[ CAS No. 61079-72-9 ]

Name: 61079-72-9|2,3,4-Trifluorobenzoic acid|98%
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Quality Control of [ 61079-72-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 61079-72-9 ]

CAS No. :	61079-72-9	MDL No. :	MFCD00061232
Formula :	C₇H₃F₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WEPXLRANFJEOFZ-UHFFFAOYSA-N
M.W :	176.09	Pubchem ID :	302932
Synonyms :

Calculated chemistry of [ 61079-72-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.28
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.12
Log Po/w (XLOGP3) :	1.75
Log Po/w (WLOGP) :	3.06
Log Po/w (MLOGP) :	2.9
Log Po/w (SILICOS-IT) :	2.5
Consensus Log Po/w :	2.27

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.34
Solubility :	0.808 mg/ml ; 0.00459 mol/l
Class :	Soluble
Log S (Ali) :	-2.15
Solubility :	1.25 mg/ml ; 0.00707 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.61
Solubility :	0.436 mg/ml ; 0.00248 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.4

Safety of [ 61079-72-9 ]

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

Application In Synthesis of [ 61079-72-9 ]

* 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 [ 61079-72-9 ]
Downstream synthetic route of [ 61079-72-9 ]

[ 61079-72-9 ] Synthesis Path-Upstream 1~14

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[ 61079-72-9 ]
[ 455-38-9 ]
[ 455-86-7 ]
[ 4519-39-5 ]
[ 65-85-0 ]

Reference： [1] Journal of Physical Chemistry A, 2000, vol. 104, # 2, p. 352 - 361

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Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609

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Reference： [1] Journal of Physical Chemistry A, 2000, vol. 104, # 2, p. 352 - 361

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Reference： [1] European Journal of Organic Chemistry, 2003, # 3, p. 447 - 451
[2] Journal of Physical Chemistry A, 2000, vol. 104, # 2, p. 352 - 361

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Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609

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Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609

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Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609

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[ 189283-51-0 ]

Yield	Reaction Conditions	Operation in experiment
73.4%	at 120℃; for 2 h; Cooling with ice	Solid sodium hydroxide (4.52 g, 113 mmol) was added in portions to an ice-cooled and stirred solution of 2,3,4-trifluorobenzoic acid (5.0 g, 28 mmol) in dimethylimidazolidinone (10 mL), and the mixture was heated to 120 °C for 2 h during which TLC analysis showed the disappearance of 2,3,4-trifluorobenzoic acid. Reaction mixture was cooled to room temperature and acidified (pH 5–6) with 2 N hydrochloric acid (7.5 mL). The white solid separated out was filtered, washed with excess of water and dried. White solid (3.6 g, 73.4 percent); mp: 174–177 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ (ppm) 6.94–7.01 (m, 1H, aromatic),7.64–7.68 (m, 1H,). IR (KBr, cm^-1) 3208.9 (OH), 1654.1 (C=O), 1625.7 (C=C) (aromatic), 1315.2 (C–O).

Reference： [1] Journal of Fluorine Chemistry, 2003, vol. 121, # 1, p. 97 - 99
[2] Medicinal Chemistry Research, 2015, vol. 24, # 9, p. 3516 - 3528
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2455 - 2458

9
[ 80-73-9 ]
[ 61079-72-9 ]
[ 189283-51-0 ]

Reference： [1] Patent: US6166246, 2000, A,

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[ 61079-72-9 ]
[ 175968-39-5 ]
[ 189283-51-0 ]

Reference： [1] Journal of Fluorine Chemistry, 2003, vol. 121, # 1, p. 97 - 99

11
[ 61079-72-9 ]
[ 197520-71-1 ]

Yield	Reaction Conditions	Operation in experiment
97.1%	at 90 - 95℃; for 3.5 h;	A stirred solution of 2,3,4-trifluorobenzoic acid (5) (10 g, 56.8 mmol) in concentrated H2SO4 (98percent, 33.0 g) was treated dropwise with the mixture of concentrated HNO3 (65percent, 6.0g) and H2SO4 (98percent, 6.3g) for 3.5 h between 90 and 95 °C. The reaction progress was monitored by TLC (30percent ethylacetate in hexane). After completion of the reaction, the reaction mixture was cooled to room temperature and ice-water (50g) was added. The precipitation was separated by centrifugation and dried between 50 and 55 °C for 8 h. The crude product was purified by column chromatography using 20percent ethylacetate:hexane as eluent. The solvent was removed under reduced pressure to afford a white solid 6 (12.2 g) in 97.1percent yield.
92%	for 2.5 h;	A 3 litre three neck round bottom flask was charged with 125 ml H₂SO₄. Fuming nitric acid was added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) was added in 5 g portions over 90 minutes. The dark brownish yellow solution was stirred for 60 minutes at which time the reaction was complete. The reaction mixture was poured into 1 litre of an ice: water mixture and extracted with diethyl ether (3 x 600 ml). The combined extracts were dried (MgSO₄) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 min after which time it was filtered to give 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-I) detected.
92%	for 2.5 h;	A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3.x.600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected.

92%	for 2.5 h;	2, 3,4-Trifluoro-5-nitro-benzoic acid 2A 3 liter three neck round bottom flask is charged with 125 ml H2504. Fuming nitricacid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1(25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solutionis stirred for 60 mm at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3 x 600 ml). The combinedorganic extracts are dried (Mg504) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 mm after which time it is filtered togive 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) nilz 220 (M-1) detected.
78%	With sulfuric acid; nitric acid In water	Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; ¹H-NMR (400 MHz; DMSO)δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95,1 23.30 (d, J_C-F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid In water	Step a Preparation of 5-Nitro-2,3,4-trifluorobenzoic Acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; ¹H-NMR (400 MHz; DMSO) δ14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid In water	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 percent yield; m.p.;¹H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-_F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid In water	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 percent yield; m.p.;¹H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0. 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-_F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	for 0.75 h;	To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; ¹H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, J_C-F=270.1, 10.7 Hz), 148.35 (dd, J_C-F=267.0, 9.2 Hz), 141.23 (dt, J_C-F=253.4 Hz), 133.95, 123.30 (d, J_C-F=2.2 Hz), 116.92 (dd, J_C-F=18.2, 3.8 Hz); ¹⁹F-NMR (376 MHz; DMSO) δ -120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
75%	at 0 - 20℃; for 6 h;	Example 1; Preparation of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid; [00238] Step A; 2,3,4-Trifluoro-5-mtrobenzoic acid; Fuming HNO₃ 90percent (549.0 g,7.84 mol corrected for 90percent wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H₂SO₄ over 18 minutes with stirring. The solution OfHNO₃ was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H₂SO₄ in a second flask with ice- water bath cooling over an hour. When addition was complete, the reaction solution was allowed to warm to room temperature. After 5 hours, the reaction was complete as determined by HPLC and the reaction mixture (brown solution) was poured into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice over 10 minutes. The yellow slurry was cooled to 14 °C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 ⁰C under high vacuum overnight to yield 1035.9 g (75percent) of 2,3,4-trifluoro-5-nitrobenzoic acid as a yellowish solid. HPLC was 98 apercent (220 nm) and 100percent (254 nm). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (IH, apparent dt, J 1.9, 7, Ar-H); ¹⁹F NMR (376 EPO <DP n="51"/>MHz, DMSOd₆) δ -153.9, -131.5, -120.9. ¹³C NMR (100 MHz, DMSO-d₆) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F, dd, J 265, 13), 154 (C-F, dd, J 265, 10), 163 (COOH). IR v^/cnf¹ 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
75%	at 0 - 20℃; for 6.3 h;	Fuming HNO₃ 90percent (549.0 g,7.84 mol corrected for 90percent wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H₂SO₄ over 18 minutes with stirring. The solution Of HNO₃ was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H₂SO₄ in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14 °C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven- dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 ⁰C under high vacuum overnight to yield 1035.9 g (75percent) of compound 2 as a yellowish solid. HPLC was 98 apercent (220 nm) and 100percent (254 nm). ¹H NMR (400 MHz, d₆ DMSO) δ 8.44 (IH, apparent dt, J 1.9, 7, Ar-H). ¹⁹F NMR (376 MHz, d₆ DMSO) δ -153.9, -131.5, -120.9. ¹³C NMR (100 MHz, d₆ DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, 7251, 10), 148 (C-F₅ dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR v_mJcm^A 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
74.3%	at 15 - 25℃; for 6.25 h;	Trifluorobenzoic acid (70 Kg₅ 398 MoI) in sulphuric acid (96 wtpercent; 194 L) and hexamethyldisiloxane (6,5 Kg₅ 40 MoI)₅ at 23 ⁰C, was added a 1:1 mixture of sulphuric acid (96 wtpercent) and nitric acid (98 wtpercent) (total 70.1 Kg)₅ over 75 min. The temperature of the reaction mixture was maintained between 15 and 25 ⁰C during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg)₅ keeping the temperature of the ice micture below 0 °C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0 ⁰C₅ then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L)₅ and the solid was then suspended in water (280 L) and stirred for 2 hours at 0 °C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45 ⁰C for 2 days, to provide 2,3₅4-Trifluoro-5-nitro benzoic acid (69.4 Kg₅ 74.3percent yiled). ¹H NMR (400 MHz₅ d₆ DMSO) δ 8.44 (IH, apparent dt, J 2, 7, Ar-H). ¹⁹F NMR (376 MHz, d₆ DMSO) δ -153.9, -131.5, -120.9. ¹³C NMR (100 MHz₅ d₆ DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F₅ dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR v_mjcm ^l 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
50%	With sulfuric acid; nitric acid In sulfuric acid at 5 - 20℃; for 2 h;	Example 1 5-FLUORO-6-(2-FLUORO-4-IODO-DHENYLAMINO)-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBOXYLIC ACID (2-- OH-ETHOXY)-AMIDE Step A: Preparation of 2. 3. 4-trifluoro-5-nitrobenzoic acid Fuming HNO3 was added dropwise to the cold (5 TO-10° C) conc. H2SO4 (5L) and stirred in a three-necked round bottom flask (20L), maintaining the temperature between 5 to- 10° C. Then was added 2, 3, E-TRIFTUOROBENZOIC acid (1 kg, 5.6 mol) in portions, maintaining the temperature at 5O C and after completion of the addition the reaction mixture was allowed to warm to room temperature, stirred for 2h and (the suspension becomes light yellow solution) then poured into 30 kg of crushed ice. The mixture was extracted with ether (3 X 4.0 L) and the organic extracts were washed with water (2 X 2L), brine (2.0 L), dried over anhydrous MGS04, filtered and evaporated under vacuum. The residue (cream colored solid) obtained is re-crystallized from hot chloroform provided the title compound as a solid (yellow). Yield : 880G (50percent), mp. 128-129 OC

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[4] Patent: WO2013/142182, 2013, A2, . Location in patent: Page/Page column 21
[5] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1905 - 1917
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[8] Patent: EP1202724, 2003, B1,
[9] Patent: EP1202724, 2003, B1,
[10] Patent: US7030119, 2006, B1, . Location in patent: Page/Page column 39
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[12] Patent: WO2007/2157, 2007, A2, . Location in patent: Page/Page column 2; 63
[13] Patent: WO2007/2157, 2007, A2, . Location in patent: Page/Page column 68
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[15] Patent: US2004/116710, 2004, A1, . Location in patent: Page 9; 16
[16] Patent: US2003/216460, 2003, A1,
[17] Patent: US5994575, 1999, A,
[18] Patent: US6136823, 2000, A,
[19] Patent: WO2008/89459, 2008, A1, . Location in patent: Page/Page column 42

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[ 197520-71-1 ]

Reference： [1] Patent: US6160171, 2000, A,

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[ 391211-97-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With lithium amide In tetrahydrofuran	A solution of 2,3,4-uorobenzoic acid (1.35 g, 7.68 mmol), 2-uoro-4-iodoaniline (1.91 g, 8.06 mmol), and lithium amide (0.702 g,30.6 mmol) in tetrahydrofuran (10.5 ml) was reacted using a standardmethod (Cai et al., 2008) to give 3,4-diuoro-2-((2-uoro-4-iodo-phenyl)amino)benzoic acid (A 2A R PAM-1, 2.99 g, 99percent) as a brown solid(Figure S1); IR (KBr) 3311, 1673, 1602, 1520, 1500, 1444, 1273,768 cm−1;1H NMR (400 MHz CD 3 OD) δ = 7.89 (1 H, ddd, J = 2.3, 6.0,9.2 Hz), 7.48 (1 H, dd, J = 1.8, 10.5 Hz), 7.41 (1 H, ddd, J = 1.4, 1.8,8.5 Hz), 6.91 (1 H, ddd, J = 7.3, 9.4, 9.4 Hz), 6.75 (1 H, ddd, J = 5.6,8.5, 8.5 Hz);13C NMR (100 MHz acetone-d 6 ) δ = 169.9, 155.7 (dd,J C,F = 252.1, 4.8 Hz), 155.6 (d, J C,F = 252.1 Hz), 143.6 (dd,J C,F = 247.8, 14.9 Hz), 137.4 (dd, J C,F = 7.7, 2.9 Hz), 135.0 (d,J C,F = 3.8 Hz), 131.9(d, J C,F = 11.5 Hz), 129.8 (dd, J C,F = 9.6, 3.8 Hz),125.8 (d, J C,F = 21.0 Hz), 123.8 (d, J C,F = 5.8 Hz), 116.4, 110.1 (d,J C,F = 18.2 Hz), 84.7 (d, J C,F = 6.7 Hz); HRMS-ESI: m/z [M-H]-calcdfor C13H6F3INO2, 391.9395; measured, 391.9414.
80%	With lithium amide In tetrahydrofuran at 45 - 55℃; for 1.25 - 2.5 h;	Example 2. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) A solution of 2-fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich, Catalog No. 30,660-6) and 2,3,4- trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich, Cat No. 33,382-4) in 38 mL tetrahydrofuran (THF) was prepared and a portion (about 5percent) of this solution was added to a stirring slurry of lithium amide (5 g, 0.22 mol) in 40 mL THF at 50-55 C. After about 15-30 min. an exotherm followed by gas release and color change are observed. The remaining portion of the (8) and (7) solution was added slowly over 1-2 hr while maintaining temperatures within 45-55^°C. The mixture was stirred until the reaction was deemed complete (by HPLC (Conditions C). The final mixture was then cooled to 20-25^°C and transferred to another reactor containing 6 N hydrochloric acid (47 mL) followed by 25 mL acetonitrile, stirred, and the bottom aqueous phase was discarded after treatment with 40 mL 50percent sodium hydroxide solution. The organic phase was concentrated under reduced pressure and 57 mL acetone was added. The mixture was heated to 50^°C, stirred, and added with 25 mL warm (40-50^°C) water and cooled to 25-30^°C to allow crystallization to occur (within 1-4 hours). Once the crystallization occurred, the mixture was further cooled to 0 to -5^°C and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in vacuum oven at about 55^°C. Overall chemical yield was 21.4 g, 80percent. EPO <DP n="15"/>¹H NMR (400 MHz, (CD₃)₂SO): δ 13.74 (bs, 1H), 9.15 (m, 1 H), 7.80 (dd, 1H), 7.62 (d, 1H), 7.41 (d, 1H), 7.10 (q, 1H), 6.81 (m, 1H).
78%	Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -78 - -67℃; for 0.5 h; Stage #2: With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -78 - 20℃;	TO a stirred suspension of 2,3, 4-trifluorobenzoic acid (78g, 0.44 moles) in dry THE (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained BELOW-67C. A dark orange solution was formed and this was stirred for another 20 minutes AT-67C. The mixture was designated as Solution A. To a stirred solution of 2-fluoro-4-iodoaniline (105g, 0.44 moles, Aldrich) in dry THF (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained below- 67C. The dark brown suspension was stirred for an additional 30 minutes at- 67C. The mixture was designated as Solution B. Solution A was transferred to solution B via a cannula under positive nitrogen pressure at-65C at such a rate to keep the temperature BELOW-55C. Then the mixture was slowly warmed to RT and stirred overnight. The reaction mixture was quenched with dry HC1 in diethyl ether (1.5 L, freshly prepared, PH-1-2. The solution was filtered through a layer of Celite. The filtrate was washed with aq. HC1 (2M, 2XLL), brine and dried. Solvent was removed under reduced pressure to give a solid, which was suspended in hexanes-acetone (9: 1, v/v, 150 mL) and stirred for 30 minutes. 3,4- dufluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid was obtained by filtration as a white solid (135g, 78percent, mp. 195-197C).

72%	With lithium amide In acetonitrile for 0.75 h; Heating / reflux	Example 2B. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide method To a stirring solution of 2,3,4-trifluorobenzoic acid (13) (5.0 g, 28.4 mmol) and 2-fluoro-4- iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL), under N₂ atmosphere was added lithium amide (2.61 g, 113.6 mmol) in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature and quenched with 1 N HCI and then water. The yellowish white precipitate was filtered, washed with water. The solid was triturated in CH₂CI₂ (30 mL) for 1h, filtered and dried in a vacuum oven at 45^°C for 14 hours to give 8.Og (72percent) of compound (9) as an off-white solid, mp 201.5-203 ^°C.
53%	With lithium amide In tetrahydrofuran at 0 - 58℃; for 12 h; Cooling with liquid nitrogen	3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (SC-1-148 Acid) [0020] A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (73; 2.38 g, 10.05 mmol), 2,3,4-trifluorobenzoic acid, (74; 1.8 g, 10.225 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0° C. and LiNH₂(561.2 mg, 24.45 mmol) was added in portions 3 portions over 10 min. The reaction was then warmed to 58° C. and stirred for 12 h. 1 N HCl was then added to the reaction mixture at 0° C. to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 10 mL portions of Et₂O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat) and dried over Na₂SO₄. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO₂using hexane/EA and provided 2.11 g (53percent) of a white solid. mp: 199.0-200.1° C. (lit^:200-201° C.). SiO₂TLC R_f0.51 (2:1 hexane/EA). ¹H NMR (MeOD-d₄): δ 7.86 (m, 1 H), 7.46 (d, J=1.6 Hz, 1 H), 7.38 (d, J=1.6 Hz, 1 H), 7.18 (m, 1 H, OH), 6.86 (m, 1 H), 6.72 (m, 1 H), 2.31 (m, 1 H, NH). Anal Calcd for C₁₃H₇F₃INO₂: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.
53%	With lithium amide In tetrahydrofuran at 0 - 58℃; Inert atmosphere	A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (38; 2.38 g, 10.0 mmol), 2,3,4-trifluorobenzoic acid, (37; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 °C and LiNH₂ (561.2 mg, 24.45 mmol) was added in 3 portions over 10 min. The reaction was then warmed to an internal temperature of 58 °C and stirred for 12 h. The mixture was cooled to 0 °C and 1 N HC1 was added maintaining the reaction mixture at 0 °C to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et₂0, washed three times with 5 mL portions of 1 N HC1, washed with NaCl (aq, sat), and dried over Na₂S0₄. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on Si0₂ using 2: 1 hexane/EA to provide 2.11 g (53percent) of a white solid. MP = 199.0 - 200.1 °C (lit. MP = 200 - 201 °C). Si0₂ TLC R_f 0.51 (2: 1 hexane/EA). 1H NMR (400 MHz, MeOD-d₄): δ 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, = 1.8 Hz and J₂ = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for Ci3H₇F₃IN0₂: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.
53%	With lithium amide In tetrahydrofuran at 0 - 58℃; for 12.5 h;	A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (26; 2.38 g, 10.0 mmol), 2,3,4-trifluorobenzoic acid, (25; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 ^oC and LiNH₂ (561.2 mg, 24.45 mmol) was added in 3 portions over a 10 min interaval. The reaction was then warmed to an internal temperature of 58 ^oC and stirred for 12 h. The mixture was cooled to 0 ^oC and 1 N HCl was added maintaining the reaction mixture below 5 ^oC to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et₂O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat), and dried over Na₂SO₄. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO₂ using 2:1 hexane/EA to provide 2.11 g (53percent) of a white solid. MP = 199.0 - 200.1 ^oC (lit. MP = 200 - 201 ^oC). ADDIN EN.CITE Davis2005453454517Davis, Edward M.Nanninga, Thomas N.Tjiong, Howie I.Winkle, Derick D.Utilization of Lithium Amide in the Synthesis of N-Arylanthranilic Acids and N-ArylanthranilamidesOrg. Process Res. Dev.Org. Process Res. Dev.843-846920051083-6160&xD;1520-586Xhttp://pubs.acs.org/doi/pdfplus/10.1021/op0501242https://pubs-acs-org.autorpa.lib.fju.edu.tw/doi/pdfplus/10.1021/op050124210.1021/op0501242³ SiO₂ TLC R_f0.51 (2:1 hexane/EA). ¹H NMR (400 MHz, MeOD-d₄): δ 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, J₁ = 1.8 Hz and J₂ = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for C₁₃H₇F₃INO₂: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.

Reference： [1] Neuropharmacology, 2019, vol. 144, p. 122 - 132
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[3] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[4] Patent: WO2006/134469, 2006, A1, . Location in patent: Page/Page column 13-14
[5] Patent: WO2004/56789, 2004, A1, . Location in patent: Page 16; 23-24; 28; 31-32; 37-38
[6] Patent: WO2006/134469, 2006, A1, . Location in patent: Page/Page column 14
[7] Patent: US2014/135519, 2014, A1, . Location in patent: Paragraph 0020
[8] Patent: WO2015/38743, 2015, A1, . Location in patent: Paragraph 0141; 0142
[9] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 13, p. 2294 - 2301
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6501 - 6504

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[ 61079-72-9 ]
[ 284030-57-5 ]

Reference： [1] Patent: WO2013/142182, 2013, A2,

[ 61079-72-9 ] Synthesis Path-Downstream 1~49

1
[ 456-22-4 ]
[ 1201-31-6 ]
[ 455-86-7 ]
[ 446-17-3 ]
[ 61079-72-9 ]
[ 121602-93-5 ]
[ 1583-58-0 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1996,p. 605 - 609

2
[ 61079-72-9 ]
[ 455-38-9 ]
[ 455-86-7 ]
[ 4519-39-5 ]
[ 65-85-0 ]

Reference： [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361

3
[ 1489-53-8 ]
[ 124-38-9 ]
[ 61079-72-9 ]

Reference： [1]European Journal of Organic Chemistry,2003,p. 447 - 451
[2]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361

4
[ 13194-68-8 ]
[ 61079-72-9 ]
[ 212628-45-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6171 - 6174
[2]Synthetic Communications,2002,vol. 32,p. 411 - 417
[3]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6501 - 6504

5
[ 61079-72-9 ]
[ 175968-39-5 ]
[ 189283-51-0 ]

Reference： [1]Journal of Fluorine Chemistry,2003,vol. 121,p. 97 - 99

6
[ 61079-72-9 ]
[ 189283-51-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydroxide; In 1-methyl-pyrrolidin-2-one; at 188℃; for 3h;Inert atmosphere;	To a solution of 2,3,4-trifluorobenzoic acid (500 g, 2.84 mol) in NMP (3.5 L) under argon, is added Sodium hydroxide (459 g, 1 1.47 mol) in portions. Reaction mixture is refluxed at 188 C under argon for 3 hrs. The progress of reaction is monitored by LCMS. Reaction is complete after 3hrs. The reaction mixture is cooled to approx. 90-100C and NMP is removed by vacuum distillation at 1 12-1 15C using a rotary evaporator. The residue is diluted with water (16 L), cooled below 10 C and acidified to pH 2 using pre- chilled 12N HCI. The precipitate was filtered, the solid was washed with cold water (1.5 L) and dried in vacuum oven at 45 C for at least 18 hrs to obtain 617.92 g of 3,4-difluoro-2-hydroxybenzoic acid as a 1 :1 mixture with NMP. Actual weight of Compound 4 is 393.6 g (80% yield).
73.4%	With sodium hydroxide; at 120℃; for 2h;Cooling with ice;	Solid sodium hydroxide (4.52 g, 113 mmol) was added in portions to an ice-cooled and stirred solution of 2,3,4-trifluorobenzoic acid (5.0 g, 28 mmol) in dimethylimidazolidinone (10 mL), and the mixture was heated to 120 C for 2 h during which TLC analysis showed the disappearance of 2,3,4-trifluorobenzoic acid. Reaction mixture was cooled to room temperature and acidified (pH 5-6) with 2 N hydrochloric acid (7.5 mL). The white solid separated out was filtered, washed with excess of water and dried. White solid (3.6 g, 73.4 %); mp: 174-177 C. 1H-NMR (400 MHz, DMSO-d6): delta (ppm) 6.94-7.01 (m, 1H, aromatic),7.64-7.68 (m, 1H,). IR (KBr, cm-1) 3208.9 (OH), 1654.1 (C=O), 1625.7 (C=C) (aromatic), 1315.2 (C-O).
	With sodium hydroxide; In 1-methyl-pyrrolidin-2-one; at 188℃; for 3h;Inert atmosphere;	To a solution of 2,3,4-trifluorobenzoic acid (500 g, 2.84 mol) in NMP (3.5 L) under argon, was added sodium hydroxide (459 g, 1 1.47 mol) in portions. The reaction mixture was refluxed at 188 C under argon for 3 hrs. The progress of the reaction was monitored by LCMS. The reaction was complete after 3 hrs. The reaction mixture was cooled to approximately 90- 100C and NMP was removed by vacuum distillation at 1 12-1 15C using a rotary evaporator. The residue was diluted with water (16 L), cooled below 10 C and acidified to pH 2 using pre-chilled 12N HCI. The precipitate was filtered, the solid was washed with cold water (1.5 L) and dried in a vacuum oven at 45 C for at least 18 hrs to obtain the 3,4-difluoro-2-hydroxybenzoic acid as a 1 :1 mixture with NMP. The actual weight of 3,4-difluoro-2-hydroxybenzoic acid was 393.6 g (80% yield).

Reference： [1]Journal of Fluorine Chemistry,2003,vol. 121,p. 97 - 99
[2]Patent: WO2019/153080,2019,A1 .Location in patent: Paragraph 00278
[3]Medicinal Chemistry Research,2015,vol. 24,p. 3516 - 3528
[4]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2455 - 2458
[5]Patent: WO2019/119145,2019,A1 .Location in patent: Paragraph 00214

7
[ 61079-72-9 ]
[ 197520-71-1 ]

Yield	Reaction Conditions	Operation in experiment
97.1%	With sulfuric acid; nitric acid; at 90 - 95℃; for 3.5h;	A stirred solution of 2,3,4-trifluorobenzoic acid (5) (10 g, 56.8 mmol) in concentrated H2SO4 (98%, 33.0 g) was treated dropwise with the mixture of concentrated HNO3 (65%, 6.0g) and H2SO4 (98%, 6.3g) for 3.5 h between 90 and 95 C. The reaction progress was monitored by TLC (30% ethylacetate in hexane). After completion of the reaction, the reaction mixture was cooled to room temperature and ice-water (50g) was added. The precipitation was separated by centrifugation and dried between 50 and 55 C for 8 h. The crude product was purified by column chromatography using 20% ethylacetate:hexane as eluent. The solvent was removed under reduced pressure to afford a white solid 6 (12.2 g) in 97.1% yield.
92%	With sulfuric acid; nitric acid; for 2.5h;	A 3 litre three neck round bottom flask was charged with 125 ml H2SO4. Fuming nitric acid was added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) was added in 5 g portions over 90 minutes. The dark brownish yellow solution was stirred for 60 minutes at which time the reaction was complete. The reaction mixture was poured into 1 litre of an ice: water mixture and extracted with diethyl ether (3 x 600 ml). The combined extracts were dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 min after which time it was filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-I) detected.
92%	With sulfuric acid; nitric acid; for 2.5h;	A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3×600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected.

92%	With sulfuric acid; nitric acid; for 2.5h;	2, 3,4-Trifluoro-5-nitro-benzoic acid 2A 3 liter three neck round bottom flask is charged with 125 ml H2504. Fuming nitricacid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1(25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solutionis stirred for 60 mm at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3 x 600 ml). The combinedorganic extracts are dried (Mg504) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 mm after which time it is filtered togive 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) nilz 220 (M-1) detected.
88%	With sulfuric acid; nitric acid; at 90℃; for 5h;	Compound 1 (5 g, 28.41 mmol) was added to a solution of concentrated sulfuric acid (15 ml) and heated to 90 C.Then, a mixed acid of concentrated H2SO4 (3.2 g, 98%) and HNO3 (3 g, 68%) was added dropwise, and reacted for 5 hours.After cooling to room temperature, the mixture was poured into EtOAc (EtOAc)EtOAc.An oil of 5.5 g was obtained in a yield of 88%.
78%	With sulfuric acid; nitric acid; In water;	Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO)delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95,1 23.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; In water;	Step a Preparation of 5-Nitro-2,3,4-trifluorobenzoic Acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) delta14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; In water;	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 % yield; m.p.;1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; In water;	Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 % yield; m.p.;1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0. 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78%	With sulfuric acid; nitric acid; for 0.75h;	To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta -120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
75%	With sulfuric acid; nitric acid; at 0 - 20℃; for 6h;	Example 1; Preparation of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid; [00238] Step A; 2,3,4-Trifluoro-5-mtrobenzoic acid; Fuming HNO3 90% (549.0 g,7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution OfHNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice- water bath cooling over an hour. When addition was complete, the reaction solution was allowed to warm to room temperature. After 5 hours, the reaction was complete as determined by HPLC and the reaction mixture (brown solution) was poured into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice over 10 minutes. The yellow slurry was cooled to 14 C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75%) of 2,3,4-trifluoro-5-nitrobenzoic acid as a yellowish solid. HPLC was 98 a% (220 nm) and 100% (254 nm). 1H NMR (400 MHz, DMSO-d6) delta 8.44 (IH, apparent dt, J 1.9, 7, Ar-H); 19F NMR (376 EPO <DP n="51"/>MHz, DMSOd6) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz, DMSO-d6) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F, dd, J 265, 13), 154 (C-F, dd, J 265, 10), 163 (COOH). IR v^/cnf1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
75%	With sulfuric acid; nitric acid; at 0 - 20℃; for 6.3h;Product distribution / selectivity;	Fuming HNO3 90% (549.0 g,7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution Of HNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14 C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven- dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75%) of compound 2 as a yellowish solid. HPLC was 98 a% (220 nm) and 100% (254 nm). 1H NMR (400 MHz, d6 DMSO) delta 8.44 (IH, apparent dt, J 1.9, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz, d6 DMSO) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, 7251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmJcmA 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
74.3%	With Hexamethyldisiloxane; sulfuric acid; nitric acid; at 15 - 25℃; for 6.25h;Product distribution / selectivity;	Trifluorobenzoic acid (70 Kg5 398 MoI) in sulphuric acid (96 wt%; 194 L) and hexamethyldisiloxane (6,5 Kg5 40 MoI)5 at 23 0C, was added a 1:1 mixture of sulphuric acid (96 wt%) and nitric acid (98 wt%) (total 70.1 Kg)5 over 75 min. The temperature of the reaction mixture was maintained between 15 and 25 0C during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg)5 keeping the temperature of the ice micture below 0 C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0 0C5 then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L)5 and the solid was then suspended in water (280 L) and stirred for 2 hours at 0 C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45 0C for 2 days, to provide 2,354-Trifluoro-5-nitro benzoic acid (69.4 Kg5 74.3% yiled). 1H NMR (400 MHz5 d6 DMSO) delta 8.44 (IH, apparent dt, J 2, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz5 d6 DMSO) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmjcm l 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
50%	With sulfuric acid; nitric acid; In sulfuric acid; at 5 - 20℃; for 2h;	Example 1 5-FLUORO-6-(2-FLUORO-4-IODO-DHENYLAMINO)-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBOXYLIC ACID (2-- OH-ETHOXY)-AMIDE Step A: Preparation of 2. 3. 4-trifluoro-5-nitrobenzoic acid Fuming HNO3 was added dropwise to the cold (5 TO-10 C) conc. H2SO4 (5L) and stirred in a three-necked round bottom flask (20L), maintaining the temperature between 5 to- 10 C. Then was added 2, 3, E-TRIFTUOROBENZOIC acid (1 kg, 5.6 mol) in portions, maintaining the temperature at 5O C and after completion of the addition the reaction mixture was allowed to warm to room temperature, stirred for 2h and (the suspension becomes light yellow solution) then poured into 30 kg of crushed ice. The mixture was extracted with ether (3 X 4.0 L) and the organic extracts were washed with water (2 X 2L), brine (2.0 L), dried over anhydrous MGS04, filtered and evaporated under vacuum. The residue (cream colored solid) obtained is re-crystallized from hot chloroform provided the title compound as a solid (yellow). Yield : 880G (50%), mp. 128-129 OC
	With sulfuric acid; nitric acid; for 2.5h;	Example 1; Step A: 2,3,4-Trifluoro-5-nitro-benzoic acid 2 . A 3 liter three neck round bottom flask is charged with 125 mL H2SO4. Fuming nitric acid is added (8.4 mL, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 minutes at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3×600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 minutes after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected.
29 g (92%)	With sulfuric acid; nitric acid;	Step A 2,3,4-Trifluoro-5-nitro-benzoic acid A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3*600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid.
	With sulfuric acid; potassium nitrate; In hexane;	(1) 2,3,4-Trifluoro-5-nitrobenzoic acid: 2,3,4-Trifluorobenzoic acid (1 g) was added to sulfuric acid (5 ml), and potassium nitrate (630 mg) was gradually added to the mixture under cooling on ice. The resultant mixture was stirred overnight at room temperature, and the reaction mixture was poured onto crushed ice. The mixture was extracted with diethyl ether, and the organic phase was dried over magnesium sulfate. The solvent was removed through distillation, and n-hexane was added to the residue, to thereby collect the solid of the title compound (1 g) by filtration. Form: colorless powder Melting point: 127-135 C. 1 H--NMR(CDC kappa3)delta; 8.67-8.71(m, 1H)
	With potassium nitrate; In hexane; sulfuric acid;	Referential Example 5 Synthesis of 2,3,4-Trifluoro-5-nitrobenzoic Acid 2,3,4-Trifluorobenzoic acid (2.5 g) was dissolved in concentrated sulfuric acid (15 ml). Potassium nitrate (1.62 g) was added to the solution under ice cooling. The temperature of the reaction mixture was (given back to room temperature to conduct stirring for 2 days. The reaction mixture was poured into ice water (300 ml) and extracted with ether (200 ml). An organic layer was dried and concentrated. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (3.06 g) as a pale yellow powder. 1 H-NMR (d6 -DMSO) delta: 8.40-8.47(m,1H).
	With sulfuric acid; nitric acid; at 5 - 20℃; for 2h;	00128] Step A: 2,3,4-Trifluoro-5-nitrobenzoic acid:[00129] Fuming nitric acid (1.7 ml) is added dropwise to concentrated sulfuric acid (25 ml) while maintaining the temperature at 5 - 10 C. 2,3,4-Trifluorobenzoic acid (5 g, 28 mmoles) is added in small portion to this solution while keeping the reaction temperature at 5 C. After completion the reaction mixture is stirred at room temperature for an additional 2 hours and poured into ice. The mixture is extracted with ether (3 x 75 ml). The organic layers are combined, washed with brine, dried (MgSO4). The solvent is removed, and the crude product is recrystallized from hot chloroform to obtain the title compound.

Reference： [1]Journal of Chemical Research,2015,vol. 39,p. 326 - 327
[2]Patent: WO2007/76245,2007,A2 .Location in patent: Page/Page column 18
[3]Patent: US2003/232869,2003,A1 .Location in patent: Page 9; 16
[4]Patent: WO2013/142182,2013,A2 .Location in patent: Page/Page column 21
[5]Patent: CN109438362,2019,A .Location in patent: Paragraph 0100-0105
[6]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917
[7]Patent: US6469004,2002,B1
[8]Patent: US6506798,2003,B1
[9]Patent: EP1202724,2003,B1
[10]Patent: EP1202724,2003,B1
[11]Patent: US7030119,2006,B1 .Location in patent: Page/Page column 39
[12]Patent: WO2007/2092,2007,A1 .Location in patent: Page/Page column 49-50
[13]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 2; 63
[14]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 68
[15]Patent: WO2005/9975,2005,A2 .Location in patent: Page/Page column 51-52
[16]Patent: US2004/116710,2004,A1 .Location in patent: Page 9; 16
[17]Patent: US2003/216460,2003,A1
[18]Patent: US5994575,1999,A
[19]Patent: US6136823,2000,A
[20]Patent: WO2008/89459,2008,A1 .Location in patent: Page/Page column 42

8
[ 42016-93-3 ]
[ 61079-72-9 ]
[ 303175-44-2 ]

Yield	Reaction Conditions	Operation in experiment
60%		[0269] To a solution of 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (75 g, 0.426 mol) in anhydrous tetrahydrofuran at -78 C. under nitrogen was added slowly lithium bis(trimethylsilyl)amide (426 mL, 0.426 mol, 1.0 M solution in THF). The dark brown reaction mixture was stirred for 15 minutes at -65 C. (inside temp). This is referred to as Solution A. [0270] To a solution of 2-chloro-4-iodoaniline (108 g, 0.426 mol) in anhydrous tetrahydrofuran (1000 mL) at -78 C. (outside) under nitrogen was added slowly lithium bis(trimethylsilyl)amide (852 mL, 0.852 mol, Aldrich, 1.0 M solution in THF). The dark green solution was stirred for 0.5 hours. This is referred to as Solution B. [0271] Solution A was transferred to Solution B using positive nitrogen pressure. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with 2.5 L dry ether (saturated with hydrogen chloride gas) until the pH was about 1.0. The precipitated solid was filtered off through Celite and washed thoroughly with ether. [0272] The filtrate was washed with 1N HCl (2×500 mL), brine (2×500 mL), dried and concentrated to give a light brown solid (143 g) which was crystallized from methanol (450 mL) and methylene chloride (1.25 L) to afford 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid (104 g, 60% yield) as an off-white powder: m.p. 226-227 C.; 1H NMR (400 MHz, DMSO-d6) delta 13.83 (br s), 9.26 (s), 7.85 (ddd, J=8.9, 6.1, 1.9 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.54 (dd, J=8.6, 1.9 Hz, 1H), 7.18 (dt, J=7.3, 9.3 Hz, 1H), 6.74 (dd, J=8.5, 7.1 Hz, 1H); [0273] 19F-NMR (376 MHz, DMSO-d6) delta -129.9, -141.9. Anal. Calcd/found for C13H7NO2F2ClI: C, 38.13/37.33; H, 1.72/1.60; N, 3.42/3.31.
60%		Step A Preparation of 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic Acid To a solution of 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (75 g, 0.426 mol) in anhydrous tetrahydrofuran at -78 C. under nitrogen was added slowly lithium bis(trimethylsilyl)amide (426 mL, 0.426 mol, 1.0 M solution in THF). The dark brown reaction mixture was stirred for 15 min at -65 C. (inside temp). This is referred to as Solution A. To a solution of 2-chloro-4-iodoaniline (108 g, 0.426 mol) in anhydrous tetrahydrofuran (1000 mL) at -78 C. (outside) under nitrogen was added slowly lithium bis(trimethylsilyl)amide (852 ml, 0.852 mol, Aldrich, 1.0 M solution in THF). The dark green solution was stirred for 0.5 h. This is referred to as Solution B. Solution A was transferred to Solution B using positive nitrogen pressure. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with 2.5 L dry ether (saturated with hydrogen chloride gas) until the pH was about 1.0. The precipitated solid was filtered off through Celite and washed thoroughly with ether. The filtrate was washed with 1 N HCl (2500 mL), brine (2500 mL), dried and concentrated to give a light brown solid (143 g) which was crystallized from methanol (450 mL) and methylene chloride (1.25 L) to afford 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid (104 g, 60% yield) as an off-white powder: mp: 226-227 C.; 1H NMR (400 MHz, DMSO-d6) delta 13.83 (br s), 9.26 (s), 7.85 (ddd, J=8.9, 6.1, 1.9 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.54 (dd, J=8.6, 1.9 Hz, 1H), 7.18 (dt, J=7.3, 9.3 Hz, 1H), 6.74 (dd, J=8.5, 7.1 Hz, 1H); 19F-NMR (376 MHz, DMSO-d6) delta -129.9, -141.9. Anal. Calcd/found for C13H7NO2F2ClI: C, 38.13/37.33; H, 1.72/1.60; N, 3.42/3.31. aa0-5aa
	In acetonitrile;	EXAMPLE 11 Sequential Addition Procedure Using Lithium Amide as the Base (Solid Addition) Lithium amide procedure to make 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid To an inerted flask fitted with a stir bar was added 8 g (31.6 mmol) 2-chloro-4-iodoaniline, 6 g (34 mmol) 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> and 50 mL acetonitrile. 2.7 g (117 mmol) lithium amide was added at room temperature in portions over 2 days. The reaction was heated to 60 C. for about 1 hour, then cooled to room temperature and quenched by the addition of aqueous hydrochloric acid. After cooling to 0 C. to -15 C., the reaction was filtered and the cake washed with an acetonitrile/water mixture. The wet cake was dried in a vacuum oven resulting in 12.8 g (98%) of 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid (CIPFA).

With aqueous hydrochloric acid; In water; acetonitrile;

Alternate Addition Procedures Using Lithium Hydride and/or Lithium Amide EXAMPLE 13 Lithium hydride coupling procedure to make 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid To an inerted 22 L three-neck flask fitted with a condenser, mechanical stirrer, thermocouple, and dropping funnel was added 85 g (10.6 mol) lithium hydride, 823 g (3.25 mol) 2-chloro-4-iodoaniline and 6 L acetonitrile. A solution of 630 g (3.58 mol) 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> in 7 L acetonitrile was added causing a temperature rise to about 60 C. The slurry was stirred at 60 C. to 70 C. for 44 hours, after which time a solution is formed. To this was added a mixture of 1.75 L (21 mol) of 37% aqueous hydrochloric acid and 4.5 L of water. The resulting product slurry was cooled to 0 C. to -15 C., and after about 1 hour of stirring, the product was collected by filtration, and the filter cake washed with 8 L of 1:1 acetonitrile/water. The wet cake was dried in a vacuum yielding 1.2 Kg (90%) of 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid.

Reference： [1]Organic Process Research and Development,2005,vol. 9,p. 843 - 846
[2]Patent: US2004/6245,2004,A1 .Location in patent: Page 22-23
[3]Patent: US2003/232889,2003,A1 .Location in patent: Page/Page column 16; 17
[4]Synthetic Communications,2005,vol. 35,p. 2265 - 2270
[5]Patent: US2004/39208,2004,A1
[6]Patent: US2004/39208,2004,A1
[7]Antiviral Research,2020,vol. 178

9
[ 4214-74-8 ]
[ 61079-72-9 ]
[ 1018456-19-3 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 1: 3,4-Difluoro-2-(3,5-dichloro-2-pyridylamino)benzoic acid. Under nitrogen atmosphere, a solution of 3,5-dichloro-2-pyridylamine (1.63 g, 10 mmol; Aldrich, code 135925) and 2,3,4-trifluorobenzoic acid (1.76 g, 10 mmol; Aldrich, code 333824) in anhydrous THF (15 ml) cooled to -78°C is added drop by drop with a solution of 1.06 M of LiHMDS (lithium hexamethyldisilazane) in THF (28.4 ml, 30 mmol). At the end of the addition the reaction mixture is allowed to warm to room temperature and left under stirring for 24 hours. After evaporation of the solvent under reduced pressure, the residue is divided and taken up in HC1 1M (50 ml) and ethyl acetate (2 x 50 ml). The organic phases are pooled and washed in sequence with water (50 ml), with a saturated NaCl solution (50 ml) and anhydrified over Na2SO4. After evaporation of the solvent the residue is purified by chromatography on silica gel eluting with ethyl acetate and with a 9/1 ethyl acetate/methanol mixture. The product-containing fractions are pooled and the solvent is evaporated off to give 3,4-difluoro-2-(3,5-dichloro-2-pyridylamino)benzoic acid.

Reference： [1]Patent: EP1908751,2008,A1 .Location in patent: Page/Page column 6

10
[ 61079-72-9 ]
[ 212631-79-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; heptane; ethylbenzene / 0.25 h / -78 °C 1.2: 43 percent / tetrahydrofuran; heptane; ethylbenzene / 96 h / 20 °C 2.1: dicyclohexylcarbodiimide / tetrahydrofuran; dimethylformamide / 0.25 h 2.2: 1-hydroxybenzotriazole hydrate; 4-dimethylaminopyridine / tetrahydrofuran; dimethylformamide / 1.5 h / 20 °C 2.3: 73 percent / diisopropyl ethyl amine / tetrahydrofuran; dimethylformamide / 48 h / 20 °C

Reference： [1]Shpiro, Natalia; Marquez, Rodolfo [Synthetic Communications, 2005, vol. 35, # 17, p. 2265 - 2270]

11
[ 61079-72-9 ]
[ 518342-58-0 ]
[ 568599-39-3 ]

Yield	Reaction Conditions	Operation in experiment
59%		[0258] A mixture of the product of Step A, 2-fluoro-4-[(trimethylsilyl)ethynyl]aniline (3.85 g, 18.6 mmol) and 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (3.27 g, 18.6 mmol) was dissolved in dry THF (25 mL). The flask was fitted with a pressure-equalising dropping funnel and the entire apparatus evacuated and flushed with N2. The solution was then cooled to -78 C. (acetone/dry ice) and a solution of 1.06 M LiHMDS (52.64 mL, 55.8 mmol) was added dropwise from the dropping funnel. Following this addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 15 hours. The reaction solvent was removed under reduced pressure and the resulting residue partitioned between 1 M HCl (100 mL) and EtOAc (2×100 mL). The combined EtOAc fractions were then washed with water (100 mL) and saturated NaCl (100 mL), dried (Na2SO4), and the EtOAc removed under reduced pressure to afford a crude product which was purified by chromatography on flash silica (10% EtOAc/hexanes as eluant), giving the desired product as a pale yellow solid (3.99 g, 59%); m.p. (EtOAc/hexanes) 164-167 C. 1H NMR [400 MHz, (CD3)2SO] delta 13.70 (br s, 1H), 9.31 (br s, 1H), 7.82 (ddd, J=9.1, 6.1, 2.0 Hz, 1H), 7.34 (dd, J=12.0, 1.9 Hz, 1H), 7.18(ddd, J=8.3, 1.9,0.8 Hz, 1H), 7.16 (td, J=9.5, 7.3 Hz, 1H), 6.93 (ddd, J=8.9, 8.3, 5.4 Hz, 1H), 0.22 (s, 9H). [0259] Anal. Calcd for C18H16F3NO2Si: C, 59.5; H, 4.4; N, 3.9. Found: C, 59.7; H, 4.7; N, 3.9.
59%	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 15h;	A mixture of 2-FLUORO-4 [ (trimethylsilyl) ethynyl] aniline (3.85g, 18.6 mmol) and 2,3, 4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (3.27g, 18.6 mmol) was dissolved in dry THF (25 mL). The flask was fitted with a pressure-equilizing dropping funnel and the entire apparatus evacuated and flushed with nitrogen. The solution was then cooled to-78C and a solution of 1.06M LIHMDS (52.64 mL, 55.8 mmol) was added dropwise from the dropping funnel. Following this addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 15 hours. The reaction solvent was removed under reduced pressure and the resulting residue partitioned between 1 M HCl (100 mL) and EtOAc (2xlOOmL). The combined EtOAc fractions were then washed with water (100 mL) and brine (100 mL), dried over NA2S04, and the EtOAc removed under reduced pressure to afford a crude product which was purified by chromatography on flash silica (10% ETOAC/HEXANES), affording 3, 4-DIFLUORO-2- { [2-fluoro- 4 (trimethylsilylethynyl) phenyl] amino} benzoic acid as a pale yellow solid (3.99g, 59%); m.; (EtoAc/hexanes) 164-167C.
59%	With lithium hexamethyldisilazane; In tetrahydrofuran; water; at -78 - 20℃; for 15h;Cooling with acetone-dry ice;	Step B: Preparation of 3,4-difluoro-2-[[2-fluoro-4(trimethylsilylethynyl)phenyl] aminolbenzoic acid A mixture of the product of Step A, 2-FLUORO-4-[(TRIMETHYLSILYL) ETHYNYL] ANILINE (3.85 g, 18.6 MMOL) and 2,3, 4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (3.27 g, 18.6 MMOL) was dissolved in dry THF (25 mL). The flask was fitted with a pressure-equalising dropping funnel and the entire apparatus evacuated and flushed with N2. The solution was then cooled to-78C (acetone/dry ice) and a solution of 1.06 M LIHMDS (52.64 mL, 55.8 MMOL) was added dropwise from the dropping funnel. Following this addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 15 hours. The reaction solvent was removed under reduced pressure and the resulting residue partitioned between 1 M HCI (100 mL) and EtOAc (2 X 100 mL). The combined EtOAc fractions were then washed with water (100 mL) and saturated NACI (100 mL), dried (NA2SO4), and the EtOAc removed under reduced pressure to afford a crude product which was purified by chromatography on flash silica (10% EtOAc/hexanes as eluat), giving the desired product as a pale yellow solid (3.99 g, 59%); m. p. (EtOAc/hexanes) 164-167C. H NMR [400 MHz, (CD3) 2SO] a 13.70 (br s, 1 H), 9.31 (br s, 1 H), 7.82 (ddd, J = 9.1, 6.1, 2.0 Hz, 1 H), 7.34 (dd, J = 12.0, 1.9 Hz, 1 H), 7.18 (ddd, J = 8.3, 1.9, 0.8 Hz, 1 H), 7.16 (td, J = 9.5, 7.3 Hz, 1 H), 6.93 (ddd, J = 8.9, 8.3, 5.4 Hz, 1 H), 0.22 (s, 9 H). Anal. Calcd FOR C, 8H, 6F3NO2SI : C, 59.5 ; H, 4.4 ; N, 3.9. Found: C, 59.7 ; H, 4.7 ; N, 3.9.

Reference： [1]Patent: US2004/6245,2004,A1 .Location in patent: Page 21
[2]Patent: WO2004/56789,2004,A1 .Location in patent: Page 55
[3]Patent: WO2005/7616,2005,A1 .Location in patent: Page/Page column 17-18

12
[ 61079-72-9 ]
[ 619-45-4 ]
[ 568597-59-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1 Methyl 4-[[2.3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]-amino]benzoate To a solution of 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (1.00 g, 5.68 mmol) in dry THF (10 mL) at -78 C. under nitrogen was added slowly, lithium bis(trimethylsilyl)amide (5.36 mL, 5.68 mmol, 1.06 M solution in THF). The resulting solution was stirred for 15 minutes at this temperature. This is referred to as Solution A. To a solution of methyl 4-aminobenzoate (857 mg, 5.68 mmol) in dry THF (10 mL) at -78 C. (outside) under nitrogen was added slowly, lithium bis(trimethylsilyl)amide (10.71 mL, 11.36 mmol, 1.06 M solution in THF). The resulting solution was stirred for 15 minutes. This is referred to as Solution B. Solution A was transferred to Solution B using positive nitrogen pressure. The reaction mixture was stirred at ambient temperature overnight. The resulting yellow suspension was poured into 1 M HCl solution (150 mL) and extracted with EtOAc (2*100 mL). The EtOAc fractions were then combined and washed with water (200 mL) and brine (200 mL), then dried (Na2SO4), filtered through Celite, and the solvent removed under reduced pressure to afford crude 3,4-difluoro-2-[[4-(methoxycarbonyl)-phenyl]amino]benzoic acid as a cream solid (1.89 g). 1H NMR [400 MHz, (CD3)2SO] delta 13.38 (br s, 1H), 9.25 (br s, 1H), 7.84-7.76 (m, 2H), 7.29-7.13 (m, 2H), 6.93 (dd, J=8.8, 3.0 Hz, 2H), 3.84 (s, 3H).

Reference： [1]Patent: US2003/232889,2003,A1 .Location in patent: Page/Page column 14

13
[ 61079-72-9 ]
[ 773873-68-0 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine; methanol; thionyl chloride;	Methyl 4-Amino-2,6-difluorobenzoate (Compound H1) A solution of <strong>[61079-72-9]trifluorobenzoic acid</strong> (150 mg, 0.85 mmol, Aldrich) in 0.5 ml of SOCl2 was heated under reflux for 2 h. The reaction mixture was cooled to room temperature, and excess of SOCl2 was removed under reduced pressure. The residue was dissolved in 1 ml of pyridine and 0.2 ml of methanol. After stirring at room temperature for 30 min, solvent was removed and the residue was purified by column chromatography (ethyl acetate/hexane 1/10) to give methyl trifluorobenzoate as a colorless oil.
	In pyridine; methanol; thionyl chloride;	Methyl 4-Amino-2,6-difluorobenzoate (Compound I) A solution of <strong>[61079-72-9]trifluorobenzoic acid</strong> (150 mg, 0.85 mmol, Aldrich) in 0.5 ml of SOCl2 was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and excess of SOCl2 was removed under reduced pressure. The residue was dissolved in 1 ml of pyridine and 0.2 ml of methanol. After stirring at room temperature for 30 min, solvent was removed and the residue was purified by column chromatography (ethyl acetate/hexane 1/10) to give methyl trifluorobenzoate as a colorless oil.
	In pyridine; methanol; thionyl chloride;	Methyl 4-Amino-2,6-difluorobenzoate (Compound H1) A solution of <strong>[61079-72-9]trifluorobenzoic acid</strong> (150 mg, 0.85 mmol, Aldrich) in 0.5 ml of SOCl2 was heated under reflux for 2h. The reaction mixture was cooled to room temperature, and excess of SOCl2 was removed under reduced pressure. The residue was dissolved in 1 ml of pyridine and 0.2 ml of methanol. After stirring at room temperature for 30 min, solvent was removed and the residue was purified by column chromatography (ethyl acetate/hexane 1/10) to give methyl trifluorobenzoate as a colorless oil.

Reference： [1]Patent: US5965606,1999,A
[2]Patent: US5663357,1997,A
[3]Patent: US5675024,1997,A

14
[ 61079-72-9 ]
ice-water [ No CAS ]
[ 197520-71-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; nitric acid;	Reference Example 1 A mixed solution of 10.56 g (60 mmol) of 2,3,4-trifluorobenzoic acid and 15.6 ml of sulfuric acid was ice-cooled, and 11.4 ml of a fumed nitric acid was added dropwise thereto at 5 to 30 C. and the mixture was stirred at the same temperature for 5 hours to complete the reaction. After completion of the reaction, the resulting reaction mixture was added to 400 ml of ice-water, and then, extracted twice with 150 ml of ethyl acetate. The combined organic layers were washed with 100 ml of water, dried over anhydrous magnesium sulfate, and then, filtered and evaporated to dryness. The resulting product obtained by evaporation to dryness was added to 50 ml of water and the mixture was stirred to wash the product. After collecting the precipitates by filtration, the precipitates were dried under reduced pressure to obtain 10.0 g (45.2 mmol) of 2,3,4-trifluoro-5-nitrobenzoic acid. Melting point: 134-135 C. 1 H-NMR (DMSO, 400 MHz) delta (ppm)=8.68 (H, ddd, Ar-H)

Reference： [1]Patent: US6160171,2000,A

15
[ 80-73-9 ]
[ 61079-72-9 ]
[ 189283-51-0 ]

Yield	Reaction Conditions	Operation in experiment
95.1%	With sodium hydroxide;	EXAMPLE 1 1.76 g (0.01 mole) of 2,3,4-trifluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 150 C. for 2 hours to give rise to a reaction. After the completion of the reaction, part of 1,3-dimethyl-2-imidazolidinone was recovered. The resulting reaction mixture was diluted with 500 ml of water and then subjected to precipitation with a 10% aqueous hydrochloric acid solution. The resulting material was cooled in an ice bath. The resulting crystals were collected by filtration, washed with water, and dried to obtain 1.66 g of 3,4-difluorosalicylic acid. The isolated yield was 95.1% relative to the 2,3,4-trifluorobenzoic acid used. (Properties of 3,4-difluorosalicylic acid) Melting point: 176.8 to 178.2 C. (Confirmation data) MS m/z: 174 (M+) 60 MHz 1 H-NMR (DMSO-d6 +CDCl3) delta value: 6.63-7.20 (m, 1H), 7.47-7.90 (m, 1H), 8.33 (brs, 2H) IR (KBr tablet, cm-1): 3431, 3211, 3104, 3079, 3022, 2942, 2864, 2677, 2546, 2343, 1658, 1573, 1540, 1512, 1470, 1445, 1384, 1316, 1277, 1214, 1200, 1149, 1054, 909, 831, 785, 716, 689, 609

Reference： [1]Patent: US6166246,2000,A

16
[ 61079-72-9 ]
[ 212631-85-1 ]

Yield	Reaction Conditions	Operation in experiment
63%	With manganese(IV) oxide; sulfuric acid; bromine; acetic anhydride In acetic acid at 20 - 60℃; for 101h;
53%	Stage #1: 2,3,4,-trifluorobenzoic acid With sodium bromate; potassium sulfate In water at 90℃; Stage #2: With sulfuric acid In water at 90℃; for 2h;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; Chugai Pharmaceutical (in: Roche) - WO2006/109661, 2006, A1 Location in patent: Page/Page column 16-17; 2/3
[2]Current Patent Assignee: ROCHE HOLDING AG; Chugai Pharmaceutical (in: Roche) - WO2006/109661, 2006, A1 Location in patent: Page/Page column 17-18; 3/3

17
[ 61079-72-9 ]
[ 203916-59-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With manganese(IV) oxide; sulfuric acid; iodine; acetic anhydride; acetic acid; at 20 - 50℃;	It was added acetic acid (1.2 L) and acetic anhydride (0.63 L) to the 5L flask. Sulfuric acid (1.6 L)so as not to exceed 40 C (104 F) while cooling with ice and mixed into the same flask. I 2(70 g) further at room temperature, activated MnO 2 (70 g) and 2,3,4-tri-fluoro-benzoic acid(120 g, 0.68 mol) was added in the form of a solid while stirring well. While stirring thesuspension of the resulting black purple at 50 C, the I 2 (70 g) and MnO 2 (70 g) after 2-3hours, after 4-6 hours I 2 (33 g) and MnO 2 (37 g) was further added. 24After time, the reactionmixture was added to ice (2 L). Three times with methylene chloride (1.6 L + 1.0 L + 1.0 L) extracted the organic layer of purplewas obtained, an excess of 2 times with 0.2N aqueous sodium thiosulfate solution for thepurpose of removal of iodine (2.0 L + 1.0 L ) Upon washing the organic layer was changed to paleyellow. To give a clear organic layer unclouded and washed four times for the purpose ofremoving the acetic acid contained in the organic layer was 1.0 L of water. The organic layer wasdried over anhydrous sodium sulfate (1.3 kg), and the solvent was evaporated under reducedpressure, the objective compound as a white powder 2,3,4-tri-fluoro-5-iodo - benzoic acid (192 g,94%) Obtained. Note that if necessary EtOAc: Hexane = 1: 9 (v / v) can be washed with a solution.

Reference： [1]Patent: WO2006/109661,2006,A1 .Location in patent: Page/Page column 15-16; 1/3
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1795 - 1801
[3]Patent: JP2016/34901,2016,A .Location in patent: Paragraph 0039; 0040; 0041
[4]Angewandte Chemie - International Edition,2019,vol. 58,p. 226 - 230
Angew. Chem.,2019,vol. 131,p. 232 - 236,5
[5]Patent: WO2007/21001,2007,A1 .Location in patent: Page/Page column 11
[6]Patent: WO2007/21001,2007,A1 .Location in patent: Page/Page column 10-11
[7]Patent: WO2007/21001,2007,A1 .Location in patent: Page/Page column 9-10

18
[ 1117-37-9 ]
[ 61079-72-9 ]
ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; triethylamine;N,N-dimethyl-formamide; In tetrahydrofuran; toluene;	Reference Example 22 Ethyl 3-dimethylamino-2-(2,3,4-trifluorobenzoyl)acrylate A mixed solution of 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (10.3g, 58.5mmol), thionyl chloride (6.4ml, 87.8mmol) and a catalytic amount of dimethylformamide was heated under reflux for 30 minutes. After letting the reaction solution cool, the reaction solution was concentrated under a reduced pressure, toluene (30ml) was added to the residue, and concentration under a reduced pressure was performed again. The residue obtained was then dissolved in tetrahydrofuran (20ml), and the resulting solution was added to a tetrahydrofuran (40ml) solution of ethyl beta-dimethylaminoacrylate (9.20g, 64.3mmol) and triethylamine (10.2ml, 73.1mmol) while stirring and cooling with ice. The reaction mixture was then stirred at room temperature for 1.5 hours and then heated under reflux for 16.5 hours. After letting the reaction solution cool, the precipitated solids were removed by filtration and the filtrate was concentrated under a reduced pressure. The residue was then applied to a silica gel chromatography, and 15.1g (86%) of the title compound was obtained from an n-hexane:ethyl acetate = 3:1 eluate. 1H-NMR (400MHz, CDCl3) delta: 1.00 (3H, t, J=7.1Hz), 2.88 (3H, brs), 3.33 (3H, brs), 4.01 (2H, q, J=7.1Hz), 6.95-7.01 (1H, m), 7.34 (1H, brs), 7.80 (1H, s).

Reference： [1]Patent: EP1336611,2003,A1

19
[ 29632-74-4 ]
[ 61079-72-9 ]
[ 391211-97-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With lithium amide; In tetrahydrofuran;	A solution of 2,3,4-uorobenzoic acid (1.35 g, 7.68 mmol), 2-uoro-4-iodoaniline (1.91 g, 8.06 mmol), and lithium amide (0.702 g,30.6 mmol) in tetrahydrofuran (10.5 ml) was reacted using a standardmethod (Cai et al., 2008) to give 3,4-diuoro-2-((2-uoro-4-iodo-phenyl)amino)benzoic acid (A 2A R PAM-1, 2.99 g, 99%) as a brown solid(Figure S1); IR (KBr) 3311, 1673, 1602, 1520, 1500, 1444, 1273,768 cm-1;1H NMR (400 MHz CD 3 OD) delta = 7.89 (1 H, ddd, J = 2.3, 6.0,9.2 Hz), 7.48 (1 H, dd, J = 1.8, 10.5 Hz), 7.41 (1 H, ddd, J = 1.4, 1.8,8.5 Hz), 6.91 (1 H, ddd, J = 7.3, 9.4, 9.4 Hz), 6.75 (1 H, ddd, J = 5.6,8.5, 8.5 Hz);13C NMR (100 MHz acetone-d 6 ) delta = 169.9, 155.7 (dd,J C,F = 252.1, 4.8 Hz), 155.6 (d, J C,F = 252.1 Hz), 143.6 (dd,J C,F = 247.8, 14.9 Hz), 137.4 (dd, J C,F = 7.7, 2.9 Hz), 135.0 (d,J C,F = 3.8 Hz), 131.9(d, J C,F = 11.5 Hz), 129.8 (dd, J C,F = 9.6, 3.8 Hz),125.8 (d, J C,F = 21.0 Hz), 123.8 (d, J C,F = 5.8 Hz), 116.4, 110.1 (d,J C,F = 18.2 Hz), 84.7 (d, J C,F = 6.7 Hz); HRMS-ESI: m/z [M-H]-calcdfor C13H6F3INO2, 391.9395; measured, 391.9414.
80%	With lithium amide; In tetrahydrofuran; at 45 - 55℃; for 1.25 - 2.5h;Product distribution / selectivity;	Example 2. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) A solution of 2-fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich, Catalog No. 30,660-6) and 2,3,4- trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich, Cat No. 33,382-4) in 38 mL tetrahydrofuran (THF) was prepared and a portion (about 5%) of this solution was added to a stirring slurry of lithium amide (5 g, 0.22 mol) in 40 mL THF at 50-55 C. After about 15-30 min. an exotherm followed by gas release and color change are observed. The remaining portion of the (8) and (7) solution was added slowly over 1-2 hr while maintaining temperatures within 45-55C. The mixture was stirred until the reaction was deemed complete (by HPLC (Conditions C). The final mixture was then cooled to 20-25C and transferred to another reactor containing 6 N hydrochloric acid (47 mL) followed by 25 mL acetonitrile, stirred, and the bottom aqueous phase was discarded after treatment with 40 mL 50% sodium hydroxide solution. The organic phase was concentrated under reduced pressure and 57 mL acetone was added. The mixture was heated to 50C, stirred, and added with 25 mL warm (40-50C) water and cooled to 25-30C to allow crystallization to occur (within 1-4 hours). Once the crystallization occurred, the mixture was further cooled to 0 to -5C and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in vacuum oven at about 55C. Overall chemical yield was 21.4 g, 80%. EPO <DP n="15"/>1H NMR (400 MHz, (CD3)2SO): delta 13.74 (bs, 1H), 9.15 (m, 1 H), 7.80 (dd, 1H), 7.62 (d, 1H), 7.41 (d, 1H), 7.10 (q, 1H), 6.81 (m, 1H).
78%		TO a stirred suspension of 2,3, 4-trifluorobenzoic acid (78g, 0.44 moles) in dry THE (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained BELOW-67C. A dark orange solution was formed and this was stirred for another 20 minutes AT-67C. The mixture was designated as Solution A. To a stirred solution of 2-fluoro-4-iodoaniline (105g, 0.44 moles, Aldrich) in dry THF (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained below- 67C. The dark brown suspension was stirred for an additional 30 minutes at- 67C. The mixture was designated as Solution B. Solution A was transferred to solution B via a cannula under positive nitrogen pressure at-65C at such a rate to keep the temperature BELOW-55C. Then the mixture was slowly warmed to RT and stirred overnight. The reaction mixture was quenched with dry HC1 in diethyl ether (1.5 L, freshly prepared, PH-1-2. The solution was filtered through a layer of Celite. The filtrate was washed with aq. HC1 (2M, 2XLL), brine and dried. Solvent was removed under reduced pressure to give a solid, which was suspended in hexanes-acetone (9: 1, v/v, 150 mL) and stirred for 30 minutes. 3,4- dufluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid was obtained by filtration as a white solid (135g, 78%, mp. 195-197C).

72%	With lithium amide; In acetonitrile; for 0.75h;Heating / reflux;Product distribution / selectivity;	Example 2B. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide method To a stirring solution of 2,3,4-trifluorobenzoic acid (13) (5.0 g, 28.4 mmol) and 2-fluoro-4- iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL), under N2 atmosphere was added lithium amide (2.61 g, 113.6 mmol) in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature and quenched with 1 N HCI and then water. The yellowish white precipitate was filtered, washed with water. The solid was triturated in CH2CI2 (30 mL) for 1h, filtered and dried in a vacuum oven at 45C for 14 hours to give 8.Og (72%) of compound (9) as an off-white solid, mp 201.5-203 C.
55%	With lithium amide; In tetrahydrofuran; at 200℃; for 0.05h;Microwave irradiation;	General procedure: Benzoic acid, aniline, in a 5 mL microwave vialCharged with LiNH2 and THF.The vessel was microwaved at 200 C. for 3 minutes.Then, cool the reaction tube to room temperature,The mixture is treated with 1 M HCl aq.It was diluted with (20 mL) and extracted with CHCl 3 (20 mL × 3).The organic layers are combined, washed with brine and dried over anhydrous Na 2 SO 4,It concentrated under reduced pressure.Silica gel column chromatography of the residuePurification with (CHCl 3/10% AcOH-MeOH solution = 100/0 ? 90/10) gave the title compound.
53%	With lithium amide; In tetrahydrofuran; at 0 - 58℃; for 12h;Cooling with liquid nitrogen;	3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (SC-1-148 Acid) [0020] A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (73; 2.38 g, 10.05 mmol), 2,3,4-trifluorobenzoic acid, (74; 1.8 g, 10.225 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 C. and LiNH2 (561.2 mg, 24.45 mmol) was added in portions 3 portions over 10 min. The reaction was then warmed to 58 C. and stirred for 12 h. 1 N HCl was then added to the reaction mixture at 0 C. to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 10 mL portions of Et2O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat) and dried over Na2SO4. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using hexane/EA and provided 2.11 g (53%) of a white solid. mp: 199.0-200.1 C. (lit: 200-201 C.). SiO2 TLC Rf 0.51 (2:1 hexane/EA). 1H NMR (MeOD-d4): delta 7.86 (m, 1 H), 7.46 (d, J=1.6 Hz, 1 H), 7.38 (d, J=1.6 Hz, 1 H), 7.18 (m, 1 H, OH), 6.86 (m, 1 H), 6.72 (m, 1 H), 2.31 (m, 1 H, NH). Anal Calcd for C13H7F3INO2: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.
53%	With lithium amide; In tetrahydrofuran; at 0 - 58℃;Inert atmosphere;	A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (38; 2.38 g, 10.0 mmol), 2,3,4-trifluorobenzoic acid, (37; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 C and LiNH2 (561.2 mg, 24.45 mmol) was added in 3 portions over 10 min. The reaction was then warmed to an internal temperature of 58 C and stirred for 12 h. The mixture was cooled to 0 C and 1 N HC1 was added maintaining the reaction mixture at 0 C to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et20, washed three times with 5 mL portions of 1 N HC1, washed with NaCl (aq, sat), and dried over Na2S04. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on Si02 using 2: 1 hexane/EA to provide 2.11 g (53%) of a white solid. MP = 199.0 - 200.1 C (lit. MP = 200 - 201 C). Si02 TLC Rf 0.51 (2: 1 hexane/EA). 1H NMR (400 MHz, MeOD-d4): delta 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, = 1.8 Hz and J2 = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for Ci3H7F3IN02: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.
53%	With lithium amide; In tetrahydrofuran; at 0 - 58℃; for 12.5h;	A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (26; 2.38 g, 10.0 mmol), 2,3,4-trifluorobenzoic acid, (25; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 oC and LiNH2 (561.2 mg, 24.45 mmol) was added in 3 portions over a 10 min interaval. The reaction was then warmed to an internal temperature of 58 oC and stirred for 12 h. The mixture was cooled to 0 oC and 1 N HCl was added maintaining the reaction mixture below 5 oC to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et2O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat), and dried over Na2SO4. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using 2:1 hexane/EA to provide 2.11 g (53%) of a white solid. MP = 199.0 - 200.1 oC (lit. MP = 200 - 201 oC). ADDIN EN.CITE Davis2005453454517Davis, Edward M.Nanninga, Thomas N.Tjiong, Howie I.Winkle, Derick D.Utilization of Lithium Amide in the Synthesis of N-Arylanthranilic Acids and N-ArylanthranilamidesOrg. Process Res. Dev.Org. Process Res. Dev.843-846920051083-6160&xD;1520-586Xhttp://pubs.acs.org/doi/pdfplus/10.1021/op0501242https://pubs.acs.org/doi/pdfplus/10.1021/op050124210.1021/op05012423 SiO2 TLC Rf 0.51 (2:1 hexane/EA). 1H NMR (400 MHz, MeOD-d4): delta 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, J1 = 1.8 Hz and J2 = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for C13H7F3INO2: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.

Reference： [1]Neuropharmacology,2019,vol. 144,p. 122 - 132
[2]Angewandte Chemie - International Edition,2013,vol. 52,p. 8551 - 8556
Angew. Chem.,2013,vol. 125,p. 8713 - 8718,6
[3]Patent: WO2006/134469,2006,A1 .Location in patent: Page/Page column 13-14
[4]Patent: WO2004/56789,2004,A1 .Location in patent: Page 16; 23-24; 28; 31-32; 37-38
[5]Patent: WO2006/134469,2006,A1 .Location in patent: Page/Page column 14
[6]Patent: JP2019/89712,2019,A .Location in patent: Paragraph 0065; 0066; 0067; 0068
[7]Patent: US2014/135519,2014,A1 .Location in patent: Paragraph 0020
[8]Patent: WO2015/38743,2015,A1 .Location in patent: Paragraph 0141; 0142
[9]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2294 - 2301
[10]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6501 - 6504

20
[ 61079-72-9 ]
2,3,4-trifluoro-5-iodobenzoic acid lithium salt [ No CAS ]

Reference： [1]Patent: WO2007/21001,2007,A1 .Location in patent: Page/Page column 12

21
[ 38762-41-3 ]
[ 61079-72-9 ]
[ 934664-20-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		To a solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and 4-bromo-2- chloroaniline (1.2 g, 5.68 mmol) in acetonitrile (10 mL) was added lithium amide (0.39 g, EPO <DP n="166"/>17.04 mmol) and the reaction stirred at 60 0C for 1.5 hours. The mixture was cooled to room temperature and then to 0 0C and acidified with aq. hydrochloric acid. The obtained precipitate was collected by filtration and washed with cold water and dried in vacuo to afford 2-[(4~bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic acid (1.92 g, 94% yield) as a beige solid. MS (EI) for C13H7BrClF2NO2: 363 (MH+).
94%		To a solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and 4-bromo- 2-chloroaniline (1.2 g, 5.68 mmol) in acetonitrile (10 mL) was added lithium amide (0.39 g, 17.04 mmol) and the reaction stirred at 60 0C for 1.5 hours. The mixture was cooled to room temperature and then to 0 0C and acidified with aq. hydrochloric acid. The obtained precipitate was collected by filtration and washed with cold water and dried in vacuo to afford 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic acid (1.92 g, 94% yield) as a beige solid. MS (EI) for C13H7BrClF2NO2: 363 (MH+). [00310] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, 2-[(4-iodo-2-fluorophenyl)amino]-3- fluorobenzoic acid was prepared. MS (EI) for Ci3HgF2INO2: 376 (MH+).
94%		To a solution of 2,3,4-trifluorobenzoic acid (I g, 5.68 mmol) and 4-bromo-2- chloroaniline (1.2 g, 5.68 mmol) in acetonitrile (10 mL) was added lithium amide (0.39 g, 17.04 mmol) and the reaction stirred at 60 C for 1.5 hours. The mixture was cooled to room temperature and then to 0 0C and acidified with aq. hydrochloric acid. The obtained precipitate was collected by filtration and washed with cold water and dried in vacuo to <n="180"/>afford 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic acid (1.92 g, 94% yield) as a beige solid. MS (EI) for C3H7BrClF2NO2: 363 (MH+).

Reference： [1]Patent: WO2007/44515,2007,A1 .Location in patent: Page/Page column 164-165
[2]Patent: WO2008/76415,2008,A1 .Location in patent: Page/Page column 328
[3]Patent: WO2008/124085,2008,A2 .Location in patent: Page/Page column 178-179

22
[ 61079-72-9 ]
C₇H₂ClF₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid; at 20 - 200℃; for 0.175h;microwave irradiation;	Example 13; 5-r(ethylamino)sulfonyll-2,3,4-trifluoro-7V-r5-alpha-methyl-l-phenylethyl)-l,3,4- thiadiazol-2-vH benzamide; Intermediate 16; 5-r(ethylamino)sulfonvH-2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong>; 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (210 mg) in chlorosulfonic acid (1.5 ml, 22.92 mmol) was stirred at room temperature for 30 seconds, then microwave 200 0C for 10 min. The reaction mixture was cooled to room temperature and dumped on ice (10 g) slowly. Ethyl acetate (50 ml) was added and extracted twice with ethyl acetate (10 mL X2). The combined organic phase was dried over MgSC^ .Ethylamine (1.8 ml) in THF (2.0 M) was added, stirred at room temperature for 10 min and washed with 1 N HCl (10 ml). The organic phase was dried over MgSC^ and concentrated to give crude 5-[(ethylamino)sulfonyl]-2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong>, which was carried to the next step without further purification.

Reference： [1]Patent: WO2008/70707,2008,A1 .Location in patent: Page/Page column 40-41

23
cis-2,6-dimethylmorpholine [ No CAS ]
[ 61079-72-9 ]
[ 914935-65-2 ]

Yield	Reaction Conditions	Operation in experiment
72%		To a stirred solution of 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (25.0 g, 142 mmol) in THF (250 mL), was added lithium bis(trimethylsilyl) amide (IM in THF) (156 mL, 156 mmol ) at -78 C under a nitrogen atmosphere, and the solution was stirred for 45 minutes. To this was added a premixed solution of cis-2,6-dimethylmorpholine (17.4 mL, 142 mmol) and lithium bis(trimethylsilyl) amide (IM in THF) (156 mL, 156 mmol) (which was stirred for 45 minutes at -78 0C, before the addition) and stirring continued for 1 hour at -78 0C. The reaction mixture was brought to room temperature and stirring continued for an additional 12 hours. Solvents were evaporated, and the residue was dissolved in ethyl acetate. It was washed with IN HCl, followed by water and finally with brine. The combied organic layers were dried over anhydrous sodium sulfate and concentrated to give the title product as a semisolid. Yield: 27.5 g, (72 %). MS (ES) MH+: 271 for Ci3Hi5F2NO3 <n="78"/>1H NMR (DMSOd6): delta 1.2 (s, 6H), 2.9 (d, 2H), 3.1 (d, 2H), 3.9 (m, 2H), 7.2 (s, IH), 7.3 (t, IH), 8.1 (m, IH).
72%		To a stirred solution of 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (25.0 g, 142 mmol) in THF (250 mL), was added lithium bis(trimethylsilyl)amide (IM in THF, 156 mL, 156 mmol ) at -78 C under nitrogen atmosphere and the solution stirred for 45 min. To this was added a premixed solution of cis-2,6-dimethylmorpholine (17.4 mL, 142 mmol) and lithium bis(trimethylsilyl)amide (IM in THF, 156 mL, 156 mmol) (which was stirred for 45 minutes at -78 C, before the addition was made) and stirring continued for 1 h at -78 C. It was brought to room temperature and stirring continued for additional 12 hours. Solvents were evaporated and the residue dissolved in ethyl acetate, which was washed with IN HCl, water and brine. The organic layer was dried and concentrated to give the title compound as semi-solid. Yield: 27.5 g, (72 %). MS (ES) M+H+: 271.2 for C13H15F2NO3 1H NMR (400 MHz - CDCl3) delta: 1.2 (s, 6H), 2.9 (d, 2H), 3.1 (d, 2H), 3.9 (m, 2H), 7.2 (s, 1H), 7.3 (t, 1H), 8.1 (m, 1H).

Reference： [1]Patent: WO2009/4382,2009,A2 .Location in patent: Page/Page column 76-77
[2]Patent: WO2010/43893,2010,A1 .Location in patent: Page/Page column 82

24
[ 61079-72-9 ]
[ 144284-24-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With lithium borohydride In tetrahydrofuran

Reference： [1]Location in patent: scheme or table Tecle, Haile; Shao, Jianxing; Li, Yanhong; Kothe, Michael; Kazmirski, Steven; Penzotti, Julie; Ding, Yuan-Hua; Ohren, Jeffrey; Moshinsky, Deb; Coli, Rocco; Jhawar, Nidhi; Bora, Emilia; Jacques-O'Hagan, Suzanne; Wu, Joe [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 226 - 229]

25
[ 1086562-05-1 ]
[ 61079-72-9 ]
[ 1086562-22-2 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7344 - 7347

26
[ 61079-72-9 ]
[ 1206164-23-9 ]

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9350 - 9354
[2]Organic Letters,2010,vol. 12,p. 1000 - 1003

27
[ 68-12-2 ]
[ 61079-72-9 ]
2,3,4-trifluoro-5-formylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidine (21.2 g, 150 mmol) was dissolved in tetrahydrofuran (120 ml). After cooling to -78 C., an n-hexane solution of n-butyllithium (2.67 M, 47 ml, 126 mmol) was added dropwise to this solution, followed by stirring at the same temperature for 35 minutes. A solution of <strong>[61079-72-9]2,3,4-trifluoro-benzoic acid</strong> (10.6 g, 60.2 mmol) in tetrahydrofuran (60 ml) was added dropwise at -78 C., and the mixture was stirred at the same temperature for 50 minutes. DMF (9.0 g, 122 mmol) was added, and the mixture was further stirred for 1 hour The reaction mixture was added to ice-cold 3N hydrochloric acid (100 ml), the temperature was raised to room temperature and extracted with ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A mixed solvent of ethyl acetate (20 ml) and n-heptane (40 ml) was added to the obtained residue, and the mixture was heated to 60 C. and suspended, then n-heptane (60 ml) was further added at the same temperature, did. The mixture was cooled to 0 C. and stirred at the same temperature for 30 minutes The precipitated crystals were filtered, washed with a mixed solvent of ethyl acetate and n-heptane (1: 10), and dried under reduced pressure to give the title compound (9.0 g, 73%). The mother liquor was distilled off under reduced pressure, ethyl acetate (3.0 ml) was added to the obtained residue, and the solution was heated to 50 C. for dissolution, followed by addition of n-heptane (15 ml). After solid precipitation was confirmed, it was cooled to 0 C. and stirred at the same temperature for 1 hour and 15 minutes. The precipitated crystals were filtered, washed with a mixed solvent of ethyl acetate and n-heptane (1: 10), and then dried under reduced pressure to give the title compound (1.6 g, 13%). These title compounds were used together (total yield: 86%).

Reference： [1]Patent: WO2007/21001,2007,A1 .Location in patent: Page/Page column 12-13
[2]Patent: JP2016/34900,2016,A .Location in patent: Paragraph 0095-0098
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 2950 - 2973

28
[ 67-56-1 ]
[ 61079-72-9 ]
[ 773873-68-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With thionyl chloride; at 65℃; for 72h;Inert atmosphere; Cooling with ice;	General procedure: A solution of 2,4,6-<strong>[61079-72-9]trifluorobenzoic acid</strong> (47) or 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (48) (0.3 g, 1.7 mmol) in dry methanol (10 mL) was prepared in a three-necked, round-bottom flask fitted with a reflux condenser and a calcium chloride tube. The flask was placed in an ice/water bath, thionyl chloride (1.4 mL) was then added dropwise, and the mixture was heated at 60-65 C for three days under argon. After removal of solvent, the resulting residue was purified by extraction with pentane in the case of 49 and using column chromatography on silica gel (hexane/diethyl ether 6:1) for 50.Methyl 2,4,6-trifluorobenzoate (49): Colorless oil, yield 85% (lit. [41] N. Punja, Eur. Pat. Appl. (1981) EP 31199 19810701, CAS Registry number 79538-28-6.[41] Bp 105-110 C/15 mmHg). 1H NMR (CDCl3) delta 3.94 (s, 3H, OCH3), 6.72 (dd, 3J = 3J = 8.3, 2H, H3 and H5).Methyl 2,3,4-trifluorobenzoate (50): Colorless oil, yield 81%. 1H NMR (CDCl3) delta 3.95 (s, 3H, OCH3), 7.03 (m, 1H, H6), 7.74 (m, 1H, H5).

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 1439 - 1447

29
[ 37517-78-5 ]
[ 61079-72-9 ]
[ 157766-27-3 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 6608 - 6623

30
[ 61079-72-9 ]
[ 284030-57-5 ]

Reference： [1]Patent: WO2013/142182,2013,A2
[2]Patent: CN109438362,2019,A

31
[ 61079-72-9 ]
[ 284030-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sulfuric acid; nitric acid / 2.5 h 2: ammonium hydroxide / water / 2.5 h / 0 - 20 °C 3: hexane; tetrahydrofuran; methanol / 0.5 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: sulfuric acid; nitric acid / 5 h / 90 °C 2: ammonium hydroxide / water / 6 h / 0 °C 3: methanol / 1 h / 0 °C
	Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid 2: ammonium hydroxide / water / 5 h / 0 - 20 °C 3: hexane; tetrahydrofuran; methanol / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2013/142182, 2013, A2
[2]Current Patent Assignee: SHENZHEN TARGETRX INC - CN109438362, 2019, A
[3]Current Patent Assignee: BIOCON LIMITED - WO2021/116901, 2021, A1

32
[ 42016-93-3 ]
[ 61079-72-9 ]
[ 303175-44-2 ]
C₁₃H₇ClF₂INO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 94% 2: 6%	Stage #1: 2-chloro-4-iodoaniline; 2,3,4,-trifluorobenzoic acid With sodium amide Inert atmosphere; Stage #2: With hydrogenchloride In water Inert atmosphere;

Reference： [1]Davis, Edward M.; Nanninga, Thomas N.; Tjiong, Howie I.; Winkle, Derick D. [Organic Process Research and Development, 2005, vol. 9, # 6, p. 843 - 846]

33
[ 61079-72-9 ]
[ 157373-08-5 ]

Yield	Reaction Conditions	Operation in experiment
636 g	With pyridine; oxalyl dichloride; In toluene; at 60 - 70℃; for 2.76667h;	<strong>[61079-72-9]2,3,4-Trifluorobenzoic acid</strong> (100 g, 568 mmo1, 1.0 eq.) was suspended in toluene(1000 mL) and treated with pyridine (0.254 mL, 3.15 mmol, 0.0055 eq.). The resultingsuspension was heated to 60 to 70 C, whereupon the mixture became a clear yellowish solution. At this temperature, oxalyl chloride (94.4 g, 729 mmol, 1.3 eq.) was slowly added over 156minutes. After complete addition, the mixture was kept stirring for 10 min until complete.Toluene (360 mL) was partially removed by distillation under vacuum Gacket temperature: 60 to70 C, pressure: 200 to 100 mbar). The solution was cooled to room temperature, resulting in636 g of a yellowish and slightly turbid solution that was stored under N2 atmosphere and used inthe subsequent step without any further treatment. HPLC purity: 99.2%-area
636 g	With pyridine; oxalyl dichloride; In toluene; at 60 - 70℃; for 2.76667h;	<strong>[61079-72-9]2,3,4-Trifluorobenzoic acid</strong> (100 g, 568 mmol, 1.0 eq.) was suspended in toluene (1000 mL) and treated with pyridine (0.254 mL, 3.15 mmol, 0.0055 eq.). The resulting suspension was heated to 60 to 70 C, whereupon the mixture became a clear yellowish solution. At this temperature, oxalyl chloride (94.4 g, 729 mmol, 1.3 eq.) was slowly added over 156 minutes. After complete addition, the mixture was kept stirring for 10 min until complete. Toluene (360 mL) was partially removed by distillation under vacuum (jacket temperature: 60 to 70 C, pressure: 200 to 100 mbar). The solution was cooled to room temperature, resulting in 636 g of a yellowish and slightly turbid solution that was stored under N2 atmosphere and used in the subsequent step without any further treatment. HPLC purity: 99.2%-area.

Reference： [1]Patent: WO2014/59422,2014,A1 .Location in patent: Paragraph 000139
[2]Patent: WO2017/4393,2017,A1 .Location in patent: Paragraph 00126

34
[ 62-53-3 ]
[ 61079-72-9 ]
[ 1609454-48-9 ]

Yield	Reaction Conditions	Operation in experiment
44%	With lithium amide; In tetrahydrofuran; at 0 - 58℃; for 7h;	SC-1-175 Acid [0024] A 250 mL round bottom flask was charged with aniline (0.57 mL, 5 7 mmol), 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong>, (1 g, 5.7 mmol), and 15 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 C. and LiNH2 (327 mg, 14.25 mmol) was added in portions 2 portions over 10 min The reaction was then warmed to 58 C. (external temperature) and stirred for 7 h. 1 N HCl was then added to the reaction mixture at 0 C. to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 5 mL portions of Et2O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat) and dried over Na2SO4. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using hexane/EA and provided 606 mg (44%) yellow crystals. mp: 162.1-162.6 C. SiO2 TLC Rf 0.61 (2:1 hexane/EA).
44%	With lithium amide; In tetrahydrofuran; at 0℃; for 7h;Inert atmosphere; Heating;	A 250 mL round bottom flask was charged with aniline (24) (0.57 mL, 5.7 mmol), 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (37), (1 g, 5.7 mmol), and 15 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 C and LiNH2 (327 mg, 14.25 mmol) was added in portions 2 portions over 10 min. The reaction was then warmed to 58 C (external temperature) and stirred for 7 h. 1 N HC1 was then added to the reaction mixture at 0 C to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 5 mL portions of Et20, washed three times with 5 mL portions of 1 N HC1, washed with NaCl (aq, sat) and dried over Na2S04. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on Si02 using hexane/EA and provided 606 mg (44 %) yellow crystals. MP = 162.1 - 162.6 C. Si02 TLC R/0.61 (2: 1 hexane/EA). 1H NMR (500 MHz, CDC13): delta 6.73-6.78 (m, 1 H, Ar), 7.05 (d, 2 H, J = 7.5 Hz, Ar), 7.10 (t, 1 H, J = 7.4 Hz), 7.32 (t, 2 H, J= 7.6 Hz), 7.87-7.90 (m, 1 H, Ar), 8.99 (s, 1 H, OH).

Reference： [1]Patent: US2014/135519,2014,A1 .Location in patent: Paragraph 0024
[2]Patent: WO2015/38743,2015,A1 .Location in patent: Paragraph 0160
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2294 - 2301

35
[ 348-54-9 ]
[ 61079-72-9 ]
3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With lithium amide; In tetrahydrofuran; at 0℃; for 4.16667h;Heating; Inert atmosphere;	A 100 mL dry round bottom flask was charged with 2-fluoroaniline (0.27 mL, 2.97 mmol), 2,3,4- <strong>[61079-72-9]trifluorobenzoic acid</strong>, (528 mg, 3 mmol), and 7 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 C and LiNH2 (165.2 mg, 7.2 mmol) was added in 2 portions over a 10 min interval. The reaction was then warmed to 58 C (external temperature) and stirred for 4 h. 1 N HC1 was then added to the reaction mixture at 0 C to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 5 mL portions of Et20, washed three times with 5 mL portions of 1 N HC1, washed with NaCl (aq, sat), and dried over Na2S04. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on Si02 using hexane/EA to provide 471 mg (59 %) of white crystals. MP = 170 - 172 C. Si02 TLC Rf 0.55 (2: 1 hexane/EA). 1H NMR (400 MHz, CDC13): delta 6.72-6.78 (dt, 1 H, J = 6.8 Hz and J = 9.1 Hz, Ar), 7.00-7.13 (m, 4 H, Ar), 7.87-7.91 (ddd, 1 H, J = 2.1 Hz, J = 5.8 Hz and J = 9.1 Hz, Ar), 8.92 (s, 1 H, C02H). Anal Calcd for Ci3H8F3N02: C, 58.44; H, 3.02; N, 5.24. Found: C, 58.41; H, 3.02; N, 5.23.

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 772 - 780
[2]Patent: WO2015/38743,2015,A1 .Location in patent: Paragraph 0163
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2294 - 2301

36
2-fluoro-4-iodo-N-methylaniline [ No CAS ]
[ 61079-72-9 ]
3,4-difluoro-2-((2-fluoro-4-iodophenyl)(methyl)amino)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With lithium amide; In tetrahydrofuran; at 0℃;Inert atmosphere; Heating;	A 100 mL dry round bottom flask was charged with 2-fluoro-4-iodo-N-methylaniline (270 mg, 1.07 mmol), 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong>, (192 mg, 1.09 mmol), and 10 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 C and LiNH2 (60 mg, 2.6 mmol) was added in portions 2 portions over 5 min. The reaction was then warmed to 58 C (external temperature) and stirred for 48 h. 1 N HC1 was then added to the reaction mixture at 0 C to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 5 mL portions of Et20, washed three times with 5 mL portions of 1 N HC1, washed with NaCl (aq, sat) and dried over Na2S04. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on Si02 using 3 : 1 hexane/EA and recrystallized from toluene and hexanes to provide 286 mg (66 %) of brown crystals. MP = 86.2 - 89.1 C. Si02 TLC i?/0.45 (2: 1 hexane/EA). 1H NMR (500 MHz, CDCls): delta 3.34 (s, 3 H), 6.97 (t, 1 H, J= 8.8 Hz, Ar), 7.24-7.27 (m, 1 H, Ar), 7.35-7.37 (dd, 1 H, J = 2.0 Hz and J = 11.4 Hz, Ar), 7.50 (d, 1 H, J = 8.6 Hz, Ar), 8.07-8.10 (m, 1 H, Ar). Anal Calcd for C14H9F3INO2. 0.0436 % C6H5CH3: C, 41.78; H, 2.29; N, 3.40. Found: C, 41.77; H, 2.42; N, 3.35.
66%	With lithium amide; In tetrahydrofuran; at 0℃;Heating;	A 100 mL dry round bottom flask was charged with 2-fluoro-4-iodo-N-methylaniline (35) (270 mg, 1.07 mmol), 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong>, 2, (192 mg, 1.09 mmol), and 10 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 oC and LiNH2 (60 mg, 2.6 mmol) was added in portions 2 portions over 5 min. The reaction was then warmed to 58 oC (external temperature) and stirred for 48 h. 1 N HCl was then added to the reaction mixture at 0 oC to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 5 mL portions of Et2O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat) and dried over Na2SO4. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using 3:1 hexane/EA and recrystallized from toluene and hexanes to provide 286 mg (66 %) of brown crystals. MP = 86.2 - 89.1 oC. SiO2 TLC Rf 0.45 (2:1 hexane/EA). 1H NMR (500 MHz, CDCl3): delta 3.34 (s, 3 H), 6.97 (t, 1 H, J = 8.8 Hz, Ar), 7.24-7.27 (m, 1 H, Ar), 7.35-7.37 (dd, 1 H, J = 2.0 Hz and J = 11.4 Hz, Ar), 7.50 (d, 1 H, J = 8.6 Hz, Ar), 8.07-8.10 (m, 1 H, Ar). Anal Calcd for C14H9F3INO2. 0.0436 % C6H5CH3: C, 41.78; H, 2.29; N, 3.40. Found: C, 41.77; H, 2.42; N, 3.35.

Reference： [1]Patent: WO2015/38743,2015,A1 .Location in patent: Page/Page column 0167
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2294 - 2301

37
[ 92-88-6 ]
[ 61079-72-9 ]
4,4'-bis(2,3,4-trifluorobenzoyloxy)biphenyl [ No CAS ]

Reference： [1]Journal of Materials Chemistry C,2015,vol. 3,p. 3574 - 3581

38
[ 171753-74-5 ]
[ 61079-72-9 ]
2-((2R,6R)-2,6-dimethylmorpholino)-3,4-difluorobenzoic Acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 9078 - 9095

39
[ 67-56-1 ]
[ 61079-72-9 ]
2-methoxy-3,4-difluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		General procedure: The magnesium shavings (8.4 g, 350 mmol) and a few of iodine crystals were placed into two-necked flask with condenser and thermometer, heated to fully disappear iodine. After cooling an absolute methanol (115 ml) and absolute toluene (250 ml) were added. A mixture was refluxed to fully dissolve of magnesium shavings. Methanol was removed from the reaction mass. After cooling acid 1b (30 g, 155 mmol) was added. The reaction mixture was refluxed for 2 hrs, cooled, added 10% HCl (250 ml) and separated an organic lay. The water lay extracted with toluene (2 x 150 ml). The organics were combined, dried (over Na2SO4). The solvent removed in vacuo. The residue crystallized from hexane.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2455 - 2458

40
[ 506-59-2 ]
[ 61079-72-9 ]
C₉H₈F₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.2 g		Compound <strong>[61079-72-9]2,3,4-trifluoro-benzoic acid</strong> (1.0g, 5.67mmoL) were dissolved in 10ml of dichloromethane was added 2mL of thionyl chloride, followed by stirring at 80 4 hours, then thionyl chloride to spin , was added 10mL of dichloromethane, added triethylamine (2.3mL, 17.4mmol) and dimethylamine hydrochloride (0.46g, 5.67mmoL), stirred for 4 hours at room temperature, was added 10mL of water and 10mL of methylene chloride, the organic phase over sodium sulfate,Spin dry and has passed through the column was a pale yellow oily liquid (1.2 g of), this was dissolved in 10 ml of DMF oil, 2 g of solid potassium carbonate, anhydrous piperazine (1g), was heated to 120 deg.] C and stirred overnight. After the reaction was cooled to room temperature, 100 ml of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off the solvent, the residue was purified by column chromatography to give 2,3-difluoro -N, N- dimethyl-4- (piperazin-1-yl) benzamide (400mg).

Reference： [1]Patent: CN105712928,2016,A .Location in patent: Paragraph 0173; 0174

41
[ 61079-72-9 ]
[ 934660-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridine; oxalyl dichloride / toluene / 2.77 h / 60 - 70 °C 2.1: potassium phosphate / ethanol; water / 0.48 h / 10 - 20 °C / pH 11.9 2.2: 0.53 h / 10 - 20 °C 3.1: acetic acid; hydrogenchloride; 10% Pd/C; hydrogen / ethanol; water / 12 h / 25 °C / 1500.15 Torr / Inert atmosphere; Autoclave 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 3.47 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: EXELIXIS INC; JOHNSON MATTHEY PLC - WO2017/4393, 2017, A1

42
[ 581-43-1 ]
[ 61079-72-9 ]
C₂₄H₁₀F₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; for 24h;	In a 200 mL eggplant type flask equipped with a calcium chloride tube, 3.33 g (18.9 mmol) of 2,3,4-<strong>[61079-72-9]trifluorobenzoic acid</strong> (r-1)1.40 g (8.75 mmol) of 2,6-dihydroxynaphthalene (r-2)2.40 g (19.0 mmol) of N, N'-diisopropylcarbodiimide (DIPC)0.21 g (1.7 mmol) of 4-dimethylaminopyridine (DMAP) was dissolved in 50 mL of tetrahydrofuran (THF) and stirred at room temperature for 24 hours.The solid obtained by filtration was added to 50 mL of THF and stirred for 24 hours. After filtration, the obtained crystals were placed in 100 mL of dichloromethane and stirred for 24 hours.The crystals obtained after filtration were recrystallized from chlorobenzene to obtain a compound (No. 4).

Reference： [1]Patent: JP2017/206480,2017,A .Location in patent: Paragraph 0093-0094

43
[ 61079-72-9 ]
[ 16483-98-0 ]
2,3,4-trifluoro-N-(2-oxo-1,2-diphenylethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap; [1,3-bis(2,6-diisopropyl-phenyl)imidazol-2-ylidene] silver(I) chloro; palladium diacetate; lithium carbonate; In 1,4-dioxane; at 110℃; for 18h;	Pd(OAc) 2 (2.8 mg, mmol) and chloro [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene]silver (6.6 mg, 10 mol%), ) were added to the reaction vessel.DMAP (1 equiv), Li2CO3 (1 equiv), carboxylic acid compound 1d (22.0 mg,0.125 mmol), 2H-azepine compound 2a (24.2 mg, 0.125 mmol), dioxane (2 mL), warmed to 110 C,Reaction for 18 hours. The reaction solution is cooled to room temperature, and the solvent is removed under reduced pressure, and then subjected to column chromatography to give the corresponding alpha-amino ketone derivative.3da, its structure is determined by nuclear magnetic and high resolution mass spectrometry, see Figure 8, Figure 9 and Figure 13, the yield is up to63%.The nuclear magnetic data of the alpha-amino ketone derivative 3da obtained in this example is as follows:2,3,4-trifluoro-N-(2-oxo-1,2-diphenylethyl)benzamide(3da).White solid (29.1 mg, yield 63%).

Reference： [1]Patent: CN109096138,2018,A .Location in patent: Paragraph 0153-0158
[2]Journal of Organic Chemistry,2019,vol. 84,p. 2200 - 2208

44
[ 61079-72-9 ]
[ 606093-58-7 ]

Reference： [1]Patent: CN109438362,2019,A

45
[ 28957-04-2 ]
[ 61079-72-9 ]
(1S,5S,6S,6aR,9S,11aS,11bS,14R)-1,5,6-trihydroxy-4,4-dimethyl-8-methylene-7-oxododecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-14-yl 2,3,4-trifluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;	General procedure: Oridonin (100 mg, 0.27 mmol) wasmixed with 4-methoxycinnamic acid (48 mg, 0.27 mmol),EDCI(157 mg, 0.82 mmol) and DMAP(101 mg, 0.82 mmol) in drydichloromethane(10 mL) and stirred at room temperature overnight.The mixturewas poured into 1MHCl solution, and extractedwith dichloromethane. The organic layer was combined, washedwith water and saturated NaCl solutions, dried over anhydrousMgSO4, filtered, and concentrated in vacuo. The crude product waspurified by column chromatography to give the compound 20(122 mg, 86%) as a white solid

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 365 - 379

46
[ 61079-72-9 ]
[ 393-01-1 ]

Reference： [1]Journal of Organic Chemistry,2020,vol. 85,p. 3110 - 3124

47
[ 61079-72-9 ]
[ 391210-10-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: lithium amide / tetrahydrofuran; acetonitrile; water 2: 1,1'-carbonyldiimidazole / acetonitrile; toluene / 20 - 25 °C 3: hydrogenchloride / water / 22 - 25 °C
	Multi-step reaction with 4 steps 1: lithium amide / tetrahydrofuran; acetonitrile; water 2: acetonitrile / 20 - 25 °C 3: toluene / 20 - 25 °C 4: hydrogenchloride / water / 22 - 25 °C
	Multi-step reaction with 3 steps 1.1: lithium amide / tetrahydrofuran / 4 h / 10 - 50 °C / Inert atmosphere; Large scale 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 5 h / 5 - 25 °C / Inert atmosphere; Large scale 2.2: 5 - 10 °C / Inert atmosphere; Large scale 3.1: hydrogenchloride / acetonitrile; toluene; water / 16 h / 5 °C / Large scale

Reference： [1]Current Patent Assignee: PFIZER INC - US11066358, 2021, B1
[2]Current Patent Assignee: PFIZER INC - US11066358, 2021, B1
[3]Current Patent Assignee: SPRINGWORKS THERAPEUTICS, INC - US11084780, 2021, B1

48
[ 20350-15-6 ]
[ 61079-72-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
10%	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	3.4. General Synthetic Methods for Compounds 2-16 General procedure: Benzoic acid-derived reagent (1-2 equivalent) was added to a solution of 1 (50.0 mg, 0.18 mmol), DMAP (21.8 mg, 0.18 mmol), and EDCl (110.7 mg, 0.71 mmol) in 15 mL drydichloromethane (DCM ). The reaction mixture was stirred at 45 °C, and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-3 h, the reaction mixture was quenched with water and diluted with DCM. The organic layer was separated , and the solvent was removed under reduced pressure. The residue was purified by silica gel CC followed by semi-preparative HPLC to yield unreacted 1 and derivatives 2-16 (Figures S4-S48).
10%	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	3.4. General Synthetic Methods for Compounds 2-16 General procedure: Benzoic acid-derived reagent (1-2 equivalent) was added to a solution of 1 (50.0 mg, 0.18 mmol), DMAP (21.8 mg, 0.18 mmol), and EDCl (110.7 mg, 0.71 mmol) in 15 mL drydichloromethane (DCM ). The reaction mixture was stirred at 45 °C, and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-3 h, the reaction mixture was quenched with water and diluted with DCM. The organic layer was separated , and the solvent was removed under reduced pressure. The residue was purified by silica gel CC followed by semi-preparative HPLC to yield unreacted 1 and derivatives 2-16 (Figures S4-S48).

Reference： [1]Lu, Xu-Xiu; Jiang, Yao-Yao; Wu, Yan-Wei; Chen, Guang-Ying; Shao, Chang-Lun; Gu, Yu-Cheng; Liu, Ming; Wei, Mei-Yan [Marine Drugs, 2022, vol. 20, # 1]
[2]Lu, Xu-Xiu; Jiang, Yao-Yao; Wu, Yan-Wei; Chen, Guang-Ying; Shao, Chang-Lun; Gu, Yu-Cheng; Liu, Ming; Wei, Mei-Yan [Marine Drugs, 2022, vol. 20, # 1]

49
[ 20350-15-6 ]
[ 61079-72-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
28%	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	3.4. General Synthetic Methods for Compounds 2-16 General procedure: Benzoic acid-derived reagent (1-2 equivalent) was added to a solution of 1 (50.0 mg, 0.18 mmol), DMAP (21.8 mg, 0.18 mmol), and EDCl (110.7 mg, 0.71 mmol) in 15 mL drydichloromethane (DCM ). The reaction mixture was stirred at 45 °C, and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-3 h, the reaction mixture was quenched with water and diluted with DCM. The organic layer was separated , and the solvent was removed under reduced pressure. The residue was purified by silica gel CC followed by semi-preparative HPLC to yield unreacted 1 and derivatives 2-16 (Figures S4-S48).
28%	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	3.4. General Synthetic Methods for Compounds 2-16 General procedure: Benzoic acid-derived reagent (1-2 equivalent) was added to a solution of 1 (50.0 mg, 0.18 mmol), DMAP (21.8 mg, 0.18 mmol), and EDCl (110.7 mg, 0.71 mmol) in 15 mL drydichloromethane (DCM ). The reaction mixture was stirred at 45 °C, and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-3 h, the reaction mixture was quenched with water and diluted with DCM. The organic layer was separated , and the solvent was removed under reduced pressure. The residue was purified by silica gel CC followed by semi-preparative HPLC to yield unreacted 1 and derivatives 2-16 (Figures S4-S48).

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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

[ CAS No. 61079-72-9 ]

Quality Control of [ 61079-72-9 ]

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Product Details of [ 61079-72-9 ]

Calculated chemistry of [ 61079-72-9 ]

Physicochemical Properties

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Lipophilicity

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Medicinal Chemistry

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[ 61079-72-9 ] Synthesis Path-Upstream 1~14

[ 61079-72-9 ] Synthesis Path-Downstream 1~49

Pharmaceutical Intermediates of [ 61079-72-9 ]

Cobimetinib Related Intermediates

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Fluorinated Building Blocks

Aryls

Carboxylic Acids

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[ 61079-72-9 ]

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[ 61079-72-9 ]