[ CAS No. 64695-92-7 ] {[proInfo.proName]}

Name: 64695-92-7|4-Fluoro-2-methyl-5-nitrobenzoic acid|98%
Brand: Ambeed
SKU: A885564
Price: 7.0 USD
Availability: InStock
Rating: 92 (28 reviews)

,{[proInfo.pro_purity]}

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

2D 3D

Structure of 64695-92-7 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 64695-92-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 64695-92-7 ]

SDS Specification

Alternatived Products of [ 64695-92-7 ]

Product Details of [ 64695-92-7 ]

CAS No. :	64695-92-7	MDL No. :	MFCD11847453
Formula :	C₈H₆FNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IBZJPGGBZMXXCE-UHFFFAOYSA-N
M.W :	199.14	Pubchem ID :	22313101
Synonyms :

Calculated chemistry of [ 64695-92-7 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.15
TPSA :	83.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.0
Log Po/w (XLOGP3) :	1.74
Log Po/w (WLOGP) :	2.16
Log Po/w (MLOGP) :	1.27
Log Po/w (SILICOS-IT) :	-0.02
Consensus Log Po/w :	1.23

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.36
Solubility :	0.877 mg/ml ; 0.00441 mol/l
Class :	Soluble
Log S (Ali) :	-3.1
Solubility :	0.157 mg/ml ; 0.00079 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.82
Solubility :	2.99 mg/ml ; 0.015 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 64695-92-7 ]

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

Application In Synthesis of [ 64695-92-7 ]

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

Upstream synthesis route of [ 64695-92-7 ]
Downstream synthetic route of [ 64695-92-7 ]

[ 64695-92-7 ] Synthesis Path-Upstream 1~1

1
[ 321-21-1 ]
[ 64695-92-7 ]
[ 1079991-68-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	at 0 - 20℃; for 6 h; Inert atmosphere	[000146] To a stirred solution of 4-fluoro-2-methylbenzoic acid 83 (500 mg, 3.24 mmol) in concentrated sulfuric acid (2.5 mL) under inert atmosphere was added potassium nitrate (655 mg, 6.49 mmol) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL), filtered the precipitated solid and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5percent MeOH/ CH2C12 to afford compound 84 (300 mg, 60percent) as brown syrup. TLC: 10percent MeOH/ CH2C12 (R 0.3); 1H-NMR (DMSO-d6, 500 MHz): ö 13.56 (br s, 1H), 8.52 (d, J= 8.0 Hz, 1H), 7.61 (d, J 12.5 Hz, 1H), 2.63 (s, 3H).

Reference： [1] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000146
[2] Patent: WO2018/53157, 2018, A1, . Location in patent: Page/Page column 146

[ 64695-92-7 ] Synthesis Path-Downstream 1~30

1
[ 352-70-5 ]
[ 75-36-5 ]
[ 64695-92-7 ]

Yield	Reaction Conditions	Operation in experiment
	(i) AlCl₃, (ii) HNO₃, H₂SO₄; Multistep reaction;

Reference： [1]Cervena; Sindelar; Kopicova; et al. [Collection of Czechoslovak Chemical Communications, 1977, vol. 42, # 6, p. 2001 - 2017]

2
[ 64695-92-7 ]
[ 658085-42-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogen;palladium 10% on activated carbon; In ethanol; under 1551.49 Torr; for 3h;	A) To a solution of 2-methyl-5-nitro-4-fluorobenzoic acid (1.77 g, 8. 9 mmol, for preparation see Coll. Czech. Chem. Commun. 1977, 42, [2001)] in ethanol (15 mL) was added 10% Pd/C (50 mg) and the mixture was subjected to hydrogenation under 30 psi of pressure. After 3 h, hydrogen was removed and the mixture was filtered and the filtrate was concentrated [IN VACUUM] to afford 2-methyl-5- [AMINO-4-FLUOROBENZOIC] acid (1.45 g, 97%). LC/MS; [(M+H) +=] 170.

Reference： [1]Patent: WO2004/13145,2004,A1 .Location in patent: Page 34

3
[ 64695-92-7 ]
[ 1191428-67-7 ]

Yield	Reaction Conditions	Operation in experiment
	With borane-THF In tetrahydrofuran at 5 - 25℃; for 16h;

Reference： [1]Location in patent: scheme or table Worm, Karin; Weaver, Damian G.; Green, Rosalyn C.; Saeui, Christopher T.; Dulay, Doreen-Marie S.; Barker, William M.; Cassel, Joel A.; Stabley, Gabriel J.; DeHaven, Robert N.; LaBuda, Christopher J.; Koblish, Michael; Brogdon, Bernice L.; Smith, Steven A.; Dolle, Roland E. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5004 - 5008]

4
[ 321-21-1 ]
[ 64695-92-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With nitric acid;sulfuric acid; at 0℃; for 0.75h;	Example 62.2-[2-(1 ,3-benzothiazol-5-yl)-1 H-imidazol-4-yl]-N,N,6-trimethyl-1-[2-(methyloxy)ethyl]-1 H- -5-carboxamideStep 1 . 4-fluoro-2-methyl-5-nitrobenzoic acid: nitric acid (0.4 ml, 8.06 mmol) was added to a stirred solution of <strong>[321-21-1]4-fluoro-2-methylbenzoic acid</strong> (1 g, 6.49 mmol) in sulfuric acid (4.7 ml, 88 mmol) at 0C. Stirred for 45 mins, diluted with ethyl acetate and poured into ice water. The aqueous phase was extracted with EtOAc twice, the combined EtOAc layers were washed with brine, dried over sodium sulfate. The EtOAc layer was concentrated, and purified via Biotage (SNAP Cartridge KP Sil 25 g, 0-5% Methanol/Dichloromethane, 1 % Acetic acid) to yield 4-fluoro-2-methyl-5-nitrobenzoic acid (1 .08 g, 5.42 mmol, 84 % yield). 1H NMR (600 MHz, CDCI3) delta 8.85 (d, J = 7.55 Hz, 1 H), 7.24 (d, J = 1 1.33 Hz, 1 H), 2.76 (s, 3 H); MS (m/z) 200.1 (M+H)+.
67%	With sulfuric acid; nitric acid; at 0℃; for 1.75h;Inert atmosphere;	Step 2: A cooled mixture of fuming nitric acid (2.5 ml.) and cone, sulfuric acid (25 ml.) was slowly added to <strong>[321-21-1]4-fluoro-2-methyl-benzoic acid</strong> (9 g, 58.3 mmol) at 0 'C under N2 atmosphere over a period of 45 min. Reaction mixture was allowed to stir at 0 'C for 1 h. Starting material consumption was monitored by the TLC. Upon completion of the reaction the reaction mass was poured onto crushed ice and extracted in ethyl acetate (3x 100 ml_). Combined extract was washed with water, brine solution and dried over anhydrous Na2S04. The solid obtained was washed with pet ether to afford the pure product 4-fluoro-2-methyl-5-nitro-benzoic acid. Yield (7.8 g, 67%; and off-color solid). LCMS: 198.0 (M-H)+; H NMR (400 MHz, DMSO-cfe) delta 13.60 (br, s, 1 H), 8.52 (d, J = 8.0 Hz, 1 H), 7.61 (d, J= 12.5 Hz, 1 H), 2.61 (s, 3H).
60%	With sulfuric acid; potassium nitrate; at 0 - 20℃; for 6h;Inert atmosphere;	[00059] To a stirred solution of <strong>[321-21-1]4-fluoro-2-methylbenzoic acid</strong> 2 (500 mg, 3.24 mmol) in concentrated sulfuric acid (2.5 mL) under inert atmosphere was added potassium nitrate (655 mg, 6.49 mmol) at 0 C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL), filtered the precipitated solid and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 3 (300 mg, 60%) as brown syrup. TLC: 10% MeOH/ CH2C12 (Rf. 0.3); FontWeight="Bold" FontSize="10" H-NMR (DMSO- 500 MHz): delta 13.56 (br s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 7.61 (d, J= 12.5 Hz, 1H), 2.63 (s, 3H).

Reference： [1]Patent: WO2011/123609,2011,A1 .Location in patent: Page/Page column 67
[2]Patent: WO2013/106409,2013,A1 .Location in patent: Page/Page column 86
[3]Patent: WO2017/48954,2017,A1 .Location in patent: Paragraph 00059
[4]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5004 - 5008

5
[ 64695-92-7 ]
[ 109-85-3 ]
[ 1338346-21-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine In ethanol at 100℃; for 3h;	62.2 Step 2. 2-methyl-4-[2-(methyloxy)ethyl]amino}-5-nitrobenzoic acid: 4-fluoro-2-methyl-5- nitrobenzoic acid (1 .08 g, 5.42 mmol), 2-(methyloxy)ethylamine (0.476 mL, 5.42 mmol), and DIEA (0.967 mL, 5.42 mmol) in Ethanol (5 mL) were heated at 100°C, stirred for 3 hours. The reaction was partitioned between ethyl acetate and brine, foam formed. The aqueous layer was separated and adjusted PH < 4 with 1 N hydrochloric acid, then extracted with EtOAc. The combined EtOAc layers were dried over sodium sulfate, filtered, concentrated, air-dried to yield 2-methyl-4-[2-(methyloxy)ethyl]amino}-5- nitrobenzoic acid (1 .2 g, 4.72 mmol, 87 % yield). MS (m/z) 255.2 (M+H)+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/123609, 2011, A1 Location in patent: Page/Page column 67

6
[ 64695-92-7 ]
[ 1338346-22-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / ethanol / 3 h / 100 °C 2: hydrogen / palladium on activated charcoal / methanol

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/123609, 2011, A1

7
[ 64695-92-7 ]
[ 1338345-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / ethanol / 3 h / 100 °C 2: hydrogen / palladium on activated charcoal / methanol 3: sodium hydrogensulfite / ethanol; water / 100 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/123609, 2011, A1

8
[ 64695-92-7 ]
[ 1338345-45-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / ethanol / 3 h / 100 °C 2.1: hydrogen / palladium on activated charcoal / methanol 3.1: sodium hydrogensulfite / ethanol; water / 100 °C 4.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dmap / N,N-dimethyl-formamide / 20 °C 4.2: 0.17 h 5.1: sodium carbonate

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/123609, 2011, A1

9
[ 64695-92-7 ]
(x)C₂HF₃O₂*C₂₄H₂₄N₆O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / ethanol / 3 h / 100 °C 2.1: hydrogen / palladium on activated charcoal / methanol 3.1: sodium hydrogensulfite / ethanol; water / 100 °C 4.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dmap / N,N-dimethyl-formamide / 20 °C 4.2: 0.17 h

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/123609, 2011, A1

10
[ 64695-92-7 ]
[ 1447363-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/106409, 2013, A1

11
[ 64695-92-7 ]
[ 1447363-97-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: 2-methyltetrahydrofuran / 0.5 h / 105 °C 3.2: 55 - 65 °C

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/106409, 2013, A1

12
[ 64695-92-7 ]
[ 1447363-98-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2.1: 1,1'-carbonyldiimidazole / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere 3.1: 2-methyltetrahydrofuran / 0.5 h / 105 °C 3.2: 55 - 65 °C 4.1: potassium hexamethylsilazane / N,N-dimethyl-formamide / 6 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: sulfuric acid 2: potassium carbonate / N,N-dimethyl-formamide 3: neat (no solvent) 4: toluene / Reflux

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/106409, 2013, A1
[2]Current Patent Assignee: MERCK KGAA - WO2013/106409, 2013, A1

13
[ 64695-92-7 ]
[ 1447364-00-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid 2: potassium carbonate / N,N-dimethyl-formamide

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/106409, 2013, A1

14
[ 64695-92-7 ]
[ 1447364-01-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sulfuric acid 2: potassium carbonate / N,N-dimethyl-formamide 3: neat (no solvent)

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/106409, 2013, A1

15
[ 64695-92-7 ]
1-(2-methylphenyl)piperazine dihydrochloride [ No CAS ]
[ 1447363-95-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	11B.3 Step 3 Step 3: To a stirred solution of 4-fluoro-2-methyl-5-nitro-benzoic acid (5.0 g, 25.10 mmol) in anhydrous DMF (100 mL), potassium carbonate (10.4 g, 75.3 mmol) was added under N2 atmosphere followed by 1 -o-tolyl-piperazine 2 HCI (8.13 g, 32.6 mmol). The reaction mixture was allowed to stir at room temperature overnight. The progress of the reaction was checked by TLC, upon completion of the reaction, solvent was removed in vacuo. The residue obtained was acidified with cone. HCI (~ pH = 2-3). Yellow solid obtained was filtered and washed with water (3x75 mL), diethyl ether and dried under vacuo to obtain the pure product 2-methyl-5- nitro-4-(4-o-tolyl-piperazin-1 -yl)-benzoic acid. Yield (6.5 g, 73%; and yellow solid). LCMS: 356.0 (M+H)+; H NMR (400 MHz, DMSO-cfe) δ 8.32 (s, 1 H), 7.21 (s, 1 H), 7.19-7.14 (m, 2H), 7.09 (d, J = 7.7 Hz, 1 H), 7.00 (t, J = 7.3 Hz, 1 H), 4.64 (br, s, 1 H), 3.29-3.27 (m, 4H), 2.98-2.95 (m, 4H), 2.58 (s, 3H), 2.28 (s, 3H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/106409, 2013, A1 Location in patent: Page/Page column 86-87

16
[ 67-56-1 ]
[ 64695-92-7 ]
[ 1163287-01-1 ]

Reference： [1]Patent: WO2013/106409,2013,A1 .Location in patent: Page/Page column 90

17
[ 321-21-1 ]
[ 64695-92-7 ]
[ 1079991-68-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sulfuric acid; potassium nitrate; at 0 - 20℃; for 6.0h;Inert atmosphere;	[000146] To a stirred solution of 4-fluoro-2-methylbenzoic acid 83 (500 mg, 3.24 mmol) in concentrated sulfuric acid (2.5 mL) under inert atmosphere was added potassium nitrate (655 mg, 6.49 mmol) at 0 C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL), filtered the precipitated solid and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 84 (300 mg, 60%) as brown syrup. TLC: 10% MeOH/ CH2C12 (R 0.3); 1H-NMR (DMSO-d6, 500 MHz): oe 13.56 (br s, 1H), 8.52 (d, J= 8.0 Hz, 1H), 7.61 (d, J 12.5 Hz, 1H), 2.63 (s, 3H).
	With nitric acid; acetic acid; at 80℃; for 6.0h;Inert atmosphere;	To a stirred solution of 4-fluoro-2-methylbenzoic acid 16 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered anddried in vacuo to afford mixture of compounds 17 and 18 (5.3 g, 40%) as white solid. TLC: 70%EtOAc/ hexanes(R 0.4); ?H NMR (DMSO-d6, 400 MHz): oe 13.30 (br s, 2H), 8.52 (d, J = 8.0Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J= 12.5 Hz, 2H), 7.56 (t, J= 9.3 Hz, 1H), 2.63(s, 6H), 2.48 (s, 3H); (?H NMR showed mixture of compounds 17 & 18 in the ratio of 2: 1).

Reference： [1]Patent: WO2015/138895,2015,A1 .Location in patent: Paragraph 000146
[2]Patent: WO2018/53157,2018,A1 .Location in patent: Page/Page column 146

18
[ 64695-92-7 ]
C₁₅H₁₁NO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 20 - 30 °C / Inert atmosphere 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 8 h / 20 °C
	Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 60 °C / Inert atmosphere 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 8 h

Reference： [1]Current Patent Assignee: ASSEMBLY BIOSCIENCES, INC.; INDIANA UNIVERSITY - WO2015/138895, 2015, A1
[2]Current Patent Assignee: INDIANA UNIVERSITY; ASSEMBLY BIOSCIENCES, INC. - WO2017/48954, 2017, A1

19
[ 64695-92-7 ]
5-amino-4-((2-carboxyphenyl) thio)-2-methylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 20 - 30 °C / Inert atmosphere 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 8 h / 20 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 60 °C / Inert atmosphere 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 8 h 3: palladium on activated charcoal; hydrogen / methanol / 16 h / Inert atmosphere

20
[ 64695-92-7 ]
7-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4] thiazepine-8-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 20 - 30 °C / Inert atmosphere 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 8 h / 20 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 20 °C / Inert atmosphere 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 18 h / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 60 °C / Inert atmosphere 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 8 h 3: palladium on activated charcoal; hydrogen / methanol / 16 h / Inert atmosphere 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 18 h / Inert atmosphere

21
[ 64695-92-7 ]
[ 4892-02-8 ]
4-((2-(methoxycarbonyl) phenyl)thio)-2-methyl-5-nitrobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With caesium carbonate In N,N-dimethyl-formamide at 20 - 30℃; for 4h; Inert atmosphere;	13 Synthesis of 4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-5-nitrobenzoic acid (85) [000147] To a stirred solution of methyl 2-mercaptobenzoate 1(514mg, 3.08 mmol) in DMF (10 mL) under inert atmosphere were added cesium carbonate (1 .81 g, 5.57 mmol), compound84 (560 mg, 2.78 mmol) at RT; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to 2 with 1 N HC1, filtered the precipitated solid and dried in vacuo to afford compound 85 (500 mg, 52%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (R 0.4); 1H-NMR (DMSO-d6, 400 MHz): ö 13.47 (br s, 1H), 8.59 (s, 1H), 7.94 (d, J= 7.2 Hz, 1H), 7.68-7.60 (m, 3H), 6.83 (s, 1H), 3.72 (s, 3H), 2.40 (s, 3H).
52%	With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere;	1 Synthesis of 4-((2-(methoxycarbo ethyl-5-nitrobenzoic acid (4): [00060] To a stirred solution of methyl 2-mercaptobenzoate 1 (514 mg, 3.08 mmol) in DMF (10 mL) under inert atmosphere were added cesium carbonate (1.81 g, 5.57 mmol), compound 3 (560 mg, 2.78 mmol) at RT; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to ~2 with 1 N HC1, filtered the precipitated solid and dried in vacuo to afford compound 4 (500 mg, 52%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.4); ^-NMR (DMSO-6, 400 MHz): δ 13.47 (br s, 1H), 8.59 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.68-7.60 (m, 3H), 6.83 (s, 1H), 3.72 (s, 3H), 2.40 (s, 3H).

Reference： [1]Current Patent Assignee: INDIANA UNIVERSITY; ASSEMBLY BIOSCIENCES, INC. - WO2015/138895, 2015, A1 Location in patent: Paragraph 000147
[2]Current Patent Assignee: ASSEMBLY BIOSCIENCES, INC.; INDIANA UNIVERSITY - WO2017/48954, 2017, A1 Location in patent: Paragraph 00060

22
[ 64695-92-7 ]
C₂₀H₁₆N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 60 °C / Inert atmosphere 2: lithium hydroxide monohydrate; water / tetrahydrofuran / 8 h 3: palladium on activated charcoal; hydrogen / methanol / 16 h / Inert atmosphere 4: 1,1'-carbonyldiimidazole / tetrahydrofuran / 18 h / Inert atmosphere 5: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: INDIANA UNIVERSITY; ASSEMBLY BIOSCIENCES, INC. - WO2017/48954, 2017, A1

23
[ 64695-92-7 ]
[ 765-30-0 ]
N-cyclopropyl-4-fluoro-2-methyl-5-nitro-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.68 g	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2.5h;	P2.A vclopropyl-4-fluoro-2-methyl-5-nitro-benzamide (Intermediate 1-4) To a solution of 4-fluoro-2-methyl-5-nitro-benzoic acid (CAS 64695-92-7, 5.00 g, 25.1 mmol) in N,N- dimethylformamide (226 mL) were added at room temperature N,N-diisopropylethylamine (11 .2 mL, 65.3 mmol, 2.60 equiv.) and cyclopropylamine (1.74 mL, 25.1 mmol, 1.00 equiv.), followed by addition of 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (10.5 g, 27.6 mmol, 1.10 equiv.). The reaction mixture was stirred at room temperature for 2 hours. HATU (0.95 g, 2.5 mmol, 0.10 equiv.) and cyclopropylamine (0.16 ml_, 2.5 mmol, 0.10 equiv.) were added again to the reaction mixture and it was stirred for additional 30 minutes. It was then diluted with sodium bicarbonate sat. aq. and water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the crude product by flash chromatography over silica gel (gradient of 0-50% ethyl acetate in cyclohexane) afforded the desired product (2.68 g, 11 .3 mmol).LC-MS (method 1): Rt 0.73, /z = 239 (M+H+).-NMR (400 MHz, CDCh, ppm) <5 = 8.07 (d, J = 7.34 Hz, 1 H) 7.13 - 7.20 (m, 1 H) 6.00 (br s, 1 H) 2.91 (tq, J = 7.11 , 3.58 Hz, 1 H) 2.55 (s, 3 H) 0.89 - 0.96 (m, 2 H) 0.63 - 0.69 (m, 2 H).

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/175822, 2021, A1 Location in patent: Page/Page column 49-50

24
[ 64695-92-7 ]
4-fluoro-2-methyl-N-(2,2,2-trifluoroethyl)-5-(2,2,2-trifluoroethylcarbamothioylamino)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C 2: iron; acetic acid / 1 h / 80 °C 3: triethylamine / dichloromethane / 4 h / 20 °C