349-02-0|4-Fluoro-3-nitrobenzamide| Ambeed

Structure of 349-02-0

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Quality Control of [ 349-02-0 ] Purity: 98% SDS Specification

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Product Details of [ 349-02-0 ]

CAS No. :	349-02-0
Formula :	C₇H₅FN₂O₃
M.W :	184.13
SMILES Code :	O=C(N)C1=CC=C(F)C([N+]([O-])=O)=C1
MDL No. :	MFCD11110229
Boiling Point :	No data available
InChI Key :	XQKXDVBKKZWIAZ-UHFFFAOYSA-N
Pubchem ID :	21884184

Safety of [ 349-02-0 ]

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

Computational Chemistry of [ 349-02-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	43.32
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	88.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.61
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	0.64
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.25
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.	0.54
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	-0.72
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.46

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.59
Solubility	4.69 mg/ml ; 0.0255 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.08
Solubility	1.52 mg/ml ; 0.00827 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	-1.65
Solubility	4.14 mg/ml ; 0.0225 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	No
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.	-6.97 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)	1.7

Application In Synthesis of [ 349-02-0 ]

* 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.

Downstream synthetic route of [ 349-02-0 ]

[ 349-02-0 ] Synthesis Path-Downstream 1~37

1
[ 400-94-2 ]
[ 349-02-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With ammonia; In methanol; toluene; at 20℃; for 0.25h;	acyl chloride was dissolved in toluene. Ammonia in MeOH was added dropwise to the solution, resulting in yellow precipitation formation. The mixture was stirred 15 minutes at rt. Then, 1 M HCl was added. The solid was collected by filtration, washed with water and dried under vacuum to afford the pure product as yellow solid: 740 mg, 67% yield
	With ammonium hydroxide; In tetrahydrofuran; water; at 0℃; for 0.583333h;	A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous ammonium hydroxide (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH/CH2Cl2) to afford the title compound as a white solid.
	With ammonium hydroxide; In tetrahydrofuran; water; at 0℃; for 0.583333h;	A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.

With ammonia; In dichloromethane; at -78℃; for 0.333333h;

Example 183; 2-phenyl-7-[(3S)-piperidin-3-vIoxy1-lH-benziinidazole-4-carboxamide; 4-fluoro-3-nitrobenzamide; To 4-fluoro-3-nitrobenzoic acid (12.0 g, 64.8 mmol) is added CH2Cl2 (300 mL), oxalyl chloride (16.7 mL, 195 mmol) and approximately 0.100 mL DMF drop wise. The mixture is stirred at rt for three hours whereupon the reaction is cooled to -78 0C and liquid NH3 is bubbled through the solution for approximately twenty minutes. The resulting yellow solid is purified by MPLC (SiO2; 100% hexanes to 100% EtOAc) to afford the title compound (9.00 g, 76 % yield). LCMS (ES, M-H=I 83).

References: [1]Patent: US2012/316148,2012,A1 .Location in patent: Page/Page column 202; 203.
[2]Bulletin de la Classe des Sciences, Academie Royale de Belgique,1921,vol. <5> 7,p. 536.
Chemisches Zentralblatt,1922,vol. 93,p. 22.
[3]Patent: US2012/129811,2012,A1 .Location in patent: Page/Page column 41.
[4]Patent: US2012/302569,2012,A1 .Location in patent: Page/Page column 25.
[5]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 131.

2
[ 60-29-7 ]
[ 400-94-2 ]
[ 7664-41-7 ]
[ 349-02-0 ]

References: [1]Bulletin de la Classe des Sciences, Academie Royale de Belgique,1921,vol. <5> 7,p. 536.
Chemisches Zentralblatt,1922,vol. 93,p. 22.

3
[ 349-02-0 ]
[ 100-46-9 ]
[ 68502-38-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5652 - 5655.

4
[ 349-02-0 ]
C₁₄H₁₁N₃O₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5652 - 5655.

5
resin bound 3-nitro-4-fluoro-benzoate [ No CAS ]
[ 349-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; for 1h;	Commercially available Fmoc protected Rink resin (0.5 g, 0.3 mmol) was added to a peptide reaction vessel followed by a 40% piperidine: DIMETHYLFORMAMIDE (DMF) (v/v) solution (5 mL, 0.6 mmol/g). The mixture was shaken for 1 h using a wrist action shaker and the DMF was removed by vacuum filtration. The 40% piperidine: DMF solution (5 mL) was again added to the mixture. The mixture was shaken for 30 min and the DMF was removed by vacuum filtration. The reaction product was sequentially washed with an excess of DMF and MeOH, then a final wash with CH2C12 to provide a resin-bound amine Compound la used in the next step without characterization. A 4-fluoro-3-nitrobenzoic acid Compound lb (2.31 g, 12.5 mmol) and 1-HYDROXYBENZOTRIAZOLE (1.69 g, 12.5 mmol) were added in one portion to a 50 mL round bottom flask containing DMF (10 mL) and CH2C12 (10 mL) followed by 1,3- diisopropylcarbodiimide (1.95 mL, 12.5 mmol). The solution was then stirred for 30 min and added to the 50 mL reaction vessel containing Compound la (2. 5g, 1.25 mmol). The mixture was shaken for 16 h and the solvent was removed by vacuum filtration. The reaction product was sequentially washed with an excess of DMF, CH2CL2 and MeOH, then a final wash with CH2CK to give a resin-bound 4-fluoro-3- nitro-benzamide Compound LC. To characterize Compound lc, an aliquot of the washed product (20 mg) was cleaved from the resin using 50% TFA in CH2CL2 (1 mL), shaken for 1 h and filtered, then washed with MeOH and characterized: ESMS M/Z 185 (M+H). DMF (2 mL) and a 4-benzylpiperidine Compound ld (0. 5g, 2. 85MMOL) were added to the reaction vessel containing Compound LC (0.2 G,-0. 1 mmol) then diisopropylethylamine (0.174mL, lmmol) was added. The mixture was shaken over a 2 day period and turned from a pale yellow color to a yellow-orange color, then the solvent was removed by vacuum filtration. The reaction product was sequentially washed with an excess of DMF, CH2C12 and MeOH, then a final wash with CH2C12 to give a resin-bound nitro substituted piperidine Compound LE. DMF (2 mL) and tin (II) chloride dihydrate (0.45g, 2MMNOL) were added to the reaction vessel containing Compound le (0. 2G,-0. 1 mmol). The mixture was shaken overnight and turned from a yellow-orange color to almost colorless, then the solvent was removed by vacuum filtration. The reaction product was sequentially washed with an excess of DMF, CH2C12 and MeOH, then a final wash with CH2CL2 to give a resin- bound aminated Compound lf. Phenyl isocyanate (0.4 mL) was added to the reaction vessel containing Compound lf (0.2 G,-0. 1 mmol) and CH2CI2 (2 mL). The mixture was shaken for 48 h and the solvent was removed by vacuum filtration. The reaction product was sequentially washed with an excess of DMF, CHUCK and MeOH, then a final wash with CHUCK to give a resin-bound amino substituted Compound lg. The washed Compound Ig was cleaved from the resin using 50% TFA in CHUCK (1 mL), shaken for 1 h and filtered, then washed with MeOH. The filtrates were combined and concentrated to provide a crude trifluoroacetate salt. The salt was purified by column chromatography on silica gel (9: 1 CH2CL2 : MeOH was used as the eluent) to provide Compound 1 (16 mg, 38% yield) as a pale yellow solid. ESMS INTO 429 (M+H).

References: [1]Patent: WO2004/89901,2004,A2 .Location in patent: Page 64; 65.

6
[ 349-02-0 ]
[ 912369-47-2 ]

Yield	Reaction Conditions	Operation in experiment
63%		solution containing tert-butyl (35)-3-hydroxypiperidine-l-carboxylate (3.97 g, 19.7 mmol) dissolved in 5.00 mL of DMF is added sodium hydride (473 mg, 19.7 mmol). The resulting solution is stirred at rt for thirty minutes followed by the addition of 4-fluoro-3-nitrobenzoic acid (3.29 g, 17.9 mmol) dissolved in 5.00 mL DMF. The mixture is stirred for twelve hours at rt or until LCMS indicates complete conversion to product. To the reaction mixture is then added 20 mL water and the resulting solid is filtered and dried under reduced pressure to afford the title compound (4.15 g, 63% yield). LCMS (ES, M+H=366).

References: [1]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 132.

7
[ 349-02-0 ]
[ 144-55-8 ]
4-fluoro-3-trifluoroacetylaminobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; hydrogenchloride; acetic acid; trifluoroacetic anhydride;platinum (IV) oxide;	Reference Example 35 4-Fluoro-3-trifluoroacetylaminobenzonitrile 4-Fluoro-3-nitrobenzamide (640 mg) and 5 mg of platinum(IV) oxide were added to 10 ml of acetic acid, and the mixture was stirred at atmospheric pressure under a hydrogen atmosphere at room temperature for 2 hours. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue. The insoluble material was collected by filtration and washed with brine. To the obtained material was added 5 ml of pyridine, and trifluoroacetic anhydride was added dropwise to the mixture under ice-cooling. The resulting mixture was stirred for 30 minutes. Dilute hydrochloric acid was added to the reaction mixture, and the precipitates were collected by filtration and washed with water to give 312 mg of 4-fluoro-3-trifluoroacetylaminobenzonitrile. 1H-NMR(CDCl3) delta ppm: 7.20-7.40 (1H, m), 7.50-7.60 (1H, m), 8.15 (1H, br-s), 8.70 (1H, dd, J=7.1Hz, 2.0Hz)

References: [1]Patent: EP1020434,2000,A1 .

8
[ 349-02-0 ]
[ 814-75-5 ]
4-fluoro-3-nitrophenyl(1-methyl-2-oxo-propyl)formamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	Preparation 91 To a suspension of <strong>[349-02-0]4-fluoro-3-nitrophenylformamide</strong> (5.60g) and potassium carbonate (5.44g) in N,N-dimethylformamide (28ml) was added 2-bromo-3-butanone (4.1ml) and the mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-fluoro-3-nitrophenyl(1-methyl-2-oxo-propyl)formamide (6.83g). APCl-mass;m/z255(M+H) NMR(DMSO, delta):1.32(3H,d,J=7.0Hz), 2.10(3H,s), 4.75(1H,q,J=7.0Hz), 7.78-7.86 (2H,m), 8.14-8.19(1H,m), 8.54(1H,s)

References: [1]Patent: EP1264820,2002,A1 .

9
[ 349-02-0 ]
3-amino-4-ethoxy-benzamide [ No CAS ]

References: [1]Patent: US2012/129843,2012,A1 .

10
[ 349-02-0 ]
[ 1377581-90-2 ]

References: [1]Patent: US2012/129843,2012,A1 .

11
[ 349-02-0 ]
[ 67-63-0 ]
[ 1369838-81-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 23℃; for 5h;	Intermediate 5: Step b 4-Isopropoxy-3-nitro-benzamide To a solution of iPrOH (0.619 mL, 8.09 mmol) in THF (25 mL) at 0 C. was added a 0.5 M solution of KHMDS in toluene (16.2 mL, 8.09 mmol) followed by 4-fluoro-3-nitro-benzamide (993 mg, 5.39 mmol, intermediate 5, step a). The resulting brown suspension was stirred at 0 C. for 1 h, then was allowed to warm to 23 C. and was stirred for an additional 4 h. The mixture was partially concentrated to remove THF and was diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as an orange solid which was used without further purification in the next reaction.
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 23℃; for 5h;	Intermediate 14: Step b4-Isopropoxy-3-nitro-benzamide To a solution of iPrOH (0.619 mL, 8.09 mmol) in THF (25 mL) at 0 C., added a 0.5 M solution of KHMDS in toluene (16.2 mL, 8.09 mmol) followed by 4-fluoro-3-nitro-benzamide (993 mg, 5.39 mmol, intermediate 14, step a). The resulting brown suspension was stirred at 0 C. for 1 h, then was allowed to warm to 23 C. and was stirred for an additional 4 h. The mixture was partially concentrated to remove THF and was diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as an orange solid which was used without further purification in the next reaction.
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 23℃;	Intermediate 13: Step b 4-Isopropoxy-3-nitro-benzamide To a solution of iPrOH (0.619 mL, 8.09 mmol) in THF (25 mL) at 0 C., added a 0.5 M solution of KHMDS in toluene (16.2 mL, 8.09 mmol) followed by 4-fluoro-3-nitro-benzamide (993 mg, 5.39 mmol, intermediate 13, step a). The resulting brown suspension was stirred at 0 C. for 1 h, then was allowed to warm to 23 C. and was stirred for an additional 4 h. The mixture was partially concentrated to remove THF and was diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as an orange solid which was used without further purification in the next reaction.

	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 23℃; for 5h;	Intermediate 23: Step b 4-Isopropoxy-3-nitro-benzamide To a solution of iPrOH (0.619 mL, 8.09 mmol) in THF (25 mL) at 0 C., added a 0.5 M solution of KHMDS in toluene (16.2 mL, 8.09 mmol) followed by 4-fluoro-3-nitro-benzamide (993 mg, 5.39 mmol, intermediate 23, step a). The resulting brown suspension was stirred at 0 C. for 1 h, then was allowed to warm to 23 C. and was stirred for an additional 4 h. The mixture was partially concentrated to remove THF and was diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as an orange solid which was used without further purification in the next reaction.
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 23℃;	To a solution of iPrOH (0.619 mL, 8.09 mmol) in THF (25 mL) at 0 C., added a 0.5 M solution of KHMDS in toluene (16.2 mL, 8.09 mmol) followed by Intermediate 24 (0.993 g, 5.39 mmol). The resulting brown suspension was stirred at 0 C. for 1 h, then was allowed to warm to 23 C. and was stirred for an additional 4 h. The mixture was partially concentrated to remove THF and was diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as an orange solid which was used without further purification.
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at 0 - 23℃; for 5h;	To a solution of i-PrOH (0.619 mL, 8.09 mmol) in THF (25 mL) at 0 C. was added a 0.5 M solution of KHMDS in toluene (16.2 mL, 8.09 mmol) followed by 4-fluoro-3-nitro-benzamide (993 mg, 5.39 mmol, intermediate 2, step a). The resulting brown suspension was stirred at 0 C. for 1 h, then was allowed to warm to 23 C. and was stirred for an additional 4 h. The mixture was partially concentrated to remove THF and was diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as an orange solid which was used without further purification in the next reaction.

References: [1]Patent: US2012/129897,2012,A1 .Location in patent: Page/Page column 19-20.
[2]Patent: US2012/129872,2012,A1 .Location in patent: Page/Page column 27.
[3]Patent: US2012/129843,2012,A1 .Location in patent: Page/Page column 32.
[4]Patent: US2012/129842,2012,A1 .Location in patent: Page/Page column 43.
[5]Patent: US2012/129811,2012,A1 .Location in patent: Page/Page column 41.
[6]Patent: US2012/302569,2012,A1 .Location in patent: Page/Page column 25.

12
[ 349-02-0 ]
[ 141-52-6 ]
4-ethoxy-3-nitro-benzoic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20℃; for 0.25h;	Intermediate 6: Step a 4-Ethoxy-3-nitro-benzamide A mixture of 4-fluoro-3-nitro-benzamide (1.18 g, 6.39 mmol, intermediate 5, step a) and EtOH (5 mL) was treated with a solution of sodium ethoxide in EtOH (21 wt. %, 4.77 mL, 12.78 mmol, Aldrich) and the resulting brown suspension was stirred at room temperature for 15 min. The mixture was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated and the residue was purified by flash column chromatography (Silica gel, 60-100% EtOAc-Hept) affording the title compound as a yellow powder.
	In ethanol; at 20℃; for 0.25h;	Intermediate 15: Step a 4-Ethoxy-3-nitro-benzamide A mixture of 4-fluoro-3-nitro-benzamide (1.18 g, 6.39 mmol, intermediate 13, step a) and EtOH (5 mL) was treated with a solution of sodium ethoxide in EtOH (21 wt. %, 4.77 mL, 12.78 mmol, Aldrich) and the resulting brown suspension was stirred at room temperature for 15 min. The mixture was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated and the residue was purified by flash column chromatography (Silica gel, 60-100% EtOAc-Hept) affording the title compound as a yellow powder.
	In ethanol; at 20℃; for 0.25h;	Intermediate 25: Step a 4-Ethoxy-3-nitro-benzamide A mixture of 4-fluoro-3-nitro-benzamide (1.18 g, 6.39 mmol, intermediate 23, step a) and EtOH (5 mL) was treated with a solution of sodium ethoxide in EtOH (21 wt. %, 4.77 mL, 12.78 mmol, Aldrich) and the resulting brown suspension was stirred at room temperature for 15 min. The mixture was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated and the residue was purified by flash column chromatography (Silica gel, 60-100% EtOAc-Hept) affording the title compound as a yellow powder.

References: [1]Patent: US2012/129897,2012,A1 .Location in patent: Page/Page column 20.
[2]Patent: US2012/129843,2012,A1 .Location in patent: Page/Page column 33.
[3]Patent: US2012/129842,2012,A1 .Location in patent: Page/Page column 44.

13
[ 349-02-0 ]
[ 1377837-78-9 ]

References: [1]Patent: US2012/129897,2012,A1 .

14
[ 349-02-0 ]
[ 1153956-60-5 ]

References: [1]Patent: US2012/129897,2012,A1 .
[2]Patent: US2012/129872,2012,A1 .
[3]Patent: US2012/129843,2012,A1 .
[4]Patent: US2012/129842,2012,A1 .
[5]Patent: US2012/129811,2012,A1 .
[6]Patent: US2012/302569,2012,A1 .

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Yield	Reaction Conditions	Operation in experiment
97%	With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; acetonitrile; at 0 - 20℃; for 4h;	To a solution of4(1.0 g, 5.4 mmol) in 4:1 CH3CN/DMF (20 ml/ 5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.7 g, 10.8 mmol) and HOBt-NH3(1.6 g, 10.8 mmol) at 0oC. After stirring at rt for 4 h, the mixture was diluted with distilled water and extracted three times with EtOAc. The combined organic layers were washed with sat?d aq. NaHCO3solution and brine, dried over MgSO4, and concentrated under reduced pressure to give a crude product which was purified by column chromatography (SiO2, Hexane:EtOAc = 1:3) to give 4-fluoro-3-nitrobenzamide (960 mg, 5.2 mmol, 97% yield) as a yellow powder;1H NMR (400 MHz, CD3OD) delta (ppm) 8.64 (dd,J= 7.1, 2.3 Hz, 1H), 8.23 - 8.27 (m, 1H), 7.53 (dd,J= 10.7, 8.7 Hz, 1H).A solution of 4-fluoro-3-nitrobenzamide obtained above (50 mg, 1.3 mmol) ini-PrOH (5 ml) was treated with DIPEA (0.14 ml, 3.8 mmol) and 2-aminoethanol (0.05 ml, 3.8 mmol). After stirring at 90oC for 5 h, solvent was removed under reduced pressure to give a crude product which was purified by column chromatography (SiO2, CH2Cl2:MeOH:NH4OH:H2O = 80:20:1:1) to give5aas a yellow powder (50 mg, 0.21 mmol, 79% yield)
96%		A mixture of 4-fluoro-3-nitrobenzoic acid (10 g, 54.0 mmcl) in thionyl chloride (30 mL was stirred at 80 C for 2 hr, then the mixture was concentrated. The residue was dissolved in dry dichloromethane (DCM) (100 mL), cooled to 0 C, and a solution of ammonia in dry THEwas added dropwise at 0 C. The reaction mixture was stirred at 0 C for 1 h then water (50mL) was added and the solid was isolated by filtration, washed with Et20 and dried in vacua to give 4-fluoro-3-nitrobenzamide (9.5 g, 51.6 mmol, 96 % yield) as a yellow solid. LCMS (LCMS Method A): Rt = 1.259 mi [M+H] = 185.0
		Intermediate 5: Step a 4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.

		Intermediate 14: Step a4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.
		Intermediate 13: Step a 4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.
		Intermediate 23: Step a 4-Fluoro-3-nitro-benzamide A round bottom flask fitted with a reflux condenser vented through an aqueous sodium hydroxide solution was charged with 4-fluoro-3-nitro-benzoic acid (5.0 g, 27.0 mmol, Aldrich). Thionyl chloride (20 mL) was added and the resulting suspension was heated in an 80 C. oil bath for 3 h. The mixture was concentrated and the residual oil was dissolved in THF (20 mL) and added slowly via pipette to an ice-cold solution of concentrated aqueous NH4OH (20 mL). The resulting bright yellow mixture was stirred at 0 C. for 35 min. The mixture was partially concentrated to remove THF and the residual solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (Silica gel, 1-3% EtOH-CH2Cl2) to afford the title compound as a white solid.

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7596 - 7602.
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3213 - 3215.
[3]Patent: WO2017/175156,2017,A1 .Location in patent: Page/Page column 98; 99.
[4]Patent: US2012/129897,2012,A1 .Location in patent: Page/Page column 19.
[5]Patent: US2012/129872,2012,A1 .Location in patent: Page/Page column 26-27.
[6]Patent: US2012/129843,2012,A1 .Location in patent: Page/Page column 31.
[7]Patent: US2012/129842,2012,A1 .Location in patent: Page/Page column 43.
[8]Patent: US2012/129811,2012,A1 .
[9]Patent: US2012/302569,2012,A1 .
[10]Patent: US2012/316148,2012,A1 .
[11]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 379 - 384.
[12]Patent: WO2006/106326,2006,A1 .

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References: [1]Patent: US2012/129872,2012,A1 .

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References: [1]Patent: US2012/129872,2012,A1 .

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References: [1]Patent: US2012/129872,2012,A1 .

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4-isopropoxy-3-[4-(3-methyl-benzo[b]thiophen-2-yl)thiazol-2-ylamino]benzamide hydrobromide [ No CAS ]

References: [1]Patent: US2012/129872,2012,A1 .

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4-isopropoxy-3-[4-(1-methyl-1H-benzoimidazol-2-yl)thiazol-2-ylamino]benzamide trifluoroacetate [ No CAS ]

References: [1]Patent: US2012/129872,2012,A1 .

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4-isopropoxy-3-[4-(1-methyl-1H-indazol-5-yl)thiazol-2-ylamino]benzamide trifluoroacetate [ No CAS ]

References: [1]Patent: US2012/129872,2012,A1 .

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[ 1377977-48-4 ]

References: [1]Patent: US2012/129843,2012,A1 .

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4-isopropoxy-3-[4-(2,4,6-trimethyl-pyridin-3-yl)-thiazol-2-ylamino]-benzamide trifluoroacetate [ No CAS ]

References: [1]Patent: US2012/129843,2012,A1 .

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4-isopropoxy-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide hydrobromide [ No CAS ]

References: [1]Patent: US2012/129843,2012,A1 .

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Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 23℃; for 3h;	Intermediate 29: Step a 4-tert-Butoxy-3-nitro-benzamide To a solution of 4-fluoro-3-nitro-benzamide (770 mg, 4.18 mmol, intermediate 23, step a) in THF (20 mL) was added a solution of potassium tert-butoxide (938.5 mg, 8.36 mmol) in THF (20 mL). The resulting red solution was stirred at 23 C. for 3 h. The reaction mixture was concentrated and was partitioned between water and EtOAc (sat. aq. NaCl was added to aid phase separation). The separated aq. phase was extracted with EtOAc and the combined organic extracts were washed with sat. aq. NaCl. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was partially purified by flash column chromatography (Silica gel, 0-5% MeOH-CH2Cl2), yielding impure title compound which was used as is in the next reaction.

References: [1]Patent: US2012/129842,2012,A1 .Location in patent: Page/Page column 46.

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