[ CAS No. 345-24-4 ] {[proInfo.proName]}

Name: 345-24-4|5-Bromo-2,4-difluoronitrobenzene|97%
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Quality Control of [ 345-24-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 345-24-4 ]

Product Details of [ 345-24-4 ]

CAS No. :	345-24-4	MDL No. :	MFCD00129166
Formula :	C₆H₂BrF₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OOUUWURPSUSDTD-UHFFFAOYSA-N
M.W :	237.99	Pubchem ID :	223078
Synonyms :

Calculated chemistry of [ 345-24-4 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	42.88
TPSA :	45.82 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) :	-5.88 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	2.64
Log Po/w (WLOGP) :	3.48
Log Po/w (MLOGP) :	2.49
Log Po/w (SILICOS-IT) :	1.26
Consensus Log Po/w :	2.28

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.28
Solubility :	0.124 mg/ml ; 0.000522 mol/l
Class :	Soluble
Log S (Ali) :	-3.25
Solubility :	0.133 mg/ml ; 0.000559 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.19
Solubility :	0.152 mg/ml ; 0.000638 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.17

Safety of [ 345-24-4 ]

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

Application In Synthesis of [ 345-24-4 ]

* 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 [ 345-24-4 ]
Downstream synthetic route of [ 345-24-4 ]

[ 345-24-4 ] Synthesis Path-Upstream 1~7

1
[ 345-24-4 ]
[ 452-92-6 ]

Yield	Reaction Conditions	Operation in experiment
59.1%	With water; iron; ammonium chloride In tetrahydrofuran; ethanol at 95℃; for 1.5 h; Heating / reflux	A 250-mL RB-flask, charged with 5-bromo-2,4-difluoronitrobenzene (5.04 g, 21.3 [MMOL),] saturated [NH4CL] (25.0 mL), iron powder (5.00 g, 89.5 mmol), ethanol (100 mL), THF (50.0 mL) and water (25.0 mL) was refluxed at [95 °C] for 1.5 hours. After cooling to room temperature, saturated [NAHCO3] (100 mL) was added and the mixture was filtered through Celite and the Celite was washed with EtOAc (3 x 50 mL). The combined filtrates were washed with H20 and brine, dried over [MGSO4,] filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc: hexanes 1: 9) to afford 5- bromor-2, [4-DIFLUOROANILINE] (2.61 g, [59. 1percent). 1H] NMR (400 MHz, [CDC13)] 5 6.97 (dd, 1H, J = 7.2, 6.7 Hz), 6.85 (t, 1H, [J] = 8.2 Hz), 3.63 (br, 2H).

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 16, p. 3870 - 3882
[2] Patent: WO2004/5257, 2004, A1, . Location in patent: Page 67-68
[3] Journal of the American Chemical Society, 1956, vol. 78, p. 2593,2596

2
[ 348-57-2 ]
[ 345-24-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sulfuric acid; nitric acid In water at 0 - 20℃; for 0.166667 h;	To a suspension of [1-] bromo-2,4-difluorobenzene (53.0 mmol, 6.00 mL) in concentrated [H2SO4] (38.5 mL) at [0 C] was added dropwise concentrated HN03 (34.0 mL) maintaining internal temperature below [20 C.] The resulting mixture was stirred for 10 min at [0 C,] then poured into ice/water with vigorous stirring. The mixture was extracted with [ET20] (3 x 100 mL). The combined organic extracts were washed with aqueous [NAHC03] solution (3 x 100 mL) and brine, dried over [MGSO4,] filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc: hexanes 1: 9) to afford 5-bromo-2,4- difluoronitrobenzene as a yellow oil (12.2 g, [97percent). LH] NMR (400 MHz, [CDC13)] [5] 8.45 (t, 1H, J = 7.5 Hz), 7.16 (dd, 1H, J = 11.0, 8.6 Hz); ESMS [M/E] : 240,238, 223,221, 112
95%	at 0 - 7℃; for 1.75 h;	To a 0 C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was < 7 C. The resulting mixture was stirred for 1 h at 0 C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The CH2Cl2 extract was washed with brine (1?500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95percent). 1H NMR (300 MHz, CDCl3) ? 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H), 8.39 (t, J=7.2 Hz, 1H).
95%	With sulfuric acid; nitric acid In water at 0 - 7℃; for 1.75 h;	1-BROMO-2,4-DIFLUORO-5-NITROBENZENE: To a 0° C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H₂SO₄ (76.8 mL) was added HNO₃ (68.0 mL) over 45 min at such a rate that the internal temperature was <7° C. The resulting mixture was stirred for 1 h at 0° C, poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH₂Cl₂ (400 mL). The CH₂Cl₂ extract was washed with brine (1*500 mL), dried over Na₂SO₄, filtered and evaporated to give the product as a yellow oil (23.5 g, 95percent). ¹H NMR (300 MHz, CDCl₃) δ 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H), 8.39 (t, J=7.2 Hz, 1H).

95%	at 0 - 7℃; for 1.75 h;	1-Bromo-2,4-difluoro-5-nitrobenzene: To a 0° C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H₂SO₄(76.8 mL) was added HNO₃(68.0 mL) over 45 min at such a rate that the internal temperature was <7° C. The resulting mixture was stirred for 1 h at 0° C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH₂Cl₂(400 mL). The organic layers were washed with brine (1.x.500 mL), dried over Na₂SO₄, filtered and evaporated to give the product as a yellow oil (23.5 g, 95percent). ¹H NMR (CDCl₃) δ 8.39 (t, J=7.2 Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H).
95%	at 0 - 7℃; for 1.75 h;	To a 0° C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and H₂SO₄(76.8 mL) was added HNO₃(68.0 mL) over 45 min at such a rate that the internal temperature was <7° C. The resulting mixture was stirred for 1 h at 0° C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH₂Cl₂(400 mL). The organic layers were washed with brine (1.x.500 mL), dried over Na₂SO₄, filtered and evaporated to give the product as a yellow oil (23.5 g, 95percent yield). ¹H NMR (CDCl₃) δ 8.39 (t, J=7.2 Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H).
95%	at 0 - 7℃; for 1.75 h;	1-Bromo-2,4-difluoro-5-nitrobenzene: To a 0° C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and H₂SO₄(76.8 mL) was added HNO₃(68.0 mL) over 45 min at such a rate that the internal temperature was <7° C. The resulting mixture was stirred for 1 h at 0° C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH₂Cl₂(400 mL). The organic layers were washed with brine (1.x.500 mL), dried over Na₂SO₄, filtered and evaporated to give the product as a yellow oil (23.5 g, 95percent yield). ¹H NMR (CDCl₃) δ 8.39 (t, J=7.2 Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H).
95%	at 0 - 7℃; for 1.75 h;	To a 0° C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H₂SO₄(76.8 mL) was added HNO₃(68.0 mL) over 45 min at such a rate that the internal temperature was <7° C. The resulting mixture was stirred for 1 h at 0° C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH₂Cl₂(400 mL). The organic layers were washed with brine (1.x.500 mL), dried over Na₂SO₄, filtered and evaporated to give the product as a yellow oil (23.5 g, 95percent). ¹H NMR (CDCl₃) δ 8.39 (t, J=7.2Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9Hz, 1H).
93.3%	at 0 - 20℃; for 0.166667 h;	Step D: To a suspension of l-bromo-2,4-difluorobenzene (1 1.7 mL, 104 mmol) in 96 mL concentrated H₂SO₄ at 0 °C was added concentrated HNO₃ (85 mL) dropwise maintaining the temperature below 20 °C. The resulting mixture was stirred for 10 minutes at 0 °C, then poured into a mixture of ether and ice water with vigorous stirring. The aqueous phase was separated and extracted with ether. The combined organic phases were washed with aqueous aHC0₃ and brine, dried and concentrated. The residue was purified using silica gel column chromatography with 15percent acetone in hexanes to provide 1-bromo- 2,4-difluoro-5-nitrobenzene (23 g, 96.6 mmol, 93.3percent yield) as yellow oil.
72%	at 0 - 20℃; for 0.166667 h;	To a suspension of l-bromo-2,4-difluorobenzene (lOg, 52.1mmol, l.Oeq) in cold H2SO4 (37.9mL) was added Conc.HN0₃ (33.3mL) in a dropwise manner keeping the internal temp 20°C, stirred for 10 min at 0°C then, the reaction mixture was poured into a mixture of diethyl ether (250mL) and ice water (250mL) with vigorous stirring. The organic layer was separated and the aqueous layer was again extracted with Et₂0 (250mL). The combined organic layer was washed with Satd. sodium bicarbonate (2 X 200 mL) followed by satd. brine (2 X 200 mL) solution. The separated organic layer was dried over Na₂S0₄ and concentrated under reduced pressure to give crude product which was purified by column chromatography (SiO 100-200 mesh) using 15percent EtOAc in pet ether as an eluent to give l-bromo-2,4-difluoro-5 -nitrobenzene (52g, 72percent yield) as a yellow color liquid. LCMS: M+H]+ 272.23.
91%	With KNO₃ In conc. H₂ SO₄	1-Bromo-2,4-difluoro-5-nitrobenzene: To a stirred solution of 1-bromo-2,4-difluorobenzene (0.512 g, 2.65 mmol, Aldrich, used as received) in conc. H₂ SO₄ (5.0 mL) at 0° C., KNO₃ (0.275 g, 2.72 mmol) was added in one lot. The resulting solution was allowed to warm to 28° C. and stirred at that temperature overnight. It was then poured into ice (50 g) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over anhydrous Na₂ SO₄, removed under vacuum and the resulting oil dried further under vacuum to afford 0.576 g (91percent) of the pure (¹ H NMR) title compound as a light red oil; ¹ H NMR (CDCl₃); δ7.141 (dd, 1H, J₁ =10.2 Hz, J₂ =7.8 Hz), 8.375 (t, 1H, J=7.5 Hz).

Reference： [1] Synthesis, 1998, # 8, p. 1101 - 1103
[2] Patent: WO2004/5257, 2004, A1, . Location in patent: Page 67
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 16, p. 3870 - 3882
[4] Patent: US2005/154020, 2005, A1, . Location in patent: Page/Page column 8
[5] Patent: US2005/154022, 2005, A1, . Location in patent: Page/Page column 9
[6] Patent: US2006/79522, 2006, A1, . Location in patent: Page/Page column 12
[7] Patent: US2006/79523, 2006, A1, . Location in patent: Page/Page column 13
[8] Patent: US2006/79524, 2006, A1, . Location in patent: Page/Page column 13
[9] Patent: US2006/79683, 2006, A1, . Location in patent: Page/Page column 11-12
[10] Patent: WO2011/146335, 2011, A1, . Location in patent: Page/Page column 102
[11] Patent: WO2017/147700, 2017, A1, . Location in patent: Paragraph 00261
[12] Journal of the American Chemical Society, 1956, vol. 78, p. 2593,2596
[13] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379
[14] Journal of Organic Chemistry, 1995, vol. 60, # 18, p. 5838 - 5842
[15] Patent: US5631373, 1997, A,
[16] Patent: WO2006/21454, 2006, A2, . Location in patent: Page/Page column 92; 93
[17] Patent: US6235740, 2001, B1,
[18] Journal of Medicinal Chemistry, 2008, vol. 51, # 17, p. 5243 - 5263
[19] Patent: US5514680, 1996, A,

3
[ 446-35-5 ]
[ 345-24-4 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 14, p. 1659 - 1664
[2] Patent: US5734073, 1998, A,

4
[ 345-24-4 ]
[ 153505-36-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 17, p. 5243 - 5263

5
[ 345-24-4 ]
[ 108-59-8 ]
[ 893620-44-5 ]

Yield	Reaction Conditions	Operation in experiment
20.5 g	Stage #1: With sodium hydride In 1,4-dioxane; mineral oil at 11 - 20℃; for 17.75 h; Stage #2: With hydrogenchloride In water for 7 h; Reflux Stage #3: With iron In acetic acid at 100℃; for 7 h;	a) 2-(4-Bromo-5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester/ 2-(2-Bromo-5-fluoro-4-nitro-phenyl)-malonic acid dimethyl ester A suspension of NaH (60 percent in mineral oil, 20.2 g, 504 mmol) in dioxane (233 ml) was cooled to11 °C. A solution of 1-bromo-2,4-difluoro-5-nitrobenzene (50 g, 26.5 ml, 210 mmol) anddimethyl malonate (33.3 g, 28.9 ml, 242 mmol) in dioxane (467 ml) was carefully added at 11 — 14 °C within 45 minutes (gas evolution). After completion of the addition the reaction mixture was kept at 12 °C for another hour and then warmed to room temperature. After 16 hours the reaction mixture was cooled to 10 °C and 100 ml saturated aqueous ammonium chloride solutionwas added. The reaction mixture was diluted with tert-butyl methyl ether, water and saturated aqueous ammonium chloride solution. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with saturated aqueous ammonium chloride solution and brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate heptane as eluent. The title compoundswere obtained as yellow liquid (53.7 g) as a 2.6:1 mixture and used for the next reaction without further purification.. A mixture of 2-(4-bromo-5 -fluoro-2-nitro-phenyl)-malonic acid dimethyl ester 2-(2-bromo-5- fluoro-4-nitro-phenyl)-malonic acid dimethyl ester (2.6:1 mixture, 53.7 g, 153 mmol) and 6 Maqueous hydrochloric acid (767 ml) was heated to reflux for 7 hours and then cooled to 5 °C. The precipitate was filtered, washed with water and with n-pentane and then coevaporated 3 times with toluene to give 25.9 g of a mixture of the title compounds as white solid. The mother liquor was extracted with ethyl acetate and the combined organic phases dried over sodium sulfate. The solvent was evaporated and the residue triturated with n-pentane and then coevaporated with toluene to give 11.42 g of a mixture of the title compounds as an off-white solid. This material was combined with the first crop to give a total of 37.32 g of the title compounds as a 2.6 :1 mixture which was used for the next reaction without further purification.A suspension of (4-bromo-5-fluoro-2-nitrophenyl)-acetic acid/ (2-bromo-5-fluoro-4-nitro- phenyl)-acetic acid (2.6:1 mixture, 37.3 g, 134 mmol) and iron (30.0 g, 537 mmol) in acetic acid (671 ml) was heated to 100 °C for 7 hours and then cooled to room temperature. Remaining elemental iron was removed with a magnetic rod. Ice water (900 ml) was added to the reaction mixture. The precipitate was filtered off, washed four times with water and then suspended in anice-cold aqueous solution of 25 percent HC1 (300 ml) and conc. HC1 (50 ml). After stuffing for 10 minutes the precipitate was filtered off and washed four times with water.The precipitate was suspended in a mixture of 1 M aqueous Na2CO3 (400 ml) solution and 0.1 M NaOH (100 ml) and stirred for 40 minutes. The precipitate was filtered off and washed four times with 0.1 M aqueous NaOH, three times with water and once with diisopropylether to givetitle compound as light grey solid (20.5 g). MS ESI (m/z): 228.0/ 230.0 [(M-H)i.1H NMR (DMSO-D6, 400 MHz): (ppm) = 10.47 (bs, 1H), 7.3 1-7.28 (m, 1H), 7.01-6.99 (m, 1H), 3.49 (s, 2H).

Reference： [1] Patent: WO2014/40969, 2014, A1, . Location in patent: Page/Page column 29-30
[2] Patent: WO2014/202493, 2014, A1, . Location in patent: Page/Page column 54; 55

6
[ 345-24-4 ]
[ 124-41-4 ]
[ 935288-20-3 ]
[ 1352244-77-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 449 - 464
[2] Patent: WO2012/125603, 2012, A1, . Location in patent: Page/Page column 33-34
[3] Patent: US2015/111885, 2015, A1, . Location in patent: Paragraph 0510; 0511

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[ 345-24-4 ]
[ 124-41-4 ]
[ 935288-20-3 ]
[ 1352244-77-9 ]

[ 345-24-4 ] Synthesis Path-Downstream 1~88

1
[ 348-57-2 ]
[ 345-24-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sulfuric acid; nitric acid; In water; at 0 - 20℃; for 0.166667h;	To a suspension of [1-] bromo-2,4-difluorobenzene (53.0 mmol, 6.00 mL) in concentrated [H2SO4] (38.5 mL) at [0 C] was added dropwise concentrated HN03 (34.0 mL) maintaining internal temperature below [20 C.] The resulting mixture was stirred for 10 min at [0 C,] then poured into ice/water with vigorous stirring. The mixture was extracted with [ET20] (3 x 100 mL). The combined organic extracts were washed with aqueous [NAHC03] solution (3 x 100 mL) and brine, dried over [MGSO4,] filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc: hexanes 1: 9) to afford 5-bromo-2,4- difluoronitrobenzene as a yellow oil (12.2 g, [97%). LH] NMR (400 MHz, [CDC13)] [5] 8.45 (t, 1H, J = 7.5 Hz), 7.16 (dd, 1H, J = 11.0, 8.6 Hz); ESMS [M/E] : 240,238, 223,221, 112
95%	With sulfuric acid; nitric acid; at 0 - 7℃; for 1.75h;	To a 0 C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was < 7 C. The resulting mixture was stirred for 1 h at 0 C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The CH2Cl2 extract was washed with brine (1?500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95%). 1H NMR (300 MHz, CDCl3) ? 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H), 8.39 (t, J=7.2 Hz, 1H).
95%	With sulfuric acid; nitric acid; In water; at 0 - 7℃; for 1.75h;	1-BROMO-2,4-DIFLUORO-5-NITROBENZENE: To a 0 C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was <7 C. The resulting mixture was stirred for 1 h at 0 C, poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The CH2Cl2 extract was washed with brine (1*500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95%). 1H NMR (300 MHz, CDCl3) delta 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H), 8.39 (t, J=7.2 Hz, 1H).

95%	With sulfuric acid; nitric acid; at 0 - 7℃; for 1.75h;	1-Bromo-2,4-difluoro-5-nitrobenzene: To a 0 C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was <7 C. The resulting mixture was stirred for 1 h at 0 C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The organic layers were washed with brine (1×500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95%). 1H NMR (CDCl3) delta 8.39 (t, J=7.2 Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H).
95%	With sulfuric acid; nitric acid; at 0 - 7℃; for 1.75h;	To a 0 C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was <7 C. The resulting mixture was stirred for 1 h at 0 C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The organic layers were washed with brine (1×500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95% yield). 1H NMR (CDCl3) delta 8.39 (t, J=7.2 Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H).
95%	With sulfuric acid; nitric acid; at 0 - 7℃; for 1.75h;	1-Bromo-2,4-difluoro-5-nitrobenzene: To a 0 C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was <7 C. The resulting mixture was stirred for 1 h at 0 C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The organic layers were washed with brine (1×500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95% yield). 1H NMR (CDCl3) delta 8.39 (t, J=7.2 Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H).
95%	With sulfuric acid; nitric acid; at 0 - 7℃; for 1.75h;	To a 0 C. mixture of 1-bromo-2,4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was <7 C. The resulting mixture was stirred for 1 h at 0 C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The organic layers were washed with brine (1×500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95%). 1H NMR (CDCl3) delta 8.39 (t, J=7.2Hz, 1H), 7.14 (ddd, J=0.3, 7.8, 9.9Hz, 1H).
93.3%	With sulfuric acid; nitric acid; at 0 - 20℃; for 0.166667h;	Step D: To a suspension of l-bromo-2,4-difluorobenzene (1 1.7 mL, 104 mmol) in 96 mL concentrated H2SO4 at 0 C was added concentrated HNO3 (85 mL) dropwise maintaining the temperature below 20 C. The resulting mixture was stirred for 10 minutes at 0 C, then poured into a mixture of ether and ice water with vigorous stirring. The aqueous phase was separated and extracted with ether. The combined organic phases were washed with aqueous aHC03 and brine, dried and concentrated. The residue was purified using silica gel column chromatography with 15% acetone in hexanes to provide 1-bromo- 2,4-difluoro-5-nitrobenzene (23 g, 96.6 mmol, 93.3% yield) as yellow oil.
72%	With sulfuric acid; nitric acid; at 0 - 20℃; for 0.166667h;	To a suspension of l-bromo-2,4-difluorobenzene (lOg, 52.1mmol, l.Oeq) in cold H2SO4 (37.9mL) was added Conc.HN03 (33.3mL) in a dropwise manner keeping the internal temp 20C, stirred for 10 min at 0C then, the reaction mixture was poured into a mixture of diethyl ether (250mL) and ice water (250mL) with vigorous stirring. The organic layer was separated and the aqueous layer was again extracted with Et20 (250mL). The combined organic layer was washed with Satd. sodium bicarbonate (2 X 200 mL) followed by satd. brine (2 X 200 mL) solution. The separated organic layer was dried over Na2S04 and concentrated under reduced pressure to give crude product which was purified by column chromatography (SiO 100-200 mesh) using 15% EtOAc in pet ether as an eluent to give l-bromo-2,4-difluoro-5 -nitrobenzene (52g, 72% yield) as a yellow color liquid. LCMS: M+H]+ 272.23.
0.576 g (91%)	With KNO3; In conc. H2 SO4;	1-Bromo-2,4-difluoro-5-nitrobenzene: To a stirred solution of 1-bromo-2,4-difluorobenzene (0.512 g, 2.65 mmol, Aldrich, used as received) in conc. H2 SO4 (5.0 mL) at 0 C., KNO3 (0.275 g, 2.72 mmol) was added in one lot. The resulting solution was allowed to warm to 28 C. and stirred at that temperature overnight. It was then poured into ice (50 g) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over anhydrous Na2 SO4, removed under vacuum and the resulting oil dried further under vacuum to afford 0.576 g (91%) of the pure (1 H NMR) title compound as a light red oil; 1 H NMR (CDCl3); delta7.141 (dd, 1H, J1 =10.2 Hz, J2 =7.8 Hz), 8.375 (t, 1H, J=7.5 Hz).
	With sulfuric acid; nitric acid; In water; at 0 - 10℃; for 0.5h;	To a solution of 1-bromo-2,4-difiuorobenzene (0.13 mol) in conc.H2S04 (150 mL) is added dropwise 60% HN03 (30 mL) at 0 C over 20 min. After stirring at 0-10 C for 10 min, the reaction mixture is poured into ice-water (800 g) and extracted with ether. The separated organic layer is washed with sat. NaHC03 and brine, dried over MgS04 and evaporated in vacuo to give a crude 1-bromo-2,4-difluoro-5-nitrobenzene. Rf: 0.57 (hexane:EtOAc=7:1). 1H NMR (CDCI3) 6 7.14 (dd, 1H), 8.39 (dd, 1H)
	With nitric acid; In sulfuric acid;	A. 1-Bromo-2,4-difluoro-5-nitrobenzene To 2,4-difluorobromobenzene (10 mL, 85.5 mmol) in conc. sulfuric acid (50 mL) was added 90% HNO3 (4.57 mL, 97.3 mmol) dissolved in conc. sulfuric acid (10 mL) at room temperature. The reaction was stirred for 1 h then slowly poured over ice water. The mixture was extracted with CH2Cl2 and washed with saturated bicarbonate solution. The solvent was removed in vacuo to give title compound 485A.
	With KNO3; In conc. H2 SO4;	1-Bromo-2,4-difluoro-5-nitrobenzene To a stirred solution of 1-bromo-2,4-difluorobenzene (0.512 g, 2.65 mmol, Aldrich, used as received) in conc. H2 SO4 (5.0 mL) at 0 C., KNO3 (0.275 g, 2.72 mmol) was added in one portion. The resulting solution was allowed to warm to 28 C. and was stirred at that temperature overnight. It was then poured into ice (50 g) and extracted with ethylacetate (50 mL). The extract was dried over Na2 SO4, and evaporated to afford 0.576 g (91%) pure title compound as light red oil; 1 H NMR (CDCl3); delta7.141 (dd, 1H, J1 10.2 Hz, J2 =7.8 Hz), 8.375 (t, 1H, J=7.5 Hz).

Reference： [1]Synthesis,1998,p. 1101 - 1103
[2]Patent: WO2004/5257,2004,A1 .Location in patent: Page 67
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882
[4]Patent: US2005/154020,2005,A1 .Location in patent: Page/Page column 8
[5]Patent: US2005/154022,2005,A1 .Location in patent: Page/Page column 9
[6]Patent: US2006/79522,2006,A1 .Location in patent: Page/Page column 12
[7]Patent: US2006/79523,2006,A1 .Location in patent: Page/Page column 13
[8]Patent: US2006/79524,2006,A1 .Location in patent: Page/Page column 13
[9]Patent: US2006/79683,2006,A1 .Location in patent: Page/Page column 11-12
[10]Patent: WO2011/146335,2011,A1 .Location in patent: Page/Page column 102
[11]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00261
[12]Journal of the American Chemical Society,1956,vol. 78,p. 2593,2596
[13]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379
[14]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[15]Patent: US5631373,1997,A
[16]Patent: WO2006/21454,2006,A2 .Location in patent: Page/Page column 92; 93
[17]Patent: US6235740,2001,B1
[18]Journal of Medicinal Chemistry,2008,vol. 51,p. 5243 - 5263
[19]Patent: US5514680,1996,A

2
[ 345-24-4 ]
[ 6000-44-8 ]
[ 170098-95-0 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842

3
[ 345-24-4 ]
[ 6000-44-8 ]
Sodium; (4-bromo-5-fluoro-2-nitro-phenylamino)-acetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

4
[ 345-24-4 ]
[ 762298-01-1 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882

5
[ 345-24-4 ]
[ 762298-05-5 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882

6
[ 345-24-4 ]
[ 762298-07-7 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882

7
[ 345-24-4 ]
[ 949096-74-6 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882

8
[ 345-24-4 ]
[ 762300-01-6 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882

9
[ 345-24-4 ]
SNAP 102739 [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882

10
[ 345-24-4 ]
[ 762297-97-2 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3870 - 3882

11
[ 345-24-4 ]
[ 212208-83-8 ]

Reference： [1]Synthesis,1998,p. 1101 - 1103
[2]Patent: WO2011/146335,2011,A1

12
[ 345-24-4 ]
[ 212269-88-0 ]

Reference： [1]Synthesis,1998,p. 1101 - 1103

13
[ 345-24-4 ]
[ 212208-84-9 ]

Reference： [1]Synthesis,1998,p. 1101 - 1103

14
[ 345-24-4 ]
[ 212208-85-0 ]

Reference： [1]Synthesis,1998,p. 1101 - 1103

15
[ 345-24-4 ]
N-[6-(2,4-Difluoro-phenoxy)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[b]thiophen-5-yl]-methanesulfonamide [ No CAS ]

Reference： [1]Synthesis,1998,p. 1101 - 1103

16
[ 345-24-4 ]
[ 212208-82-7 ]

Reference： [1]Synthesis,1998,p. 1101 - 1103
[2]Patent: WO2011/146335,2011,A1

17
[ 345-24-4 ]
[ 170098-97-2 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[2]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

18
[ 345-24-4 ]
7-Bromo-6-fluoro-1,4-dihydro-5-nitroquinoxaline-2,3-dione [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[2]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

19
[ 345-24-4 ]
[ 623-33-6 ]
N-(4-bromo-5-fluoro-2-nitrophenyl)glycine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide;	1) By using 7.61 g (54.5 mmol) of glycine ethyl ester hydrochloride, 15 ml of THF, 7.64 ml of triethylamine, 10 ml of DMF and 11.8 g (49.6 mmol) of <strong>[345-24-4]5-bromo-2,4-difluoronitrobenzene</strong>, 10.5 g (60%) of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard): delta: 1.33 (3H, t, J=7.4 Hz), 4.04 (2H, d, J=4.9 Hz), 4.30 (2H, q, J=7.4 Hz), 6.46 (1H, d, J=10.9 Hz), 8.44 (1H, d, J=7.3 Hz), 8.49 (1H, bs).

Reference： [1]Patent: US6096743,2000,A

20
[ 345-24-4 ]
[ 124-41-4 ]
[ 778599-56-7 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; for 24h;Heating / reflux;	A mixture of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (0.010 mol) and NaOMe (0.05Q mol) indioxane (20 mL) is stirred and under reflux conditions for 24 h. After being cooled to roomtemperature, the reaction mixture is poured into water and extracted with EtOAc. The separatedorganic layer is washed with brine, dried over MgS04 and evaporated in vacuo to give 1-bromo-2,4-dimethoxy-5-nitrobenzene as brown solids.Rf: 0.50 (hexane:EtOAc=1:1). 1H NMR (CDCI3) 5 3.999 (s, 3H), 4.001 (s, 3H), 6.52 (s, 1H), 8.25(s,1H)

Reference： [1]Patent: WO2006/21454,2006,A2 .Location in patent: Page/Page column 92; 93

21
tetrahydroabietylamine [ No CAS ]
[ 345-24-4 ]
[ 727400-88-6 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate;aluminum nickel; In ethyl acetate; N,N-dimethyl-formamide;	a. 5-bromo-2-dehydroabietylamino-4-fluoroaniline Prepared analogously to Example 1b by reacting <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> [prepared according to J. Amer. Chem. Soc. 78 (1956) 2593-2596] with dihydroabietylamine and potassium carbonate in DMF and subsequent catalytic hydrogenation on Raney nickel in ethyl acetate. Yield: 64% of theory

Reference： [1]Patent: US2005/14810,2005,A1

22
[ 345-24-4 ]
[ 153505-36-3 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5243 - 5263

23
[ 345-24-4 ]
[ 108-59-8 ]
[ 1207293-52-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In 1,4-dioxane; mineral oil; at 20℃;Cooling;	l-Bromo-2,4-difluoro-5-nitrobenzene (2 g) is combined with 30 niL dioxane and 1.1 mL dimethylmalonate. While cooling by means of an ice bath, 0.8 g of a 60 % sodium hydride suspension in mineral oil is added batchwise. Then the mixture is stirred at RT until the reaction is complete. The reaction mixture is combined with 5 mL saturated NH4Cl solution and extracted repeatedly with DCM. The combined organic phases are dried, filtered and freed from the volatile constituents in vacuo. The crude product is further used directly.

Reference： [1]Patent: WO2010/12747,2010,A1 .Location in patent: Page/Page column 14-15

24
[ 345-24-4 ]
[ 1351168-48-3 ]

Reference： [1]Patent: WO2011/146335,2011,A1

25
[ 345-24-4 ]
[ 1351168-49-4 ]

Reference： [1]Patent: WO2011/146335,2011,A1

26
[ 345-24-4 ]
[ 1351168-50-7 ]

Reference： [1]Patent: WO2011/146335,2011,A1

27
[ 345-24-4 ]
[ 1351166-84-1 ]

Reference： [1]Patent: WO2011/146335,2011,A1

28
[ 109-01-3 ]
[ 345-24-4 ]
[ 124-41-4 ]
[ 1352244-78-0 ]
[ 1352244-79-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

29
[ 345-24-4 ]
[ 1352244-24-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

30
[ 345-24-4 ]
[ 1352244-35-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

31
[ 345-24-4 ]
[ 1352244-36-0 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

32
[ 345-24-4 ]
[ 1352244-37-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

33
[ 345-24-4 ]
(14Z)-6-chloro-17-(4-methylpiperazin-1-yl)-19-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1⁽²⁰⁾,3⁽²²⁾,4,6,9⁽²¹⁾,10,12,14,16,18-decaene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

34
[ 345-24-4 ]
(14Z)-6-chloro-10-(propane-2-sulfonyl)-17-(4-methylpiperazin-1-yl)-19-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]-docosa-1⁽²⁰⁾,3⁽²²⁾,4,6,9⁽²¹⁾,10,12,14,16,18-decaene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

35
[ 345-24-4 ]
(14Z)-6-chloro-10-(2-methanesulfonyl-methyl-amino)-17-(4-methylpiperazin-1-yl)-19-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1⁽²⁰⁾,3⁽²²⁾,4,6,9⁽²¹⁾,10,12,14,16,18-decaene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

36
[ 345-24-4 ]
[ 1352244-69-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

37
[ 345-24-4 ]
[ 1352244-71-3 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

38
[ 345-24-4 ]
[ 1352244-73-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 449 - 464

39
[ 345-24-4 ]
[ 1381878-60-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5887 - 5900

40
[ 345-24-4 ]
[ 1381878-52-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5887 - 5900

41
[ 345-24-4 ]
[ 1381878-16-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5887 - 5900

42
[ 345-24-4 ]
[ 1826-67-1 ]
[ 1381878-59-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5887 - 5900

43
[ 345-24-4 ]
[ 1352244-79-1 ]

Reference： [1]Patent: WO2012/125603,2012,A1

44
[ 345-24-4 ]
[ 108-59-8 ]
[ 1207293-52-4 ]
[ 1581753-71-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In 1,4-dioxane; mineral oil; at 11 - 20℃; for 17.75h;	a) 2-(4-Bromo-5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester/ 2-(2-Bromo-5-fluoro-4- nitro-phenvP-malonic acid dimethyl ester A suspension of NaH (60% in mineral oil, 20.2 g, 504 mmol) in dioxane (233 ml) was cooled to 11C. A solution of l-bromo-2,4-difluoro-5-nitrobenzene (50 g, 26.5 ml, 210 mmol) and dimethyl malonate (33.3 g, 28.9 ml, 242 mmol) in dioxane (467 ml) was carefully added at 11- 14C within 45 minutes (gas evolution). After completion of the addition the reaction mixture was kept at 12C for another hour and then warmed to room temperature. After 16 hours the reaction mixture was cooled to 10C and 100 ml saturated aqueous ammonium chloride solution was added. The reaction mixture was diluted with tert-butyl methyl ether, water and saturated aqueous ammonium chloride solution. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with saturated aqueous ammonium chloride solution and brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/ heptane as eluent. The title compounds were obtained as yellow liquid (53.7 g) as a 2.6: 1 mixture and used for the next reaction without further purification. MS ESI (m/z): 348.1/ 350.3 [(M-H)"]. 1H NMR (CDCI3, 400 MHz) of 2-(4-Bromo-5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester: < (ppm) = 8.37-8.35 (m, 1H), 7.36-7.33 (m, 1H), 5.36 (s, 1H), 3.82 (s, 6H). 1H NMR (CDCI3, 400 MHz) of 2-(2-Bromo-5-fluoro-4-nitro-phenyl)-malonic acid dimethyl ester: (ppm) = 8.33-8.30 (m, 1H), 7.60-7.56 (m, 1H), 5.27 (s, 1H), 3.76 (s, 6H).
	With sodium hydride; In 1,4-dioxane; mineral oil; at 11 - 20℃; for 17.75h;	a) 2-(4-Bromo-5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester/ 2-(2-Bromo-5-fluoro-4-nitro-phenyl)-malonic acid dimethyl ester A suspension of NaH (60 % in mineral oil, 20.2 g, 504 mmol) in dioxane (233 ml) was cooled to11 C. A solution of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (50 g, 26.5 ml, 210 mmol) anddimethyl malonate (33.3 g, 28.9 ml, 242 mmol) in dioxane (467 ml) was carefully added at 11 - 14 C within 45 minutes (gas evolution). After completion of the addition the reaction mixture was kept at 12 C for another hour and then warmed to room temperature. After 16 hours the reaction mixture was cooled to 10 C and 100 ml saturated aqueous ammonium chloride solutionwas added. The reaction mixture was diluted with tert-butyl methyl ether, water and saturated aqueous ammonium chloride solution. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with saturated aqueous ammonium chloride solution and brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate heptane as eluent. The title compoundswere obtained as yellow liquid (53.7 g) as a 2.6:1 mixture and used for the next reaction without further purification.MS ESI (mz): 348.1 350.3 [(M-H)i.1H NMR (CDC13, 400 MHz) of 2-(4-Bromo-5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester: (ppm) = 8.37-8.35 (m, 1H), 7.36-7.33 (m, 1H), 5.36 (s, 1H), 3.82 (s, 6H).1H NMR (CDC13, 400 MHz) of 2-(2-Bromo-5-fluoro-4-nitro-phenyl)-malonic acid dimethyl ester: (ppm) = 8.33-8.30 (m, 1H), 7.60-7.56 (m, 1H), 5.27 (s, 1H), 3.76 (s, 6H).

Reference： [1]Patent: WO2014/40969,2014,A1 .Location in patent: Page/Page column 28-29
[2]Patent: WO2014/202493,2014,A1 .Location in patent: Page/Page column 54

45
[ 345-24-4 ]
[ 108-59-8 ]
[ 1565112-12-0 ]
[ 1581753-72-1 ]

Yield	Reaction Conditions	Operation in experiment
		b) (4-Bromo-5-fluoro-2-nitrophenyl)-acetic acid/ (2-Bromo-5-fluoro-4-nitro-phenyl)-acetic acid A mixture of 2-(4-bromo-5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester/ 2-(2-bromo-5- fluoro-4-nitro-phenyl)-malonic acid dimethyl ester (2.6: 1 mixture, 53.7 g, 153 mmol) and 6 M aqueous hydrochloric acid (767 ml) was heated to reflux for 7 hours and then cooled to 5C. The precipitate was filtered, washed with water and with n-pentane and then coevaporated 3 times with toluene to give 25.9 g of a mixture of the title compounds as white solid. The mother liquor was extracted with ethyl acetate and the combined organic phases dried over sodium sulfate. The solvent was evaporated and the residue triturated with n-pentane and then coevaporated with toluene to give 11.42 g of a mixture of the title compounds as an off-white solid. This material was combined with the first crop to give a total of 37.32 g of the title compounds as a 2.6 : 1 mixture which was used for the next reaction without further purification. MS ESI (m/z): 232.0/ 233.9 [(M-C02-H)"]. 1H NMR (DMSO-D6, 400 MHz) of 2-(4-Bromo-5-fluoro-2-nitrophenyl)acetic acid: (ppm) = 8.50-8.47 (m, 1H), 7.70-7.67 (m, 1H), 4.00 (s, 2H). 1H NMR (DMSO-D6, 400 MHz) of (2-Bromo-5-fluoro-4-nitro-phenyl)-acetic acid: (ppm) = 8.40-8.37 (m, 1H), 7.78-7.74 (m, 1H), 3.87 (s, 2H).
		a) 2-(4-Bromo-5-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester/ 2-(2-Bromo-5-fluoro-4-nitro-phenyl)-malonic acid dimethyl ester A suspension of NaH (60 % in mineral oil, 20.2 g, 504 mmol) in dioxane (233 ml) was cooled to11 C. A solution of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (50 g, 26.5 ml, 210 mmol) anddimethyl malonate (33.3 g, 28.9 ml, 242 mmol) in dioxane (467 ml) was carefully added at 11 - 14 C within 45 minutes (gas evolution). After completion of the addition the reaction mixture was kept at 12 C for another hour and then warmed to room temperature. After 16 hours the reaction mixture was cooled to 10 C and 100 ml saturated aqueous ammonium chloride solutionwas added. The reaction mixture was diluted with tert-butyl methyl ether, water and saturated aqueous ammonium chloride solution. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were washed with saturated aqueous ammonium chloride solution and brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate heptane as eluent. The title compoundswere obtained as yellow liquid (53.7 g) as a 2.6:1 mixture and used for the next reaction without further purification.A mixture of 2-(4-bromo-5 -fluoro-2-nitro-phenyl)-malonic acid dimethyl ester 2-(2-bromo-5- fluoro-4-nitro-phenyl)-malonic acid dimethyl ester (2.6:1 mixture, 53.7 g, 153 mmol) and 6 Maqueous hydrochloric acid (767 ml) was heated to reflux for 7 hours and then cooled to 5 C. The precipitate was filtered, washed with water and with n-pentane and then coevaporated 3 times with toluene to give 25.9 g of a mixture of the title compounds as white solid. The mother liquor was extracted with ethyl acetate and the combined organic phases dried over sodium sulfate. The solvent was evaporated and the residue triturated with n-pentane and then coevaporated with toluene to give 11.42 g of a mixture of the title compounds as an off-white solid. This material was combined with the first crop to give a total of 37.32 g of the title compounds as a 2.6 :1 mixture which was used for the next reaction without further purification.MS ESI (m/z): 232.0/ 233.9 [(M-C02-H)i.H NMR (DMSO-D6, 400 MHz) of 2-(4-Bromo-5-fluoro-2-nitrophenyl)acetic acid: 5(ppm) =8.50-8.47 (m, 1H), 7.70-7.67 (m, 1H), 4.00 (s, 2H).1H NMR (DMSO-D6, 400 MHz) of (2-Bromo-5-fluoro-4-nitro-phenyl)-acetic acid: 5(ppm) =8.40-8.37 (m, 1H), 7.78-7.74 (m, 1H), 3.87 (s, 2H).

Reference： [1]Patent: WO2014/40969,2014,A1 .Location in patent: Page/Page column 29
[2]Patent: WO2014/202493,2014,A1 .Location in patent: Page/Page column 54; 55

46
[ 345-24-4 ]
N-[4-(2,4-difluorophenoxy)-2-fluoro-5-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)phenyl]methanesulfonamide [ No CAS ]

Reference： [1]Patent: US2014/275026,2014,A1

47
[ 345-24-4 ]
N-(4-(2,4-difluorophenoxy)-2-fluoro-5-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)phenyl)methanesulfonamide [ No CAS ]

Reference： [1]Patent: US2014/275026,2014,A1

48
[ 345-24-4 ]
N-[2-(2,4-difluorophenoxy)-4-fluoro-5-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)phenyl]methanesulfonamide [ No CAS ]

Reference： [1]Patent: US2014/275026,2014,A1

49
[ 345-24-4 ]
N-(2-(2,4-difluorophenoxy)-4-fluoro-5-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)phenyl)methanesulfonamide [ No CAS ]

Reference： [1]Patent: US2014/275026,2014,A1

50
[ 345-24-4 ]
5-bromo-2,4-bis(2,4-difluorophenoxy)aniline [ No CAS ]

Reference： [1]Patent: US2014/275026,2014,A1

51
[ 345-24-4 ]
N-(5-bromo-2,4-bis(2,4-difluorophenoxy)phenyl)methanesulfonamide [ No CAS ]

Reference： [1]Patent: US2014/275026,2014,A1

52
[ 367-27-1 ]
[ 345-24-4 ]
1-bromo-2-(2,4-difluorophenoxy)-4-fluoro-5-nitrobenzene [ No CAS ]
1-bromo-4-(2,4-difluorophenoxy)-2-fluoro-5-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 1h;	Example 11A 1-bromo-2-(2,4-difluorophenoxy)-4-fluoro-5-nitrobenzene [0864] A mixture of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (0.5 g, 2.10 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in DMSO (10.50 mL) was treated dropwise with 2,4-difluorophenol (0.273 g, 2.10 mmol), stirred for 60 minutes at ambient temperature and partitioned between ethyl acetate and water, adjusting the pH to 6 with 1 M HCl. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate in heptanes) afforded the title compound and 1-bromo-4-(2,4-difluorophenoxy)-2-fluoro-5-nitrobenzene as an inseparable mixture (0.59 g, 81%).

Reference： [1]Patent: US2014/275026,2014,A1 .Location in patent: Paragraph 0864

53
[ 367-27-1 ]
[ 345-24-4 ]
4,4'-(4-bromo-6-nitro-1,3-phenylene)bis(oxy)bis(1,3-difluorobenzene) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 1h;	Example 13A 4,4?-(4-bromo-6-nitro-1,3-phenylene)bis(oxy)bis(1,3-difluorobenzene) [0872] To a solution of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (0.3 g, 1.26 mmol) and cesium carbonate (0.86 g, 2.65 mmol) in DMSO (6.3 mL) was added dropwise 2,4-difluorophenol (0.27 g, 2.10 mmol). The mix was stirred for 60 minutes at ambient temperature and partitioned between ethyl acetate and water, adjusting the pH to 6 with HCl. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated to afford the title compound (0.578 g, 100%).

Reference： [1]Patent: US2014/275026,2014,A1 .Location in patent: Paragraph 0872

54
[ 345-24-4 ]
5-bromo-4-((2-chloropyridin-4-yl)oxy)-2-fluoroaniline [ No CAS ]

Reference： [1]Patent: US2014/315917,2014,A1

55
[ 345-24-4 ]
5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline [ No CAS ]

Reference： [1]Patent: US2014/315917,2014,A1

56
[ 345-24-4 ]
N-(5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide [ No CAS ]

Reference： [1]Patent: US2014/315917,2014,A1

57
[ 17368-12-6 ]
[ 345-24-4 ]
4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		A 0 C. mixture of 2-chloro-4-hydroxypyridine (817 mg, 6.30 mmol) in DMF (30 mL) was treated with NaH (60% in mineral oil, 277 mg, 6.93 mmol), stirred for 1 h, treated with <strong>[345-24-4]5-bromo-2,4-difluoronitrobenzene</strong> (1.50 g, 6.30 mmol) and heated at 90 C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2*) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine (1.16 g, 53%). MS (ESI) m/z: (M+H+): 348.9.

Reference： [1]Patent: US2014/315917,2014,A1 .Location in patent: Paragraph 0533

58
[ 367-27-1 ]
[ 345-24-4 ]
5-bromo-4-(2,4-difluorophenoxy)-2-fluoroaniline [ No CAS ]
5-bromo-2-(2,4-difluorophenoxy)-4-fluoroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (0.5 g, 2.10 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in DMSO (10.50 mL) was treated dropwise with 2,4-difluorophenol (0.273 g, 2.10 mmol), stirred for 60 minutes at ambient temperature and partitioned between ethyl acetate and water, adjusting the pH to 6 with 1 M HCl. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate in heptanes) afforded the title compound and 1-bromo-4-(2,4-difluorophenoxy)-2-fluoro-5-nitrobenzene as an inseparable mixture (0.59 g, 81%). Example 11B 5-bromo-4-(2,4-difluorophenoxy)-2-fluoroaniline [0865] The product from Example 11A (0.59 g, 1.69 mmol), iron (0.47 g, 8.48 mmol) and ammonium chloride (0.136 g, 2.54 mmol) were combined in a solvent mixture of ethanol (9 mL), tetrahydrofuran (9 mL) and water (3 mL) and heated at 90 C. for 2 hours. The mixture was cooled, filtered through Celite and the Celite pad was washed repeatedly with methanol. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate in heptanes) afforded the title compound and 5-bromo-2-(2,4-difluorophenoxy)-4-fluoroaniline as an inseparable mixture (0.43 g, 80%).

Reference： [1]Patent: US2014/275026,2014,A1 .Location in patent: Paragraph 0864; 0865

59
[ 367-27-1 ]
[ 345-24-4 ]
[ 124-63-0 ]
N-(5-bromo-4-(2,4-difluorophenoxy)-2-fluorophenyl)methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		A mixture of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (0.5 g, 2.10 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in DMSO (10.50 mL) was treated dropwise with 2,4-difluorophenol (0.273 g, 2.10 mmol), stirred for 60 minutes at ambient temperature and partitioned between ethyl acetate and water, adjusting the pH to 6 with 1 M HCl. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate in heptanes) afforded the title compound and 1-bromo-4-(2,4-difluorophenoxy)-2-fluoro-5-nitrobenzene as an inseparable mixture (0.59 g, 81%). Example 11B 5-bromo-4-(2,4-difluorophenoxy)-2-fluoroaniline [0865] The product from Example 11A (0.59 g, 1.69 mmol), iron (0.47 g, 8.48 mmol) and ammonium chloride (0.136 g, 2.54 mmol) were combined in a solvent mixture of ethanol (9 mL), tetrahydrofuran (9 mL) and water (3 mL) and heated at 90 C. for 2 hours. The mixture was cooled, filtered through Celite and the Celite pad was washed repeatedly with methanol. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate in heptanes) afforded the title compound and 5-bromo-2-(2,4-difluorophenoxy)-4-fluoroaniline as an inseparable mixture (0.43 g, 80%).Example 11C N-(5-bromo-4-(2,4-difluorophenoxy)-2-fluorophenyl)methanesulfonamide [0866] A mixture of the product from Example 11B (0.428 g, 1.35 mmol) and triethylamine (0.469 mL, 3.36 mmol) in dichloromethane (13.5 mL) was treated dropwise with methanesulfonyl chloride (0.23 mL, 2.96 mmol), stirred for 2 hours and concentrated. The residue was dissolved in a mixture of dioxane (4 mL) and 1M sodium hydroxide (1 mL), heated for 1 hour at 90 C., cooled and diluted with ethyl acetate. The mixture was brought to pH 7 with 1 M HCl and the organic layer was separated, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate in heptanes) afforded the title compound as the second eluting regioisomer (0.346 g, 65%).

Reference： [1]Patent: US2014/275026,2014,A1 .Location in patent: Paragraph 0864; 0865; 0866

60
[ 367-27-1 ]
[ 345-24-4 ]
[ 124-63-0 ]
N-(5-bromo-2-(2,4-difluorophenoxy)-4-fluorophenyl)methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%		A mixture of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (0.5 g, 2.10 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in DMSO (10.50 mL) was treated dropwise with 2,4-difluorophenol (0.273 g, 2.10 mmol), stirred for 60 minutes at ambient temperature and partitioned between ethyl acetate and water, adjusting the pH to 6 with 1 M HCl. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate in heptanes) afforded the title compound and 1-bromo-4-(2,4-difluorophenoxy)-2-fluoro-5-nitrobenzene as an inseparable mixture (0.59 g, 81%). Example 11B 5-bromo-4-(2,4-difluorophenoxy)-2-fluoroaniline [0865] The product from Example 11A (0.59 g, 1.69 mmol), iron (0.47 g, 8.48 mmol) and ammonium chloride (0.136 g, 2.54 mmol) were combined in a solvent mixture of ethanol (9 mL), tetrahydrofuran (9 mL) and water (3 mL) and heated at 90 C. for 2 hours. The mixture was cooled, filtered through Celite and the Celite pad was washed repeatedly with methanol. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate in heptanes) afforded the title compound and 5-bromo-2-(2,4-difluorophenoxy)-4-fluoroaniline as an inseparable mixture (0.43 g, 80%).Example 11D N-(5-bromo-2-(2,4-difluorophenoxy)-4-fluorophenyl)methanesulfonamide [0867] A mixture of the product from Example 11B (0.428 g, 1.35 mmol) and triethylamine (0.469 mL, 3.36 mmol) in dichloromethane (13.5 mL) was treated dropwise with methanesulfonyl chloride (0.23 mL, 2.96 mmol), stirred for 2 hours at ambient temperature and concentrated. The residue was dissolved in a mixture of dioxane (4 mL) and 1M sodium hydroxide (1 mL), heated for 1 hour at 90 C., cooled and diluted with ethyl acetate. The mixture was brought to pH 7 with 1 M HCl and the organic layer was separated, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate in heptanes) afforded the title compound as the first eluting regioisomer (0.057 g, 11%).

Reference： [1]Patent: US2014/275026,2014,A1 .Location in patent: Paragraph 0864; 0865; 0867

61
[ 110-96-3 ]
[ 345-24-4 ]
4-bromo-5-fluoro-N,N-diisobutyl-2-nitroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 23h;Inert atmosphere;	To a homogeneous mixture of <strong>[345-24-4]5-bromo-2,4-difluoronitrobenzene</strong> (2.0 g, 8.40 mmol) in anhydrous NMP (8 mL), at room temperature under nitrogen, was added DIPEA (4.40 mL, 25.20 mmol) followed by diisobutylamine (1.61 mL, 9.24 mmol). The mixture was stirred at 110 C. for 23 hours, then cooled to room temperature, before being diluted with Et2O then washed twice with 1N HCl (aq). The organic layer was washed with a saturated aqueous NaHCO3 solution, then brine, before being dried (Na2SO4), filtered and concentrated in vacuo to afford an oil which was purified on an Isco CombiFlash System Purified: REDISEP normal phase silica flash column (80 g), detection wavelength=254 nm, run time=35 min. Mobile Phase: (5 min at 100% hexane then 20 min gradient from 0-25% EtOAc in hexane). Concentration of the appropriate fractions afforded 4-bromo-5-fluoro-N,N-diisobutyl-2-nitroaniline (2.78 g, 95% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) delta 8.00 (d, J=7.5 Hz, 1H), 6.82 (d, J=11.2 Hz, 1H), 2.91 (d, J=7.3 Hz, 4H), 1.96-1.86 (m, 2H), 0.84 (d, J=6.6 Hz, 12H). MS(ES): m/z=347 [M+H]+, Tr=1.26 min (Method A).
54.8%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 2h;	27A. 4-bromo-5-fluoro-N,N-diisobutyl-2-nitroanilineTo a solution of <strong>[345-24-4]1-bromo-2,4-difluoro-5-nitrobenzene</strong> (1 g, 4.20 mmol) in NMP (2mL) was added diisobutylamine (0.597 g, 4.62 mmol) followed by Hunig?s base (0.88 1 mL, 5.04 mmol). The resulting reaction mixture was heated at 140 C for 2 h. LC-MS indicated completion. After cooling to RT, it was diluted with water (10 mL) and EtOAc (20 mL). The aqueous layer was further extracted with EtOAc (3x20 mL) and the combined organic layer was washed with water, brine, dried over MgSO4 , filtered andconcentrated. Purification via flash chromatography gave 27A (yellow/orange solid, 0.8 g, 2.304 mmol, 54.8 % yield). LC-MS Anal. Calc?d for C,4H20BrFN2O2 346.07, found [M+3H] 349.12. T = 4.24 mm (Method A). ?H NMR (400MHz, CHLOROFORM-d) oe 8.01 (d,J7.3 Hz, 1H), 6.83 (d,J11.2 Hz, 1H), 2.92 (d,J7.3 Hz, 4H), 1.94 (dquin, J=13.5, 6.8 Hz, 2H), 0.85 (d, J=6.4 Hz, 12H)

Reference： [1]Patent: US2016/289171,2016,A1 .Location in patent: Paragraph 2357
[2]Patent: WO2014/150677,2014,A1 .Location in patent: Page/Page column 71; 72

62
[ 15443-52-4 ]
[ 345-24-4 ]
4-bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 23h;Inert atmosphere;	To a homogeneous mixture of <strong>[345-24-4]5-bromo-2,4-difluoronitrobenzene</strong> (2.0 g, 8.40 mmol) in anhydrous NMP (8 mL), at room temperature under nitrogen, was added DIPEA (4.40 mL, 25.20 mmol) followed by N-isobutyl-cyclohexanamine (1.44 g, 9.24 mmol). The mixture was stirred at 110 C. for 23 hours, then cooled to room temperature, before being diluted with Et2O then washed twice with 1N HCl (aq). The organic layer was washed with a saturated aqueous NaHCO3 solution, then brine, before being dried (Na2SO4), filtered and concentrated in vacuo to afford an oil which was purified on an Isco CombiFlash System Purified REDISEP normal phase silica flash column (80 g), detection wavelength=254 nm, run time=35 min. Mobile Phase: (5 min at 100% hexane then 20 min gradient from 0-25% EtOAc in hexane). Concentration of the appropriate fractions afforded 4-bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline (2.71 g, 86% yield) as a red-orange solid. 1H NMR (400 MHz, DMSO-d6) delta 8.14 (d, J=7.5 Hz, 1H), 7.41 (d, J=11.4 Hz, 1H), 2.90 (d, J=7.3 Hz, 2H), 2.87-2.77 (m, 1H), 1.73-1.61 (m, 4H), 1.59-1.35 (m, 4H), 1.14-1.00 (m, 3H), 0.83 (d, J=6.6 Hz, 6H). MS(ES): m/z=373 [M+H]+, Tr=1.32 min (Method A).
2.3 g	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 19h;Inert atmosphere;	522C. 4-Bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline To a solution of <strong>[345-24-4]5-bromo-2,4-difluoronitrobenzene</strong> (1.806 g, 7.59 mmol) in anhydrous NMP (3 mL) was added diisopropylethylamine (3.98 mL, 22.77 mmol) followed by N-isobutylcyclohexanamine (1.2964 g, 8.35 mmol) in NMP (6 mL). The mixture was heated at 110 C under nitrogen. After stirring for 19 hours, the reaction was allowed to cool to room temperature before being diluted with ether. The ether solution was washed twice with iN hydrochloric acid. The organic layer was then washed twice with each saturated sodium bicarbonate solution then brine. The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo to afford a dark residue (3.06g). The crude product was purified on an Isco CombiFlash System using a 80 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a red-orange solid (2.30 g). ?H NMR (400MHz, CHLOROFORIVI-d) oe 7.99 (d, J=7.3 Hz, 1H), 6.89 (d,J=1 1.0 Hz, 1H), 2.97 - 2.90 (m, 1H), 2.89 (d, J=7.3 Hz, 2H), 1.91 - 1.77 (m, 4H), 1.71 (dt, J=13.5, 6.8 Hz, 1H), 1.67 - 1.58 (m, 1H), 1.50 - 1.38 (m, 2H), 1.34 - 1.18 (m, 2H), 1.16 - 1.02 (m, 1H), 0.92 (d, J=6.6 Hz, 6H). MS(ES): m/z = 373 [M+H].

Reference： [1]Patent: US2016/289171,2016,A1 .Location in patent: Paragraph 2022
[2]Patent: WO2015/31295,2015,A1 .Location in patent: Page/Page column 288; 289

63
4,4-difluoro-N-isobutylcyclohexanamine [ No CAS ]
[ 345-24-4 ]
4-bromo-N-(4,4-difluorocyclohexyl)-5-fluoro-N-isobutyl-2-nitroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
682 mg	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 72h;Inert atmosphere;	51 8C. 4-Bromo-N-(4,4-difluorocyclohexyl)-5 -fluoro-N-isobutyl-2-nitroaniline To a solution of <strong>[345-24-4]5-bromo-2,4-difluoronitrobenzene</strong> (537 mg, 2.258 mmol) in anhydrous. NMP (1 mL), under nitrogen, was added DIPEA (1.183 mL, 6.77 mmol)followed by 4,4-difluoro-N-isobutylcyclohexanamine (475 mg, 2.484 mmol) in NMP (2 mL). The mixture was warmed to 110 C and stirred for three days. The reaction was cooled to room temperature and diluted with ether. The diluted reaction was washed twice with iN hydrochloric acid. The organic layer was then washed twice with a saturated solution of sodium bicarbonate and then brine. The organic phase was dried over sodiumsulfate, filtered and concentrated in vacuo to afford a dark brown residue (925 .2mg). The crude product was purified on an Isco CombiFlash System using a 24 g silica column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a red-orange solid (682 mg). ?H NMR (400MHz, CHLOROFORIVI-d) oe 8.04 (d, J=7.3 Hz, 1H), 6.95 (d, J=10.8 Hz, 1H),3.13 -2.95 (m, 1H), 2.87 (d, J=7.3 Hz, 2H), 2.16 (dd, J=11.0, 3.3 Hz, 2H), 1.99- 1.75 (m,5H), 1.75 - 1.63 (m, 2H), 0.92 (d, J=6.6 Hz, 6H). MS(ES): m/z = 409 [M+H].

Reference： [1]Patent: WO2015/31295,2015,A1 .Location in patent: Page/Page column 279; 280

64
[ 345-24-4 ]
[ 124-41-4 ]
5-bromo-2-fluoro-4-methoxyaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		At 0 C., sodium methoxide (344 mg, 6.3 mmol) in dry MeOH (7 mL) was added dropwise to 1-bromo-2,4-dif- luoro-5-nitrobenzene(1 g, 4.2 mmol) in dry MeOH (l8mL). The mixture was stirred at room temperature for 10 hand then refluxed for 8 h. After extractive work up, purification by silica gel chromatography (PE:EA=1:0 to 10:1) gave a mix-ture of the two title compounds (765 mg, 72.9%) in about a 2:1 ratio as a yellow solid. LCMS: 249.9 (M+H) 10513] Zinc dust (0.95 g, 14.5 mmol) was added to the mixture of two title compounds from step 1 (725 mg, 2.9 mmol) in 2:1 MeOH:saturated aqueous NH4C1 (10 mL) at 0After stirring at room temperature for 30 mi extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA=1 :0 to 10:1) gave the title compound (260mg, 41%) as a yellow solid free ofthe corresponding regioisomet ?H NMR (400 MHz, DMSO-d5) oe 7.00 (d, J=9.6 Hz, 1H), 6.94 (d, J=13.2 Hz, 1H), 4.88 (s, 2H), 3.72 (s, 3H). LCMS: 219.9 (M+H)

Reference： [1]Patent: US2015/111885,2015,A1 .Location in patent: Paragraph 0510; 0511; 0512; 0513

65
[ 345-24-4 ]
N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide [ No CAS ]

Reference： [1]Patent: US2015/111885,2015,A1

66
[ 345-24-4 ]
N-[2-fluoro-4-methoxy-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide [ No CAS ]

Reference： [1]Patent: US2015/111885,2015,A1

67
[ 1704-62-7 ]
[ 345-24-4 ]
C₁₈H₃₀BrN₃O₆ [ No CAS ]