[ CAS No. 502496-33-5 ] {[proInfo.proName]}

Name: 502496-33-5|1-Bromo-5-fluoro-2-methyl-3-nitrobenzene|97%
Brand: Ambeed
SKU: A766285
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Quality Control of [ 502496-33-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 502496-33-5 ]

CAS No. :	502496-33-5	MDL No. :	MFCD03094189
Formula :	C₇H₅BrFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZVDFTBJXUXQPAU-UHFFFAOYSA-N
M.W :	234.02	Pubchem ID :	2773385
Synonyms :

Calculated chemistry of [ 502496-33-5 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	47.89
TPSA :	45.82 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.66 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.84
Log Po/w (XLOGP3) :	2.91
Log Po/w (WLOGP) :	3.23
Log Po/w (MLOGP) :	3.19
Log Po/w (SILICOS-IT) :	1.24
Consensus Log Po/w :	2.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.43
Solubility :	0.0873 mg/ml ; 0.000373 mol/l
Class :	Soluble
Log S (Ali) :	-3.53
Solubility :	0.0686 mg/ml ; 0.000293 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.3
Solubility :	0.116 mg/ml ; 0.000497 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 502496-33-5 ]

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 [ 502496-33-5 ]

* 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 [ 502496-33-5 ]
Downstream synthetic route of [ 502496-33-5 ]

[ 502496-33-5 ] Synthesis Path-Upstream 1~4

1
[ 446-10-6 ]
[ 502496-33-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 20℃; for 16 h;	Step 23a: 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound l-bromo-5- fluoro-2-methyl-3 -nitrobenzene (15.0 g, 100percent) as a yellow oil. 1H NMR (400 MHz, OMSO-d₆) δ 2.41 (s, 3H), 7.96 (dd, J= 8.0, 2.4 Hz, 1H), 8.02 (dd, J= 8.0, 2.4 Hz, 1H).
100%	at 20℃; for 16 h;	Step 23a: 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)[0280]To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100percent) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 2.41 (s, 3H), 7.96 (dd, J=8.0, 2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7percent) to get compound 0104-69 (5.8 g, 44percent) as yellow oil. LCMS: 204 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 1H).
100%	at 20℃; for 16 h;	Solution of trifluoroacetic acid (40 mL) of 4-fluoro-2-nitrotoluene (10.0g, 64.4mmol)To, after addition of concentrated sulfuric acid (12.5 mL), was added NBS (17.2g, 96.6mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into ice water, and the mixture was stirred for 15 minutes. And extracted with ethyl acetate, the organic layer was washed with brine, dried and concentrated to give compound 1-bromo-5-fluoro-2-methyl-3- nitrobenzene (15.0g, 100percent) as a yellow oil .

79%	at 20℃; for 21 h;	Reference Example 11; l-Bromo-5-fluoro-2-methyl-3-nitro-benzene; Prepared according to the method used in the preparation of 3-bromo-4-iV,JV- trimethyl-5-nitro-benzenesulfonamide using 4-fluoro-l-methyl-2-nitro-benzene in place of 4-iV,iV-trimethyl-3-nitro-benzenesulfonamide. The title compound was obtained as a yellow solid (68.0 g, 79 percent).NMR δ_H (300 MHz, CDCl₃) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4, IH).
77%	With N-Bromosuccinimide In sulfuric acid; trifluoroacetic acid at 20℃; for 16 h;	To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by N-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into ethyl acetate and the organic layer washed with brine, dried over MgSO₄ and evaporated to dryness to give the title compound as a pale oil which crystallised out on standing (11.76 g,77 percent).νMR δ_η (300 MHz, CDCl₃) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4,IH).
77%	With N-Bromosuccinimide In sulfuric acid; trifluoroacetic acid at 20℃; for 16 h;	To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by iV-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into EtOAc and the organic layer washed with brine, dried (MgSO₄) and concentrated in vacuo to give the title compound as a pale oil which crystallised out on standing (11.76 g, 77 percent).NMR δ_H (300 MHz, CDCl₃) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4, IH).
77%	With N-Bromosuccinimide In sulfuric acid; trifluoroacetic acid at 20℃; for 16 h;	To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifiuoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by N-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into EtOAc and the organic layer washed with brine, dried (MgSO₄) and concentrated in vacuo to give the title compound as a pale oil which crystallised out on standing (11.76 g, 77 percent).NMR δ_H (300 MHz, CDCl₃) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4, IH).

Reference： [1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 155
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0279; 0280
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0252
[4] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 66
[5] Patent: WO2008/152387, 2008, A1, . Location in patent: Page/Page column 33
[6] Patent: WO2008/152394, 2008, A1, . Location in patent: Page/Page column 38
[7] Patent: WO2008/152390, 2008, A1, . Location in patent: Page/Page column 54
[8] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 35
[9] Patent: WO2009/42607, 2009, A1, . Location in patent: Page/Page column 71
[10] Patent: EP2589592, 2018, B1, . Location in patent: Paragraph 0755; 0756
[11] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 104-105
[12] Patent: WO2007/127183, 2007, A1, . Location in patent: Page/Page column 139-140

2
[ 502496-33-5 ]
[ 502496-36-8 ]

Yield	Reaction Conditions	Operation in experiment
87.7%	With iron; ammonium chloride In ethanol; water for 5 h; Reflux	[00402] Ammonium chloride (571 mg, 10.7 mmol) was added to 1-bromo-5-fluoro-2- methyl-3-nitrobenzene (500 mg, 2.14 mmol) and iron (powder) (0.6 g, 10.68 mmol) in water (24 mL) and ethanol (24 mL). The reaction was refluxed for 5 hours then filtered through celite and the filter cake washed with ethanol (100 mL) and EtOAc (100 mL). The organics were removed in vacuo to leave an aqueous solution which was extracted with DCM (3 x 30 mL). The organics were isolated and concentrated to give crude 3-bromo-5-fluoro-2-methyl-aniline (390 mg, 1 .87 mmol, 87.7percent) which was clean by NMR and used without further purification.[00403] 1H NMR (DMSO-d6): O 6.60 (dd, J= 2.8 and 8.4 Hz, 1H), 6.42 (dd, J = 2.8 and11.6 Hz, 1 H), 5.54 (bs, 2H), 2.09 (5, 3H).
44%	Stage #1: With hydrogenchloride; iron In methanol; water for 4 h; Reflux Stage #2: With sodium hydroxide In methanol; water	A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7percent) to get compound 0104-69 (5.8 g, 44percent) as yellow oil. LCMS: 204 [M+l]⁺, 1H NMR (400 MHz, DMSO- ₆ ^ 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J= 11.2, 2.4 Hz, 1H), 6.60 (dd, J= 8.0, 2.4 Hz, 1H).
44%	With hydrogenchloride; iron In methanol; water for 4 h; Reflux	Step 23a: 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)[0280]To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100percent) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 2.41 (s, 3H), 7.96 (dd, J=8.0, 2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7percent) to get compound 0104-69 (5.8 g, 44percent) as yellow oil. LCMS: 204 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 1H).

44%

With hydrogenchloride; iron In methanol; water for 4 h; Reflux

Solution of trifluoroacetic acid (40 mL) of 4-fluoro-2-nitrotoluene (10.0g, 64.4mmol)To, after addition of concentrated sulfuric acid (12.5 mL), was added NBS (17.2g, 96.6mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into ice water, and the mixture was stirred for 15 minutes. And extracted with ethyl acetate, the organic layer was washed with brine, dried and concentrated to give compound 1-bromo-5-fluoro-2-methyl-3- nitrobenzene (15.0g, 100percent) as a yellow oil . MeOH (150mL) and the compound medium prepared in the above water (30mL) (15.0g, 64.4mmol), Fe (18.0g, 0.32mol), were stirred for 4 hours under reflux the mixture of concentrated HCl (2mL). Then the mixture with aqueous NaOH to pH12 adjusted and filtered. The solvent was removed and diluted with water. And extracted with ethyl acetate, dried, and concentrated. The residue was purified by column chromatography (chromatograph) (petroleum ether containing ethyl acetate, 7percent), compound 0104-69 (5.8g, 44percent) as a yellow oil.

Reference： [1] Organic Letters, 2017, vol. 19, # 24, p. 6518 - 6521
[2] Green Chemistry, 2018, vol. 20, # 1, p. 130 - 135
[3] Patent: WO2015/79251, 2015, A1, . Location in patent: Paragraph 00402; 00403
[4] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 155
[5] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0279; 0280
[6] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0252
[7] Patent: WO2006/46031, 2006, A1, . Location in patent: Page/Page column 35
[8] Patent: WO2009/42607, 2009, A1, . Location in patent: Page/Page column 71
[9] Patent: WO2007/127183, 2007, A1, . Location in patent: Page/Page column 140
[10] Patent: WO2009/103440, 2009, A1, . Location in patent: Page/Page column 68-69

3
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: at 20℃; Heating / reflux Stage #2: With iron; acetic acid In N,N-dimethyl-formamide for 0.666667 h; Heating / reflux Stage #3: With water; sodium carbonate In dichloromethane	Intermediate 35; 4-Bromo-6-fluoro-lH-indole; l-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and(dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refiuxed under N₂ for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refiuxed for 40 min., partitioned between DCM and saturated aq. Na₂CO₃/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39percent) as a yellow oil. MS (ESI+) for C₈H₅BrFN m/z 214 (M+H)⁺.
27%	Stage #1: With pyrrolidine In 1,4-dioxane at 20 - 100℃; for 18 h; Stage #2: With iron; acetic acid In 1,4-dioxane for 1 h; Reflux	Example 41 N4-(5-Cyclobutyl- 1 H-pyrazol-3-yl)-N2-((6-fluoro- 1 H-indol-4-yl)methyl)pyrimidine-2,4-diamine Formate (1-88) step 1 : To a solution of l-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100 °C for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50percent aq. NaOH and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (MgSO i), filtered and concentrated in vacuo. The residue was purified by Si02 chromatography eluting with an EtO Ac/petroleum ether gradient (5 to 30percent EtOAc) to afford 1.16 g (27percent) of 4-bromo-6-fluoro-lH-indole (224) -as brown solid: MS (ESI) m/z = 213.9 [M+l] +.

Reference： [1] Patent: WO2008/3703, 2008, A1, . Location in patent: Page/Page column 91
[2] Patent: WO2013/26914, 2013, A1, . Location in patent: Page/Page column 158

4
[ 502496-33-5 ]
[ 885520-70-7 ]

Reference： [1] Patent: EP2589592, 2018, B1,
[2] Patent: WO2007/122410, 2007, A1,
[3] Patent: WO2007/122410, 2007, A1,
[4] Patent: WO2008/152394, 2008, A1,
[5] Patent: WO2008/152390, 2008, A1,
[6] Patent: WO2009/103710, 2009, A1,

[ 502496-33-5 ] Synthesis Path-Downstream 1~88

1
[ 502496-33-5 ]
[ 98-80-6 ]
5-Fluoro-2-methyl-3-nitro-biphenyl [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1745 - 1750

2
[ 123-75-1 ]
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 1057369-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 110℃; for 24h;	Preparation of 4-bromo-6-fluoro- 1 H-indole; To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (1.78 g) in dimethylformamide (15 ml) was added dimethylformamide dimethyl acetal (3.0 ml) followed by pyrrolidine (0.63 ml) and heated to 110 0C. After 24 hours the cooled reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo to yield crude l-[2-(2-bromo-4-fluoro-6- nitro-rhohenyl)-vinyl]-pyrrolidine.

Reference： [1]Patent: WO2007/122410,2007,A1 .Location in patent: Page/Page column 105

3
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 1354219-92-3 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; at 80 - 90℃; for 40h;	Reference Example 14; 4-Bromo-6-fluoro-ll?~indoIe; Prepared according to the method used in the preparation of 4-bromo-lT- indole-6-sulfonic acid dimethylamide using l-bromo-5-fluoro-2-methyl-3-nitro- benzene in place of 3-bromo-4-iV,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (6.06 g, 33 %).NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.I5 IH), 7.12 (dd, J = 2.1, 9.1, IH)5 7.20-7.25 (m, IH) and 8.25 (s, IH).

Reference： [1]Patent: WO2007/122410,2007,A1 .Location in patent: Page/Page column 67

4
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
39%		Intermediate 35; 4-Bromo-6-fluoro-lH-indole; l-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and(dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refiuxed under N2 for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refiuxed for 40 min., partitioned between DCM and saturated aq. Na2CO3/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39percent) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.
27%		Example 41 N4-(5-Cyclobutyl- 1 H-pyrazol-3-yl)-N2-((6-fluoro- 1 H-indol-4-yl)methyl)pyrimidine-2,4-diamine Formate (1-88) step 1 : To a solution of l-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100 °C for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50percent aq. NaOH and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (MgSO i), filtered and concentrated in vacuo. The residue was purified by Si02 chromatography eluting with an EtO Ac/petroleum ether gradient (5 to 30percent EtOAc) to afford 1.16 g (27percent) of 4-bromo-6-fluoro-lH-indole (224) -as brown solid: MS (ESI) m/z = 213.9 [M+l] +.

Reference： [1]Patent: WO2008/3703,2008,A1 .Location in patent: Page/Page column 91
[2]Patent: WO2013/26914,2013,A1 .Location in patent: Page/Page column 158

5
[ 502496-33-5 ]
6-Fluoro-4-phenyl-1H-indole [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1745 - 1750

6
[ 502496-33-5 ]
[ 212119-15-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1745 - 1750

7
[ 502496-33-5 ]
2-(2,2-Dimethoxy-ethyl)-5-fluoro-3-nitro-biphenyl [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1745 - 1750

8
[ 502496-33-5 ]
6-Fluoro-2-(6-fluoro-4-phenyl-2,3-dihydro-indol-1-yl)-3-methyl-quinoline-4-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1745 - 1750

9
[ 502496-33-5 ]
Sodium; 6-fluoro-2-(6-fluoro-4-phenyl-2,3-dihydro-indol-1-yl)-3-methyl-quinoline-4-carboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1745 - 1750

10
[ 446-10-6 ]
[ 502496-33-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 20℃; for 16h;	Step 23a: 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)To a solution of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound l-bromo-5- fluoro-2-methyl-3 -nitrobenzene (15.0 g, 100%) as a yellow oil. 1H NMR (400 MHz, OMSO-d6) delta 2.41 (s, 3H), 7.96 (dd, J= 8.0, 2.4 Hz, 1H), 8.02 (dd, J= 8.0, 2.4 Hz, 1H).
100%	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 20℃; for 16h;	Step 23a: 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)[0280]To a solution of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) delta 2.41 (s, 3H), 7.96 (dd, J=8.0, 2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7%) to get compound 0104-69 (5.8 g, 44%) as yellow oil. LCMS: 204 [M+1]+, 1H NMR (400 MHz, DMSO-d6) delta 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 1H).
100%	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 20℃; for 16h;	Solution of trifluoroacetic acid (40 mL) of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (10.0g, 64.4mmol)To, after addition of concentrated sulfuric acid (12.5 mL), was added NBS (17.2g, 96.6mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into ice water, and the mixture was stirred for 15 minutes. And extracted with ethyl acetate, the organic layer was washed with brine, dried and concentrated to give compound 1-bromo-5-fluoro-2-methyl-3- nitrobenzene (15.0g, 100%) as a yellow oil .

79%	With sulfuric acid; dibromoisocyanuric acid; at 20℃; for 21h;Product distribution / selectivity;	Reference Example 11; l-Bromo-5-fluoro-2-methyl-3-nitro-benzene; Prepared according to the method used in the preparation of 3-bromo-4-iV,JV- trimethyl-5-nitro-benzenesulfonamide using 4-fluoro-l-methyl-2-nitro-benzene in place of 4-iV,iV-trimethyl-3-nitro-benzenesulfonamide. The title compound was obtained as a yellow solid (68.0 g, 79 %).NMR deltaH (300 MHz, CDCl3) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4, IH).
77%	With N-Bromosuccinimide; In sulfuric acid; trifluoroacetic acid; at 20℃; for 16h;	To a solution of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by N-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into ethyl acetate and the organic layer washed with brine, dried over MgSO4 and evaporated to dryness to give the title compound as a pale oil which crystallised out on standing (11.76 g,77 %).nuMR deltaeta (300 MHz, CDCl3) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4,IH).
77%	With N-Bromosuccinimide; In sulfuric acid; trifluoroacetic acid; at 20℃; for 16h;	To a solution of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by iV-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into EtOAc and the organic layer washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a pale oil which crystallised out on standing (11.76 g, 77 %).NMR deltaH (300 MHz, CDCl3) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4, IH).
77%	With N-Bromosuccinimide; In sulfuric acid; trifluoroacetic acid; at 20℃; for 16h;	To a solution of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (10.0 g, 64.4 mmol) in trifiuoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by N-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into EtOAc and the organic layer washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a pale oil which crystallised out on standing (11.76 g, 77 %).NMR deltaH (300 MHz, CDCl3) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4, IH).
	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; for 16h;	Reference Example 7: 6-Fluoroindazole-4-Boronate Ester (75) To a solution of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (3.44g) in trifluoroacetic acid (13mL) was added concentrated sulfuric acid (4mL) followed by N-bromosuccinimide (5.92g). The reaction mixture was stirred for 16 h and was then quenched with brine, extracted into ethyl acetate, and dried (MgSO4). The solvent was removed in vacuo to furnish crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96g). To a solution of crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96g) inMeOH (9OmL) was added concentrated hydrochloric acid (11.7mL) and iron (6.Ig) and the reaction mixture was heated to reflux. After 16 h, the mixture was cooled, diluted with DCM, washed with sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 3-bromo-5-fluoro-2-methyl-phenylamine (1.46g).To a solution of 3-bromo-5-fluoro-2-methyl-phenylamine (470mg) in dioxane (6mL) was added triethylamine (1.28mL), palladium acetate (25mg), 2- dicyclohexylphosphino biphenyl (161mg) and pinacol borane (1.001ml) and the mixture was heated to 8O0C for 4 h. The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield the desired title compound (466mg).
	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; for 16h;	Example 7; 6-Fluoroindazole-4-Boronate Ester 45[00244] Following the procedures of WO 2006/046031 , to a solution of 4-fluoro-2- nitrotoluene (3.44 g) in trifluoroacetic acid (13 mL) was added concentrated sulfuric acid (4mL) followed by N-bromosuccinimide (5.92 g). The reaction mixture was stirred for 16 h and was then quenched with brine, extracted into ethyl acetate, and dried (MgSO4). The solvent was removed in vacuo to furnish crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96 g).
	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 20℃; for 15h;	Concentrated sulfuric acid (2.5 ml) and N-bromosuccinimide (3.44 g) were added to a TFA solution (8 ml)containing <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (2 g), followed by stirring at room temperature for 15 hours. Then, the reaction solutionwas poured into ice water, followed by extraction with ethyl acetate. The obtained organic layer was washed with water,a saturated aqueous sodium hydrogen carbonate solution, and saturated saline and dried over anhydrous sodium sulfate.Thereafter, the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography,and light yellow oily matter was thus obtained.
	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; for 24h;Product distribution / selectivity;	Example 22; 2-(6-Fluoro-lH-indol-4-yI)-6-(4-methyl-piperazin-l-vImethvI)-4- morpholin-4-yI-thienof3,2-d1pyrimidialphae; To a solution of <strong>[446-10-6]4-fluoro-2-nitrotoluene</strong> (2.0 g) in trifluroacetic acid (8 ml) was added concentrated sulfuric acid (2.5 ml) followed by iV-bromosuccinimide (3.4 g). After stirring for 24 hours the reaction mixture was then diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo. The <n="106"/>residue was purified by flash chromatography to give l-bromo-5-fluoro-2-methyl-3- nitro-benzene (2.48 g).
	With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; for 16h;	Example 6 6-Fluoroindazole-4-Boronate Ester 7a <n="141"/>[00285] To a solution of 4-fluoro-2-nitxotoluene (3.44g) in trifluoroacetic acid(13mL) was added concentrated sulfuric acid (4mL) followed by N-bromosuccinimide (5.92g). The reaction mixture was stirred for 16 h and was then quenched with brine, extracted into ethyl acetate, and dried (MgSO4). The solvent was removed in vacuo to furnish crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96g).

Reference： [1]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 155
[2]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0279; 0280
[3]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0252
[4]Patent: WO2007/122410,2007,A1 .Location in patent: Page/Page column 66
[5]Patent: WO2008/152387,2008,A1 .Location in patent: Page/Page column 33
[6]Patent: WO2008/152394,2008,A1 .Location in patent: Page/Page column 38
[7]Patent: WO2008/152390,2008,A1 .Location in patent: Page/Page column 54
[8]Patent: WO2006/46031,2006,A1 .Location in patent: Page/Page column 35
[9]Patent: WO2009/42607,2009,A1 .Location in patent: Page/Page column 71
[10]Patent: EP2589592,2018,B1 .Location in patent: Paragraph 0755; 0756
[11]Patent: WO2007/122410,2007,A1 .Location in patent: Page/Page column 104-105
[12]Patent: WO2007/127183,2007,A1 .Location in patent: Page/Page column 139-140

11
[ 502496-33-5 ]
[ 502496-36-8 ]

Yield	Reaction Conditions	Operation in experiment
87.7%	With iron; ammonium chloride; In ethanol; water; for 5h;Reflux;	[00402] Ammonium chloride (571 mg, 10.7 mmol) was added to 1-bromo-5-fluoro-2- methyl-3-nitrobenzene (500 mg, 2.14 mmol) and iron (powder) (0.6 g, 10.68 mmol) in water (24 mL) and ethanol (24 mL). The reaction was refluxed for 5 hours then filtered through celite and the filter cake washed with ethanol (100 mL) and EtOAc (100 mL). The organics were removed in vacuo to leave an aqueous solution which was extracted with DCM (3 x 30 mL). The organics were isolated and concentrated to give crude 3-bromo-5-fluoro-2-methyl-aniline (390 mg, 1 .87 mmol, 87.7%) which was clean by NMR and used without further purification.[00403] 1H NMR (DMSO-d6): O 6.60 (dd, J= 2.8 and 8.4 Hz, 1H), 6.42 (dd, J = 2.8 and11.6 Hz, 1 H), 5.54 (bs, 2H), 2.09 (5, 3H).
44%		A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7%) to get compound 0104-69 (5.8 g, 44%) as yellow oil. LCMS: 204 [M+l]+, 1H NMR (400 MHz, DMSO- 6 ^ 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J= 11.2, 2.4 Hz, 1H), 6.60 (dd, J= 8.0, 2.4 Hz, 1H).
44%	With hydrogenchloride; iron; In methanol; water; for 4h;Reflux;	Step 23a: 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)[0280]To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL) followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was poured into ice and water and stirred for 15 min. Extracted with ethyl acetate and the organic layer was washed with brine, dried, concentrated to get compound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) delta 2.41 (s, 3H), 7.96 (dd, J=8.0, 2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above prepared compound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) in MeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then the mixture was adjusted to pH 12 with aqueous NaOH solution and filtered. The solvent was removed and diluted with water. Extracted with ethyl acetate, dried, concentrated. The residue was purified by column chromatograph (ethyl acetate in petroleum ether, 7%) to get compound 0104-69 (5.8 g, 44%) as yellow oil. LCMS: 204 [M+1]+, 1H NMR (400 MHz, DMSO-d6) delta 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 1H).

44%	With hydrogenchloride; iron; In methanol; water; for 4h;Reflux;	Solution of trifluoroacetic acid (40 mL) of 4-fluoro-2-nitrotoluene (10.0g, 64.4mmol)To, after addition of concentrated sulfuric acid (12.5 mL), was added NBS (17.2g, 96.6mmol), the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into ice water, and the mixture was stirred for 15 minutes. And extracted with ethyl acetate, the organic layer was washed with brine, dried and concentrated to give compound 1-bromo-5-fluoro-2-methyl-3- nitrobenzene (15.0g, 100%) as a yellow oil . MeOH (150mL) and the compound medium prepared in the above water (30mL) (15.0g, 64.4mmol), Fe (18.0g, 0.32mol), were stirred for 4 hours under reflux the mixture of concentrated HCl (2mL). Then the mixture with aqueous NaOH to pH12 adjusted and filtered. The solvent was removed and diluted with water. And extracted with ethyl acetate, dried, and concentrated. The residue was purified by column chromatography (chromatograph) (petroleum ether containing ethyl acetate, 7%), compound 0104-69 (5.8g, 44%) as a yellow oil.
	With hydrogenchloride; iron; for 16h;Heating / reflux;	Reference Example 7: 6-Fluoroindazole-4-Boronate Ester (75) To a solution of 4-fluoro-2-nitrotoluene (3.44g) in trifluoroacetic acid (13mL) was added concentrated sulfuric acid (4mL) followed by N-bromosuccinimide (5.92g). The reaction mixture was stirred for 16 h and was then quenched with brine, extracted into ethyl acetate, and dried (MgSO4). The solvent was removed in vacuo to furnish crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96g). To a solution of crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96g) inMeOH (9OmL) was added concentrated hydrochloric acid (11.7mL) and iron (6.Ig) and the reaction mixture was heated to reflux. After 16 h, the mixture was cooled, diluted with DCM, washed with sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 3-bromo-5-fluoro-2-methyl-phenylamine (1.46g).To a solution of 3-bromo-5-fluoro-2-methyl-phenylamine (470mg) in dioxane (6mL) was added triethylamine (1.28mL), palladium acetate (25mg), 2- dicyclohexylphosphino biphenyl (161mg) and pinacol borane (1.001ml) and the mixture was heated to 8O0C for 4 h. The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield the desired title compound (466mg).
	With hydrogenchloride; iron; In methanol; water; for 16h;Heating / reflux;	To a solution of crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96 g) inMeOH (90 mL) was added concentrated hydrochloric acid (11.7 mL) and iron (6.1 g) and the reaction mixture was heated to reflux. After 16 h, the mixture was cooled, diluted with DCM, washed with sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 3-bromo-5-fluoro-2-methyl- phenylamine (1.46 g).
		To a solution of crude l-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96g) in MeOH (9OmL) was added concentrated hydrochloric acid (11.7mL) and iron (6.Ig) and the reaction mixture was heated to reflux. After 16 h, the mixture was cooled, diluted with DCM, washed with sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 3-bromo-5-fluoro-2- methyl-phenylamine (1.46g).
	With iron; ammonium chloride; In water; isopropyl alcohol; at 110℃; for 2h;	16.1) 3-Bromo-5-fluoro-2-methyl-phenylamine (Intermediate 48): To iron powder (325 mesh, 2.25 g, 40.3 mmol) in 30 ml water and 80 ml isopropanol was added commercially available 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (3.04 g, 13 mmol) in 45 ml isopropanol and NH4CI (1.46 g, 27.3 mmol). The resulting mixture was heated at 1100C for 2 h. After evaporation of most of the isopropanol the aq solution was extracted with ethyl acetate three times. The combined organic layers <n="71"/>were washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product was used without further purification in the next step.
	With ammonium chloride; zinc; In 1,4-dioxane; water; at 0 - 20℃; for 3h;	l-Bromo-5-fluoro-2-methyl-3 -nitrobenzene (3.04 mL, 22.0 mmol) was dissolved in a 4: 1 mixture of dioxan and water (110 mL). The solution was cooled to 0 C and Zn dust (14.4 g, 220 mmol) and NH4Cl (11.8 g. 220 mmol) were added. The reaction mixture was stirred at RT for 3 h. After complete conversion, the mixture was filtered over a pad of Celite. It was carefully rinsed with EA and the filtrate was washed with water. The organic phase was dried over Na^SCL, filtered and concentrated in vacuo to give the title compound.

Reference： [1]Organic Letters,2017,vol. 19,p. 6518 - 6521
[2]Green Chemistry,2018,vol. 20,p. 130 - 135
[3]Patent: WO2015/79251,2015,A1 .Location in patent: Paragraph 00402; 00403
[4]Patent: WO2011/130628,2011,A1 .Location in patent: Page/Page column 155
[5]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0279; 0280
[6]Patent: JP2015/187145,2015,A .Location in patent: Paragraph 0252
[7]Patent: WO2006/46031,2006,A1 .Location in patent: Page/Page column 35
[8]Patent: WO2009/42607,2009,A1 .Location in patent: Page/Page column 71
[9]Patent: WO2007/127183,2007,A1 .Location in patent: Page/Page column 140
[10]Patent: WO2009/103440,2009,A1 .Location in patent: Page/Page column 68-69
[11]Patent: WO2019/101906,2019,A1 .Location in patent: Page/Page column 41

12
[ 367-27-1 ]
[ 502496-33-5 ]
[ 927663-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h;	<strong>[502496-33-5]1-Bromo-5-fluoro-2-methyl-3-nitro-benzene</strong> (9.40 g, 41.45 mmol) was dissolved in 90 mL dry DMF, and 2,4-difluorophenol (5.93 g, 45.58 mmol) and potassium carbonate (6.70 g, 45.58 mmol) were added. The reaction mixture was placed under nitronge and heated to 120 C with stirring for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The organic phase was separated, washed with IN aqueous NaOH and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-6% EtOAc in hexanes) to give 8.484 g of 1-bromo-5-(2,4-difluoro-phenoxy)-2-methyl-3-nitro-benzene.

Reference： [1]Patent: US2007/54915,2007,A1 .Location in patent: Page/Page column 56-57

14
[ 123-75-1 ]
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 1093066-65-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	In 1,4-dioxane; at 100℃;	To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) was added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 <n="35"/>mniol). The reaction mixture was heated at 100 0C. The mixture was cooled to RT and evaporated to dryness to give l-[2-(2-bromo-4-fluoro-6-mtro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue (10.0 g, theoretical yield).
100%	In 1,4-dioxane; at 100℃;	Reference Example 44-Bromo-6-fluoro-lH-indoleTo a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) was added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 C. The mixture was cooled to RT and evaporated to dryness to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue (10.0 g, theoretical yield). To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney-Nickel (suspension in H2O, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 0C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 %).NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).
	In 1,4-dioxane; ISOPROPYLAMIDE; at 100℃; for 3h;	To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 C for 3 h. The mixture was cooled to RT and concetrated in vacuo to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney-Nickel (suspension in H20, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by <n="56"/>column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a pale oil (2.57 g, 37 %).NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).

Reference： [1]Patent: WO2008/152387,2008,A1 .Location in patent: Page/Page column 33-34
[2]Patent: WO2009/53716,2009,A1 .Location in patent: Page/Page column 56
[3]Patent: WO2008/152390,2008,A1 .Location in patent: Page/Page column 54-55

15
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 1093066-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyrrolidine; In 1,4-dioxane; at 100℃; for 3h;	To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 0C for 3 h. The mixture was cooled to RT and concetrated in vacuo to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney-Nickel (suspension in H2O, 15 mL) in MeOHrTHF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 0C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a pale oil (2.57 g, 37 %). NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).

Reference： [1]Patent: WO2008/152394,2008,A1 .Location in patent: Page/Page column 39

16
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 1181566-93-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyrrolidine; In N,N-dimethyl-formamide; at 110℃; for 4h;	Description 15. (E)-2-(2-bromo-4-fluoro-6-nitrophenyl)-N,N-dimethylethenamine To a solution of <strong>[502496-33-5]1-bromo-5-fluoro-2-methyl-3-nitrobenzene</strong> (5.0 g, 21.37 mmol) in N, N- dimethylformamide (50 ml.) was added lambda/,lambda/-dimethylformamide dimethyl acetal (8.58 ml_, 64.1 mmol) and pyrrolidine^ .767 ml_, 21.37 mmol). The reaction mixture was heated at 11O0C for 4 hours. After cooling to room temperature, the N, N- dimethylformamide was removed by evaporation. The residue was taken up in diethyl ether and water. After separation of the organic layer, the aqueous layer was re- extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and concentrated to give a red/brown oil which was used directly in the following reaction without purification.

Reference： [1]Patent: WO2009/103710,2009,A1 .Location in patent: Page/Page column 21

17
[ 502496-33-5 ]
[ 1418127-62-4 ]

Reference： [1]Patent: WO2013/8095,2013,A1

18
[ 502496-33-5 ]
[ 1418128-20-7 ]

Reference： [1]Patent: WO2013/8095,2013,A1

19
[ 502496-33-5 ]
[ 1418127-77-1 ]

Reference： [1]Patent: WO2013/8095,2013,A1

20
[ 502496-33-5 ]
[ 1418128-35-4 ]

Reference： [1]Patent: WO2013/8095,2013,A1

21
[ 73183-34-3 ]
[ 502496-33-5 ]
[ 1418128-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 6h;	To a mixture of <strong>[502496-33-5]1-Bromo-5-fluoro-2-methyl-3-nitro-benzene</strong> (5.0 g, 21.37 mmol) and bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.78 g, 1.06 mmol) in 200 ml dioxane, bis-(pinacolato)-diboron (8.14 g, 32.0 mmol) and potassium acetate (7.34 g, 74.8 mmol) were added. The mixture was heated to 100C for 6 hours. After cooling the brownish mixture was diluted with 200 ml water and extracted with EtOAc. The organic layer was washed with sodium hydrogen carbonate (1x) and brine (2x) and dried over sodium sulfate, then filtered and evaporated. The residue was purified by flash chromatography on silica (cyclohexane/EtOAc 9: 1 ) to afford the compound Intermediate 4 as a yellow oil.MS (ESI): 281 [M]+ , 1H-NMR (DMSO-d6): delta (ppm) 7.79 (d, 1 H), 7.55 (d, 1 H), 2.48 (s, 3H), 1.31 (s, 12H).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 6h;	(2) 2-(5-Fluoro-2-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, INT 2 To a mixture of <strong>[502496-33-5]1-bromo-5-fluoro-2-methyl-3-nitro-benzene</strong> (5.0 g, 21.37 mmol) and bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.78 g, 1.06 mmol) in dioxane (200 mL) was added BISPIN (8.14 g, 32.05 mmol) followed by potassium acetate (7.34 g, 74.79 mmol). The reaction mixture was stirred at 100 C. for 6 hr. After cooling the brownish mixture was diluted with water (200 mL) and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine (2*), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; cyclohexane/EtOAc 9:1) to afford INT 2 as a yellow oil. 1H NMR (DMSO-d6): delta (ppm) 7.79 (d, 1H), 7.55 (d, 1H), 2.48 (s, 3H), 1.31 (s, 12H).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 6h;	General procedure: (2) 2-(5-fluoro-2-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, INT 2 To a mixture of 1 -bromo-5-fluoro-2-methyl-3-nitro-benzene (5.0 g, 21.37 mmol) and bis(diphenylphosphino)ferrocenedichloropalladium(ll) (0.78 g, 1 .06 mmol) in dioxane (200 mL) was added BISPIN (8.14 g, 32.05 mmol) followed by potassium acetate (7.34 g, 74.79 mmol). The reaction mixture was stirred at 100 C for 6 hr. After cooling the brownish mixture was diluted with water (200 mL) and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine (2x), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; cyclohexane/EtOAc 9:1 ) to afford INT 2 as a yellow oil.1H NMR (DMSO-d6): delta (ppm) 7.79 (d, 1 H), 7.55 (d, 1 H), 2.48 (s, 3H), 1.31 (s, 12H).

	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 6h;	To a mixture of <strong>[502496-33-5]1-bromo-5-fluoro-2-methyl-3-nitro-benzene</strong> (5.0 g, 21 .37 mmol) and bis(diphenylphosphino)ferrocenedichloropalladium(ll) (0.78 g, 1 .06 mmol) in dioxane (200 mL) was added BISPIN (8.14 g, 32.05 mmol) followed by potassium acetate (7.34 g, 74.79 mmol). The reaction mixture was stirred at 100 C for 6 hr. After cooling the brownish mixture was diluted with water (200 mL) and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine (2x), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; cyclohexane/EtOAc 9:1 ) to afford INT 3 as a yellow oil.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 6h;	To a mixture of <strong>[502496-33-5]1-bromo-5-fluoro-2-methyl-3-nitro-benzene</strong> (5.0 g, 21.37 mmol) and bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.78 g, 1.06 mmol) in dioxane (200 mL) was added BISPIN (8.14 g, 32.05 mmol) followed by potassium acetate (7.34 g, 74.79 mmol). The reaction mixture was stirred at 100 C for 6 hr. After cooling the brownish mixture was diluted with water (200mL) and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine (2x), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; cyclohexane/EtOAc 9:1) to afford INT 2 as a yellow oil. ?H NMR (DMSO-d6): (ppm) 7.79 (d, 1H), 7.55 (d, 1H), 2.48 (s, 3H), 1.31 (s, 12H).

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118
[3]Patent: WO2013/8095,2013,A1 .Location in patent: Page/Page column 37
[4]Patent: US2015/152068,2015,A1 .Location in patent: Paragraph 0146; 0147; 0148
[5]Patent: WO2015/79417,2015,A1 .Location in patent: Page/Page column 30
[6]Patent: WO2016/79669,2016,A1 .Location in patent: Page/Page column 34
[7]Patent: WO2016/164580,2016,A1 .Location in patent: Page/Page column 237

22
[ 73183-34-3 ]
[ 502496-33-5 ]
[ 1418128-33-2 ]

Reference： [1]Patent: WO2013/8095,2013,A1
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472

23
[ 502496-33-5 ]
[ 1082040-44-5 ]

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

24
[ 502496-33-5 ]
[ 1422057-38-2 ]

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

25
[ 502496-33-5 ]
[ 1425929-76-5 ]

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

26
[ 502496-33-5 ]
[ 1418128-33-2 ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79251,2015,A1
[3]Patent: WO2015/79417,2015,A1
[4]Patent: WO2016/79669,2016,A1
[5]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118

27
[ 502496-33-5 ]
N-(3-(6-amino-5-(benzyloxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

28
[ 502496-33-5 ]
N-(3-(6-amino-5-hydroxypyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

29
[ 502496-33-5 ]
(2S,4R)-tert-butyl 2-(((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)methyl)-4-cyanopyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1

30
[ 502496-33-5 ]
N-(3-(6-amino-5-(((2S,4R)-4-cyanopyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

31
[ 502496-33-5 ]
N-(3-(5-(((2S,4R)-1-acryloyl-4-cyanopyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

32
[ 502496-33-5 ]
4-cyclopropyl-2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/79669,2016,A1
[4]Patent: WO2016/164580,2016,A1
[5]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118

33
[ 502496-33-5 ]
tert-butyl 3-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1
[4]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118

34
[ 502496-33-5 ]
N-(3-(6-amino-5-(azetidin-3-yloxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

35
[ 502496-33-5 ]
N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1
[4]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118

36
[ 502496-33-5 ]
tert-butyl (2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methyl-phenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1
[4]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118

37
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

38
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1
[4]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118

39
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

40
[ 502496-33-5 ]
N-(2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)-N-methyloxirane-2-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/152068,2015,A1
[2]Patent: WO2015/79417,2015,A1
[3]Patent: WO2016/164580,2016,A1

41
[ 502496-33-5 ]
3-amino-5-fluoro-2-methyl-phenol [ No CAS ]

Reference： [1]Patent: WO2015/79251,2015,A1

42
[ 502496-33-5 ]
3-((7-(2,2-dimethoxyethoxy)-6-methoxyquinazolin-4-yl)amino)-5-fluoro-2-methylphenol acetic acid salt [ No CAS ]

Reference： [1]Patent: WO2015/79251,2015,A1

43
[ 502496-33-5 ]
5-fluoro-3-((6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl)amino)-2-methylphenol [ No CAS ]

Reference： [1]Patent: WO2015/79251,2015,A1

44
[ 502496-33-5 ]
2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetic acid hydrochloride salt [ No CAS ]

Reference： [1]Patent: WO2015/79251,2015,A1

45
[ 502496-33-5 ]
ethyl 2-((4-((5-fluoro-3-hydroxy-2-methylphenyl)amino)-6-methoxyquinazolin-7-yl)oxy)acetate [ No CAS ]

Reference： [1]Patent: WO2015/79251,2015,A1

46
[ 502496-33-5 ]
tert-butyl (2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(fluoroethyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

47
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(fluoroethylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1
[2]Patent: WO2016/79669,2016,A1

48
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(N-fluoroethylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1
[2]Patent: WO2016/79669,2016,A1

49
[ 502496-33-5 ]
[³H₃]-N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1
[2]Patent: WO2016/79669,2016,A1

50
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-((4-methoxybenzyl)(2-((triisopropylsilyl)oxy)ethyl)amino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

51
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-((2-hydroxyethyl)(4-methoxybenzyl)amino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

52
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-((2-chloroethyl)(4-methoxybenzyl)amino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

53
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-((2-fluoroethyl)(4-methoxybenzyl)amino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

54
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1
[2]Patent: WO2016/79669,2016,A1

55
[ 502496-33-5 ]
tert-butyl (2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118

56
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-aminoethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

57
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(N-(2-[¹⁸F]fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

58
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-((3-fluoropropyl)amino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

59
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(N-(3-fluoropropyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

60
[ 502496-33-5 ]
N-(3-(6-amino-5-(2-(N-(2-[¹⁸F]fluoropropyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2016/79669,2016,A1

61
[ 502496-33-5 ]
(2S,4R)-tert-butyl 2-(((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)methyl)-4-cyanopyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/164580,2016,A1

62
[ 502496-33-5 ]
[ 885520-70-7 ]

Reference： [1]Patent: EP2589592,2018,B1
[2]Patent: WO2007/122410,2007,A1
[3]Patent: WO2007/122410,2007,A1
[4]Patent: WO2008/152394,2008,A1
[5]Patent: WO2008/152390,2008,A1
[6]Patent: WO2009/103710,2009,A1

63
[ 1188-33-6 ]
[ 502496-33-5 ]
[ 1354219-92-3 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; for 0.5h;Inert atmosphere; Reflux;	N,N-dimethylformamide dimethylacetal (7.7 g) was added to a DMF (20 ml) solution containing the light yellowoily matter obtained in the 1st step in a nitrogen atmosphere, followed by reflux for 30 minutes. The reaction solutionwas adjusted to room temperature. Water, ethyl acetate, and 1M hydrochloric acid were added, and then the organiclayer was separated. The obtained organic layer was washed with 1M hydrochloric acid (x3) and saturated saline anddried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and deepbrown oily matter was thus obtained

Reference： [1]Patent: EP2589592,2018,B1 .Location in patent: Paragraph 0755; 0757

64
[ 502496-33-5 ]
[ 885698-71-5 ]

Reference： [1]Patent: WO2007/127183,2007,A1

65
[ 502496-33-5 ]
[ 955978-85-5 ]

Reference： [1]Patent: WO2008/152394,2008,A1
[2]Patent: WO2008/152390,2008,A1
[3]Patent: US2020/24281,2020,A1
[4]Patent: WO2020/16453,2020,A1

66
[ 502496-33-5 ]
[ 1093075-26-3 ]

Reference： [1]Patent: WO2008/152390,2008,A1

67
[ 502496-33-5 ]
C₂₉H₃₄FN₇O₃S [ No CAS ]

Reference： [1]Patent: WO2008/152390,2008,A1

68
[ 502496-33-5 ]
[ 1184297-93-5 ]

Reference： [1]Patent: WO2009/103440,2009,A1

69
[ 502496-33-5 ]
[ 1181566-66-4 ]

Reference： [1]Patent: WO2009/103710,2009,A1

70
[ 502496-33-5 ]
[ 1181566-64-2 ]

Reference： [1]Patent: WO2009/103710,2009,A1

71
[ 502496-33-5 ]
[ 1181566-98-2 ]

Reference： [1]Patent: WO2009/103710,2009,A1

72
[ 502496-33-5 ]
[ 1181567-00-9 ]

Reference： [1]Patent: WO2009/103710,2009,A1

73
[ 502496-33-5 ]
[ 1181566-96-0 ]

Reference： [1]Patent: WO2009/103710,2009,A1

74
[ 502496-33-5 ]
[ 1181566-95-9 ]

Reference： [1]Patent: WO2009/103710,2009,A1

75
[ 502496-33-5 ]
C₂₆H₃₈⁽²⁾HClFNO₄SSi [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

76
[ 502496-33-5 ]
1-bromo-3-chloro-5-fluoro-2-methyl-benzene [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

77
[ 502496-33-5 ]
1-bromo-2-(bromomethyl)-3-chloro-5-fluorobenzene [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

78
[ 502496-33-5 ]
1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

79
[ 502496-33-5 ]
(R)-N-((R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

80
[ 502496-33-5 ]
(R)-2-amino-2-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanol [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

81
[ 502496-33-5 ]
(S)-N-((R)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

82
[ 502496-33-5 ]
(S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate [ No CAS ]

Reference： [1]Patent: WO2019/101906,2019,A1

83
[ 502496-33-5 ]
tert-butyl 3-(4-(3-amino-5-fluoro-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472

84
[ 502496-33-5 ]
tert-butyl 3-(4-(3-amino-5-fluoro-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472

85
[ 502496-33-5 ]
tert-butyl 3-(4-(3-(4-cyclopropylbenzamido)-5-fluoro-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472

86
[ 502496-33-5 ]
4-cyclopropyl-N-(5-fluoro-2-methyl-3-(5-(piperidin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472

87
[ 502496-33-5 ]
N-(3-(5-(1-acryloylpiperidin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropylbenzamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472

88
[ 502496-33-5 ]
N-(3-(5-(1-acryloylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropylbenzamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1467 - 1472

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 502496-33-5 ] {[proInfo.proName]}

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Calculated chemistry of [ 502496-33-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 502496-33-5 ]

Application In Synthesis of [ 502496-33-5 ]

[ 502496-33-5 ] Synthesis Path-Upstream 1~4

[ 502496-33-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 502496-33-5 ]

Fluorinated Building Blocks

Bromides

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Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 502496-33-5 ]