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[ CAS No. 107650-20-4 ] {[proInfo.proName]}

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2D 3D

Chemical Structure| 107650-20-4

Chemical Structure| 107650-20-4

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Quality Control of [ 107650-20-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 107650-20-4 ]

Product Details of [ 107650-20-4 ]

CAS No. :	107650-20-4	MDL No. :	MFCD07357316
Formula :	C₈H₆BrNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DXUUJILVHXQDCV-UHFFFAOYSA-N
M.W :	260.04	Pubchem ID :	13770008
Synonyms :

Calculated chemistry of [ 107650-20-4 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	54.89
TPSA :	83.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.25
Log Po/w (XLOGP3) :	2.33
Log Po/w (WLOGP) :	2.36
Log Po/w (MLOGP) :	1.58
Log Po/w (SILICOS-IT) :	0.24
Consensus Log Po/w :	1.55

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.11
Solubility :	0.204 mg/ml ; 0.000785 mol/l
Class :	Soluble
Log S (Ali) :	-3.71
Solubility :	0.0502 mg/ml ; 0.000193 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.39
Solubility :	1.05 mg/ml ; 0.00404 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.15

Safety of [ 107650-20-4 ]

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

Application In Synthesis of [ 107650-20-4 ]

* 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 [ 107650-20-4 ]
Downstream synthetic route of [ 107650-20-4 ]

[ 107650-20-4 ] Synthesis Path-Upstream 1~10

1
[ 1975-50-4 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 20℃; for 5 h;	Step 1: 5-bromo-2-methyl-3-nitrobenzoic acid To stirred solution of 2-methyl-3-nitrobenzoic acid (50 g, 276.2 mmol) in conc. H₂SO₄ (200 mL), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43.4 g, 151.8 mmol) was added portion wise at room temperature and reaction mass was stirred at room temperature for 5 h. On completion, reaction mass was poured on ice cold water, solid precipitated was filtered, resulting residue was washed with water and dried under vacuum to give the desired compound (71.7 g, 100percent).
100%	Stage #1: at 20℃; for 5 h; Stage #2: Cooling	[01 123] Step 1 : 5-bromo-2-methyl-3-nitrobenzoic acid[01 124] To stirred solution of 2-methyl-3-nitrobenzoic acid (50 g, 276.2 mmol) in cone.H2SO4 (200 mL), l ,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43.4 g, 151.8 mmol) was added portion wise at room temperature and reaction mass was stirred at room temperature for 5 h. On completion, reaction mass was poured on ice cold water, solid precipitated was filtered, resulting residue was washed with water and dried under vacuum giving the desired compound (71 .7 g, 100percent)
100%	at 0℃; for 5 h;	To a stirred solution of 2-methyl-3-nitrobenzoic acid (5.00 g, 27.6 mmol) in H₂SO₄ (20 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (4.34 g, 15.20 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 hours. The reaction mixture was poured onto ice cold water, the resultant precipitated solid was collected, washed with water and dried in vacuo to give the titled compound as a white solid (7.28 g, quantitative yield). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm; 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).

99.8%	for 5 h;	A 5000 mL three neck RBF equipped with an overhead stirrer was charged with 2-methyl-3-nitro benzoic acid (150.0 g, 0.82 mol) and concentrated H₂SO₄ (600 mL). To this solution was added 1,3-dibromo-5,5-dimethylhydantoin (130.7 g, 0.455 mol) over ten minutes with vigorous stirring. The reaction was vigorously stirred at ambient temperature for 5 hours. The reaction mixture was then added to H₂O (4000 mL) chilled in an ice bath over 30 minutes. This mixture was then filtered, the solids washed twice with H₂O and further dried under vacuum to yield 217.7 g (99.8percent) of an off-white solid. ¹H NMR (CDCl₃) δ 8.18 (s, 1H), 7.95 (s, 1H), 2.59 (s, 3H).
99%	at 20℃; for 5 h;	To a mixture of 2-methyl-3-nitrobenzoic acid (150 g, 820 mmol) in concentrate sulphuric acid (600 ml.) was added 1 ,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (130.7 g, 457 mmol). The reaction mixture was stirred at room temperature for 5 hrs and then the reaction mixture was carefully added to 4L of ice-water. The solid precipitated out, which was washed with 1.5 L water. The solid was filtered off and dried in a heated desiccator at 30-40⁰C overnight to give 5-bromo-2-methyl-3-nitrobenzoic acid (220 g, 99percent), which was used in the next step without further purification.LC/MS (ESI) 257 [M+H]⁺ Rt 3.07 min
98.2%	at 20℃; for 5 h;	[01036] Step 2: 5-bromo-2-methyl-3-nitrobenzoic acid[01037] l,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (13.0 g, 45.7 mmol) was added to a mixture of 2-methyl-3-nitrobenzoic acid (15 g, 82.8 mmol) in cone. H₂S0₄ (60 mL), and the reaction mixture stirred at room temperature for 5 h. After completion of reaction, the mixture was slowly poured onto ice cold water (400 mL). The precipitated was filtered and dried under vacuum to obtain desired 5-bromo-2-methyl-3-nitrobenzoic acid (21 g, 98.2percent).
98%	at 20℃; for 5 h;	5-bromo-2-methyl-3-nitrobenzoic acid stirred solution of 2-methyl-3-nitrobenzoic acid (100 g, 552 mmol) in cone. H₂S0₄ (400 mL), l,3-dibromo-5,5-dimethyl-2,4- imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid (140 g, 98percent). The isolated compound was taken directly into the next step. 1H NMR (DMSO-J₆, 400 MHz) δ 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid In water at 20℃; for 5 h;	0323] Step 1: Synthesis of 5-brom -2-methyl-3-nitrobenzoic acid [0324] To stirred solution of 2-methyl-3-nitrobenzoic acid (100 g, 552 mmol) in cone. H₂SO₄ (400 mL), l,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid (140 g, 98percent). The isolated compound was taken directly into the next step. 1H NMR (DMSO-J₆, 400 MHz) δ 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
98%	at 20℃; Cooling with ice	[00182] Preparation of5-bromo-2-methyl-3-nitrobenzoic acid C2-l. To a mixture of compound C2-O (15 g, 82.8 mmol) in cone. H2S04 (60 mL) in an ice-water bath was added 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (13.4 g, 46.8 mmol) portionwise over 30 mins. After the mixture was stirred at room temperature overnight, the reactionmixture was added slowly to ice-water (400 mL). The precipitation was collected and dried to yield compound C2-1 as a white solid ((21.2 g, yield: 98percent), which was used directly in the next step without further purification. MS (ESfl: m/z 257.9 and 259.9 (M1).
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In sulfuric acid at 20℃; for 5 h;	5-bromo-2-methyl-3-nitrobenzoic acid To a stirred solution of 2-methyl-3- nitrobenzoic acid (100 g, 552 mmol) in cone. H₂SO₄ (400 mL), l,3-dibromo-5,5-dimethyl-2,4- imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid (140 g, 98percent>). The isolated compoundwas taken directly into the next step. 1H NMR (OMSO-d₆, 400 MHz) δ 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
98%	at 20℃;	The N-bromo succinimide (15g, 84.3mmol) is added to the 2-methyl-3-nitro-benzoic acid (15g, 82.8mmol) in the strong sulphuric acid solution (60 ml), then the reaction solution stirring the mixture at room temperature for overnight. After, when the reaction is complete, the reaction solution slowly into ice water (400 ml). The precipitate filtered, and drying in vacuum, to obtain it is expected the product 2-methyl-3-nitro-5-bromobenzoic acid 21g, the yield is 98percent.
96%	at 20℃; for 5 h;	a) S-BromG-2-roeth I-3-idtrii-ber.zoic acidTo a stirred solution of 2-methyl-3-nitro benzoic acid (300 g, 1647 mmol) in cone. H₂S0₄ (1.5 L) was added l ,3-dibromo-5,5 dimethyl -2,4-imadazolidinedione (258 g, 906 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was slowly added to ice water (4 L), and solid was precipitated out. The solid was filtered off and washed with water (1.2 L), pet ether (1 1) and dried to afford the title compound as a white solid (41 1 g, 96 percent), which was used without further purification. ^lU NMR (DMSO_; 400 MHz) : δ 2.446 (s, 3H), 8.136 (s, 1H), 8.294 (s, 1H). LCMS (ES-) m/z = 257.93 (M-H)-
96%	at 20℃; for 5 h; Inert atmosphere	To a stirred solution of 2-methyl-3-nitro benzoic acid (300 g, 1647 mmol) in conc. H₂SO₄(1.5 L) was added 1,3-dibromo-5,5 dimethyl-2,4-imadazolidinedione (258 g, 906 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was slowly added to ice water (4 L), and solid was precipitated out. The solid was filtered off and washed with water (1.2 L), pet ether (1 l) and dried to afford the title compound as a white solid (411 g, 96percent), which was used without further purification. ¹H NMR (DMSO, 400 MHz): δ2.446 (s, 3H), 8.136 (s, 1H), 8.294 (s, 1H). LCMS (ES−) m/z=257.93 (M−H)⁻
95.4%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid In tetrahydrofuran; water at 80℃; for 7.5 h;	In a 500-ml four-necked flask, 2-methyl-3-nitrobenzoic acid (20 g, 110 mmol) was charged. Thereto, tetrahydrofuran (200 ml) and 64percent sulfuric acid (100 ml) were added sequentially. The mixture was heated and stirred at an external temperature of 8O⁰C in an oil bath. After confirmation of dissolution of 2-methyl-3-nitrobenzoic acid, 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (6.3 g, 22 mmol) was added. After this, 1, 3-dibromo-5, 5- dimethylimidazolidine-2, 4-dione was added in 6.3 g (22 mmol) increments every 1 hour (total 18.9 g, 66 mmol). 7.5 hours after the start of reaction, the oil bath was removed, and the solution was cooled to room temperature. Water (200 ml) was added dropwise over about 40 minutes. The mixture was further stirred for 1 hour in an ice bath. Precipitated crystals were collected by filtration, and the crystals were washed with tap water (100 ml) . The crystals were dried under reduced pressure at 50°C, to yield the title compound (27.3 g, 105 mmol) (yield 95.4percent) . ¹H-NMR (MeOH-d₄, TMS, 300 MHz) δ (ppm): 2.53 (s, 3H), 8.08 (d, IH, J = 2.1 Hz) , 8.16 (d, IH, J = 2.1 Hz) .¹³C-NMR (MeOH-d₄, TMS, 300 MHz) δ (ppm) 15.87, 120.03, <n="186"/>130 . 12 , 132 . 47 , 137 . 05, 137 .20 , 153. 94, 167 . 97 . Melting point : 183 .3°C
90%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In sulfuric acid at 20℃; for 2 h; Cooling with ice	c) 2-methyl-3-nitrobenzoic acid (50g, 276mmol) was dissolved in 200mL of concentrated sulfuric acid, then under ice bath was added 1,3-dibromo-5,5-dimethylhydantoin (47.3g, 166mmol), stirred for 2 hours at room temperature. The reaction solution was slowly poured into a large amount of ice water to precipitate a large number of off-white solid, filtered and the solid washed with 1L of water, washed with 1L petroleum ether, and dried to give Compound E 64g, yield 90percent.
84%	at 20℃; for 5 h;	To a stirred solution of 2-methyl-3-nitrobenzoic acid (10 g, 55 mmol) in conc. H₂SO₄ (40 mL), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (9 g, 32 mmol) was added portion wise at room temperature and reaction was stirred at room temperature for 5 h. Then the reaction mass was poured on an ice cold water. Solid was filtered, and the resulting residue was washed with water and dried under vacuum to afford 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 84percent) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 2.51 (s, 3H)
81%	at 0 - 20℃; for 6 h;	To stirred solution of 2-methyl-3-nitrobenzoic acid (25 g, 138.1 mmol) in cone. H₂S0₄ (100 mL) at 0 °C, l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (23.7 g, 82.87 mmol) was added portion wise and the reaction mass was stirred at rt for 6 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mass was poured on ice cold water, the solid precipitated was filtered, washed with water and dried under reduced pressure to afford the title compound (29 g, 81percent).
7 g	at 0 - 40℃; for 5 h;	2-Methyl-3-nitrobenzoic acid (5 g) was dissolved in conc. H2S04 (20 mL) at 0°C. To this solution, NBS (6.2 g) was added gradually. The resulting mixture was stirred at 0°C for 2 hours, and then warmed to 40°C. After stirring at 40°C for 3 hours, the mixture was poured into ice/water. The white solid precipitate was filtered and dried to afford the title compound (7 g) as off-white solid. MS (ESI): C8H6BrNO4 requires 259; found no mass.
7 g	at 0 - 40℃; for 5 h;	Description 137 5-Bromo-2-methyl-3-nitrobenzoic acid (P137)2-Methyl-3-nitrobenzoic acid (5.0 g) was dissolved in conc. H2S04 (20 mL) at 0°C. To this solution, NBS (6.2 g) was added gradually. The resulting mixture was stirred at 0°C for 2 hours, and thenwarmed to 40°C. After stirring at 40°C for 3 hours, the mixture was poured into ice water. Thewhite solid precipitate was filtered and dried to give the title compound (7.0 g) as off-white solid.MS (ESI): C8H6BrNO4 requires 259; found no mass.

Reference： [1] Patent: US2012/264734, 2012, A1, . Location in patent: Page/Page column 100
[2] Patent: WO2012/142513, 2012, A1, . Location in patent: Page/Page column 288
[3] Patent: US2014/107122, 2014, A1, . Location in patent: Paragraph 0157; 0158
[4] Patent: WO2003/99275, 2003, A1, . Location in patent: Page 101
[5] Patent: US2007/219212, 2007, A1, . Location in patent: Page/Page column 23
[6] Patent: WO2007/102883, 2007, A2, . Location in patent: Page/Page column 19; 36
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3227 - 3231
[8] Patent: WO2012/118812, 2012, A2, . Location in patent: Page/Page column 311
[9] Patent: WO2013/155317, 2013, A1, . Location in patent: Page/Page column 44
[10] Patent: WO2013/155464, 2013, A1, . Location in patent: Paragraph 0323; 0324
[11] Patent: WO2014/18866, 2014, A1, . Location in patent: Paragraph 00181; 00182
[12] Patent: WO2015/57859, 2015, A1, . Location in patent: Paragraph 085
[13] Patent: CN105037360, 2016, B, . Location in patent: Paragraph 0199; 0200; 0201
[14] Patent: WO2011/140325, 2011, A1, . Location in patent: Page/Page column 94
[15] Patent: US2014/256739, 2014, A1, . Location in patent: Paragraph 0826
[16] Patent: WO2008/16184, 2008, A1, . Location in patent: Page/Page column 183-184
[17] Patent: CN105481790, 2016, A, . Location in patent: Paragraph 0198; 0199; 0200; 0203
[18] Patent: US2017/8904, 2017, A1, . Location in patent: Paragraph 0422-0423
[19] Patent: WO2014/100665, 2014, A1, . Location in patent: Paragraph 0551
[20] Patent: WO2015/200650, 2015, A1, . Location in patent: Paragraph 0655-0657
[21] Patent: WO2015/180613, 2015, A1, . Location in patent: Page/Page column 23
[22] Patent: WO2015/180612, 2015, A1, . Location in patent: Page/Page column 80; 81

2
[ 79669-49-1 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sulfuric acid; nitric acid In acetone at -5 - 0℃; for 2.25 h; Cooling with acetone-ice	Step 1: Synthesis of 5-bromo-2-methyl-3-nitrobenzoic acid A solution of 5-bromo-2-methylbenzoic acid (5.0 g, 23 mmol) in concentrated H₂SO₄ (27 ml, 512 mmol) was cooled to 5° C. in an acetone/ice bath. A mixture of concentrated nitric acid (1.9 ml, 30 mmol) and concentrated H₂SO₄ (2.8 ml, 52 mmol) was added dropwise to the reaction mixture at -5 to 0° C. over 15 minutes. The yellow reaction mixture was stirred at -5 to 0° C. for 2 hours during which time a yellow precipitate formed. The reaction mixture was poured onto ice (150 g) and the precipitate was then collected by filtration. The precipitate was air dried to give the title compound (5.5 g, 52percent) as a pale yellow solid. LC-MS 57percent, 1.82 min (3.5 minute LC-MS method), no ionization; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.29 (s, 1H) 8.13 (d, J=1.58 Hz, 1H) 2.43 (s, 3H).

Reference： [1] Patent: US2012/264734, 2012, A1, . Location in patent: Page/Page column 172

3
[ 77-48-5 ]
[ 1975-50-4 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	at 20℃; for 5 h;	To stirred solution of 2-methyl-3-nitrobenzoic acid(10 g, 55 mmol) in conc. H2504 (40 mE), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (9 g, 32 mmol) wasadded portion wise at room temperature and reaction wasstirred at room temperature for 5 hours. Then the reactionmass was poured on an ice cold watet Solid was filtered, andthe resulting residue was washed with water and dried undervacuum to afford 5-Bromo-2-methyl-3-nitrobenzoic acid(12 g, 84percent) as a light yellow solid. 1H NMR: (400 MHz, DMSO-d6): δ 8.28 (d, J=2.0Hz, 1H), 8.13(d, J=2.0 Hz, 1H), 2.51(s, 3H). Chemical Formula: C8H613rNO4; MolecularWeight: 260.04. Total H count from ‘HNMR data: 5.

Reference： [1] Patent: US2018/177750, 2018, A1, . Location in patent: Paragraph 1230-1234

4
[ 220514-28-3 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
12.9 g	With lithium hydroxide monohydrate; water In tetrahydrofuran at 25℃;	To the solution of compound K501-A (14.0 g, 51.1 mmol) in THF (90 mL) was added LiOH (6.4g, 153 mmol)and H2O (30 mL). The reaction mixture was stirred at 25°C overnight and then concentrated. The remaining liquid wasdiluted with Et2O (60 mL) and water (100 mL). The organic layer was separated. The water layer was adjusted with 2NHCl to pH = 2,extracted with EtOAc (150 mL). The organic layers were washed with sat. brine (200 mL), dried, filteredand concentrated to afford K501-B (12.9 g) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 2.0 Hz, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 2.45 (s, 3H)

Reference： [1] Patent: EP3404024, 2018, A1, . Location in patent: Paragraph 0108; 0109

5
[ 67-56-1 ]
[ 107650-20-4 ]
[ 220514-28-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	Reflux	[00183J Preparation of methyl 5-bromo-2-methyl-3-nitrobenzoate (‘2-2, A mixture of 5.bromo-2-methyl-3-nitrobenzoic acid (‘2-1(21.2 g, 81.5 mmol) in SOC12 (100 mL) washeated to retlux until the mixture became clear (about 1.5 hrs). The reaction mixture was cooled and concentrated in vacuo, The residue was added portionwise to 250 mL of MeOH. The resulting mixture was stirred overnight under refluxing. The reaction mixture was cooled and concentrated. The residue was dissolved in 300 mL of hA, washed sequentially with sat. aq. NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel, PE:EA (20:1, v:v)) to yield compound C2-2 as a light yellow solid (21.2 g, yield: 95percent).
94.8%	at 75℃; for 12 h;	To a solution of 5-bromo-2-methyl-3-nitro-benzoic acid (1 g, 3.85 mmol, 1 equivalent) in MeOH (20 mL) was added H₂SO₄ (3.78 g, 38.5 mmol, 2.05 mL, 10 equivalents). The mixture was stirred at 75° C. for 12 hrs. When the reaction was complete, the pH of the mixture was adjusted to 7 with saturated sodium bicarbonate aqueous solution, then extracted with ethyl acetate (20 mL*3). The combined organic phase was dried over sodium sulfate and concentrated to give methyl 5-bromo-2-methyl-3-nitro-benzoate (7.1, 1 g, 3.65 mmol, 94.8percent yield) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.14 (d, J=2.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 3.96 (s, 3H), 2.58 (s, 3H).
87%	Reflux	A mixture of 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 41 mmol) in SOCl₂/MeOH (v:v=1:10) (250 mL) was heated to reflux overnight. The reaction mixture was cooled and concentrated. The residue was dissolved in 300 mL of ethyl acetate. The organic layer was washed sequentially with sat. aq. NaHCO₃ and brine, dried over Na₂SO₄, and concentrated. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate (20:1, v:v)) to afford the desired compound (11 g, yield: 87percent). ¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 3.95 (s, 3H), 2.57 (s, 3H)

87%

Reflux

A mixture of 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 41 mmol) in 50C12/MeOH(v:v=1:10) (250 mE) was heated to reflux overnight. The reaction mixture was cooled and concentrated. The residue was dissolved in 300 mE of EA. The organic layer was washed sequentially with sat. aq. NaHCO3 and brine, dried over Na2504, and concentrated. The residue was purified by chromatography (silica gel, PE:EA (20:1, v:v)) to afford Methyl 5-bromo-2- methyl-3-nitrobenzoate (11 g, yield: 87percent). 1H NMR: (400 MHz, CDC13): ö 8.12 (d, J=2.0 Hz, 1H), 7.97(d, J=2.0 Hz, 1H), 3.95(s, 3H), 2.57(s, 3H). Chemical Formula: C9H813rN04; Molecular Weight: 272.96. Total H count from ‘HNMR data: 8.

Reference： [1] Patent: WO2014/18866, 2014, A1, . Location in patent: Paragraph 00181; 00183
[2] Patent: US2018/265517, 2018, A1, . Location in patent: Paragraph 0318-0321
[3] Patent: US2017/8904, 2017, A1, . Location in patent: Paragraph 0422; 0424
[4] Patent: US2018/177750, 2018, A1, . Location in patent: Paragraph 1235-1239
[5] Patent: CN105481790, 2016, A, . Location in patent: Paragraph 0198; 0199; 0200; 0204

6
[ 107650-20-4 ]
[ 74-88-4 ]
[ 220514-28-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;	To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (7.28 g, 28.0 mmol) in DMF (100 mL) was added sodium carbonate (11.9 g, 112 mmol) and methyl iodide (15.9 g, 112 mmol). The reaction mixture was stirred at 60° C. for 8 hours. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate. The combined filtrate was washed with water and the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a solid. (7.74 g, quantitative yield). ¹H-NMR (400 MHz, CDCl₃) δ (ppm); 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
99%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;	[0998] Step 2: methyl 5-bromo-2-meth -3-nitrobenzene[0999] To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (287 g, 1 103 mmol) in DMF (1 50 mL), sodium carbonate (468 g, 4415 mmol) and methyl iodide (626.63 g, 4415 mmol) were added. Resulting reaction mass was heated at 60 °C for 8 h. On completion, solid precipitated was filtered, residue washed with diethyl ether (5 times). Combined organic layers were dried, concentrated under reduced pressure giving the desired compound (302 g, 99percent) which was used for further reaction.
98%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 12 h;	To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (29 g, 111.9 mmol) in DMF (300 mL), sodium carbonate (48 g, 447.8 mmol) and Mel (63.59 g, 447.8 mmol) were added. The resulting reaction mass was heated at 60 °C for 12 h.The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (30 g, 98percent)

97%	With sodium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 8 h;	Methyl 5-bromo-2-methyl-3-nitrobenzoate To a stirred solution of 5-bromo-2- methyl-3-nitrobenzoic acid (285 g, 1105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 °C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate (1L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97percent yield). The isolated compound was taken directly into the next step. 1H NMR (CDC1₃, 400 MHz) δ 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
97%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;	[0325] Step 2: Synthesis of methyl -bromo-2-methyl-3-nitrobenzoate [0326] To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (285 g, 1105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 °C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate (1L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97percent yield). The isolated compound was taken directly into the next step. 1H NMR (CDC1₃, 400 MHz) δ 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
97%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;	Methyl 5-bromo-2-methyl-3-nitrobenzoate To a stirred solution of 5-bromo-2- methyl-3-nitrobenzoic acid (285 g, 1 105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 °C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate (1L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97percent yield). The isolated compound was taken directly into the next step. 1H NMR (CDCls, 400 MHz) δ 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
95%	With sodium carbonate In N,N-dimethyl-formamide at 20 - 55℃; for 10 h;	To a solution of 5-bromo-2-methyl-3-nitrobenzoic acid (10 g, 38.5 mmol) in DMF (100 mL) were added sodium carbonate (16.30 g, 154 mmol) and methyl iodide (9.62 mL, 154 mmol) at room temperature and the reaction mixture was stirred at 55 °C for 10 hours. On completion, the reaction mixture was filtered and the inorganic solid residue was washed with ethyl acetate. The filtrate was concentrated under vacuum till dry and re- dissolved in ethyl acetate before washing with 5 percent sodium bicarbonate solution (70 mL) followed by 5.0 M HC1 solution (30 mL). The organic layer was finally washed with brine, dried over sodium sulfate and concentrated to yield 10 g (95percent) of the title compound. ^JH NMR (CDC1₃, 300 MHz) δ ppm: 8.12 (d, J= 1.8 Hz, 1H), 7.98 (d, J= 2.1 Hz, 1H), 3.94 (s, 3H), 2.56 (s, 3H). MS (ESI+): 275.9 (M+H)⁺.
94.5%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;	[01038] Step 3: methyl 5-bromo-2-methyl-3-nitrobenzoate [01039] To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (16 g, 61.5 mmol) in DMF (160 mL), was added iodomethane (35.7 g, 248 mmol) and sodium carbonate (26.3 g, 248 mmol). The resulting reaction mixture was stirred at 60 °C for 8h. On completion, the reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrates were concentrated under vacuum till dry and re-dissolved in ethyl acetate before washing with 5percent sodium bicarbonate solution (700 mL) followed by 5M HC1 solution (300 mL). The organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 5-bromo-2-methyl-3-nitrobenzoate (16 g, 94.5percent).
94%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;	The 2-methyl-3-nitro-5-bromobenzoic acid (16g, 61.5mmol) dissolved in DMF (160 ml) solution, then to add iodomethane (35.7g, 248mmol) and sodium carbonate (26.3g, 248mmol). Reaction solution 60 °C stirring 8h. After, when the reaction is complete, the reaction system filter in order to remove the inorganic salt, filtered salt of washing with ethyl acetate. After combining the filtrate in vacuo, diluted by adding acetic acid ethyl ester, using 5percent sodium bicarbonate aqueous solution (700 ml) washing, then using 5M hydrochloric acid solution (300 ml) washing. The organic phase after washing of salt water, drying with anhydrous sodium sulfate, vacuum concentration to obtain 5-bromo-2-methyl-3-nitro-benzoic acid methyl ester 16g, the yield is 94percent.
92%	With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;	To a mixture of methyl 5-bromo-2-methyl-3-nitrobenzoic acid (5 g, 19.2 mmol) and iodomethane (4.79 ml. and 76.9 mmol) in DMF (70 ml.) was added sodium carbonate (6.46 g, 76.9 mmol). The reaction mixture was stirred at 6O⁰C for 8 hrs and then diluted with water (25 ml_). The solution was filtered. The filtrate was sepertated and the inorganic phase was washed with ethyl acetate (3x50 ml_). The combined organic phases were concentrated under reduced pressure. The resulting residue was redissoved in ethyl acetate (600 m L), washed with 5percent sodium bicarbonate solution (250 mL) and 5M HCI (100 mL). The organic conbined phases were washed with brine (200 mL), separated, dried over MgSψ4 filtered and concentrated to give methyl 5-bromo-2-methyl-3- nitrobenzoate (4.78 g, 92percent), which was used in the next step without further purification.LC/MS (ESI) 274 [M+H]⁺ Rt 3.76 min

Reference： [1] Patent: US2014/107122, 2014, A1, . Location in patent: Paragraph 0159; 0160
[2] Patent: WO2012/142513, 2012, A1, . Location in patent: Page/Page column 261
[3] Patent: WO2014/100665, 2014, A1, . Location in patent: Paragraph 0552; 0553
[4] Patent: WO2015/200650, 2015, A1, . Location in patent: Paragraph 0655; 0658-0659
[5] Patent: WO2013/155317, 2013, A1, . Location in patent: Page/Page column 45
[6] Patent: WO2013/155464, 2013, A1, . Location in patent: Paragraph 0325; 0326
[7] Patent: WO2015/57859, 2015, A1, . Location in patent: Paragraph 085
[8] Patent: WO2015/104677, 2015, A1, . Location in patent: Page/Page column 56
[9] Patent: WO2012/118812, 2012, A2, . Location in patent: Page/Page column 311-312
[10] Patent: CN105037360, 2016, B, . Location in patent: Paragraph 0202; 0203; 0204
[11] Patent: WO2007/102883, 2007, A2, . Location in patent: Page/Page column 19; 35
[12] Patent: US2012/264734, 2012, A1, . Location in patent: Page/Page column 101
[13] Patent: WO2015/110999, 2015, A1, . Location in patent: Page/Page column 64

7
[ 107650-20-4 ]
[ 885518-49-0 ]

Reference： [1] Patent: WO2012/118812, 2012, A2,
[2] Patent: CN105037360, 2016, B,

8
[ 107650-20-4 ]
[ 1346574-57-9 ]

Reference： [1] Patent: US2014/256739, 2014, A1,

9
[ 107650-20-4 ]
[ 1000342-11-9 ]

Reference： [1] Patent: WO2012/118812, 2012, A2,
[2] Patent: WO2012/142513, 2012, A1,
[3] Patent: US2012/264734, 2012, A1,
[4] Patent: WO2013/155317, 2013, A1,
[5] Patent: WO2013/155464, 2013, A1,
[6] Patent: US2014/107122, 2014, A1,
[7] Patent: WO2015/57859, 2015, A1,
[8] Patent: WO2015/110999, 2015, A1,
[9] Patent: WO2015/104677, 2015, A1,
[10] Patent: CN105037360, 2016, B,
[11] Patent: US2017/8904, 2017, A1,
[12] Patent: US2018/177750, 2018, A1,

10
[ 107650-20-4 ]
[ 1403254-99-8 ]

Reference： [1] Patent: US2012/264734, 2012, A1,
[2] Patent: WO2013/155317, 2013, A1,
[3] Patent: WO2013/155464, 2013, A1,
[4] Patent: WO2015/57859, 2015, A1,

[ 107650-20-4 ] Synthesis Path-Downstream 1~23

1
[ 107650-20-4 ]
C₈H₅BrClNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 0 - 20℃; for 1h;	In a 200-ml flask, <strong>[107650-20-4]5-bromo-2-methyl-3-nitrobenzoic acid</strong> (5.O g, 19.2 mmol) was charged. Tetrahydrofuran (100 ml) was added thereto, and <strong>[107650-20-4]5-bromo-2-methyl-3-nitrobenzoic acid</strong> was dissolved. The reaction solution was ice-cooled, and oxalyl chloride (25 ml) was added. To this, N,N-dimethylformamide (5 ml) was slowly added dropwise (foamed heavily, a white solid was precipitated) . After dropwise addition, the mixture was stirred for 1 hour at room temperature, and then the reaction solution was concentrated under reduced pressure. Tetrahydrofuran was added to the residue and suspended. Under ice cooling, methanol (50 ml) was added dropwise thereto. (The reaction solution foamed heavily and the solid was dissolved. Since unreacted raw materials were observed in the reaction solution, the reaction solution was concentrated under reduced pressure again, tetrahydrofuran (50 ml) and oxalyl chloride (25 ml) were added to the concentrate, and the mixture was concentrated under reduced pressure. Tetrahydrofuran (50 ml) was added again, methanol (25 ml) was added dropwise thereto, and the mixture was stirred for 1 hour at room temperature. Raw materials were almost disappeared.) The reaction solution was neutralized with a 8N aqueous sodium hydroxide solution, tap water (100 ml) was added and the mixture was extracted twice with ethyl acetate (200 ml) . The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml) and saturated brine (100 ml), and dried over sodium sulfate, and concentrated under reduced pressure. The residue was dried overnight at room temperature under reduced pressure, to yield the title compound (4.87 g, <n="187"/>17.77 mmol) as a yellow white solid (yield 93%).1H-NMR (CDCl3, TMS, 300 MHz) delta (ppm) : 2.56 (s, 3H), 3.95 (s, 3H), 7.97 (d, IH, J = 2.1 Hz), 8.11 (d, IH, J = 2.1 Hz).13C-NMR (CDCl3, TMS, 300 MHz) delta (ppm) 15. 96, 52 . 96, 119.26, 129.55, 132 . 14 , 134 .75, 136. 54 , 152 . 37 , 165. 56. High resolution mass spectrometry (CgH8NO4 ) Theoretical value : [M+] 272 . 9637 Measured value : [M+] 272 . 9638Melting point: 48.6-49.8C

Reference： [1]Patent: WO2008/16184,2008,A1 .Location in patent: Page/Page column 184-185

2
[ 107650-20-4 ]
[ 100-39-0 ]
[ 630400-00-9 ]

Yield	Reaction Conditions	Operation in experiment
83.8%		A 5000 mL three neck RBF equipped with an overhead stirrer and thermometer was charged with 5-bromo-2-methyl-3-nitro benzoic acid (116.2 g, 0.45 mol), THF (1 L), and benzyl bromide (84.90 mL, 0.715 mol). To the stirring solution was added diisopropyl ethylamine (78 mL, 0.450 mol). The reaction was then brought to reflux. After 5.5 hours at reflux, the reaction was cooled to 40 C. and pyrrolidine (83 mL, 1.00 mol) was added. The reaction was stirred 10 minutes at 40 C., and then allowed to cool to ambient temperature over approximately 20 minutes. The reaction was diluted with EtOAc and washed 23% HCl, 1H20, 1* saturated NaCl, dried (MgSO4), and concentrated. The brown oil was taken up in DCM and slurried with approximately 300 g of silica gel. The slurry was filtered, solids washed with EtOAc, and the filtrate was concentrated to afford a yellow oil. Upon trituration in hexanes, 244.9 g (83.8%) of off white powder was obtained. 1H NMR (CDCl3) delta 8.10 (s, 1H), 7.96 (s, 1H), 7.41 (m, 5H), 5.37 (s, 2H), 2.55 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3227 - 3231
[2]Patent: WO2003/99275,2003,A1 .Location in patent: Page 102
[3]Patent: US2007/219212,2007,A1 .Location in patent: Page/Page column 24

3
[ 1975-50-4 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;Product distribution / selectivity;	Step 1: 5-bromo-2-methyl-3-nitrobenzoic acid To stirred solution of 2-methyl-3-nitrobenzoic acid (50 g, 276.2 mmol) in conc. H2SO4 (200 mL), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43.4 g, 151.8 mmol) was added portion wise at room temperature and reaction mass was stirred at room temperature for 5 h. On completion, reaction mass was poured on ice cold water, solid precipitated was filtered, resulting residue was washed with water and dried under vacuum to give the desired compound (71.7 g, 100%).
100%		[01 123] Step 1 : 5-bromo-2-methyl-3-nitrobenzoic acid[01 124] To stirred solution of 2-methyl-3-nitrobenzoic acid (50 g, 276.2 mmol) in cone.H2SO4 (200 mL), l ,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43.4 g, 151.8 mmol) was added portion wise at room temperature and reaction mass was stirred at room temperature for 5 h. On completion, reaction mass was poured on ice cold water, solid precipitated was filtered, resulting residue was washed with water and dried under vacuum giving the desired compound (71 .7 g, 100%)
100%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 0℃; for 5h;	To a stirred solution of 2-methyl-3-nitrobenzoic acid (5.00 g, 27.6 mmol) in H2SO4 (20 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (4.34 g, 15.20 mmol) at 0 C. The reaction mixture was stirred at 0 C. for 5 hours. The reaction mixture was poured onto ice cold water, the resultant precipitated solid was collected, washed with water and dried in vacuo to give the titled compound as a white solid (7.28 g, quantitative yield). 1H-NMR (400 MHz, DMSO-d6) delta ppm; 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).

99.8%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; for 5h;	A 5000 mL three neck RBF equipped with an overhead stirrer was charged with 2-methyl-3-nitro benzoic acid (150.0 g, 0.82 mol) and concentrated H2SO4 (600 mL). To this solution was added 1,3-dibromo-5,5-dimethylhydantoin (130.7 g, 0.455 mol) over ten minutes with vigorous stirring. The reaction was vigorously stirred at ambient temperature for 5 hours. The reaction mixture was then added to H2O (4000 mL) chilled in an ice bath over 30 minutes. This mixture was then filtered, the solids washed twice with H2O and further dried under vacuum to yield 217.7 g (99.8%) of an off-white solid. 1H NMR (CDCl3) delta 8.18 (s, 1H), 7.95 (s, 1H), 2.59 (s, 3H).
99%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;	To a mixture of 2-methyl-3-nitrobenzoic acid (150 g, 820 mmol) in concentrate sulphuric acid (600 ml.) was added 1 ,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (130.7 g, 457 mmol). The reaction mixture was stirred at room temperature for 5 hrs and then the reaction mixture was carefully added to 4L of ice-water. The solid precipitated out, which was washed with 1.5 L water. The solid was filtered off and dried in a heated desiccator at 30-400C overnight to give 5-bromo-2-methyl-3-nitrobenzoic acid (220 g, 99%), which was used in the next step without further purification.LC/MS (ESI) 257 [M+H]+ Rt 3.07 min
98.2%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;	[01036] Step 2: 5-bromo-2-methyl-3-nitrobenzoic acid[01037] l,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (13.0 g, 45.7 mmol) was added to a mixture of 2-methyl-3-nitrobenzoic acid (15 g, 82.8 mmol) in cone. H2S04 (60 mL), and the reaction mixture stirred at room temperature for 5 h. After completion of reaction, the mixture was slowly poured onto ice cold water (400 mL). The precipitated was filtered and dried under vacuum to obtain desired 5-bromo-2-methyl-3-nitrobenzoic acid (21 g, 98.2%).
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;	5-bromo-2-methyl-3-nitrobenzoic acid stirred solution of 2-methyl-3-nitrobenzoic acid (100 g, 552 mmol) in cone. H2S04 (400 mL), l,3-dibromo-5,5-dimethyl-2,4- imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid (140 g, 98%). The isolated compound was taken directly into the next step. 1H NMR (DMSO-J6, 400 MHz) delta 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; In water; at 20℃; for 5h;	0323] Step 1: Synthesis of 5-brom -2-methyl-3-nitrobenzoic acid [0324] To stirred solution of 2-methyl-3-nitrobenzoic acid (100 g, 552 mmol) in cone. H2SO4 (400 mL), l,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid (140 g, 98%). The isolated compound was taken directly into the next step. 1H NMR (DMSO-J6, 400 MHz) delta 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃;Cooling with ice;	[00182] Preparation of5-bromo-2-methyl-3-nitrobenzoic acid C2-l. To a mixture of compound C2-O (15 g, 82.8 mmol) in cone. H2S04 (60 mL) in an ice-water bath was added 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (13.4 g, 46.8 mmol) portionwise over 30 mins. After the mixture was stirred at room temperature overnight, the reactionmixture was added slowly to ice-water (400 mL). The precipitation was collected and dried to yield compound C2-1 as a white solid ((21.2 g, yield: 98%), which was used directly in the next step without further purification. MS (ESfl: m/z 257.9 and 259.9 (M1).
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In sulfuric acid; at 20℃; for 5h;	5-bromo-2-methyl-3-nitrobenzoic acidTo a stirred solution of 2-methyl-3- nitrobenzoic acid (100 g, 552 mmol) in cone. H2SO4 (400 mL), l,3-dibromo-5,5-dimethyl-2,4- imidazolidinedione (88 g, 308 mmol) was added in a portion wise manner at room temperature and the reaction mixture was then stirred at room temperature for 5 h. The reaction mixture was poured onto ice cold water, the precipitated solid was filtered off, washed with water and dried under vacuum to afford the desired compound as a solid (140 g, 98%>). The isolated compoundwas taken directly into the next step. 1H NMR (OMSO-d6, 400 MHz) delta 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
98%	With N-Bromosuccinimide; sulfuric acid; at 20℃;	The N-bromo succinimide (15g, 84.3mmol) is added to the 2-methyl-3-nitro-benzoic acid (15g, 82.8mmol) in the strong sulphuric acid solution (60 ml), then the reaction solution stirring the mixture at room temperature for overnight. After, when the reaction is complete, the reaction solution slowly into ice water (400 ml). The precipitate filtered, and drying in vacuum, to obtain it is expected the product 2-methyl-3-nitro-5-bromobenzoic acid 21g, the yield is 98%.
98%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;	2-methyl-3-nitrobenzoic acid (20 mmol, 1.0 equiv) was dissolved in concentrated sulfuric acid ( 15mL ), then 1,3-Dibromo-5,5-dimethylhydantoin ( 11mmol, 0.55 equiv) was added. The reaction mixture stirred at room temperature for 5 h. Upon completion of the reaction as determined by TLC, the reaction mixture was poured into ice water. The precipitate was filtered off, dried in vacuum to afford the desired compound 2 as a solid. Yield: 98%. 1H NMR(400 MHz, DMSO-d6) delta 8.31(s, 1H), 8.17(s, 1H), 2.43(s, 3H).
96%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;	a) S-BromG-2-roeth I-3-idtrii-ber.zoic acidTo a stirred solution of 2-methyl-3-nitro benzoic acid (300 g, 1647 mmol) in cone. H2S04 (1.5 L) was added l ,3-dibromo-5,5 dimethyl -2,4-imadazolidinedione (258 g, 906 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was slowly added to ice water (4 L), and solid was precipitated out. The solid was filtered off and washed with water (1.2 L), pet ether (1 1) and dried to afford the title compound as a white solid (41 1 g, 96 %), which was used without further purification. lU NMR (DMSO; 400 MHz) : delta 2.446 (s, 3H), 8.136 (s, 1H), 8.294 (s, 1H). LCMS (ES-) m/z = 257.93 (M-H)-
96%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;Inert atmosphere;	To a stirred solution of 2-methyl-3-nitro benzoic acid (300 g, 1647 mmol) in conc. H2SO4 (1.5 L) was added 1,3-dibromo-5,5 dimethyl-2,4-imadazolidinedione (258 g, 906 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was slowly added to ice water (4 L), and solid was precipitated out. The solid was filtered off and washed with water (1.2 L), pet ether (1 l) and dried to afford the title compound as a white solid (411 g, 96%), which was used without further purification. 1H NMR (DMSO, 400 MHz): delta2.446 (s, 3H), 8.136 (s, 1H), 8.294 (s, 1H). LCMS (ES-) m/z=257.93 (M-H)-
95.4%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; In tetrahydrofuran; water; at 80℃; for 7.5h;	In a 500-ml four-necked flask, 2-methyl-3-nitrobenzoic acid (20 g, 110 mmol) was charged. Thereto, tetrahydrofuran (200 ml) and 64% sulfuric acid (100 ml) were added sequentially. The mixture was heated and stirred at an external temperature of 8O0C in an oil bath. After confirmation of dissolution of 2-methyl-3-nitrobenzoic acid, 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (6.3 g, 22 mmol) was added. After this, 1, 3-dibromo-5, 5- dimethylimidazolidine-2, 4-dione was added in 6.3 g (22 mmol) increments every 1 hour (total 18.9 g, 66 mmol). 7.5 hours after the start of reaction, the oil bath was removed, and the solution was cooled to room temperature. Water (200 ml) was added dropwise over about 40 minutes. The mixture was further stirred for 1 hour in an ice bath. Precipitated crystals were collected by filtration, and the crystals were washed with tap water (100 ml) . The crystals were dried under reduced pressure at 50C, to yield the title compound (27.3 g, 105 mmol) (yield 95.4%) . 1H-NMR (MeOH-d4, TMS, 300 MHz) delta (ppm): 2.53 (s, 3H), 8.08 (d, IH, J = 2.1 Hz) , 8.16 (d, IH, J = 2.1 Hz) .13C-NMR (MeOH-d4, TMS, 300 MHz) delta (ppm) 15.87, 120.03, <n="186"/>130 . 12 , 132 . 47 , 137 . 05, 137 .20 , 153. 94, 167 . 97 . Melting point : 183 .3C
90%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In sulfuric acid; at 20℃; for 2h;Cooling with ice;	c) 2-methyl-3-nitrobenzoic acid (50g, 276mmol) was dissolved in 200mL of concentrated sulfuric acid, then under ice bath was added 1,3-dibromo-5,5-dimethylhydantoin (47.3g, 166mmol), stirred for 2 hours at room temperature. The reaction solution was slowly poured into a large amount of ice water to precipitate a large number of off-white solid, filtered and the solid washed with 1L of water, washed with 1L petroleum ether, and dried to give Compound E 64g, yield 90%.
90.1%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;	The starting material S57 (10.0 g, 55.2 mmol) was dissolved in 50 mL of concentrated sulfuric acid, and 1,3 -dibromo-5,5-dimethylhydantoin (8.6 g, 30.7 mmol) was added and stirred at room temperature for 5 hours. The reaction solution is poured into crushed ice,A large amount of solid is precipitated, filtered, washed with water, washed with petroleum ether.Drying a yellow-white solid S 58 (13 g, yield 90.1%).
84%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 5h;	To a stirred solution of 2-methyl-3-nitrobenzoic acid (10 g, 55 mmol) in conc. H2SO4 (40 mL), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (9 g, 32 mmol) was added portion wise at room temperature and reaction was stirred at room temperature for 5 h. Then the reaction mass was poured on an ice cold water. Solid was filtered, and the resulting residue was washed with water and dried under vacuum to afford 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 84%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 8.28 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 2.51 (s, 3H)
81%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 0 - 20℃; for 6h;	To stirred solution of 2-methyl-3-nitrobenzoic acid (25 g, 138.1 mmol) in cone. H2S04 (100 mL) at 0 C, l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (23.7 g, 82.87 mmol) was added portion wise and the reaction mass was stirred at rt for 6 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mass was poured on ice cold water, the solid precipitated was filtered, washed with water and dried under reduced pressure to afford the title compound (29 g, 81%).
81%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃;	To a solution of 5-bromo-2-methyl-3- nitrobenzoic acid (35 g, 135 mmol, 1.0 eq) in MeOH (1.2 L) at room temperature was added cone. H2SO4 (5 mL), the mixture was heated to reflux and stirred for 8 h. LCMS showed no starting materials left. It was concentrated under reduced pressure to remove most MeOH, diluted with EtOAc (200 mL), washed with sat. NaHC03 (100 mL x 2), the organic layer was dried over Na2S04, and concentrated in vacuo to give the desired product methyl 5-bromo-2- methyl-3 -nitrobenzoate (30 g, crude), which was used directly in the next step without further purification. NMR (300 MHz, DMSO-tfc): delta 8.14 (s, 1H), 8.00 (s, 1H), 3.96 (s, 3H), 2.58 (s, 3H).
7 g	With N-Bromosuccinimide; sulfuric acid; at 0 - 40℃; for 5h;	2-Methyl-3-nitrobenzoic acid (5 g) was dissolved in conc. H2S04 (20 mL) at 0C. To this solution, NBS (6.2 g) was added gradually. The resulting mixture was stirred at 0C for 2 hours, and then warmed to 40C. After stirring at 40C for 3 hours, the mixture was poured into ice/water. The white solid precipitate was filtered and dried to afford the title compound (7 g) as off-white solid. MS (ESI): C8H6BrNO4 requires 259; found no mass.
7 g	With N-Bromosuccinimide; sulfuric acid; at 0 - 40℃; for 5h;	Description 137 5-Bromo-2-methyl-3-nitrobenzoic acid (P137)2-Methyl-3-nitrobenzoic acid (5.0 g) was dissolved in conc. H2S04 (20 mL) at 0C. To this solution, NBS (6.2 g) was added gradually. The resulting mixture was stirred at 0C for 2 hours, and thenwarmed to 40C. After stirring at 40C for 3 hours, the mixture was poured into ice water. Thewhite solid precipitate was filtered and dried to give the title compound (7.0 g) as off-white solid.MS (ESI): C8H6BrNO4 requires 259; found no mass.
36 g	With N-Bromosuccinimide; sulfuric acid; at 60℃;Inert atmosphere;	3-Nitro-2-methylbenzoic acid (27.1 g, 150 mmol) was dissolved in 100 mL of sulfuric acid and heated to 60 C. NBS (29.36 g, 165 mmol) was added in portions. After addition, the reaction solution was stirred for 5 hours, and then cooled to room temperature. The reaction solution was added with 500 mL of ice water and stirred for 30 minutes. The mixture was filtered, and the filter cake was rinsed with water and dried to give 36 g of title product.

Reference： [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 100
[2]Patent: WO2012/142513,2012,A1 .Location in patent: Page/Page column 288
[3]Patent: US2014/107122,2014,A1 .Location in patent: Paragraph 0157; 0158
[4]Patent: WO2003/99275,2003,A1 .Location in patent: Page 101
[5]Patent: US2007/219212,2007,A1 .Location in patent: Page/Page column 23
[6]Patent: WO2007/102883,2007,A2 .Location in patent: Page/Page column 19; 36
[7]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3227 - 3231
[8]Patent: WO2012/118812,2012,A2 .Location in patent: Page/Page column 311
[9]Patent: WO2013/155317,2013,A1 .Location in patent: Page/Page column 44
[10]Patent: WO2013/155464,2013,A1 .Location in patent: Paragraph 0323; 0324
[11]Patent: WO2014/18866,2014,A1 .Location in patent: Paragraph 00181; 00182
[12]Patent: WO2015/57859,2015,A1 .Location in patent: Paragraph 085
[13]Patent: CN105037360,2016,B .Location in patent: Paragraph 0199; 0200; 0201
[14]Bioorganic and medicinal chemistry letters,2020
[15]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 94
[16]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0826
[17]Patent: WO2008/16184,2008,A1 .Location in patent: Page/Page column 183-184
[18]Patent: CN105481790,2016,A .Location in patent: Paragraph 0198; 0199; 0200; 0203
[19]Patent: CN110016014,2019,A .Location in patent: Paragraph 0111-0113
[20]Patent: US2017/8904,2017,A1 .Location in patent: Paragraph 0422-0423
[21]Patent: WO2014/100665,2014,A1 .Location in patent: Paragraph 0551
[22]Patent: WO2015/200650,2015,A1 .Location in patent: Paragraph 0655-0657
[23]Patent: WO2019/10295,2019,A1 .Location in patent: Page/Page column 145; 146
[24]Patent: WO2015/180613,2015,A1 .Location in patent: Page/Page column 23
[25]Patent: WO2015/180612,2015,A1 .Location in patent: Page/Page column 80; 81
[26]Patent: US2019/345139,2019,A1 .Location in patent: Paragraph 0291

4
[ 107650-20-4 ]
[ 74-88-4 ]
[ 220514-28-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (7.28 g, 28.0 mmol) in DMF (100 mL) was added sodium carbonate (11.9 g, 112 mmol) and methyl iodide (15.9 g, 112 mmol). The reaction mixture was stirred at 60 C. for 8 hours. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate. The combined filtrate was washed with water and the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a solid. (7.74 g, quantitative yield). 1H-NMR (400 MHz, CDCl3) delta (ppm); 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
99%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;Product distribution / selectivity;	[0998] Step 2: methyl 5-bromo-2-meth -3-nitrobenzene[0999] To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (287 g, 1 103 mmol) in DMF (1 50 mL), sodium carbonate (468 g, 4415 mmol) and methyl iodide (626.63 g, 4415 mmol) were added. Resulting reaction mass was heated at 60 C for 8 h. On completion, solid precipitated was filtered, residue washed with diethyl ether (5 times). Combined organic layers were dried, concentrated under reduced pressure giving the desired compound (302 g, 99%) which was used for further reaction.
98%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 12h;	To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (29 g, 111.9 mmol) in DMF (300 mL), sodium carbonate (48 g, 447.8 mmol) and Mel (63.59 g, 447.8 mmol) were added. The resulting reaction mass was heated at 60 C for 12 h.The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (30 g, 98%)

97%	With sodium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 8h;	Methyl 5-bromo-2-methyl-3-nitrobenzoate To a stirred solution of 5-bromo-2- methyl-3-nitrobenzoic acid (285 g, 1105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate (1L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97% yield). The isolated compound was taken directly into the next step. 1H NMR (CDC13, 400 MHz) delta 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
97%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	[0325] Step 2: Synthesis of methyl -bromo-2-methyl-3-nitrobenzoate [0326] To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (285 g, 1105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate (1L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97% yield). The isolated compound was taken directly into the next step. 1H NMR (CDC13, 400 MHz) delta 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
97%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	Methyl 5-bromo-2-methyl-3-nitrobenzoateTo a stirred solution of 5-bromo-2- methyl-3-nitrobenzoic acid (285 g, 1 105 mmol) in DMF (2.8L) at room temperature was added sodium carbonate (468 g, 4415 mmol) followed by addition of methyl iodide (626.6 g, 4415 mmol). The resulting reaction mixture was heated at 60 C for 8 h. After completion (monitored by TLC), the reaction mixture was filtered (to remove sodium carbonate) and washed with ethyl acetate (1L X 3). The combined filtrate was washed with water (3L X 5) and the aqueous phase was back extracted with ethyl acetate (1L X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a solid (290g, 97% yield). The isolated compound was taken directly into the next step. 1H NMR (CDCls, 400 MHz) delta 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
95%	With sodium carbonate; In N,N-dimethyl-formamide; at 20 - 55℃; for 10h;	To a solution of 5-bromo-2-methyl-3-nitrobenzoic acid (10 g, 38.5 mmol) in DMF (100 mL) were added sodium carbonate (16.30 g, 154 mmol) and methyl iodide (9.62 mL, 154 mmol) at room temperature and the reaction mixture was stirred at 55 C for 10 hours. On completion, the reaction mixture was filtered and the inorganic solid residue was washed with ethyl acetate. The filtrate was concentrated under vacuum till dry and re- dissolved in ethyl acetate before washing with 5 % sodium bicarbonate solution (70 mL) followed by 5.0 M HC1 solution (30 mL). The organic layer was finally washed with brine, dried over sodium sulfate and concentrated to yield 10 g (95%) of the title compound. JH NMR (CDC13, 300 MHz) delta ppm: 8.12 (d, J= 1.8 Hz, 1H), 7.98 (d, J= 2.1 Hz, 1H), 3.94 (s, 3H), 2.56 (s, 3H). MS (ESI+): 275.9 (M+H)+.
95%	With sodium carbonate; In N,N-dimethyl-formamide; for 8h;	To a stirred solution of 1 (20 mmol, 1.0 equiv) and sodium carbonate (40 mmol, 2.0 equiv) in DMF (50 mL) was added iodomethane (24 mmol, 1.2 equiv) and the reaction mixture stirred at room temperature for 8 h. Upon completion of the reaction as determined by TLC, the reaction mixture was poured into ice water. The precipitate was filtered off, washed with water and dried in vacuum to afford the desired compound 2 as a solid. Yield: 95%. 1H NMR(400 MHz, DMSO-d6) delta 7.33(s, 1H), 7.26 (s, 1H), 3.87 (s, 3H), 2.28 (s, 3H).
94.5%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	[01038] Step 3: methyl 5-bromo-2-methyl-3-nitrobenzoate [01039] To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (16 g, 61.5 mmol) in DMF (160 mL), was added iodomethane (35.7 g, 248 mmol) and sodium carbonate (26.3 g, 248 mmol). The resulting reaction mixture was stirred at 60 C for 8h. On completion, the reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrates were concentrated under vacuum till dry and re-dissolved in ethyl acetate before washing with 5% sodium bicarbonate solution (700 mL) followed by 5M HC1 solution (300 mL). The organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 5-bromo-2-methyl-3-nitrobenzoate (16 g, 94.5%).
94%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	The 2-methyl-3-nitro-5-bromobenzoic acid (16g, 61.5mmol) dissolved in DMF (160 ml) solution, then to add iodomethane (35.7g, 248mmol) and sodium carbonate (26.3g, 248mmol). Reaction solution 60 C stirring 8h. After, when the reaction is complete, the reaction system filter in order to remove the inorganic salt, filtered salt of washing with ethyl acetate. After combining the filtrate in vacuo, diluted by adding acetic acid ethyl ester, using 5% sodium bicarbonate aqueous solution (700 ml) washing, then using 5M hydrochloric acid solution (300 ml) washing. The organic phase after washing of salt water, drying with anhydrous sodium sulfate, vacuum concentration to obtain 5-bromo-2-methyl-3-nitro-benzoic acid methyl ester 16g, the yield is 94%.
92%	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	To a mixture of methyl 5-bromo-2-methyl-3-nitrobenzoic acid (5 g, 19.2 mmol) and iodomethane (4.79 ml. and 76.9 mmol) in DMF (70 ml.) was added sodium carbonate (6.46 g, 76.9 mmol). The reaction mixture was stirred at 6O0C for 8 hrs and then diluted with water (25 ml_). The solution was filtered. The filtrate was sepertated and the inorganic phase was washed with ethyl acetate (3x50 ml_). The combined organic phases were concentrated under reduced pressure. The resulting residue was redissoved in ethyl acetate (600 m L), washed with 5% sodium bicarbonate solution (250 mL) and 5M HCI (100 mL). The organic conbined phases were washed with brine (200 mL), separated, dried over MgStheta4 filtered and concentrated to give methyl 5-bromo-2-methyl-3- nitrobenzoate (4.78 g, 92%), which was used in the next step without further purification.LC/MS (ESI) 274 [M+H]+ Rt 3.76 min
	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;Product distribution / selectivity;	Step 2: Synthesis of methyl 5-bromo-2-methyl-3-nitrobenzoate To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (287 g, 1103 mmol) in DMF (150 mL), sodium carbonate (468 g, 4415 mmol) and methyl iodide (626.63 g, 4415 mmol) were added. Resulting reaction mass was heated at 60 C. for 8 h. On completion, solid precipitated was filtered, residue washed with diethyl ether (5 times). Combined organic layers were dried, concentrated under reduced pressure giving the desired crude compound (302 g, 99%).
	With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;	Example 16:Methyl 5-bromo-2-methyl-3-nitrobenzoateTo a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (25 g, 96 mmol) in DMF (300 mL), sodium carbonate (40.8 g, 385 mmol) and iodomethane(24.05 mL, 385 mmol) were added. Resulting reaction mass was heated at 60 00 for 16 h. On completion of reaction, solvent was evaporated to dryness. Ice cold water was added to the reaction mixture. The solid precipitated was filtered, and dried to yield the title compound.Yield: 25.2 g (90 %); 1H NMR (DMSO-d6, 300 MHz): 68.32 (d, J= 1.8 Hz,1H), 8.14 (d, J= 2.1 Hz, 1H), 3.87 (5, 3H), 2.40 (5, 3H); MS (ESl+): m/z 275.1[M+H] HPLC Purity: 93.99 %.

Reference： [1]Patent: US2014/107122,2014,A1 .Location in patent: Paragraph 0159; 0160
[2]Patent: WO2012/142513,2012,A1 .Location in patent: Page/Page column 261
[3]Patent: WO2014/100665,2014,A1 .Location in patent: Paragraph 0552; 0553
[4]Patent: WO2015/200650,2015,A1 .Location in patent: Paragraph 0655; 0658-0659
[5]Patent: WO2013/155317,2013,A1 .Location in patent: Page/Page column 45
[6]Patent: WO2013/155464,2013,A1 .Location in patent: Paragraph 0325; 0326
[7]Patent: WO2015/57859,2015,A1 .Location in patent: Paragraph 085
[8]Patent: WO2015/104677,2015,A1 .Location in patent: Page/Page column 56
[9]Bioorganic and medicinal chemistry letters,2020
[10]Patent: WO2012/118812,2012,A2 .Location in patent: Page/Page column 311-312
[11]Patent: CN105037360,2016,B .Location in patent: Paragraph 0202; 0203; 0204
[12]Patent: WO2007/102883,2007,A2 .Location in patent: Page/Page column 19; 35
[13]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 101
[14]Patent: WO2015/110999,2015,A1 .Location in patent: Page/Page column 64

5
[ 107650-20-4 ]
[ 4637-24-5 ]
methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%		b) Methyl 6-bromo-lH-indole-4-carboxylateTo a stirred solution of 5-Bromo-2-methyi-3~nitro-be«zoic acid (140 g, 538.4 mmol) in DMF (550 ml) was added DMF-DMA (599 mL, 4846 mmol) at room temperature. The reaction mixture was stirred at 1 15 C for 18 h. The reaction mixture was then concentrated in vacuo. The residual contents (176 g, 536.5 mmol) were dissolved in acetic acid (696 mL) and added to a suspension of Iron (329.2 g, 5902 mmol) in acetic acid (1.4 L) at 50 C. After completion of addition, the reaction mixture was stirred at 80-90 C for 4 h. The reaction mixture was then filtered through a celite pad. The filtrate was poured onto ice water (1 L) and extracted with diethyl ether (3 X 700 ml). The combined organic layers were washed with sat NaHC03, brine, and dried over anhydrous Na2S04, filtered, and evaporated under vaccum. The crude product was purified by silica gel chromatography (eluent: 10 % ethyl acetate in pet ether) and afforded the title compound as a solid (80g, 59%). .H NMR (DMSO-d6; 400 MHz) delta: 3.980 (s, 3H), 7.168 (d, J = 3.2 Hz, 1H), 7.334 (d, J = 3.2 Hz, 1H), 7.734 (s, 1H), 8.017 (s, 1H), 8.384 (brs, 1H); LCMS (ES-) m/z = 251.9 (M-H).
59%		To a stirred solution of <strong>[107650-20-4]5-bromo-2-methyl-3-nitro-benzoic acid</strong> (140 g, 538.4 mmol) in DMF (550 ml) was added DMF-DMA (599 mL, 4846 mmol) at room temperature. The reaction mixture was stirred at 115 C. for 18 h. The reaction mixture was then concentrated in vacuo. The residual contents (176 g, 536.5 mmol) were dissolved in acetic acid (696 mL) and added to a suspension of iron (329.2 g, 5902 mmol) in acetic acid (1.4 L) at 50 C. After completion of addition, the reaction mixture was stirred at 80-90 C. for 4 h. The reaction mixture was then filtered through a Celite pad. The filtrate was poured onto ice water (1 L) and extracted with diethyl ether (3×700 ml). The combined organic layers were washed with sat NaHCO3, brine, and dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by silica gel chromatography (eluent: 10% ethyl acetate in pet ether) and afforded the title compound as a solid (80 g, 59%). 1H NMR (DMSO-d6, 400 MHz) delta: 3.980 (s, 3H), 7.168 (d, J=3.2 Hz, 1H), 7.334 (d, J=3.2 Hz, 1H), 7.734 (s, 1H), 8.017 (s, 1H), 8.384 (brs, 1H); LCMS (ES-) m/z=251.9 (M-H).

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 94-95
[2]Patent: US2014/256739,2014,A1 .Location in patent: Paragraph 0828

6
[ 107650-20-4 ]
[ 885518-49-0 ]

Reference： [1]Patent: WO2012/118812,2012,A2
[2]Patent: CN105037360,2016,B
[3]Medicinal Chemistry Research,2020,vol. 29,p. 17 - 32

7
[ 107650-20-4 ]
[ 1346702-54-2 ]

Reference： [1]Patent: WO2012/118812,2012,A2

8
[ 107650-20-4 ]
[ 1000342-11-9 ]

Reference： [1]Patent: WO2012/118812,2012,A2
[2]Patent: US2012/264734,2012,A1
[3]Patent: WO2013/155317,2013,A1
[4]Patent: WO2013/155464,2013,A1
[5]Patent: US2014/107122,2014,A1
[6]Patent: WO2015/57859,2015,A1
[7]Patent: WO2015/110999,2015,A1
[8]Patent: WO2015/104677,2015,A1
[9]Patent: CN105037360,2016,B
[10]Patent: US2017/8904,2017,A1
[11]Patent: US2018/177750,2018,A1
[12]Medicinal Chemistry Research,2020,vol. 29,p. 17 - 32
[13]Bioorganic and medicinal chemistry letters,2020

9
[ 77-48-5 ]
[ 1975-50-4 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sulfuric acid; at 20℃; for 5h;	To stirred solution of 2-methyl-3-nitrobenzoic acid(10 g, 55 mmol) in conc. H2504 (40 mE), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (9 g, 32 mmol) wasadded portion wise at room temperature and reaction wasstirred at room temperature for 5 hours. Then the reactionmass was poured on an ice cold watet Solid was filtered, andthe resulting residue was washed with water and dried undervacuum to afford 5-Bromo-2-methyl-3-nitrobenzoic acid(12 g, 84%) as a light yellow solid. 1H NMR: (400 MHz, DMSO-d6): delta 8.28 (d, J=2.0Hz, 1H), 8.13(d, J=2.0 Hz, 1H), 2.51(s, 3H). Chemical Formula: C8H613rNO4; MolecularWeight: 260.04. Total H count from ?HNMR data: 5.

Reference： [1]Patent: US2018/177750,2018,A1 .Location in patent: Paragraph 1230-1234

10
[ 107650-20-4 ]
[ 1403257-49-7 ]

Reference： [1]Patent: US2012/264734,2012,A1
[2]Patent: WO2012/142513,2012,A1
[3]Patent: WO2013/155317,2013,A1
[4]Patent: WO2013/155464,2013,A1
[5]Patent: US2014/107122,2014,A1
[6]Patent: WO2015/57859,2015,A1
[7]Patent: WO2015/110999,2015,A1
[8]Patent: CN105037360,2016,B
[9]Patent: US2017/8904,2017,A1
[10]Patent: US2018/177750,2018,A1
[11]Bioorganic and medicinal chemistry letters,2020

11
[ 107650-20-4 ]
[ 1403254-99-8 ]

Reference： [1]Patent: US2012/264734,2012,A1
[2]Patent: WO2013/155317,2013,A1
[3]Patent: WO2013/155464,2013,A1
[4]Patent: WO2015/57859,2015,A1

12
[ 107650-20-4 ]
[ 1403257-80-6 ]

Reference： [1]Patent: WO2012/142513,2012,A1
[2]Patent: US2012/264734,2012,A1
[3]Patent: WO2013/155464,2013,A1
[4]Patent: US2017/8904,2017,A1
[5]Patent: US2018/177750,2018,A1

13
[ 107650-20-4 ]
[ 1403257-79-3 ]

Reference： [1]Patent: US2012/264734,2012,A1
[2]Patent: WO2012/142513,2012,A1
[3]Patent: WO2013/155317,2013,A1
[4]Patent: WO2013/155464,2013,A1
[5]Patent: US2014/107122,2014,A1
[6]Patent: WO2015/57859,2015,A1
[7]Patent: WO2015/110999,2015,A1
[8]Patent: CN105037360,2016,B
[9]Patent: US2017/8904,2017,A1
[10]Patent: US2018/177750,2018,A1
[11]Bioorganic and medicinal chemistry letters,2020

14
[ 79669-49-1 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
82.5%		To a stirred mixture 2 (20 g, 93.023 mmol) was added tocooled conc. H2SO4 (100 ml) at -10 C lot wise. After10 min nitrating mixture (prepared as mixing KNO3 (9.39 g,93.023 mmol) with conc. H2SO4 (100 ml) was added dropwise at -10 C. Resulting reaction mass was stirred at-10 C for 1 h. On completion, reaction mixture waspoured on ice-cold water; Solid was precipitated out, filteredand dried under vacuum to afford compound 3.Yield: 82.50%. 1HNMR (DMSO-d6, 400 MHz) delta 13.85(bs, 1H); 8.37 (s, 1H); 8.18 (s, 1H); 2.50 (s, 3H). LCMS:m/e 260/262 (M+ 1).
52%	With sulfuric acid; nitric acid; In acetone; at -5 - 0℃; for 2.25h;Cooling with acetone-ice;	Step 1: Synthesis of 5-bromo-2-methyl-3-nitrobenzoic acid A solution of <strong>[79669-49-1]5-bromo-2-methylbenzoic acid</strong> (5.0 g, 23 mmol) in concentrated H2SO4 (27 ml, 512 mmol) was cooled to 5 C. in an acetone/ice bath. A mixture of concentrated nitric acid (1.9 ml, 30 mmol) and concentrated H2SO4 (2.8 ml, 52 mmol) was added dropwise to the reaction mixture at -5 to 0 C. over 15 minutes. The yellow reaction mixture was stirred at -5 to 0 C. for 2 hours during which time a yellow precipitate formed. The reaction mixture was poured onto ice (150 g) and the precipitate was then collected by filtration. The precipitate was air dried to give the title compound (5.5 g, 52%) as a pale yellow solid. LC-MS 57%, 1.82 min (3.5 minute LC-MS method), no ionization; 1H NMR (500 MHz, DMSO-d6) delta ppm 8.29 (s, 1H) 8.13 (d, J=1.58 Hz, 1H) 2.43 (s, 3H).

Reference： [1]Medicinal Chemistry Research,2020,vol. 29,p. 17 - 32
[2]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 172

15
[ 107650-20-4 ]
3-amino-5-bromo-2-methylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With iron; ammonium chloride; In ethanol; water; for 18h;Reflux;	To a mechanically stirred mixture of <strong>[107650-20-4]5-bromo-2-methyl-3-nitrobenzoic acid</strong> ( 4.0 g,15.38 mmol) and ammonium chloride (8.0 g, 149.6 mmol) in ethanol (80 mL) and water(80 mL) was added iron powder (2.8 g, 50.1 mmol). The reaction mixture was heated to reflux (70 oc oil bath) and stirred for 18 hr. The reaction mixture was diluted with EtOH(80 mL), filtered through a pad ofCelite, washed with EtOH (40 mL) and evaporated tonear dryness under vacuum. The remaining brown residue was triturated with a smallvolume of water, filtered, washed with cold water, and dried under vacuum to give 3-amino-5-bromo-2-methylbenzoic acid (2.70 g, 11.7 mmol, 76% yield) as a beige solid. 1H NMR (400MHz, MeOH-d4) 8 = 7.16 (br. s., 1 H), 7.00 (br. s., 1 H), 2.26 (br. s., 3 H).20MS(ES)+ m/e 230.0 [M+H]+

Reference： [1]Patent: WO2013/173441,2013,A2 .Location in patent: Page/Page column 94

16
[ 67-56-1 ]
[ 107650-20-4 ]
[ 220514-28-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With thionyl chloride;Reflux;	[00183J Preparation of methyl 5-bromo-2-methyl-3-nitrobenzoate (?2-2, A mixture of 5.bromo-2-methyl-3-nitrobenzoic acid (?2-1(21.2 g, 81.5 mmol) in SOC12 (100 mL) washeated to retlux until the mixture became clear (about 1.5 hrs). The reaction mixture was cooled and concentrated in vacuo, The residue was added portionwise to 250 mL of MeOH. The resulting mixture was stirred overnight under refluxing. The reaction mixture was cooled and concentrated. The residue was dissolved in 300 mL of hA, washed sequentially with sat. aq. NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel, PE:EA (20:1, v:v)) to yield compound C2-2 as a light yellow solid (21.2 g, yield: 95%).
94.8%	With sulfuric acid; at 75℃; for 12h;	To a solution of 5-bromo-2-methyl-3-nitro-benzoic acid (1 g, 3.85 mmol, 1 equivalent) in MeOH (20 mL) was added H2SO4 (3.78 g, 38.5 mmol, 2.05 mL, 10 equivalents). The mixture was stirred at 75 C. for 12 hrs. When the reaction was complete, the pH of the mixture was adjusted to 7 with saturated sodium bicarbonate aqueous solution, then extracted with ethyl acetate (20 mL*3). The combined organic phase was dried over sodium sulfate and concentrated to give methyl 5-bromo-2-methyl-3-nitro-benzoate (7.1, 1 g, 3.65 mmol, 94.8% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) delta=8.14 (d, J=2.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 3.96 (s, 3H), 2.58 (s, 3H).
87%	With thionyl chloride;Reflux;	A mixture of 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 41 mmol) in SOCl2/MeOH (v:v=1:10) (250 mL) was heated to reflux overnight. The reaction mixture was cooled and concentrated. The residue was dissolved in 300 mL of ethyl acetate. The organic layer was washed sequentially with sat. aq. NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate (20:1, v:v)) to afford the desired compound (11 g, yield: 87%). 1H NMR (400 MHz, CDCl3): delta 8.12 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 3.95 (s, 3H), 2.57 (s, 3H)

87%	With thionyl chloride;Reflux;	A mixture of 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 41 mmol) in 50C12/MeOH(v:v=1:10) (250 mE) was heated to reflux overnight. The reaction mixture was cooled and concentrated. The residue was dissolved in 300 mE of EA. The organic layer was washed sequentially with sat. aq. NaHCO3 and brine, dried over Na2504, and concentrated. The residue was purified by chromatography (silica gel, PE:EA (20:1, v:v)) to afford Methyl 5-bromo-2- methyl-3-nitrobenzoate (11 g, yield: 87%). 1H NMR: (400 MHz, CDC13): oe 8.12 (d, J=2.0 Hz, 1H), 7.97(d, J=2.0 Hz, 1H), 3.95(s, 3H), 2.57(s, 3H). Chemical Formula: C9H813rN04; Molecular Weight: 272.96. Total H count from ?HNMR data: 8.
68.5%	With sulfuric acid;	To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoicacid 3 (15 g, 57.69 mmol) in methanol (150 ml), was addedcatalytic conc. H2SO4. Resulting reaction mass was stirredat 65 C for 15 h. On completion, methanol was evaporatedtill dryness. The residue was re-dissolved in ethyl acetateand washed with sodium bicarbonate solution; organic layerwas finally washed with brine, dried over sodium sulfateand concentrated to afford desired compound 4. Yield:68.50%. 1HNMR (DMSO-d6, 400 MHz) delta 8.37 (s, 1H);8.19 (s, 1H); 3.88 (s, 3H); 2.41 (s, 3H). LCMS: m/e 274/276(M + 1).
	With sulfuric acid; at 80℃; for 4h;	Compound E (50g, 192mmol) was dissolved in 300mL of methanol, was slowly added concentrated sulfuric acid 50mL, was heated to 80 deg.] C for 4 hours. The reaction solution was slowly poured into a large amount of ice water, was added 500mL ethyl acetate and the organic layer was washed with 200mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was distilled off under reduced pressure to give compound F 48.5g, yield 92% without purification.
	With sulfuric acid; for 8h;Reflux;	To a solution of 5 -bromo-2-methyl-3 - nitrobenzoic acid (35 g, 135 mmol, 1.0 eq) in MeOH (1.2 L) at room temperature was addedconc. H2S04 (5 mL), the mixture was heated to reflux and stirred for 8 h. LCMS showed no starting materials left. It was concentrated under reduced pressure to remove most MeOH, diluted with EtOAc (200 mL), washed with sat. NaHCO3 (100 mL x 2), the organic layer was dried over Na2SO4, and concentrated in vacuo to give the desired product methyl 5-bromo-2- methyl-3-nitrobenzoate (30 g, cmde), which was used directly in the next step without furtherpurification. ?H NMR (300 MHz, DMSO-d6): 5 8.14 (s, 1H), 8.00 (s, 1H), 3.96 (s, 3H), 2.58 (s,3H).

Reference： [1]Patent: WO2014/18866,2014,A1 .Location in patent: Paragraph 00181; 00183
[2]Patent: US2018/265517,2018,A1 .Location in patent: Paragraph 0318-0321
[3]Patent: US2017/8904,2017,A1 .Location in patent: Paragraph 0422; 0424
[4]Patent: US2018/177750,2018,A1 .Location in patent: Paragraph 1235-1239
[5]Medicinal Chemistry Research,2020,vol. 29,p. 17 - 32
[6]Patent: CN105481790,2016,A .Location in patent: Paragraph 0198; 0199; 0200; 0204
[7]Patent: WO2019/10295,2019,A1 .Location in patent: Page/Page column 146

17
[ 107650-20-4 ]
[ 1346574-57-9 ]

Reference： [1]Patent: US2014/256739,2014,A1

18
[ 107650-20-4 ]
[ 169447-70-5 ]
(S)-tert-butyl 4-(5-bromo-2-methyl-3-nitrobenzoyl)-2-methylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.8 g		Description 145(S)-tert-butyl 4-(5-bromo-2-methyl-3-nitrobenzoyl)-2-methylpiperazine-1-carboxylate (1)145)<strong>[107650-20-4]5-Bromo-2-methyl-3-nitrobenzoic acid</strong> (D137, 7 g) and DIPEA (9.40 mL) were dissolved in DMF (10 mL). To this solution, HATU (12.28 g) was added gradually. After stirring at RT for 30 mm, (5)-tert-butyl 2-methylpiperazine-1 -carboxylate (6.47 g) was added. The mixture was stirred at RT overnight. As the starting material (<strong>[107650-20-4]5-bromo-2-methyl-3-nitrobenzoic acid</strong>) still remained, more (S)-tert-butyl 2-methylpiperazine-1 -carboxylate (2.0 g) and HATU (4.0 g) were added. The mixturewas stirred at RT overnight. Water (30 mL) was added, extracted with EtOAc (2x30 mL). The organic phase was dried over Na2SO4. Filtered, the filtrate was concentrated to dryness. The residue was triturated with EtOAc, the resulting solid was filtered through a Buchner funnel, to afford the title compound (3.8 g). MS (ESI): C18H24BrN3O5 requires 441; found 464 [M+Na].

Reference： [1]Patent: WO2015/180612,2015,A1 .Location in patent: Page/Page column 83

19
[ 220514-28-3 ]
[ 107650-20-4 ]

Yield	Reaction Conditions	Operation in experiment
12.9 g	With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 25℃;	To the solution of compound K501-A (14.0 g, 51.1 mmol) in THF (90 mL) was added LiOH (6.4g, 153 mmol)and H2O (30 mL). The reaction mixture was stirred at 25C overnight and then concentrated. The remaining liquid wasdiluted with Et2O (60 mL) and water (100 mL). The organic layer was separated. The water layer was adjusted with 2NHCl to pH = 2,extracted with EtOAc (150 mL). The organic layers were washed with sat. brine (200 mL), dried, filteredand concentrated to afford K501-B (12.9 g) as yellow solid.1H NMR (400 MHz, DMSO-d6): delta 8.30 (d, J = 2.0 Hz, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 2.45 (s, 3H)

Reference： [1]Patent: EP3404024,2018,A1 .Location in patent: Paragraph 0108; 0109

20
[ 107650-20-4 ]
[ 60956-26-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfolane; sodium hydrogencarbonate; at 200℃; for 2h;	2.0 kg of sulfolane was added to the reaction vessel, and 260 g (1 mol) of <strong>[107650-20-4]2-methyl-5-bromo-3-nitrobenzoic acid</strong> and 168 g (2 mol) of sodium hydrogencarbonate were successively added, and the reaction vessel was heated to 200 C and kept for 2 h. . After the completion of the reaction, the temperature of the reaction vessel was lowered to about 130 C, and the solvent was distilled off under reduced pressure, followed by rectification to obtain 183.6 g of the title compound.

Reference： [1]Patent: CN109467509,2019,A .Location in patent: Paragraph 0088-0091

21
[ 107650-20-4 ]
[ 64-19-7 ]
C₁₁H₁₀BrNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		Starting material S58 (900 mg, 3.46 mmol) was dissolved in 6 mL of DMF, and DMF-DMA (4.14 mL, 31.15 mmol) was added and reacted at 115 C. After 18 h, the solvent was evaporated under reduced pressure. This was dissolved in 10 mL of AcOH, and added to Fe powder (2.13 g, 38.07 mmol) / 15 mL of AcOH at 50 C, and the reaction was carried out at 80 to 90 C after the addition. After 4 hours, the celite was filtered, and the filtrate was poured into ice water, and then evaporated, evaporated, evaporated Column chromatography, PE:AcOEt = 9:1 to 8:1 gave product S64 as a yellow solid (370mg, yield 42%).

Reference： [1]Patent: CN110016014,2019,A .Location in patent: Paragraph 0213; 0215; 0216

22
[ 74-96-4 ]
[ 107650-20-4 ]
ethyl 5-bromo-3-nitro-2-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 30℃; for 15h;Inert atmosphere;	5-Bromo-3-nitro-2-methylbenzoic acid (36 g, 138 mmol), ethyl bromide (22.64 g, 208 mmol) and potassium carbonate (38 g, 276 mmol) were added to 120 mL of DMF, and stirred at room temperature for 15 hours. The reaction solution was added with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 39 g of title product, which was used directly in the next step without any further purification.

Reference： [1]Patent: US2019/345139,2019,A1 .Location in patent: Paragraph 0292

23
[ 107650-20-4 ]
5-bromo-3-nitrophthalic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium permanganate; sodium hydroxide; In water; at 80℃; for 3.5h;	To a mixture of compound 734-A (<strong>[107650-20-4]5-bromo-2-methyl-3-nitrobenzoic acid</strong>, CAS number 107650-20-4, 16.0 g,0.062 mol) in H2O (240 mL) was added NaOH (4.92 g, 0.122 mol). The mixture was heated to 80 C then KMnO4 (39g, 0.123 mol) was added in portions during 3 hours. Then the mixture was stirred for 30 minutes. The reaction solutionwas filtered and the cake was washed with hot water (200 mL).The filtrate was adjusted with 2N HCl to pH = 1, extracted with EtOAc (300 mL x 3), the combined organic layers was dried over Na2SO4 and concentrated in vacuum to givecompound 734-B (5-bromo-3-nitrophthalic acid, 9.0 g, yield: 51%) as yellow solid.1H NMR (300 MHz, DMSO) delta 14.0 (br s, 1H), 8.52 (s, 1H), 8.33 (s, 1H).

Reference： [1]Patent: EP3590924,2020,A1 .Location in patent: Paragraph 0292-0293

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P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

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