2014/60742,2014,A1 .Location in patent: Page/Page column 14-15.
[5]Patent: WO2014/170677,2014,A1 .Location in patent: Page/Page column 42.
[6]Patent: WO2008/119715,2008,A1 .Location in patent: Page/Page column 61-62.
[7]Patent: WO2008/119720,2008,A1 .Location in patent: Page/Page column 56.
[8]Patent: WO2007/107567,2007,A1 .Location in patent: Page/Page column 44.
[9]Patent: WO2019/43389,2019,A1 .Location in patent: Page/Page column 19.

35
[ 348-54-9 ]
[ 19064-24-5 ]
[ 929565-65-1 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydride; In N,N-dimethyl-formamide; for 0.166667h;	To 2-fluoroaniline (1.55 g, 13.9 mmol) in anhydrous dimethylformamide (10 mL) was added sodium hydride (0.56 g, 13.9 mmol) and the reaction stirred for 10 minutes prior to the addition of <strong>[19064-24-5]2,6-difluoronitrobenzene</strong> (2 g, 15.5 mmol) dissolved in anhydrous dimethylformamide (2 mL). Upon disappearance of 2-fluoroaniline the reaction was partitioned between saturated ammonium chloride (50 mL) and ethyl acetate (50 mL) and the organics were dried over sodium sulfate. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine as a slightly impure off-white solid (1.5 g, 43%). (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine (1.5 g, 6 mmol) and a spatula tip of 5% Pd/C in methanol (100 mL) were reduced in the parr shaker. Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give 3-fluoro-N1-(2-fluoro[henyl)benzene-1,2-diamine as a brown oil (0.5 g, 38%). MS (ES) m/z 221.1

References: [1]Patent: US2007/72928,2007,A1 .Location in patent: Page/Page column 33-34.
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6067 - 6070.

Historical Records

Technical Information

• Alkyl Halide Occurrence • Arndt-Eistert Homologation • Hunsdiecker-Borodin Reaction • Passerini Reaction • Preparation of Amines • Preparation of Carboxylic Acids • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Carboxylic Acids • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Ugi Reaction

Related Functional Groups of
[ 19064-24-5 ]

Fluorinated Building Blocks

A152011 [315-14-0]

1,3,5-Trifluoro-2-nitrobenzene

Similarity: 1.00

A219193 [25892-09-5]

2,6-Difluoro-3-nitroaniline

Similarity: 0.94

A285654 [123344-02-5]

2,4-Difluoro-5-nitroaniline

Similarity: 0.94

A321735 [446-35-5]

2,4-Difluoro-1-nitrobenzene

Similarity: 0.92

A163677 [314-41-0]

1,2,3,5-Tetrafluoro-4-nitrobenzene

Similarity: 0.91

Aryls

A152011 [315-14-0]

1,3,5-Trifluoro-2-nitrobenzene

Similarity: 1.00

A219193 [25892-09-5]

2,6-Difluoro-3-nitroaniline

Similarity: 0.94

A285654 [123344-02-5]

2,4-Difluoro-5-nitroaniline

Similarity: 0.94

A321735 [446-35-5]

2,4-Difluoro-1-nitrobenzene

Similarity: 0.92

A163677 [314-41-0]

1,2,3,5-Tetrafluoro-4-nitrobenzene

Similarity: 0.91

Nitroes

A152011 [315-14-0]

1,3,5-Trifluoro-2-nitrobenzene

Similarity: 1.00

A219193 [25892-09-5]

2,6-Difluoro-3-nitroaniline

Similarity: 0.94

A285654 [123344-02-5]

2,4-Difluoro-5-nitroaniline

Similarity: 0.94

A321735 [446-35-5]

2,4-Difluoro-1-nitrobenzene

Similarity: 0.92

A163677 [314-41-0]

1,2,3,5-Tetrafluoro-4-nitrobenzene

Similarity: 0.91

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

{[proInfo.proName]}

CAS No.: 19064-24-5

{[proInfo.proName]}

CAS No.: 19064-24-5

Alternative Products

Product Details of [ 19064-24-5 ]

Safety of [ 19064-24-5 ]

Computational Chemistry of [ 19064-24-5 ] Show Less

Physicochemical Properties

Lipophilicity

Water Solubility

Pharmacokinetics

Druglikeness

Medicinal Chemistry

Application In Synthesis of [ 19064-24-5 ]

[ 19064-24-5 ] Synthesis Path-Downstream 1~35

Related Products

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 19064-24-5 ]

Fluorinated Building Blocks

Aryls

Nitroes

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Molarity Calculator

Total Compounds Calculator

Dissolution Calculator

{[proInfo.proName]}

CAS No.: 19064-24-5

{[proInfo.proName]}

CAS No.: 19064-24-5

Alternative Products

Product Details of [ 19064-24-5 ]

Safety of [ 19064-24-5 ]

Computational Chemistry of [ 19064-24-5 ] Show Less

Physicochemical Properties

Lipophilicity

Water Solubility

Pharmacokinetics

Druglikeness

Medicinal Chemistry

Application In Synthesis of [ 19064-24-5 ]

[ 19064-24-5 ] Synthesis Path-Downstream 1~35

Related Products

Historical Records

Technical Information

Categories

Related Functional Groups of [ 19064-24-5 ]

Fluorinated Building Blocks

Aryls

Nitroes

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Molarity Calculator

Total Compounds Calculator

Dissolution Calculator

Related Functional Groups of
[ 19064-24-5 ]