[ CAS No. 53484-26-7 ] {[proInfo.proName]}

Name: 53484-26-7|4-Bromo-N-methyl-2-nitroaniline|98%
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Quality Control of [ 53484-26-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 53484-26-7 ]

CAS No. :	53484-26-7	MDL No. :	MFCD00624242
Formula :	C₇H₇BrN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IFTUKVAJYOQKRS-UHFFFAOYSA-N
M.W :	231.05	Pubchem ID :	258042
Synonyms :

Calculated chemistry of [ 53484-26-7 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.27
TPSA :	57.85 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.86
Log Po/w (XLOGP3) :	3.07
Log Po/w (WLOGP) :	2.21
Log Po/w (MLOGP) :	2.18
Log Po/w (SILICOS-IT) :	0.03
Consensus Log Po/w :	1.87

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.44
Solubility :	0.083 mg/ml ; 0.000359 mol/l
Class :	Soluble
Log S (Ali) :	-3.95
Solubility :	0.0258 mg/ml ; 0.000112 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.08
Solubility :	0.194 mg/ml ; 0.000839 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.4

Safety of [ 53484-26-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 53484-26-7 ]

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

Upstream synthesis route of [ 53484-26-7 ]
Downstream synthetic route of [ 53484-26-7 ]

[ 53484-26-7 ] Synthesis Path-Upstream 1~5

1
[ 53484-26-7 ]
[ 53484-15-4 ]

Reference： [1] Patent: WO2017/176960, 2017, A1,
[2] Patent: WO2017/176960, 2017, A1,

2
[ 53484-26-7 ]
[ 337915-79-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With platinum on activated charcoal; hydrogen In ethyl acetate at 20℃; for 4 h;	To I-36.1 (5.27 g, 22.81 mmol) in ethyl acetate is added platinum on carbon (550 mg) and stirred under hydrogen (5 bar) at r.t. for 4 h. The reaction mixture is filtered through a pad of celite and concentrated. The crude product is used without further purification for the next step. Yield 96percent.

Reference： [1] Patent: US2014/275025, 2014, A1, . Location in patent: Paragraph 0618; 0626

3
[ 53484-26-7 ]
[ 69038-76-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With iron; ammonium chloride In methanol at 80℃; for 4 h;	To a solution of 4-bromo-N-methyl-2-nitroaniline (2.1 g, 9 mmol) in MeOH (50mL) was added Fe powder (2.5 g, 45 mmol) and NH4C1 (4.8 g, 90 mmol). The mixture wasstirred at 80 °C for 4 h, poured into H20 (60 mL) and extracted with EA (40 mL x 2). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 4-bromo-N’-methylbenzene-1,2-diamine (2.0 g, 99 percent) as a yellow solid. LC-MS m/z: 203.1 [M+Hj . tR = 1.64 min
96%	Stage #1: With tin(II) chloride dihdyrate In ethanol at 70℃; for 3 h; Stage #2: With potassium hydroxide In ethanol	Step 2. 4-Bromo-N⁷-methylbenzene-l ,2-diamineTo a solution of 4-bromo-N-methyl-2-nitroaniline (6 g, 25.97 mmol) in ethanol (100 ml) was added SnCl₂'2H₂0 (29 g, 128.52 mmol). The resulting solution was stirred for 3 h at 70°C, adjusted to pH 8 with potassium hydroxide (4M), extracted with ethyl acetate (2 x 200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N⁷- methylbenzene-l ,2-diamine as a white solid (5 g, 96percent).LC/MS (ES, m/z): [M+H]⁺ 202.1'H-NMR (300 MHz, CDCI₃) δ 6.93 - 6.96 (m, 1H), 6.84 (d, / = 2.1 Hz, 1H), 6.50 (d, / = 8.4 Hz, 1H), 2.85 (s, 3H)
96%	With platinum on activated charcoal; hydrogen In ethyl acetate at 20℃; for 4 h;	Step 2: Synthesis of R58 To 1-36.1(5.27 g, 22.81 mmol) in ethyl acetate is added platinum on carbon (550 mg) and stirred under hydrogen (5 bar) at r.t. for 4h. The reaction mixture is filtered through a pad of celite and concentrated. The crude product is used without further purification for the next step Yield 96percent

76.7%

With hydrogen In ethanol; ethyl acetate

b.
5-bromo-2-methylamino-aniline
Prepared analogously to Example 3d from 5-bromo-2-methylamino-nitrobenzene and Raney nickel/hydrogen in ethyl acetate/ethanol.
Yield: 76.7percent of theory, R_f value: 0.55 (silica gel; methylene chloride/ethanol=19:1).

Reference： [1] Patent: WO2017/176960, 2017, A1, . Location in patent: Paragraph 00743
[2] Patent: WO2012/119046, 2012, A2, . Location in patent: Page/Page column 207
[3] Patent: WO2014/140075, 2014, A1, . Location in patent: Page/Page column 231-232
[4] Patent: US6200976, 2001, B1,
[5] Tetrahedron Letters, 2002, vol. 43, # 41, p. 7303 - 7306
[6] Patent: US2007/112005, 2007, A1, . Location in patent: Page/Page column 68
[7] Patent: WO2003/99776, 2003, A1, . Location in patent: Page 34
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1939 - 1943
[9] Patent: WO2010/127152, 2010, A2, . Location in patent: Page/Page column 108-109
[10] Patent: KR2016/37198, 2016, A, . Location in patent: Paragraph 3394-3396

4
[ 53484-26-7 ]
[ 944718-31-4 ]

Reference： [1] Patent: WO2012/119046, 2012, A2,

5
[ 53484-26-7 ]
[ 1107627-02-0 ]

Reference： [1] Patent: WO2017/176960, 2017, A1,
[2] Patent: WO2017/176960, 2017, A1,

[ 53484-26-7 ] Synthesis Path-Downstream 1~70

1
[ 612-28-2 ]
[ 53484-26-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-Bromosuccinimide; In acetic acid; for 7h;Heating / reflux;	5.0 g (33 mmol) of N-methyl-2-nitroaniline and 5.9 g (33 mmol) of N-bromosuccinimide were added with 60 mL of acetic acid, and the whole was refluxed under heating for 7 hours. After the completion of the reaction, the reaction solution was poured into 500 mL of water, and the precipitated solid was filtered out. The solid that had been filtered out was dissolved into ethyl acetate and dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was dried at room temperature under reduced pressure to obtain 7.1 g of the orange solid of 4-bromo-N-methyl-2-nitroaniline (93% yield).
93%	With N-Bromosuccinimide; acetic acid; for 7h;Heating / reflux;	(1) Synthesis of 4-bromo-N-methyl-2-nitroaniline Pouring 60 milliliter of acetic acid over 5.0 g (33 mmol) of N-methyl-2-nitroaniline and 5.9 g (33 mmol) of N-bromosuccinimide, the resultant solution was refluxed with heating for 7 hours. After completion of the reaction, the reacted solution was poured into 500 milliliter of water, and precipitated solids were separated with filtration. Dissolving the resultant solids into ethyl acetate, the resultant solution was dried with the use of magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure, and after drying the solids under reduced pressure at room temperature, 7.1 g of 4-bromo-N-methyl-2-nitroaniline as orange solids were obtained (yield: 93 %).
93%	With N-Bromosuccinimide; acetic acid; for 7h;Reflux;	(E-1) Synthesis of 4-bromo-N-methyl-2-nitroanilline 60 mL of acetic acid was added to 5.0g (33 mmol) of N-methyl-2-nitroaniline and 5.9g (33 mmol) of N-bromosuccinimide, and the resultant was heated under reflux for 7 hours. After completion of the reaction, the reaction solution was poured to 500 mL of water, and deposited solids were filtered off. The solids which were filtered off were dissolved in ethyl acetate, and dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure at room temperature, whereby 7.1g (yield 93%) of orange solids of 4-bromo-N-methyl-2-nitroaniline were obtained.

88%

With bromine; acetic acid; at 20℃; for 4h;

In a 1000 mL three-neck flask equipped with an electric stirrer and a constant pressure funnel, 60 g (394 mmol) of N-methyl-2-nitroaniline,N-methyl-2-nitroaniline was dissolved in 230 mL of anhydrous acetic acid into a three-necked flask, and 35 mL of anhydrous acetic acid and 69.7 g (436 mmol) of anhydrous liquid bromineStirring at room temperature to open the constant pressure funnel drops of bromine in acetic acid solution,Reaction exothermic, after the completion of the reaction at room temperature 25 4h,Thin layer chromatography reaction was complete (developing solvent: methylene chloride), in the late reaction of a large number of orange solidAfter the reaction, the material in the three-necked flask was suction-filtered, and the filtrate was added with no water to precipitate solid. The solid obtained by filtration was washed once with 260 mL of 5% sodium carbonate aqueous solution and then with deionized water twice, The final standard was the final wash water pH of 7.0.The washed solid was dried in vacuo to give 80.33 g of an orange-yellow solid product in 88% yield.

Reference： [1]Patent: EP1734038,2006,A1 .Location in patent: Page/Page column 44-45
[2]Patent: EP1602648,2005,A1 .Location in patent: Page/Page column 39
[3]Patent: EP2524913,2012,A1 .Location in patent: Page/Page column 32
[4]Patent: CN105399683,2016,A .Location in patent: Paragraph 0023-0028
[5]Recueil des Travaux Chimiques des Pays-Bas,1902,vol. 21,p. 258
Recueil des Travaux Chimiques des Pays-Bas,1908,vol. 27,p. 35 Anm. 2

2
[ 53484-26-7 ]
[ 861609-58-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1902,vol. 21,p. 258
Recueil des Travaux Chimiques des Pays-Bas,1908,vol. 27,p. 35 Anm. 2
[2]Recueil des Travaux Chimiques des Pays-Bas,1902,vol. 21,p. 258
Recueil des Travaux Chimiques des Pays-Bas,1908,vol. 27,p. 35 Anm. 2

4
[ 860238-91-1 ]
[ 53484-26-7 ]

Reference： [1]Journal of the Chemical Society,1930,p. 2400

5
[ 860585-07-5 ]
[ 53484-26-7 ]

Reference： [1]Journal of the Chemical Society,1929,p. 2865

6
[ 53484-26-7 ]
[ 108-24-7 ]
acetic acid-(4-bromo-N-methyl-2-nitro-anilide) [ No CAS ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1939,vol. 58,p. 132,133

7
[ 3460-18-2 ]
[ 74-89-5 ]
[ 53484-26-7 ]

Yield	Reaction Conditions	Operation in experiment
		2,5-Dibromobenzene (5 g, 17. [8] mmol) was added to a solution of methylamine (13.8 [ML] of a 40% aq. solution) and the mixture was stirred for 16 hours, then 8 mL of THF were added and the reaction was stirred for 2 hours at room temperature and then for further 2 hours at [50C.] The reaction mixture was then cooled and extracted twice into ethyl acetate. The solvent was removed under reduced pressure and the crude was chromatographed (silica, AcOEt 2-10% in hexane) to afford 2 g of orange crystals. NMR (400 MHz, CDCl3) : 2.95 (3H, d,, J = 5 Hz, NCH3); 3.92 (3H, s, MeN); 6.7 [(D, J = 8. 5 HZ, ARYL-H) ; 7.45 (1H, DD, , J = 2 AND 8.5 HZ, ARYL-H); 7.9 (1H, BS, NH);] 8.2 (1H, d, , J = 2 Hz, aryl-H).

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1902,vol. 21,p. 258
Recueil des Travaux Chimiques des Pays-Bas,1908,vol. 27,p. 35 Anm. 2
[2]Patent: WO2003/99776,2003,A1 .Location in patent: Page 33-34

8
[ 23042-33-3 ]
[ 53484-26-7 ]

Reference： [1]Chemische Berichte,1897,vol. 30,p. 1260

9
[ 23042-33-3 ]
[ 6911-87-1 ]
[ 53484-26-7 ]

Reference： [1]Journal of the Chemical Society. Perkin Transactions 2 (2001),1996,vol. 7,p. 1321 - 1324

10
[ 7664-93-9 ]
[ 23042-33-3 ]
[ 53484-26-7 ]

Reference： [1]Chemische Berichte,1897,vol. 30,p. 1260

13
[ 7664-93-9 ]
[ 860585-07-5 ]
[ 57-13-6 ]
[ 53484-26-7 ]

Reference： [1]Journal of the Chemical Society,1929,p. 2865

14
[ 53484-26-7 ]
[ 69038-76-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With iron; ammonium chloride; In methanol; at 80℃; for 4h;	To a solution of 4-bromo-N-methyl-2-nitroaniline (2.1 g, 9 mmol) in MeOH (50mL) was added Fe powder (2.5 g, 45 mmol) and NH4C1 (4.8 g, 90 mmol). The mixture wasstirred at 80 C for 4 h, poured into H20 (60 mL) and extracted with EA (40 mL x 2). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 4-bromo-N?-methylbenzene-1,2-diamine (2.0 g, 99 %) as a yellow solid. LC-MS m/z: 203.1 [M+Hj . tR = 1.64 min
96%		Step 2. 4-Bromo-N7-methylbenzene-l ,2-diamineTo a solution of 4-bromo-N-methyl-2-nitroaniline (6 g, 25.97 mmol) in ethanol (100 ml) was added SnCl2'2H20 (29 g, 128.52 mmol). The resulting solution was stirred for 3 h at 70C, adjusted to pH 8 with potassium hydroxide (4M), extracted with ethyl acetate (2 x 200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N7- methylbenzene-l ,2-diamine as a white solid (5 g, 96%).LC/MS (ES, m/z): [M+H]+ 202.1'H-NMR (300 MHz, CDCI3) delta 6.93 - 6.96 (m, 1H), 6.84 (d, / = 2.1 Hz, 1H), 6.50 (d, / = 8.4 Hz, 1H), 2.85 (s, 3H)
96%	With platinum on activated charcoal; hydrogen; In ethyl acetate; at 20℃; under 3750.38 Torr; for 4h;	Step 2: Synthesis of R58 To 1-36.1(5.27 g, 22.81 mmol) in ethyl acetate is added platinum on carbon (550 mg) and stirred under hydrogen (5 bar) at r.t. for 4h. The reaction mixture is filtered through a pad of celite and concentrated. The crude product is used without further purification for the next step Yield 96%

76.7%	With hydrogen;aluminum nickel; In ethanol; ethyl acetate;	b. 5-bromo-2-methylamino-aniline Prepared analogously to Example 3d from 5-bromo-2-methylamino-nitrobenzene and Raney nickel/hydrogen in ethyl acetate/ethanol. Yield: 76.7% of theory, Rf value: 0.55 (silica gel; methylene chloride/ethanol=19:1).
74.5%	With ammonium chloride; zinc; In ethanol; water; at 60℃; for 1.5h;	To the solution of 4-bromo-N-methyl-2-nitroaniline (1.11 g, 4.80 mmol) in EtOH (30 mL) were added zinc powder (3.6 g, 55 mmol) and saturated NH4Cl aqueous solution (4 mL), the mixture was heated to 60 C for 1.5 h. The precipitate in the reaction mixture was filtered out and the filter cake was washed with MeOH (150 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 7/1 to 4/1) to give the title compound as brown liquid (720 mg, yield 74.5%). MS (ESI, pos.ion) m/z: 201.2 [M+H]+;1H NMR (400 MHz, CDCb) 5 (ppm): 6.93 (dd, J = 8.4, 2.2 Hz, 1H), 6.83 (d, j = 2.2 Hz, 1H), 6.50 (d, j= 8.4 Hz, 1H), 3.34 (s, 3H), 2.83 (s, 3H).
74.5%	With ammonium chloride; zinc; In ethanol; at 60℃; for 1.5h;	To 4-bromo-N-methyl-2-nitroaniline (1.11 g, 4.80 mmol)Add EtOH (30mL) solutionZinc powder (3.6 g, 55 mmol) and saturated aqueous NH4Cl (4 mL),The reaction mixture was warmed to 60 C and stirred for 1.5 hours.There are lakes in the system.After the reaction is over, filter,The filter cake was washed with MeOH (150 mL).The filtrate was concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (EtOAc/EtOAc (v/v)The title compound was obtained as a brown liquid (720 mg, yield 74.5%).
		A suspension of 4-bromo-N-methyl-2-nitroaniline (5328 mg, 22.04 mmol) in EtOH (100 ml) was treated with SnCl2.2H2O (25.61 g, 110.2 mmol) and the resulting mixture heated at 70 C. under an atmosphere of Nitrogen for 5 h. The reaction mixture was then cooled to rt and treated with ice-water (50 ml) followed by aqueous NaOH (4 N) until pH>8. This basic mixture was then extracted with EtOAc (3×150 ml) and the combined extracts washed with brine (3×100 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-d6) delta ppm=2.68 (s, 3 H), 4.74 (brs, 3 H), 6.27 (d, 1 H, J=8.4 Hz), 6.61 (dd, 1 H, J=2.0 & 8.4 Hz) and 6.66 (d, 1 H, J=2.0 Hz). MS(ES+): m/z 201.10 and 203.12[MH+].
	With tin(ll) chloride; In ethyl acetate; for 3h;Heating / reflux; Nitrogen atmosphere;	A solution of the nitroaniline from Step 1 (1.56 g, 6.75 mmol) and tin [(II)] chloride (7.62 g, 33.7 mmol) in ethyl acetate (40 mL) was refluxed under nitrogen for 3 hours. The mixture was then poured onto ice, neutralized with saturated [NAHCO3] and extracted into ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate to afford 1.5 g of crude red oil which was used without further purification. [C7H9BRO2 MASS] (calculated): [201.07] ; (found): [M+] = 201 (bromine). NMR (400 MHz, [MEOH-D4)] : 3. 88 [(3H, S, MEO)] ; 2. [8] (3H, [S,] MeN) ; [6.] 7 (1H, [a,] [I =] 8.5 Hz, [ARYL-H)] ; 6. 85 [(1H,] dd,, J = 2 and 8. 5 Hz, aryl-H); 6.9 [(1H,] d, , J = 2 Hz, aryl-H).
		Synthesis of 5-bromo-2-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)-l-methyl-lH- benzoMimidazole (EX-96)[000283] To 4-bromo-l-fluoro-2-nitrobenzene (R-41) (03.27 mmol) was added a 2M methylamine solution in methanol. The solution was stirred at room temperature for 2 hours and then concentrated to give 4-bromo-./V-methyl-2-nitroaniline (R-42) which was used in the next step without further purification.[000284] To a solution of 4-bromo-N-methyl-2-nitroaniline (R-42) dissolved in EtOH (20 mL) was added tin (II) choloride dihyrate (13.1 mmol) and the resulting suspension was heated at 55 0C for 2 hours. The reaction mixture was cooled and 10% aq NaHCO3 was added. The precipitate was removed by filtration. The filtrate was concentrated and purified by preparative HPLC (MeCN gradient 10-90%) to give 4-bromo-N1-methylbenzene-l,2- diamine (R-43). MS (m/z) (M+l)+: 200.0 and 202.0.[000285] 4-Bromo-N1-methylbenzene- 1 ,2-diamine (R-43) was converted to iV-(5-bromo-2- (methylamino)phenyl)-2-(2-chloro-6-fluorophenyl)-lH-imidazole-4-carboxamide (1-34) using a similar procedure as for the synthesis of N-(2-amino-6-bromopyridin-3-yl)-2-(2- chloro-6-fluorophenyl)-lH-imidazole-4-carboxamide (1-33). MS (m/z) (M+l)+: 422.0 and 424.0.[000286] N-(5-Bromo-2-(methylamino)phenyl)-2-(2-chloro-6-fluorophenyl)-lH- imidazole-4-carboxamide (1-34) was converted to 5-bromo-2-(2-(2-chloro-6-fluorophenyl)- lH-imidazol-4-yl)-l -methyl- lH-benzo [J] imidazole (EX-96) using similar procedure as for the synthesis of 5-bromo-2-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)-lH- imidazo[4,5-b]pyridine (EX-95). 1U NMR(400 MHz, J4-CH3OH) delta 8.03 (s, IH), 7.83 (m, IH), 7.69 (m, IH), 7.61 (m, IH), 7.48 (m, IH), 7.38 (m, IH), 7.22 (m, IH), 4.21 (s, 3H). MS (m/z) (M+l)+: 404.0 and 406.0.
	With hydrogenchloride; iron; In methanol; ethanol; water; ethyl acetate; for 1h;Inert atmosphere; Reflux;	Step 1: A mixture of iron (5.88 g, 105 mmol), ethanol (16 mL) and 2 M hydrochloric acid (3.1 mL) was sparged with nitrogen for 10 min, then heated to reflux. A solution of 4-bromo-N-methyl-2-nitroaniline (1.43 g, 6.19 mmol) in ethanol (14 mL), methanol (3 mL) and ethyl acetate (2 mL) was added to the hot mixture and the reaction stirred at reflux for 1 h. After this time, the reaction was cooled to room temperature and adjusted to pH 8-9 with potassium carbonate (850 mg). The mixture was filtered through diatomaceous earth and the filter cake washed with methanol (300 mL). The filtrate was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, methylene chloride to 19:1 methylene chloride/methanol) to afford 4-bromo-N1-methylbenzene-1,2-diamine.
	With ammonium chloride; zinc; In methanol; water; at 20℃; for 2.25h;	To a solution of 4-bromo-N-methyl-2-nitroaniline (0.30 g, 1 .29 mmol), in methanol: water (2:1 , 15 ml_), zinc dust (0.84 g, 12.9), was added followed by portion wise addition of ammonium chloride (0.68 g, 12.98 mmol) over a period of 15 minutes. After complete addition, the reaction mixture was stirred at room temperature for 2h. The reaction mixture was filtered on celite pad, washed with EtOAc (100 ml_). The organic layer was washed with saturated aqueous sodium bicarbonate solution (50 ml_), water (50 ml_), brine (50 ml_), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 4-bromo-N1 - methylbenzene-1 ,2-diamine. 1 H NMR (400 MHz, DMSO-d6) d: 6.65 (d, J = 2 Hz, 1 H), 6.60 (dd, J = 2.4 Hz and 8.4 Hz, 1 H), 6.26 (d, J = 8.4 Hz, 1 H), 4.76 - 4.71 (m, 3H), 2.67 (d, J = 4.4 Hz, 3H).
	With tin(II) chloride hydrate; In ethanol; for 4h;Reflux;	General procedure: 4-(Methylamino)-3-nitrobenzenesulfonamide (2) (250 mg, 1.081 mmol, 1 equiv) dissolved in EtOH and SnCl2.2H2O (1219.8mg, 5.4058 mmol, 5 equiv) was added in five parts, and refluxed for 4h. After EtOH was evaporated, the reaction mixture was diluted with water and neutralized with NaHCO3, ethyl acetate was added, and the mixture filtered from Celite pad. The phases were separated and aqueous phase extracted with ethyl acetate. The combined organic phase was dried, filtered and concentrated. The crude 3 (153.9 mg, 70% yield) was used in the next step without purification. Mp 170.7-172.1 C, (171C [4]). HRMS m/z calculated for C7H11N3O2S [M+H]+ 202.0650 , found: 202.0644. CAS # 66315-22-8.

Reference： [1]Patent: WO2017/176960,2017,A1 .Location in patent: Paragraph 00743
[2]Patent: WO2012/119046,2012,A2 .Location in patent: Page/Page column 207
[3]Patent: WO2014/140075,2014,A1 .Location in patent: Page/Page column 231-232
[4]Patent: US6200976,2001,B1
[5]Patent: WO2019/99311,2019,A1 .Location in patent: Paragraph 000554
[6]Patent: CN109776522,2019,A .Location in patent: Paragraph 1397; 1403; 1404; 1405; 1406
[7]Tetrahedron Letters,2002,vol. 43,p. 7303 - 7306
[8]Patent: US2007/112005,2007,A1 .Location in patent: Page/Page column 68
[9]Patent: WO2003/99776,2003,A1 .Location in patent: Page 34
[10]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1939 - 1943
[11]Patent: WO2010/127152,2010,A2 .Location in patent: Page/Page column 108-109
[12]Patent: KR2016/37198,2016,A .Location in patent: Paragraph 3394-3396
[13]Patent: WO2019/99777,2019,A2 .Location in patent: Paragraph 00500; 00503; 00504
[14]Bioorganic Chemistry,2020,vol. 95

15
[ 364-73-8 ]
[ 74-89-5 ]
[ 53484-26-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol; at 80℃; for 2h;Sealed tube;	A mixture of 4-bromo- 1 -fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) in CH3NH2/MeOH(10 mL) was heated at 80 C for 2 h in a sealed tube, poured into H20 (60 mL) and extracted with EA (40 mL x 2). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 4-bromo-N-methyl-2-nitroaniline (2.1 g, 100 %) as a yellow solid. LC-MS m/z: 232.9 [M+Hf?. tR= 1.90 min.
97%	With potassium carbonate; In dichloromethane; water; at 20℃; for 2h;	Bromo-N-methyl-2-nitroaniline To a solution of 4-bromo-l-fluoro-2-nitrobenzene (6 g, 27.27 mmol) in dichloromethane (100 ml) was added potassium carbonate (7.5 g, 54.27 mmol). This was followed by the addition of CH3NH2 (20 ml, 33% aqueous), which was added dropwise with stirring at room temperature. The resulting solution was stirred for 2 h at room temperature, extracted with dichloromethane (2 x 200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N-methyl-2-nitroaniline as a red solid (6.1 g, 97%).LC/MS (ES, m/z): [M+H]+ 231.1'H-NMR (300 MHz, CDCI3) delta 8.34 (d, / = 2.4 Hz, 1H), 8.05 (s, 1H), 7.47 - 7.56 (m, 1H), 6.79 (d, / = 3.3 Hz, 1H), 3.03 (d, / = 8.1 Hz, 3H)
96%	With potassium carbonate; In dichloromethane; water; at 20℃; for 1.5h;	To a solution of 4-bromo-l-fluoro-2-nitro-benzene (1.1 g, 5.0 mmol) and K2CO3 (1.28 g, 9.26 mmol) in DCM (20 mL) was added a solution of methylamine in water (3.5 mL, mass% = 40%). The reaction mixture was stirred at rt for 1.5 hours and then diluted with water (50 mL) and the resulting mixture was extracted with DCM (80 mL x 3), the combined organic layers were dried over anhydrous Na2S04, filtered and concentrated in vacuo to give the title compound as a red solid ( 1.11 g, yield 96%).MS (ESI, pos.ion) m/z: 231.1 [M+H]+;1H NMR (400 MHz, CDCL) d (ppm): 8.31 (d, J = 2.3 Hz, 1H), 8.01 (s, 1H), 7.52 (dd, J = 9.1, 2.2 Hz, 1H), 6.75 (d, J= 9.1 Hz, 1H), 3.02 (d, J= 5.1 Hz, 3H).

93%	With potassium carbonate; In dichloromethane; water; at 20℃; for 4h;	4-Bromo-1-fluoro-2-nitrobenzene (1.5Og, 6.82mmol) and K2CO3 (1.88g, 13.6mmol) were suspended in DCM (7ml_). MeNH2 (40% in H2O, 7mL) was added slowly and the mixture stirred at room temperature for 4h. The mixture was diluted with H2O and extracted with DCM (3x40ml_). The combined DCM layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the product as a bright orange solid (1.47g, 93%).1H NMR (CDCI3): 8.32 (1 H, d, J 2.4), 8.03 (1 H, br s), 7.52 (1 H, dd, J 9.2 and 2.5), 6.76 (1 H, d, J 9.2) and 3.02 (3 H1 d, J 4.2).
	In methanol; at 20℃; for 2h;	Synthesis of 5-bromo-2-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)-l-methyl-lH- benzoMimidazole (EX-96)[000283] To 4-bromo-l-fluoro-2-nitrobenzene (R-41) (03.27 mmol) was added a 2M methylamine solution in methanol. The solution was stirred at room temperature for 2 hours and then concentrated to give 4-bromo-./V-methyl-2-nitroaniline (R-42) which was used in the next step without further purification.[000284] To a solution of 4-bromo-N-methyl-2-nitroaniline (R-42) dissolved in EtOH (20 mL) was added tin (II) choloride dihyrate (13.1 mmol) and the resulting suspension was heated at 55 0C for 2 hours. The reaction mixture was cooled and 10% aq NaHCO3 was added. The precipitate was removed by filtration. The filtrate was concentrated and purified by preparative HPLC (MeCN gradient 10-90%) to give 4-bromo-N1-methylbenzene-l,2- diamine (R-43). MS (m/z) (M+l)+: 200.0 and 202.0.[000285] 4-Bromo-N1-methylbenzene- 1 ,2-diamine (R-43) was converted to iV-(5-bromo-2- (methylamino)phenyl)-2-(2-chloro-6-fluorophenyl)-lH-imidazole-4-carboxamide (1-34) using a similar procedure as for the synthesis of N-(2-amino-6-bromopyridin-3-yl)-2-(2- chloro-6-fluorophenyl)-lH-imidazole-4-carboxamide (1-33). MS (m/z) (M+l)+: 422.0 and 424.0.[000286] N-(5-Bromo-2-(methylamino)phenyl)-2-(2-chloro-6-fluorophenyl)-lH- imidazole-4-carboxamide (1-34) was converted to 5-bromo-2-(2-(2-chloro-6-fluorophenyl)- lH-imidazol-4-yl)-l -methyl- lH-benzo [J] imidazole (EX-96) using similar procedure as for the synthesis of 5-bromo-2-(2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl)-lH- imidazo[4,5-b]pyridine (EX-95). 1U NMR(400 MHz, J4-CH3OH) delta 8.03 (s, IH), 7.83 (m, IH), 7.69 (m, IH), 7.61 (m, IH), 7.48 (m, IH), 7.38 (m, IH), 7.22 (m, IH), 4.21 (s, 3H). MS (m/z) (M+l)+: 404.0 and 406.0.
	In methanol; ethanol; at 20℃; for 1h;	To a solution of 4-bromo-1 -fluoro-2-nitrobenzene (0.50 g, 2.28 mmol), in EtOH (10 ml_), 40% methylamine in methanol (1 .0 ml.) was added and stirred at room temperature for 1 hour. The precipitated material was filtered and washed with hexanes and dried to obtain 4- bromo-N-methyl-2-nitroaniline. 1 H NMR (400 MHz, DMSO-d6) d: 8.24 (brs, 1 H), 8.15 (d, J = 2.4 Hz, 1 H), 7.67 (dd, J = 2.4 Hz and 9.2 Hz, 1 H), 6.98 (d, J = 9.2 Hz, 1 H), 2.94 (d, J = 4.8 Hz, 3H).
	In dimethyl sulfoxide;	4-Bromo-1-fluoro-2-nitrobenzene (1g, 4.545 mmol, 1 equiv) was dissolved in DMSO, methylamine (%40, 784 muL, 9.0909 mmol, 2 equiv) was added, and reaction mixture stirred at 60?C overnight. Then, the reaction mixture was poured into water and extracted with ethyl acetate. Organic layer was dried, filtered and evaporated. The crude 18 (1046 mg, 99.5% yield) was used in the next step without purification. Mp 96.9-98.4 C (97.5-98 C [12]). HRMS m/z calculated for C7H7N2O2Br [M-H]- 230.9769, found: 230.9775. CAS # 53484-26-7

Reference： [1]Patent: WO2017/176960,2017,A1 .Location in patent: Paragraph 00742
[2]Patent: WO2012/119046,2012,A2 .Location in patent: Page/Page column 206-207
[3]Patent: WO2019/99311,2019,A1 .Location in patent: Paragraph 000553
[4]Patent: WO2010/63996,2010,A2 .Location in patent: Page/Page column 52
[5]Tetrahedron Letters,2002,vol. 43,p. 7303 - 7306
[6]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1939 - 1943
[7]Patent: WO2010/127152,2010,A2 .Location in patent: Page/Page column 108-109
[8]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167
[9]Journal of the American Chemical Society,2018,vol. 140,p. 14761 - 14769
[10]Patent: WO2019/99777,2019,A2 .Location in patent: Paragraph 00500-00502
[11]Bioorganic Chemistry,2020,vol. 95

16
[ 6911-87-1 ]
[ 53484-26-7 ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 6879 - 6881

17
[ 53484-26-7 ]
[ 73183-34-3 ]
N-methyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5406 - 5409
[2]Organic and Biomolecular Chemistry,2013,vol. 11,p. 8228 - 8234

18
[ 53484-26-7 ]
N-(5-bromo-1-methyl-1H-benzoimidazol-2-yl)-benzamide [ No CAS ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 7303 - 7306

19
[ 53484-26-7 ]
[ 1026316-27-7 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 7303 - 7306

20
[ 829-02-7 ]
[ 53484-26-7 ]

Reference： [1]Journal of the Chemical Society,1929,p. 2865

21
[ 88-73-3 ]
[ 53484-26-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1902,vol. 21,p. 258
Recueil des Travaux Chimiques des Pays-Bas,1908,vol. 27,p. 35 Anm. 2

22
[ 53484-26-7 ]
[ 98-88-4 ]
[ 760212-71-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	With pyridine; at 90℃; for 7h;	6.8 g (29 mmol) of <strong>[53484-26-7]4-bromo-N-methyl-2-nitroaniline</strong> were dissolved into 20 mL of pyridine. Furthermore, 5.0 g (35 mmol) of benzoyl chloride were added, and the whole was stirred under heating at 90C for 7 hours in an argon atmosphere. After the completion of the reaction, 200 mL of ethyl acetate were added, and the whole was washed with 10-mass% hydrochloric acid, 10-mass% K2CO3, and a saturated sodium chloride solution, and dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography to obtain 9.5 g of 4'-bromo-N-methyl-2'-nitro-benzanilide as a greenish white solid (96% yield).
96%	With pyridine; at 90℃; for 7h;	(2) Synthesis of 4'-bromo-N-methyl-2'-nitro-benzanilide Dissolving 6.8 g (29 mmol) <strong>[53484-26-7]4-bromo-N-methyl-2-nitroaniline</strong> obtained in the above step (1) into 20 milliliter of pyridine, further adding 5.0 g(35 mmol) benzoyl chloride, the resultant solution was refluxed with heating at the temperature of 90 C under an atmosphere of argon gas for 7 hours. After completing the reaction, 200 milliliter of ethyl acetate was added and the resultant solution was washed with 10 % HCL, with 10 % K2CO3 and with a saturated solution of sodium chloride and then, dried with the use of magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure and the residue was refined with silicagel column chromatography (hexane: ethyl acetate = 10:1 at primary stage ? 2:1 from middle stage) resultantly obtaining 9.5 g of 4'-bromo-N-methyl-2'-amino-benzanilide as greenish white solids (yield: 96 %).
96%	With pyridine; at 90℃; for 7h;Inert atmosphere;	(E-2) Synthesis of 4'-bromo-N-methyl-2'-nitrobenzanilide 6.8g (29 mmol) of <strong>[53484-26-7]4-bromo-N-methyl-2-nitroaniline</strong> was dissolved in 20 mL of pyridine. To the resulting solution, 5.0g (35 mmol) of benzoyl chloride was added, and the resulting mixture was stirred with heating at 90C for 7 hours in the atmosphere of argon. After completion of the reaction, 200 mL of ethyl acetate was added, and an organic phase was washed with an aqueous 10% hydrochloric acid solution, an aqueous 10% potassium carbonate solution and saturated saline, and then dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and residues were purified by silica gel column chromatography, whereby 9.5g (yield 96%) of greenish white solids of 4'-bromo-N-methyl-2'-nitrobenzanilide were obtained.

94%

With pyridine; at 90℃; for 7h;Inert atmosphere;

68 g (290 mmol) of methyl-2-nitro-4-bromoaniline prepared in step was dissolved in 200 mL of pyridine, added to a 500 mL three-necked flask, and benzoyl chloride 50 g (350 mmol) was added and the mixture was heated to 90 C under argon atmosphere for 7 h. The reaction was complete by TLC (developing solvent: petroleum ether / ethyl acetate (3: 1)).Ethyl acetate (2000 mL) was added to the end of the reaction, and a large amount of pyridine hydrochloride was collected. The mixture was filtered off and the solid was washed with ethyl acetate. The resulting ethyl acetate filtrate was washed with 800 mL of 10% hydrochloric acid and the organic phase was separated. The organic phase was washed twice with 800 mL of 10% potassium carbonate solution, pH = 8, ML saturated saline solution, and the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was driedThe dried organic phase was filtered and the resulting filtrate was distilled under reduced pressure to remove the solvent. The residue obtained after distillation was added to a mixed solvent of petroleum ether / ethyl acetate (3: 1) to find that the unreacted starting material was easily dissolved, Dissolved. The solution was separated from the solid by pouring and the solution was subjected to column chromatography. The eluant: petroleum ether / ethyl acetate (3: 1) gave 28 g of product, which was purified by petroleum ether / ethyl acetate (3: 1) to obtain 63 g of a product, which yielded 91 g of a green-white solid in a total yield of 94%.

Reference： [1]Patent: EP1734038,2006,A1 .Location in patent: Page/Page column 45
[2]Patent: EP1602648,2005,A1 .Location in patent: Page/Page column 39
[3]Patent: EP2524913,2012,A1 .Location in patent: Page/Page column 32
[4]Patent: CN105399683,2016,A .Location in patent: Paragraph 0032-0035

23
[ 3460-18-2 ]
[ 53484-26-7 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With methylamine; In ethanol;	a. 5-bromo-2-methylamino-nitrobenzene Prepared analogously to Example 7a from 2,5-dibromo-nitrobenzene and methylamine solution in ethanol. Yield: 92.8% of theory, Rf value: 0.45 (silica gel; ethyl acetate/petroleum ether=1:9).

Reference： [1]Patent: US6200976,2001,B1

24
[ 53484-26-7 ]
[ 138647-49-1 ]
C₁₇H₂₃N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5063 - 5066

25
[ 833486-94-5 ]
[ 53484-26-7 ]
[ 1228654-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;palladium diacetate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 130℃;Inert atmosphere; microwave irradiation;	4-Bromo-Lambda/-methyl-2-nitroaniline (100mg, 0.43mmol), 2-nitro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)aniline (115mg, 0.43mmol), biphenyl-2-yldicyclohexylphosphine (30mg, 20mol%) and K3PO4 (275mg, 1.3mmol) were suspended in DME-H2O (4:1 , 5ml_). the mixture was purged with nitrogen then degassed by sonication. Pd(OAc)2 (5mg, 5mol%) was added, and the mixture heated to 13O0C for 10min under microwave irradiation. The cooled mixture was diluted with EtOAc and H2O. The organics were separated and the aqueous layer extracted with EtOAc (3x50ml_). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a dark brown solid (210mg). The crude material was taken on without further purification.1H NMR (DMSO): 8.29-8.14 (3 H, m), 7.90 (1 H, dd, J 9.1 and 2.3), 7.77 (1 H, td, J 8.5 and 2.3), 7.54 (2 H, br s), 7.15-7.05 (2 H, m) and 3.00 (3 H, d, J 5.0).

Reference： [1]Patent: WO2010/63996,2010,A2 .Location in patent: Page/Page column 52-53

26
[ 53484-26-7 ]
[ 1305348-57-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167
[2]Journal of the American Chemical Society,2018,vol. 140,p. 14761 - 14769
[3]Biochemistry,2020,vol. 59,p. 1756 - 1768

27
[ 53484-26-7 ]
[ 1305348-58-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167

28
[ 53484-26-7 ]
2,5-bis(4-amidinophenyl)-1-methyl-1H-benzimidazole trihydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167

29
[ 53484-26-7 ]
[ 126747-14-6 ]
[ 1305348-56-4 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium phosphate; trans-diacetylpalladium(II) bis(dicyclohexylamine); In ethanol; at 80℃; for 24h;Inert atmosphere;	DAPCy (0.3 g, 0.44 mmol %) and K3PO4 (3.8 g, 17.8 mmol) were added to a solution of 26 (2.5 g, 8.9 mmol) and p-cyanophenylboronic acid (1.55 g, 10.6 mmol) in deaireated absolute ethanol (60 mL). The vigorously stirred mixture was warmed to 80 C for 24 h under a nitrogen atmosphere. The solvent was concentrated under reduced pressure; the crystals which formed were filtered, dissolved in dichloromethane and passed through celite. Purification by column chromatography on silica gel, using hexanes/ethyl acetate (70:30, v/v) as the eluent gave 4-(4-N-methylamino-3-nitrophenyl)-benzonitrile (27) (1.35 g, 60%). Mp 194.4-195.4 C. 1H NMR (DMSO-d6, 300 MHz) delta 8.39 (d, 1H, J = 2.4 Hz), 8.14 (br s, 1H), 7.95 (dd, 1H, J = 2.4, J = 9.0 Hz), 7.83 (m, 4H), 7.12 (d, 1H, J = 9.3 Hz), 3.01 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) delta 145.9, 142.7, 134.8, 132.9, 131.5, 126.6, 124.7, 124.2, 119.0, 115.4, 109.4, 29.7. Compound 27 was used in the next step without further characterization. Pd/C (10%) (0.5 g) was added to a solution of the nitro compound 27 (4 g, 15.6 mmol) in ethanol: ethyl acetate (60 mL: 20 mL) mixture. Shaking in a Parr hydrogenator at 50 psi was continued until the uptake of hydrogen ceased; the solution was passed through celite to remove the catalyst, and concentrated under reduced pressure. Purification by crystallization from acetone gave 4-(3-amino-4-N-methylaminophenyl)-benzonitrile (28) (3.2 g, 90%). Mp 215-216 C. 1H NMR (DMSO-d6, 300 MHz) delta 7.63 (m, 4H), 7.13 (dd, 1H, J = 2.1, J = 8.1 Hz), 6.98 (d, 1H, J = 1.8 Hz), 6.72 (d, 1H, J = 8.4 Hz), 3.40 (br s, 2H), 2.92 (s, 3H). ESI-MS: m/z calcd for C14H13N3: 223.27, found: 224.0 (M++1). Compound 28 was used in the next step without further characterization. 4-Cyanobenzaldehyde (0.7 g, 5.6 mmol) and 28 (1.4 g, 5.4 mmol) were stirred in anhydrous dimethylformamide for 1 h, then sodium bisulfite (0.6 g, 5.6 mmol) was added and the resulting mixture was stirred at 130 C for 48 h, cooled to room temperature, poured into water and the resulting crystals were filtered and recrystalized from ethanol to give 29 (1.4 g, 73% yield). Mp 257-258 C. 1H NMR (DMSO-d6, 300 MHz) delta 8.10 (m, 3H), 8.03 (d, 2H, J = 8.7 Hz), 7.95 (d, 2H, J = 8.7 Hz), 7.89 (d, 2H, J = 8.7 Hz), 7.80 (d, 1H, J = 8.7 Hz), 7.72 (dd, 1H, J = 1.5, J = 8.4 Hz), 3.95 (s, 3H). 13C NMR (DMSO-d6, 75 MHz) delta 152.2, 145.2, 142.9, 137, 134.1, 132.7, 132.5, 132.3, 129.8, 127.4, 122.2, 118.6, 118.1, 117.7, 112.1, 111.2, 109.2, 31.7. ESI-MS: m/z calcd for C22H14N4: 334.12, found: 335.1 (M++1). Anal. Calcd for C22H14N4·0.2H2O: C, 78.18; H, 4.29; N, 16.58. Found: C, 78.28; H, 4.15; N, 16.88.

30
[ 53484-26-7 ]
[ 1380921-22-1 ]

Reference： [1]Patent: WO2012/76672,2012,A1
[2]Patent: US2012/309738,2012,A1

31
[ 53484-26-7 ]
[ 1380921-23-2 ]

Reference： [1]Patent: WO2012/76672,2012,A1
[2]Patent: US2012/309738,2012,A1

32
[ 53484-26-7 ]
[ 1380919-26-5 ]

Reference： [1]Patent: WO2012/76672,2012,A1
[2]Patent: US2012/309738,2012,A1

33
[ 53484-26-7 ]
[ 1380921-24-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With hydrogenchloride; In 1,4-dioxane; at 20℃;	(c) N-{2,4-Dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1 H- benzimidazol-2-ylamino]benzyl}-carbamic acid tert-butyl esterThe title compound was prepared from (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (5.47g, 16.4 mmol), 5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1- yl)aniline (5.05g, 16.4 mmol) and DIC 4.48 ml, 29 mmol) in MeCN in analogy to example 6 step(c).HPLC-method A: Rt = 2.37 min. MS m/z: 606 [M+H]+.

Reference： [1]Patent: WO2012/76672,2012,A1 .Location in patent: Page/Page column 76

34
[ 657-36-3 ]
[ 53484-26-7 ]
[ 1380921-21-0 ]

Yield	Reaction Conditions	Operation in experiment
38%	With sodium t-butanolate;tri-tert-butyl phosphine; palladium diacetate; In toluene; at 100℃;Inert atmosphere;	(a) N-Methyl-2-nitro-4-(4-trifluoromethyl-piperidin-1-yl)-anilineUnder argon sodium tert-butoxide (366 mg, 3.8 mmol) followed by palladium(ll) acetate (22 mg, 0.1 mmol) and tri-tert-butylphosphine 10percent in toluene (450 muIota_, 0.2 mmol) were added to a mixture of 4-bromo-2-nitro-N-methyl-aniline (440 mg, 1.9 mmol) and 4- (trifluoromethyl)piperidine (660 mg, 2.9 mmol) in toluene (7 mL). The reaction mixture was stirred at 100°C overnight then allowed to cool and was concentrated. The crude was purified by chromatography to give the sub-title compound.Yield: 220 mg (38percent). Rf(TLC): 0.56 (silica gel, DCM:EtOH 98:2). MS m/z: 304 [M+H]+.
38%	With sodium t-butanolate;tri-tert-butyl phosphine; palladium diacetate; In toluene; at 100℃;	(a)N-Methyl-2-nitro-4-(4-trifluoromethyl-piperidin-1-yl)-anilineUnder argon sodium tert-butoxide (366 mg, 3.8 mmol) followed by palladium(II) acetate (22 mg, 0.1 mmol) and tri-tert-butylphosphine 10percent in toluene (450 muL, 0.2 mmol) were added to a mixture of 4-bromo-2-nitro-N-methyl-aniline (440 mg, 1.9 mmol) and <strong>[657-36-3]4-(trifluoromethyl)piperidine</strong> (660 mg, 2.9 mmol) in toluene (7 mL).The reaction mixture was stirred at 100° C. overnight then allowed to cool and was concentrated.The crude was purified by chromatography to give the sub-title compound.Yield: 220 mg (38percent). Rf(TLC): 0.56 (silica gel, DCM:EtOH 98:2). MS m/z: 304 [M+H]+.

Reference： [1]Patent: WO2012/76672,2012,A1 .Location in patent: Page/Page column 74
[2]Patent: US2012/309738,2012,A1 .Location in patent: Page/Page column 37

35
[ 53484-26-7 ]
[ 944718-31-4 ]

Reference： [1]Patent: WO2012/119046,2012,A2

36
[ 53484-26-7 ]
[ 1396753-40-4 ]

Reference： [1]Patent: WO2012/119046,2012,A2

37
[ 53484-26-7 ]
[ 1396753-41-5 ]

Reference： [1]Patent: WO2012/119046,2012,A2

38
[ 53484-26-7 ]
[ 1396753-42-6 ]

Reference： [1]Patent: WO2012/119046,2012,A2

39
[ 53484-26-7 ]
[ 760212-72-4 ]

Reference： [1]Patent: EP2524913,2012,A1
[2]Patent: CN105399683,2016,A

40
[ 53484-26-7 ]
[ 760212-73-5 ]

Reference： [1]Patent: EP2524913,2012,A1
[2]Patent: CN105399683,2016,A
[3]Bioorganic Chemistry,2020,vol. 95

41
[ 875-51-4 ]
[ 74-88-4 ]
[ 53484-26-7 ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 8228 - 8234

42
[ 53484-26-7 ]
C₄₅H₅₃N₄O₈S₂^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 8228 - 8234

43
[ 53484-26-7 ]
C₄₅H₅₅N₄O₆S₂^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 8228 - 8234

44
[ 875-51-4 ]
[ 593-51-1 ]
[ 53484-26-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Step 1: Synthesis of intermediate 1-36.1 To 4-bromo-2-nitro-aniline (10 g, 46.08 mmol) in DMF (200 mL) are added potassium carbonate (15 g, 108.53 mmol) and portionwise methylamine hydrochloride (3.11 g, 46.08 mmol) and stirred overnight at r.t...The reaction mixture is filtered and concentrated. The crude product is triturated with DIPE, filtered off and dried. Yield 86%
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	To 4-bromo-2-nitro-aniline (10 g, 46.08 mmol) in DMF (200 mL) are added potassium carbonate is (15 g, 108.53 mmol) and portionwise methylamine hydrochloride (3.11 g, 46.08 mmol) and stirred overnight at r.t. The reaction mixture is filtered and concentrated. The crude product is triturated with DIPE, filtered off and dried. Yield 86%.

Reference： [1]Patent: WO2014/140075,2014,A1 .Location in patent: Page/Page column 231
[2]Patent: US2014/275025,2014,A1 .Location in patent: Paragraph 0624; 0625

45
[ 53484-26-7 ]
[ 84712-08-3 ]

Reference： [1]Patent: WO2014/140075,2014,A1
[2]Patent: US2014/275025,2014,A1

46
[ 53484-26-7 ]
C₈H₈Br₂N₂ [ No CAS ]

Reference： [1]Patent: WO2014/140075,2014,A1

47
[ 53484-26-7 ]
5-bromo-N,1-dimethyl-benzimidazol-2-amine [ No CAS ]

Reference： [1]Patent: WO2014/140075,2014,A1
[2]Patent: US2014/275025,2014,A1

48
[ 53484-26-7 ]
[ 337915-79-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With platinum on activated charcoal; hydrogen; In ethyl acetate; at 20℃; under 3750.38 Torr; for 4h;	To I-36.1 (5.27 g, 22.81 mmol) in ethyl acetate is added platinum on carbon (550 mg) and stirred under hydrogen (5 bar) at r.t. for 4 h. The reaction mixture is filtered through a pad of celite and concentrated. The crude product is used without further purification for the next step. Yield 96%.

Reference： [1]Patent: US2014/275025,2014,A1 .Location in patent: Paragraph 0618; 0626

49
[ 53484-26-7 ]
[ 380608-56-0 ]

Reference： [1]Patent: US2014/275025,2014,A1

50
[ 53484-26-7 ]
[ 53484-15-4 ]

Reference： [1]Patent: WO2017/176960,2017,A1
[2]Patent: WO2017/176960,2017,A1

51
[ 53484-26-7 ]
[ 1107627-02-0 ]

Reference： [1]Patent: WO2017/176960,2017,A1
[2]Patent: WO2017/176960,2017,A1

52
[ 53484-26-7 ]
4-(5-(5-(4-carbamimidoylphenyl)-1-methyl-1H-benzo[d]imidazol-2-yl)selenophen-2-yl)benzimidamide trihydrochloride [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 14761 - 14769

53
[ 53484-26-7 ]
4-(5-(5-(4-cyanophenyl)-1-methyl-1H-benzo[d]imidazol-2-yl)thiophen-2-yl)benzonitrile [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 14761 - 14769

54
[ 53484-26-7 ]
4-(5-(5-(4-cyanophenyl)-1-methyl-1H-benzo[d]imidazol-2-yl)selenophen-2-yl)benzonitrile [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 14761 - 14769

55
[ 53484-26-7 ]
4-(5-(5-(4-carbamimidoylphenyl)-1-methyl-1H-benzo[d]imidazol-2-yl)thiophen-2-yl)benzimidamide trihydrochloride [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 14761 - 14769

56
[ 53484-26-7 ]
1,4-bis(5-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)benzene [ No CAS ]

Reference： [1]Patent: WO2019/99777,2019,A2

57
[ 53484-26-7 ]
[ 99513-17-4 ]

Reference： [1]Patent: WO2019/99311,2019,A1
[2]Patent: CN109776522,2019,A

58
[ 53484-26-7 ]
N-(diphenylmethylene)-1,2-dimethyl-1H-benzo[d]imidazole-5-amine [ No CAS ]

Reference： [1]Patent: WO2019/99311,2019,A1
[2]Patent: CN109776522,2019,A

59
[ 53484-26-7 ]
[ 3527-19-3 ]

Reference： [1]Patent: WO2019/99311,2019,A1
[2]Patent: CN109776522,2019,A

60
[ 53484-26-7 ]
6-(4-((5-chloro-2-((1,2-dimethyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2019/99311,2019,A1
[2]Patent: CN109776522,2019,A

61
[ 53484-26-7 ]
6-(4-((5-chloro-2-((1,2-dimethyl-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2019/99311,2019,A1
[2]Patent: CN109776522,2019,A

62
[ 53484-26-7 ]
(1-methyl-2-phenyl-1H-benzo[d]imidazol-5-yl)boronic acid [ No CAS ]