[ CAS No. 153505-37-4 ] {[proInfo.proName]}

Name: 153505-37-4|4-Bromo-5-fluorobenzene-1,2-diamine|98%
Brand: Ambeed
SKU: A279764
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Quality Control of [ 153505-37-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 153505-37-4 ]

Product Details of [ 153505-37-4 ]

CAS No. :	153505-37-4	MDL No. :	MFCD08458150
Formula :	C₆H₆BrFN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NDXWAQNAHFBGML-UHFFFAOYSA-N
M.W :	205.03	Pubchem ID :	19958560
Synonyms :

Calculated chemistry of [ 153505-37-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	2.0
Molar Refractivity :	42.91
TPSA :	52.04 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.38
Log Po/w (XLOGP3) :	1.35
Log Po/w (WLOGP) :	2.19
Log Po/w (MLOGP) :	2.02
Log Po/w (SILICOS-IT) :	1.52
Consensus Log Po/w :	1.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.41
Solubility :	0.806 mg/ml ; 0.00393 mol/l
Class :	Soluble
Log S (Ali) :	-2.04
Solubility :	1.85 mg/ml ; 0.00902 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.82
Solubility :	0.312 mg/ml ; 0.00152 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.68

Safety of [ 153505-37-4 ]

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 [ 153505-37-4 ]

* 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 [ 153505-37-4 ]
Downstream synthetic route of [ 153505-37-4 ]

[ 153505-37-4 ] Synthesis Path-Upstream 1~6

1
[ 153505-36-3 ]
[ 153505-37-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With ammonium formate; zinc In methanol at 0 - 20℃; Inert atmosphere	To a flask was added 5-fluoro-2-nitroaniline (8.9 g, 57 mmol), NBS (10 g, 56 mmol), and acetic acid (500 mL), and the reaction was heated to 110 °C. Once complete it was cooled to room temperature and poured into 3 L of water. The resulting suspension was filtered and the solid was washed with 500 mL of water. Solid was air dried overnight (12.7 g, 91 percent). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J = 7.3 Hz, 1H), 7.73 (br. S., 2H), 6.94 (d, J = 11.0 Hz, 1H). 4-bromo-5-fluoro-2-nitroaniline (0.53 g, 2.255 mmol), zinc (0.89 g, 13.5 mmol), and methanol (32 ml) were added to the flask and argon was bubbled through the solution for 1 hour. Ammonium formate (1.42 g, 22.6 mmol) was then added in several portions. The reaction was then stirred at room temperature overnight and was complete by LCMS in the morning. It was filtered through a pad of celite and the filtrate was concentrated. The residue was partitioned between water and EtOAc and the organic layer was collected. The aqueous layer was back-extracted using EtOAc (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated (378 mg, 82 percent). MS (m/z) 205.0, 207.0 (M⁺, M+2⁺).
81%	With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 95℃; for 4 h;	Intermediate 11C; 4-bromo-5 -fluorobenzene- 1 ,2-diamine; To a solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and H₂0 (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol), and the mixture was heated at 95 °C for 4 hours. The cooled mixture was diluted with EtOH, filtered through diatomaceous earth until no further color came through the filter, and concentrated. The residue was dissolved in EtOAc, washed with H₂0, brine, dried (Na₂S0₄), filtered and concentrated. Hexane was added and the resulting solid collected by filtration to give the title compound (710 mg, 3.5 mmol, 81percent).
43%	With tin(ll) chloride In ethanol for 14 h; Reflux	step 2: To a suspension of 96 (1.57 g, 6.74 mmol) in EtOH (16 mL) was added SnC¾ (3.82 g, 20.2 mmol). The reaction mixture was heated at reflux for 14 h, cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and sat'd. aq. NaHCC>3 (200 mL). The resulting slurry was filtered through a pad of Celite® and the wet cake was washed with EtOAc (3 x 50 mL). The organic layer was washed sequentially with saturated NaHC03, water, and brine, dried (MgSO i), filtered and concentrated in vacuo to afford 600 mg (43percent) of 44oromo-5-fluorobenzene-l,2-diamine (98) as yellow solid: MS (ESI) m/z = 205 [M+l]

Reference： [1] Patent: EP2566477, 2015, B1, . Location in patent: Paragraph 0172; 0173
[2] Patent: WO2012/83170, 2012, A1, . Location in patent: Page/Page column 155
[3] Patent: WO2013/26914, 2013, A1, . Location in patent: Page/Page column 134
[4] Patent: US2007/259936, 2007, A1, . Location in patent: Page/Page column 175
[5] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 69

2
[ 153505-36-3 ]
[ 153505-37-4 ]

Reference： [1] Patent: US5514680, 1996, A,

3
[ 2369-11-1 ]
[ 153505-37-4 ]

Reference： [1] Patent: WO2013/26914, 2013, A1,
[2] Patent: EP2566477, 2015, B1,
[3] Patent: US5514680, 1996, A,

4
[ 656-65-5 ]
[ 153505-37-4 ]

Reference： [1] Patent: WO2012/83170, 2012, A1,

5
[ 929279-27-6 ]
[ 153505-37-4 ]

Reference： [1] Patent: WO2012/83170, 2012, A1,

6
[ 64-18-6 ]
[ 153505-37-4 ]
[ 1008360-84-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	Reflux	step 3: A mixture of 98 (600 mg, 2.93 mmol) in formic acid (5.0 mL) was heated to reflux overnight. The reaction mixture was concentrated in vacuo to afford a brown oil that was partitioned between EtOAc (300 mL) and a sat'd. aq. NaHC03 (100 mL). The organic layer was separated, dried (MgSO i), filtered and evaporated in vacuo to afford 550 mg (87percent) of 54oromo-6-fluoro-lH4oenzo[d]imidazole (100) as white solid (550 mg, 87percent): MS (ESI) m/z = 215 [M+l] +.

Reference： [1] Patent: WO2013/26914, 2013, A1, . Location in patent: Page/Page column 134
[2] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 70

[ 153505-37-4 ] Synthesis Path-Downstream 1~48

1
[ 153505-36-3 ]
[ 153505-37-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With ammonium formate; zinc; In methanol; at 0 - 20℃;Inert atmosphere;	To a flask was added 5-fluoro-2-nitroaniline (8.9 g, 57 mmol), NBS (10 g, 56 mmol), and acetic acid (500 mL), and the reaction was heated to 110 C. Once complete it was cooled to room temperature and poured into 3 L of water. The resulting suspension was filtered and the solid was washed with 500 mL of water. Solid was air dried overnight (12.7 g, 91 %). 1H NMR (400 MHz, DMSO-d6) delta 8.27 (d, J = 7.3 Hz, 1H), 7.73 (br. S., 2H), 6.94 (d, J = 11.0 Hz, 1H). <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (0.53 g, 2.255 mmol), zinc (0.89 g, 13.5 mmol), and methanol (32 ml) were added to the flask and argon was bubbled through the solution for 1 hour. Ammonium formate (1.42 g, 22.6 mmol) was then added in several portions. The reaction was then stirred at room temperature overnight and was complete by LCMS in the morning. It was filtered through a pad of celite and the filtrate was concentrated. The residue was partitioned between water and EtOAc and the organic layer was collected. The aqueous layer was back-extracted using EtOAc (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated (378 mg, 82 %). MS (m/z) 205.0, 207.0 (M+, M+2+).
81%	With iron; ammonium chloride; In tetrahydrofuran; ethanol; water; at 95℃; for 4h;	Intermediate 11C; 4-bromo-5 -fluorobenzene- 1 ,2-diamine; To a solution of <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and H20 (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol), and the mixture was heated at 95 C for 4 hours. The cooled mixture was diluted with EtOH, filtered through diatomaceous earth until no further color came through the filter, and concentrated. The residue was dissolved in EtOAc, washed with H20, brine, dried (Na2S04), filtered and concentrated. Hexane was added and the resulting solid collected by filtration to give the title compound (710 mg, 3.5 mmol, 81%).
43%	With tin(ll) chloride; In ethanol; for 14h;Reflux;	step 2: To a suspension of 96 (1.57 g, 6.74 mmol) in EtOH (16 mL) was added SnC¾ (3.82 g, 20.2 mmol). The reaction mixture was heated at reflux for 14 h, cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and sat'd. aq. NaHCC>3 (200 mL). The resulting slurry was filtered through a pad of Celite and the wet cake was washed with EtOAc (3 x 50 mL). The organic layer was washed sequentially with saturated NaHC03, water, and brine, dried (MgSO i), filtered and concentrated in vacuo to afford 600 mg (43%) of 44oromo-5-fluorobenzene-l,2-diamine (98) as yellow solid: MS (ESI) m/z = 205 [M+l]

	With ammonium chloride; zinc; In ethanol; at 20℃; for 16h;	Compound 13b (1.88 g, 0.008 mol) was dissolved in 20 mL of ethanol. Zinc powder (4.71 g, 0.072 mol) was added in portions followed by the addition of the ammonium chloride (0.86 g, 0.016 mol). The reaction mixture was stirred at room temperature overnight (16 h). The reaction mixture was filtered over a pad of celite and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate (30 mL) and washed with 25 mL of brine. The organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH, 96:4-94:6)) to provide the title Compound 13c as a dark yellow solid (1.02 g) that was used immediately in the next reaction. MS (ESI, pos. ion) m/z: 235.7 (M+1).
	With tin(II) chloride dihdyrate; In ethanol; at 70℃; for 3h;	To a solution of <strong>[153505-36-3]4-bromo-5-fluoro-2-nitroaniline</strong> (3.2 g, 13.6 mmol) in ethanol (75 mL) was added tin(II) chloride dihydrate (9.2 g, 40.8 mmol) and the reaction was heated at 70 degrees C. for 3 h. The reaction was allowed to cool, then was diluted with saturated sodium bicarbonate and water, and was extracted with ethyl acetate (3×). The extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified via chromatography (50% ethyl acetate/hexanes), providing the product, 4-bromo-5-fluoro-1,2-benzenediamine, as a tan solid.1H NMR (400 MHz, CDCl3) delta 3.5 (br s, 4H), 6.49 (d, J=9.52 Hz, 1H), 6.82 (d, J=6.6 Hz, 1H).

Reference： [1]Patent: EP2566477,2015,B1 .Location in patent: Paragraph 0172; 0173
[2]Patent: WO2012/83170,2012,A1 .Location in patent: Page/Page column 155
[3]Patent: WO2013/26914,2013,A1 .Location in patent: Page/Page column 134
[4]Patent: US2007/259936,2007,A1 .Location in patent: Page/Page column 175
[5]Patent: US2010/222345,2010,A1 .Location in patent: Page/Page column 69

2
[ 153505-37-4 ]
[ 1208-65-7 ]
(E)-5-bromo-6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; for 6h;Heating / reflux;	4-trifluoromethyl cinnamic acid (1.2 g, 0.0055, 1.1 eq) was dissolved in 30 mL of POCl3. To the solution was added Compound 13c (1.02 g, 0.005 mol), and the reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled to room temperature and then evaporated in vacuo. The residue was taken up in 50 mL of ethyl acetate, and washed with 50 mL of brine. The organic fractions were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, hexanes:EtOAc, 3:1-3:2) to provide the title Compound 13d as a light brown solid (0.80 g). 1H-NMR (400 MHz, DMSO-d6) delta (ppm): 7.63-8.09 (m, 4H) 7.4 (d, 1H, J=20.7 Hz) 6.69 (d, 1H, J=20.7 Hz) MS (ESI, pos. ion) m/z: 386.0 (M+1).

Reference： [1]Patent: US2007/259936,2007,A1 .Location in patent: Page/Page column 175

3
[ 153505-37-4 ]
[ 7732-18-5 ]
[ 95-92-1 ]
6-Bromo-7-fluoro-1,4-dihydroquinoxaline-2,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In sodium hydroxide;	6-Bromo-7-fluoro-1,4-dihydro-2,3-quinoxalinedione The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.97 mL, 13.5 mmol) and <strong>[153505-37-4]4-bromo-5-fluoro-1,2-diaminobenzene</strong> (277 mg, 1.35 mmol) was heated to reflux under N2 for 12 h. The reaction was allowed to cool to room temperature and the dark-brown solid collected by vacuum filtration and rinsed with ethanol (20 mL) and air dried to give 233 mg (67%) of a powdery brown solid. A portion of this solid (100 mg) was taken and dissolved in 5 mL 1N NaOH. The solution was treated with activated charcoal and filtered through a pad of Celite. The Celite was rinsed with 10 mL additional NaOH solution. The resulting solution was carefully acidified with 1N HCl (pH=5). Bright yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 15 mL of H2 O and dried under vacuum (0.1 torr, 78 C.) to yield 40.0 mg of yellow crystals. 1 H NMR (d6 -DMSO) delta6.99 (d,1H, J=9.3, H-8), 7.29 (d, 1H, J=6.3, H-6), 11.95 (br s, 2H, 2(NH)). EIMS m/z 260 (M+2, 96), 258 (M+(bp)), 232 (51), 230 (52), 123 (83). EIHRMS calc. for C8 H4 BrFN2 O2 256.9941, found 257.9441.

Reference： [1]Patent: US5514680,1996,A

4
[ 153505-37-4 ]
trans-1,4-dioxane-2,3-diol [ No CAS ]
[ 1210047-55-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	In ethanol; at 20℃; for 2h;	1.300 g (16.095 mmol) of 4-bromo-5-fluorobenzene-l,2-diamine (described in WO 2008/021851, p. 75-76) was dissolved in 160 ml ethanol and 1.933 g (16.095 mmol) /r°/s-2,3-dihydroxy-l,4- dioxane was added. It was stirred for 2 h at room temperature and the reaction mixture was concentrated to 3/4 by evaporation in a rotary evaporator. The resultant precipitate was filtered off and dried under high vacuum. We obtained 2.950 g (81% of theor.) of the target compound.LC-MS (method 4): R, = 1.00 min; MS (EIpos): m/z = 227 [M+H]+. 1H-NMR (400 MHz, DMSO-D6): delta [ppm] = 8.11 (d, IH), 8.58 (d, IH), 8.98-9.03 (m, 2H).

Reference： [1]Patent: WO2010/20363,2010,A1 .Location in patent: Page/Page column 76-77

5
[ 64-18-6 ]
[ 153505-37-4 ]
[ 1008360-84-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	Reflux;	step 3: A mixture of 98 (600 mg, 2.93 mmol) in formic acid (5.0 mL) was heated to reflux overnight. The reaction mixture was concentrated in vacuo to afford a brown oil that was partitioned between EtOAc (300 mL) and a sat'd. aq. NaHC03 (100 mL). The organic layer was separated, dried (MgSO i), filtered and evaporated in vacuo to afford 550 mg (87%) of 54oromo-6-fluoro-lH4oenzo[d]imidazole (100) as white solid (550 mg, 87%): MS (ESI) m/z = 215 [M+l] +.
		A solution of 4-bromo-5-fluoro-1,2-benzenediamine (2.2 g, 10.7 mmol) in formic acid (5 mL) was heated at reflux for 2 h. The reaction was then cooled to room temperature and treated with 10% aq. NaOH until the mixture was basic. The dark mixture was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with dichloromethane, then dried under vacuum, providing the product, 5-bromo-6-fluoro-1H-benzimidazole. The dichloromethane wash was also concentrated in vacuo and purified via chromatography to provide additional product. 1H NMR (400 MHz, CDCl3) delta 7.35 (d, J=8.6 Hz, 1H), 7.78 (d, J=6.1 Hz, 1H), 8.02 (s, 1H).

Reference： [1]Patent: WO2013/26914,2013,A1 .Location in patent: Page/Page column 134
[2]Patent: US2010/222345,2010,A1 .Location in patent: Page/Page column 70

6
[ 153505-37-4 ]
[ 1262317-42-9 ]

Reference： [1]Patent: WO2011/9084,2011,A2

7
[ 153505-37-4 ]
[ 1262320-51-3 ]

Reference： [1]Patent: WO2011/9084,2011,A2

8
[ 153505-37-4 ]
[ 1262320-52-4 ]

Reference： [1]Patent: WO2011/9084,2011,A2

9
[ 153505-37-4 ]
[ 15761-39-4 ]
[ 1262320-50-2 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 15: Step ITo a cold (0-4 C) solution of 4-bromo-5-fluoro-benzene-1 ,2-diamine (1 g, 4.877 mmol) and (2S)-1 -tert-butoxycarbonylpyrrolidine-2-carboxylic acid (Boc-Pro-OH) (1.050 g, 4.877 mmol) in DMF (9.754 mL) are sequentially added HATU (2.040 g, 5.365 mmol) and 2,4,6-collidine (886.5 mg, 966.7 mul_, 7.316 mmol). The reaction mixture is slowly warmed up to rt, stirred overnight, and diluted with water (20 mL). The resulting suspension is extracted with EtOAc(3 x 25 mL), and the combined extracts are washed with saturated bicarbonate solution, and brine. The organic phase is dried over sodium sulfate, and concentrated under vacuum to give crude amide (2.35 g, contaminated with 2,4,6-collidine). The residue is dissolved in acetic acid (15 mL), stirred at 50 C for 8 h, and concentrated to dryness. The residue is diluted with ethyl acetate (25 mL), washed with aq. NaHCO3 solution, and brine. The organic phase is dried over sodium sulfate, concentrated under vacuum and the residue is purified by silica gel chromatography (ethyl acetate/hexanes,40 to 60 %) to give 15 (1.74 g) as light brown solid.1 H NMR spectra in CDCl 3 and CD 3 OD showed 1.2:1 and 2:1 ratio of isomeric mixture (exchange of imidazole nitrogen) .19F spectra also showed mixture of two isomers. 1H NMR (400 MHz, CDCl3, 1.2:1 ratio of isomers): Peaks for the major isomer, delta [ppm] 7.86 (d, J = 6.2, 1 H), 7.45 (d, J = 9.2, 1 H), 6.77(s, 0.35 H), 5.02 (m, 1 H), 3.41 (m, 2 H), 2.2-1.9 (m, 2 H), 1.49 (s, 3 H). LC/MS: m/z = 303.78 (M-100+H+). 19F NMR (400 MHz, CDC13), delta [ppm] -113.4 (t), -115.7 (t).

Reference： [1]Patent: WO2011/9084,2011,A2 .Location in patent: Page/Page column 352

10
[ 153505-37-4 ]
[ 99395-88-7 ]
[ 1276025-35-4 ]

Yield	Reaction Conditions	Operation in experiment
13.6%	With rac-diaminocyclohexane; cesium fluoride;copper(l) iodide; In 1,4-dioxane; at 95℃; for 48h;Inert atmosphere;	The compound was synthesized starting from (S)-4-phenyloxazolidin-2-one (1 equiv., 0.328 g, 2 mmol), <strong>[153505-37-4]4-bromo-5-fluorobenzene-1,2-diamine</strong> (1 equiv., 0.412 g, 2 mmol), copper(I) iodide (0.1 equiv., 0.040 g, 0.2 mmol), cesium fluoride (2 equiv., 0.608 g, 4 mmol), cyclohexane-1,2-diamine (0.1 equiv., 0.024 mL, 0.2 mmol). The dried solids were given together in a reaction flask and the flask was purged with argon. A solution of cyclohexane-1,2-diamine in 4 mL dioxane was added to the flask. The reaction was stirred at 95 C. for 48 hours, before the reaction was cooled down to 45 C. and filtered through a pad of CELITE. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate product was purified via FPLC using a chloroform-methanol gradient (0?10%, product elutes at about 5%).Yield: 0.078 g (13.6%)

Reference： [1]Patent: US2011/92501,2011,A1 .Location in patent: Page/Page column 142

11
[ 153505-37-4 ]
[ 99395-88-7 ]
(S)-3-(6-fluoro-1H-benzo[d]imidazol-5-yl)-4-phenyloxazolidin-2-one trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2011/92501,2011,A1

12
[ 153505-37-4 ]
[ 1292838-10-8 ]

Reference： [1]Patent: WO2012/83170,2012,A1

13
[ 153505-37-4 ]
[ 15761-39-4 ]
[ 1262320-50-2 ]

Yield	Reaction Conditions	Operation in experiment
77%		Illustration of General Procedure 20. General Procedure 20A; (S)-tert-buty 2-(6-bromo-5-fluoro-l f-benzo[i/]imidazol-2-yl)pyrrolidine-l-carboxylate; To a solution of 4-bromo-5-fluorobenzene-l,2-diamine (1.7 g, 8.4 mmol) in DMSO (42 mL) was added (.S)-l-(ieri-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.8 g, 8.4 mmol) followed by HATU (3.5 g, 9.3 mmol) and NNf Uisopropyl-N-ethylamine (3.7 mL, 21.1 mmol), and the solution was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with H20 and brine, dried (Na2S04), filtered and concentrated. Acetic acid (40 mL) was added, and the mixture was stirred at 60 C for 4 hours. Then, the reaction mixture was cooled and concentrated. The residue was azeotroped 2 times with toluene to give crude product which was purified by flashchromatography (0-50% EtOAc/hexane) to give the title compound (2.5g, 6.4 mmol, 77%).

Reference： [1]Patent: WO2012/83170,2012,A1 .Location in patent: Page/Page column 158
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5462 - 5467

14
[ 656-65-5 ]
[ 153505-37-4 ]

Reference： [1]Patent: WO2012/83170,2012,A1

15
[ 929279-27-6 ]
[ 153505-37-4 ]

Reference： [1]Patent: WO2012/83170,2012,A1

16
[ 2369-11-1 ]
[ 153505-37-4 ]

Reference： [1]Patent: WO2013/26914,2013,A1
[2]Patent: EP2566477,2015,B1
[3]Patent: US5514680,1996,A

17
[ 153505-37-4 ]
[ 1425933-09-0 ]

Reference： [1]Patent: WO2013/26914,2013,A1

18
[ 153505-37-4 ]
[ 676137-12-5 ]
[ 1449473-87-3 ]

Reference： [1]Patent: WO2013/114250,2013,A1

19
[ 153505-37-4 ]
[ 676137-12-5 ]
[ 1449475-37-9 ]

Yield	Reaction Conditions	Operation in experiment
28%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 140℃; for 0.0833333h;Inert atmosphere; Microwave irradiation;	Preparation 73 4-Fluoro-5-neopentylbenzene-1 ,2-diamine A mixture of 4-bromo-5-fluorobenzene-1 ,2-diamine (82.1 mg, 0.400 mmol), [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (20.2 mg, 0.0276 mmol), and neopentylzinc bromide in tetrahydrofuran (0.5 M, 3.0 ml_, 1 .5 mmol) was degassed for 5 minutes using argon. The reaction mixture was heated under microwave irradiation for 5 minutes at 140C. The solution was concentrated in vacuo and purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexanes to afford the title compound (22 mg, 28%) as an orange oil. LCMS Rt = 0.94 minutes MS m/z 197 [M+H]+

Reference： [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 169; 170

20
[ 153505-37-4 ]
5-Bromo-6-fluorobenzo[c][1,2,5]thiadiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In thionyl chloride; chloroform;	Preparation 38 5-Bromo-6-fluorobenzo[c][1,2,5]thiadiazole 4-Bromo-5-fluorobenzene-1,2-diamine (500 mg, 2.4 mmol) was dissolved in 20 mL chloroform, treated in portions with thionyl chloride (580 mg, 4.9 mmol) and heated to reflux for 20 h. After cooling the mixture was diluted with 60 mL ethyl acetate, washed with 15 mL water, 15 mL saturated NaCl, dried (Na2SO4) and concentrated under vacuum. The material was chromatographed on silica with a 0-30% ethyl acetate-hexane gradient to give the title compound as a white solid (425 mg, 76%): mp 79-82 C.; 1H NMR (400 MHz, CDCl3) delta 8.33 (d, J=6.7 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) delta -102.91; EIMS m/z 232.

Reference： [1]Patent: US2014/274702,2014,A1 .Location in patent: Page/Page column

21
[ 153505-37-4 ]
5-bromo-6-fluoro-1H-1,2,3-benzotriazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With acetic acid; sodium nitrite; In water; at 20℃; for 1h;	2-Amino-4-bromo-5-fluoroaniline (9.2 g, 45 mmol) was dissolved in acetic acid (190 ml) and water (260 ml) before sodium nitrite (3.1 g, 45 mmol) in 10 mL of water was added dropwise. The reaction was stirred at room temperature for 1 hour before the solution was cooled to 0 C and ammonium hydroxide was added to adjust the pH to ~11. The mixture was extracted with EtOAc (3 x 500 mL), and the combined organics were dried over sodium sulfate, filtered, and concentrated to a brown solid (9.0 g, 71 %). MS (m/z) 215.9, 217.9 (M+, M+2+). 5-bromo-6-fluoro-1H-1,2,3-benzotriazole (1.0 g, 4.6 mmol), copper(I) iodide (88 mg, 0.46 mmol), and sodium iodide (2.8 g, 19 mmol) were added to a flask which was subsequently purged with argon. 1,4-Dioxane (7.0 ml) was added followed by N,N'-ethylenediamine (0.10 ml, 0.93 mmol). The reaction was heated to 120 C overnight. It was cooled to room temperature and partitioned between water and EtOAc. The organics were collected and the aqueous layer was back-extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered, and concentrated (420 mg, 35 %). MS (m/z) 263.9 (M+H+).

Reference： [1]Patent: EP2566477,2015,B1 .Location in patent: Paragraph 0172; 0174

22
[ 153505-37-4 ]
5-fluoro-1H-1,2,3-benzotriazol-6-amine [ No CAS ]

Reference： [1]Patent: EP2566477,2015,B1

23
[ 153505-37-4 ]
5-fluoro-6-iodo-1H-1,2,3-benzotriazole [ No CAS ]

Reference： [1]Patent: EP2566477,2015,B1

24
[ 153505-37-4 ]
[ 2533-69-9 ]
5-bromo-6-fluoro-1H-benzimidazole-2-carboxylic acid [ No CAS ]