[ CAS No. 116557-46-1 ] {[proInfo.proName]}

Name: 116557-46-1|3-Bromo-2-methoxyaniline|98%
Brand: Ambeed
SKU: A123251
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3d Animation Molecule Structure of 116557-46-1

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Quality Control of [ 116557-46-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 116557-46-1 ]

SDS Specification

Alternatived Products of [ 116557-46-1 ]

Product Details of [ 116557-46-1 ]

CAS No. :	116557-46-1	MDL No. :	MFCD13186737
Formula :	C₇H₈BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZLODWCIXZJMLJL-UHFFFAOYSA-N
M.W :	202.05	Pubchem ID :	22667735
Synonyms :

Calculated chemistry of [ 116557-46-1 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.04
TPSA :	35.25 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) :	-6.18 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.81
Log Po/w (XLOGP3) :	1.9
Log Po/w (WLOGP) :	2.05
Log Po/w (MLOGP) :	1.91
Log Po/w (SILICOS-IT) :	1.78
Consensus Log Po/w :	1.89

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.67
Solubility :	0.434 mg/ml ; 0.00215 mol/l
Class :	Soluble
Log S (Ali) :	-2.26
Solubility :	1.1 mg/ml ; 0.00546 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.02
Solubility :	0.192 mg/ml ; 0.000948 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.44

Safety of [ 116557-46-1 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P264-P280-P301+P310+P330-P302+P352+P312-P403+P233	UN#:	2810
Hazard Statements:	H301+H311+H331-H315-H319	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 116557-46-1 ]

* 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 [ 116557-46-1 ]
Downstream synthetic route of [ 116557-46-1 ]

[ 116557-46-1 ] Synthesis Path-Upstream 1~5

1
[ 98775-19-0 ]
[ 116557-46-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With iron; acetic acid In water at 80℃; for 1.5 h;	A mixture of 1-bromo-2-methoxy-3-nitrobenzene (20.1 g, 86.6 mmol) and iron powder (33.4 g, 598 mmol) in acetic acid/water (1:1, 600 mL) was heated to 80°C for 1.5 hours. After the mixture was cooled and filtered, the solid was washed with ethyl acetate and water. The organic layer was washed with saturated aqueous NaHCO₃, dried, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to give 3-bromo-2-methoxyphenylamine as yellow solid (17.4 g, yield 99percent).1H-NMR Spectrum (300MHz, DMSO-d6):δ (ppm): 3.66 (s, 3H), 5.23 (s, 2H), 6.64-6.76 (m, 3H)
96%	With ammonium chloride; zinc In ethanol; water for 1 h;	Step 2[00173j Int9 (5.12 g, 22.1 mmol) was dissolved in ethyl alcohol (150 mL) and water (50 mL). To this was added zinc (5.77 g, 88 mmol) and ammonium chloride (2.36 g, 44.1 mmol). The reaction was stirred for 1 hour, filtered and then concentrated. The crudematerial was dissolved in ethyl acetate and washed with water three times, the organic layer was then dried over sodium sulfate, filtered, concentrated and collected (4.3 g, 96percent). LC retention time 0.75 [J]. m/z: 201.8 (MHj.
96%	With hydrogenchloride; tin(ll) chloride In tetrahydrofuran at 80℃; for 16 h;	A mixture of 1-Bromo-2-methoxy-3-nitro-benzene (17.8 g, 0.0768 mol), SnCl₂(69.27 g, 0.3069 mol) and 4N HCl (80 mL) in THF (200 mL) is stirred at 80° C. for 16 h. After reaction, evaporated out THF and added NaHCO₃solution, filtered and the filtrate is extracted with ethyl acetate (3×800 mL). The combined organic phase is ished with water and brine, dried over Na₂SO₄, concentrated in vacuo to give the desired product. Yield: 14.8 g (96percent). HPLC-MS: M+H=202/204; t_Ret=1.49 min; AM12

96%	With hydrogenchloride; tin(ll) chloride In tetrahydrofuran at 80℃; for 16 h;	3-Bromo-2-methoxy-phenylamine A mixture of l-Bromo-2-methoxy-3-nitro-benzene (17.8 g, 0.0768 mol), SnCl₂ (69.27 g, 0.3069 mol) and 4N HC1 (80 mL) in THF (200 mL) is stirred at 80 °C for 16h. After reaction, evaporated out THF and added NaHC0₃ solution, filtered and the filtrate is extracted with ethyl acetate (3 x 800 mL). The combined organic phase is ished with water and brine, dried over Na₂S0₄, concentrated in vacuo to give the desired product. Yield: 14.8 g (96percent). HPLC-MS: M+H=202/204; t_Ret =1.49 min; AM12
91.87%	at 120℃; for 4 h;	To a solution of bromo-2-methoxy-3-nitrobenzene 1 (lOg, 43.lmmol, 1.Oeq) in acetic acid (lOOmL), iron powder (12.03g, 215.5mmol, 5.Oeq) was added portion wise. Reaction mixture was stirred at 120°C for 4h. After completion of the reaction, the reaction mixture was filtered, concentrated in vacuo to obtain residue which was transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 55.1 (8g, 91.87percent). MS(ES): m/z 203.49 [M+H]t (E)N-((dimethylamino)methyl ene)acetamide
85%	With ammonium chloride; zinc In ethanol; water at 20℃;	A mixture of l-bromo-2-methoxy-3-nitrobenzene from Step 1 (3 g, 11.64 mmol), zinc metal (7.61 g, 116 mmol) and ammonium chloride (6.22 g, 116 mmol) in EtOH (50 mL) and water (7.14 mL) was stirred at rt overnight. The reaction was then diluted with dichloromethane (200 mL), and filtered. The filtrate was washed with water (50 mL), dried (sodium sulfate), and concentrated. Redissolved this material in dichloromethane, and loaded onto a 80g silica gel column for purification by flash chromatography, eluting with 0-100percent EtOAc in hexanes. Afforded 3-bromo-2- methoxyaniline (2.11 g, 9.92 mmol, 85percent yield) as a colorless oil.
85%	With ammonium chloride; zinc In water at 20℃;	In rt will come from step 11-bromo-2-methoxy-3-nitrobenzene (3 g, 11.64 mmol), zinc metal (7.61 g, 116 mmol) and ammonium chloride (6.22 g, 116 mmol) And water (7.14 mL) was stirred overnight. The reaction was then diluted with dichloromethane (200 mL) and filtered. The filtrate (50 mL) was washed with water, dried (sodium sulfate) and concentrated. The material was redissolved in methylene chloride and loaded onto a 80 g silica gel column column for purification by flash chromatography with 0-100percent EtOAc in hexanes.A solution of 3-bromo-2-methoxyaniline (2.11 g, 9.92 mmol, 85percent yield) was obtained as a colorless oil.
73%	With ammonia; zinc In ethanol; water at 0 - 26℃; for 2 h;	suspension of l-bromo-2-methoxy-3-nitrobenzene (Intermediate 17, 4.45 g, 19.2 mmol) in15 mL EtOH and 20 mL 30percent NH₄OH solution was cooled to 0 ⁰C with stirring and zinc powder (6.3 g, 95.9 mmol) was added in portions to give a gray/yellow mixture. This was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was filtered through Celite and the filter cake washed with EtOAc until the filtrate was colorless. The filtrate was washed with saturated NaHCO₃ solution, the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were washed once with brine, dried over sodium sulfate and concentrated under reduced pressure to give a red/orange oil. <n="51"/>Chromatography on silica gel eluting with a gradient of 0 to 30percent ethyl acetate in hexanes gave 2.8 g (73percent) of the title compound as an orange oil.MS (ES): 202 / 204 (M+t) for C₇H₈BrNO¹H-NMR fCDCU δ: ppm 3.82 (s, 3H); 3.85 (s, 2H); 6.64 - 6.69 (m, IH); 6.77 (t, IH); 6.87 -6.92 (m, IH).

Reference： [1] Patent: EP2987787, 2016, A1, . Location in patent: Paragraph 0131
[2] Patent: WO2014/74661, 2014, A1, . Location in patent: Paragraph 00173
[3] Patent: US2014/296229, 2014, A1, . Location in patent: Paragraph 0258; 0259
[4] Patent: WO2014/154760, 2014, A1, . Location in patent: Page/Page column 55-56
[5] Patent: WO2018/75937, 2018, A1, . Location in patent: Paragraph 00487; 00495; 00496
[6] Patent: WO2015/69310, 2015, A1, . Location in patent: Paragraph 00185
[7] Patent: TWI582077, 2017, B, . Location in patent: Page/Page column 87
[8] Patent: WO2008/120003, 2008, A1, . Location in patent: Page/Page column 49-50
[9] Journal of the American Chemical Society, 1934, vol. 56, p. 1787,1790
[10] Patent: WO2010/125103, 2010, A1, . Location in patent: Page/Page column 79

2
[ 67-56-1 ]
[ 28165-50-6 ]
[ 116557-46-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 25℃; for 1.08333 h;	Preparation 22Stepl[00236j To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at room temperature was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, diisopropylazodicarboxylate (DIAD, 12.41 mL, 63.8 mmol) was then added dropwise via syringe over 5 minutes. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluent. Fractions containing the major UV-active productwere combined and concentrated under vacuum to afford 2.35 g (55percent) of a dark brown oil as the desired product. HPLC (Method N) RT = 1.33 minutes. LCMS MH+ 202/204 (observed bromide isotope pattern).
55%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 1 h;	Step 4 To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, DIAD (12.41 mL, 63.8 mmol) was then added dropwise via syringe over ~5 min. (exothermic). After the addition was complete, the reaction which had warmed due to the exothermic reaction was allowed to stir at rt for ~1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluant. Fractions containing the major uv active product were combined and concentrated under vacuum to afford 2.35 g (55percent) of a dark brown oil as the desired product. HPLC (method N) RT = 1.33 min. LCMS MH+ 202/204 (observed bromide isotope pattern).
55%	Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; for 1 h;	To a slurry of 2-amine-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 Mmol).After stirring for several minutes, DIAD (12.41 mL, 63.8 mmol) (exotherm) was added dropwise via the syringe over about 5 minutes. After the addition was complete, the reaction, which had been heated by the exothermic reaction, was stirred for about 1 h at rt. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by flash chromatography on silica gel using hexane / ethyl acetate as the eluent. The fractions containing the major product of uv activity were combined and concentrated in vacuo to afford 2.35 g (55percent) of the desired product as a dark brown oil.

Reference： [1] Patent: WO2014/74660, 2014, A1, . Location in patent: Paragraph 00236
[2] Patent: WO2015/69310, 2015, A1, . Location in patent: Paragraph 00176
[3] Patent: TWI582077, 2017, B, . Location in patent: Page/Page column 82; 83

3
[ 13073-25-1 ]
[ 74-88-4 ]
[ 116557-46-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h; Stage #2: With ammonium chloride; zinc In ethanol at 20℃; for 6 h;	[00162] Intermediate 9A. 3-Bromo-2-methoxyaniline: Potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (2.86 mL, 46.8 mmol) were added to a solution of 2- bromo-6-nitrophenol (5.10 g, 23.4 mmol) in DMF (100 mL) at room temperature and the resulting reaction mixture was stirred for 16 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (500 mL). The aqueous layer was extracted with EtOAc. The combined organics were washed with saturated aHC03 solution and brine, dried over MgS04, filtered, and evaporated. The crude was dissolved in EtOH (100 mL) and zinc (15.30 g, 233.9 mmol) and ammonium chloride (12.52 g, 233.9 mmol) were added. The reaction mixture was stirred at room temperature for 6 h. The reaction was diluted with EtOAc, filtered through CELITE®, and evaporated. The crude was purified by flash chromatography (10-20percent EtOAc/hexanes) to give Intermediate 9A (4.6 g, 97percent) as a yellow oil. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 1.38 min (Method A).

Reference： [1] Patent: WO2014/22343, 2014, A1, . Location in patent: Paragraph 00162

4
[ 13073-25-1 ]
[ 116557-46-1 ]

Reference： [1] Journal of the American Chemical Society, 1934, vol. 56, p. 1787,1790
[2] Patent: WO2014/74661, 2014, A1,
[3] Patent: WO2014/154760, 2014, A1,
[4] Patent: WO2015/69310, 2015, A1,
[5] Patent: EP2987787, 2016, A1,
[6] Patent: TWI582077, 2017, B,
[7] Patent: WO2008/120003, 2008, A1,

5
[ 578-57-4 ]
[ 116557-46-1 ]

Reference： [1] Journal of the American Chemical Society, 1934, vol. 56, p. 1787,1790

[ 116557-46-1 ] Synthesis Path-Downstream 1~85

1
[ 116557-46-1 ]
[ 860584-68-5 ]

Reference： [1]Journal of the American Chemical Society,1934,vol. 56,p. 1787,1790

2
[ 98775-19-0 ]
[ 116557-46-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With iron; acetic acid; In water; at 80℃; for 1.5h;	A mixture of 1-bromo-2-methoxy-3-nitrobenzene (20.1 g, 86.6 mmol) and iron powder (33.4 g, 598 mmol) in acetic acid/water (1:1, 600 mL) was heated to 80C for 1.5 hours. After the mixture was cooled and filtered, the solid was washed with ethyl acetate and water. The organic layer was washed with saturated aqueous NaHCO3, dried, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to give 3-bromo-2-methoxyphenylamine as yellow solid (17.4 g, yield 99%).1H-NMR Spectrum (300MHz, DMSO-d6):delta (ppm): 3.66 (s, 3H), 5.23 (s, 2H), 6.64-6.76 (m, 3H)
96%	With ammonium chloride; zinc; In ethanol; water; for 1h;	Step 2[00173j Int9 (5.12 g, 22.1 mmol) was dissolved in ethyl alcohol (150 mL) and water (50 mL). To this was added zinc (5.77 g, 88 mmol) and ammonium chloride (2.36 g, 44.1 mmol). The reaction was stirred for 1 hour, filtered and then concentrated. The crudematerial was dissolved in ethyl acetate and washed with water three times, the organic layer was then dried over sodium sulfate, filtered, concentrated and collected (4.3 g, 96%). LC retention time 0.75 [J]. m/z: 201.8 (MHj.
96%	With hydrogenchloride; tin(ll) chloride; In tetrahydrofuran; at 80℃; for 16h;	A mixture of 1-Bromo-2-methoxy-3-nitro-benzene (17.8 g, 0.0768 mol), SnCl2 (69.27 g, 0.3069 mol) and 4N HCl (80 mL) in THF (200 mL) is stirred at 80 C. for 16 h. After reaction, evaporated out THF and added NaHCO3 solution, filtered and the filtrate is extracted with ethyl acetate (3×800 mL). The combined organic phase is ished with water and brine, dried over Na2SO4, concentrated in vacuo to give the desired product. Yield: 14.8 g (96%). HPLC-MS: M+H=202/204; tRet=1.49 min; AM12

96%	With hydrogenchloride; tin(ll) chloride; In tetrahydrofuran; at 80℃; for 16h;	3-Bromo-2-methoxy-phenylamine A mixture of l-Bromo-2-methoxy-3-nitro-benzene (17.8 g, 0.0768 mol), SnCl2 (69.27 g, 0.3069 mol) and 4N HC1 (80 mL) in THF (200 mL) is stirred at 80 C for 16h. After reaction, evaporated out THF and added NaHC03 solution, filtered and the filtrate is extracted with ethyl acetate (3 x 800 mL). The combined organic phase is ished with water and brine, dried over Na2S04, concentrated in vacuo to give the desired product. Yield: 14.8 g (96%). HPLC-MS: M+H=202/204; tRet =1.49 min; AM12
91.87%	With iron; acetic acid; at 120℃; for 4h;	To a solution of bromo-2-methoxy-3-nitrobenzene 1 (lOg, 43.lmmol, 1.Oeq) in acetic acid (lOOmL), iron powder (12.03g, 215.5mmol, 5.Oeq) was added portion wise. Reaction mixture was stirred at 120C for 4h. After completion of the reaction, the reaction mixture was filtered, concentrated in vacuo to obtain residue which was transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 55.1 (8g, 91.87%). MS(ES): m/z 203.49 [M+H]t (E)N-((dimethylamino)methyl ene)acetamide
85%	With ammonium chloride; zinc; In ethanol; water; at 20℃;	A mixture of l-bromo-2-methoxy-3-nitrobenzene from Step 1 (3 g, 11.64 mmol), zinc metal (7.61 g, 116 mmol) and ammonium chloride (6.22 g, 116 mmol) in EtOH (50 mL) and water (7.14 mL) was stirred at rt overnight. The reaction was then diluted with dichloromethane (200 mL), and filtered. The filtrate was washed with water (50 mL), dried (sodium sulfate), and concentrated. Redissolved this material in dichloromethane, and loaded onto a 80g silica gel column for purification by flash chromatography, eluting with 0-100% EtOAc in hexanes. Afforded 3-bromo-2- methoxyaniline (2.11 g, 9.92 mmol, 85% yield) as a colorless oil.
85%	With ammonium chloride; zinc; In water; at 20℃;	In rt will come from step 11-bromo-2-methoxy-3-nitrobenzene (3 g, 11.64 mmol), zinc metal (7.61 g, 116 mmol) and ammonium chloride (6.22 g, 116 mmol) And water (7.14 mL) was stirred overnight. The reaction was then diluted with dichloromethane (200 mL) and filtered. The filtrate (50 mL) was washed with water, dried (sodium sulfate) and concentrated. The material was redissolved in methylene chloride and loaded onto a 80 g silica gel column column for purification by flash chromatography with 0-100% EtOAc in hexanes.A solution of 3-bromo-2-methoxyaniline (2.11 g, 9.92 mmol, 85% yield) was obtained as a colorless oil.
73%	With ammonia; zinc; In ethanol; water; at 0 - 26℃; for 2h;	suspension of l-bromo-2-methoxy-3-nitrobenzene (Intermediate 17, 4.45 g, 19.2 mmol) in15 mL EtOH and 20 mL 30% NH4OH solution was cooled to 0 0C with stirring and zinc powder (6.3 g, 95.9 mmol) was added in portions to give a gray/yellow mixture. This was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was filtered through Celite and the filter cake washed with EtOAc until the filtrate was colorless. The filtrate was washed with saturated NaHCO3 solution, the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were washed once with brine, dried over sodium sulfate and concentrated under reduced pressure to give a red/orange oil. <n="51"/>Chromatography on silica gel eluting with a gradient of 0 to 30% ethyl acetate in hexanes gave 2.8 g (73%) of the title compound as an orange oil.MS (ES): 202 / 204 (M+t) for C7H8BrNO1H-NMR fCDCU delta: ppm 3.82 (s, 3H); 3.85 (s, 2H); 6.64 - 6.69 (m, IH); 6.77 (t, IH); 6.87 -6.92 (m, IH).
		(vi) To a stirred mixture of tin(iotaiota) chloride (62.11 g, 0.328 mol) in methanol (300 ml.) and concentrated hydrochloric acid (150 ml.) at 00C was added in a single portion 1- bromo-2-methoxy-3-nitrobenzene (15.2 g, 66.0 mmol). The resultant reaction mixture was stirred at room temperature overnight, ethyl acetate (500 ml.) was added, and the mixture was made basic with the addition of 5 M aqueous sodium hydroxide. A further aliquot of ethyl acetate (500 ml.) was added, the layers were allowed to separate, and the organic fraction was separated. The resultant mixture was then further extracted with ethyl acetate (2chi). The combined organic layers were washed with water and brine, dried (magnesium sulfate), and the solvent was removed in vacuo to give 3-bromo-2-methoxy-aniline (12.8 g) as a pale tan oil. Rf 0.18 (1 :3 ethyl acetate/hexane).

Reference： [1]Patent: EP2987787,2016,A1 .Location in patent: Paragraph 0131
[2]Patent: WO2014/74661,2014,A1 .Location in patent: Paragraph 00173
[3]Patent: US2014/296229,2014,A1 .Location in patent: Paragraph 0258; 0259
[4]Patent: WO2014/154760,2014,A1 .Location in patent: Page/Page column 55-56
[5]Patent: WO2018/75937,2018,A1 .Location in patent: Paragraph 00487; 00495; 00496
[6]Patent: WO2015/69310,2015,A1 .Location in patent: Paragraph 00185
[7]Patent: TWI582077,2017,B .Location in patent: Page/Page column 87
[8]Patent: WO2008/120003,2008,A1 .Location in patent: Page/Page column 49-50
[9]Journal of the American Chemical Society,1934,vol. 56,p. 1787,1790
[10]Patent: WO2010/125103,2010,A1 .Location in patent: Page/Page column 79

3
[ 578-57-4 ]
[ 116557-46-1 ]

Reference： [1]Journal of the American Chemical Society,1934,vol. 56,p. 1787,1790

4
[ 13073-25-1 ]
[ 116557-46-1 ]

Reference： [1]Journal of the American Chemical Society,1934,vol. 56,p. 1787,1790
[2]Patent: WO2014/74661,2014,A1
[3]Patent: WO2014/154760,2014,A1
[4]Patent: WO2015/69310,2015,A1
[5]Patent: EP2987787,2016,A1
[6]Patent: TWI582077,2017,B
[7]Patent: WO2008/120003,2008,A1

5
[ 116557-46-1 ]
3'-bromo-6-nitro-2'-methoxy-biphenyl-carboxylic acid-⁽²⁾ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1934,vol. 56,p. 1787,1790

6
[ 6191-99-7 ]
[ 116557-46-1 ]
[ 928627-14-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With pyridine; at 0℃; for 1h;	(E)-N-(3-Bromo-2-methoxyphenyl)-3-ethoxyacrylamide (3c) A mixture of <strong>[116557-46-1]3-bromo-o-anisidine</strong> (2c) (4.50 g, 22.3 mmoles) and pyridine (15 mL) was placed in an icebath. (E)-3-ethoxy-2-propenoyl chloride (1) (3.75 g, 27.9 mmol) was added dropwise as the solution stirred continuously for one hour. The mixture was concentrated to remove the pyridine and was transferred to a seperatory funnel where AcOEt and water were added. Concentrated HCl was added until the aqueous layer was pH 1. The water layer was extracted twice with AcOEt and the organic layers were washed with saturated NaCl (25 mL) containing 1 M HCl (2 mL). The procedure was followed by a second wash of saturated NaCl (25 mL) containing saturated NaHCO3 (5 mL). The organic layer was finally washed with saturated NaCl (25 mL). The product layer was dried and filtered through silica gel (2) using a solvent system of 1:1 followed by 2:1 hexanes-AcOEt. The product was chromatographed (2:1 1:1 hexanes:AcOEt) and recrystallized from 10:1 hexanes-AcOEt to afford light brown-orange crystals (3.35 g, 50% yield): mp 102-104 C.; 1H NMR (400 MHz, CDCl3) 8.35 (dd, J=8.4, 1.6 Hz, 1H), 7.65 (d, J=12.4 Hz, 1H), 7.52 (bs, 1H), 7.21 (dd, J=8.4, 1.6 Hz, 1H), 6.98 (t, J=8.4 Hz, 1H), 5.36 (d, J=12.0 Hz, 1H), 3.97 (q, J=7.2 Hz, 2H), 3.86 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).
50%	With pyridine; at 0℃; for 1h;	(E)-N-(3-Bromo-2-methoxyphenyl)-3-ethoxyacrylamide (3c); A mixture of <strong>[116557-46-1]3-bromo-o-anisidine</strong> (2c) (4.50 g, 22.3 mmoles) and pyridine (15 mL) was placed in an icebath. (E)-3-ethoxy-2-propenoyl chloride (1) (3.75 g, 27.9 mmol) was added dropwise as the solution stirred continuously for one hour. The mixture was concentrated to remove the pyridine and was transferred to a seperatory funnel where AcOEt and water were added. Concentrated HCl was added until the aqueous layer was pH 1. The water layer was extracted twice with AcOEt and the organic layers were washed with saturated NaCl (25 mL) containing 1 M HCl (2 mL). The procedure was followed by a second wash of saturated NaCl (25 mL) containing saturated NaHCO3 (5 mL). The organic layer was finally washed with saturated NaCl (25 mL). The product layer was dried and filtered through silica gel (2) using a solvent system of 1:1 followed by 2:1 hexanes-AcOEt. The product was chromatographed (2:1 1:1 hexanes:AcOEt) and recrystalized from 10:1 hexanes-AcOEt to afford light brown-orange crystals (3.35 g, 50% yield): mp 102-104 C; 1H NMR (400 MHz, CDCl3) 8.35 (dd, J=8.4, 1.6 Hz, 1H), 7.65 (d, J=12.4 Hz, 1H), 7.52 (bs, 1H), 7.21 (dd, J=8.4, 1.6 Hz, 1H), 6.98 (t, J=8.4 Hz, 1H), 5.36 (d, J=12.0 Hz, 1H), 3.97 (q, J=7.2 Hz, 2H), 3.86 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).

Reference： [1]Patent: US2007/54938,2007,A1 .Location in patent: Page/Page column 7
[2]Patent: US2007/60612,2007,A1 .Location in patent: Page/Page column 6

7
[ 6192-01-4 ]
[ 116557-46-1 ]
[ 928627-14-9 ]

Yield	Reaction Conditions	Operation in experiment
47%		A solution of (E)-3-ethoxyacrylic acid (2.25 g, 19.4 mmol) in dry chloroform (100 mL) was cooled to 0 0C with stirring and a 2M solution of oxalyl chloride in dichloromethane (19.4 mL, 38.8 mmol) was added slowly over five minutes. Catalytic N,N-dimethylformamide (1-2 drops) was added, and the resulting pale yellow solution was allowed to warm to ambient temperature, and then was heated to reflux during which a large amount of gas evolved. After stirring for one hour, the solution was cooled and concentrated, redissolved in 25 mL dry chloroform, and added slowly to a stirred, ice-cold solution of <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (Intermediate 16 (Prepared as described in J. Am. Chem. Soc. 56, 1934, 1787), 2.8 g, 13.9 mmol) and pyridine (3.4 mL, 41.6 mmol) in chloroform (75 mL). The pH of the resulting orange solution was adjusted to alkaline with additional pyridine, and the solution stirred at ambient temperature overnight. The resulting orange solution was washed 3x with IN HCl, once with saturated NaHCO3 solution, then brine; dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel eluting with a gradient of 0 to 30% ethyl acetate in hexanes and concentration under reduced pressure gave the product as a yellow solid, which was recrystallized from 2-propanol / water to give 1.96 g (47%) of the title compound as off-white needles.MSJES): 300 / 302 (M+H+) for Ci2Hi4BrNO3 and 322.0 / 324.0 (M+Na*)1H-NMR fPMSO-dc) delta: ppm 1.28 (t, 3H); 3.73 (s, 3H); 3.95 (q, 2H); 5.95 (d, IH); 7.03 (t,IH); 7.30 (dd, IH); 7.49 (d, IH); 8.14 (dd, IH); 9.25 (s, IH).

Reference： [1]Patent: WO2008/120003,2008,A1 .Location in patent: Page/Page column 49

8
[ 1253380-72-1 ]
[ 116557-46-1 ]
[ 1253379-98-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 0 - 80℃;Molecular sieve;	Example 75 1-[3-Bromo-2-(methyloxy)phenyl]-4-[(2-chloro-4-fluorophenyl)methyl]-2,3- piperazinedione (E75) Methyl [[(2-chloro-4-fluorophenyl)methyl](2-oxoethyl)amino](oxo)acetate (0.57 g, 1.98 mmol, prepared as described earlier), acetic acid (0.45 ml, 7.92 mmol), and 4A molecular sieves in 1 ,2-dichloroethane (10 ml) were cooled to 00C. 3-Bromo-2- (methyloxy)aniline (0.40 g, 1.98 mmol) was added and the reaction was stirred for 10 minutes. Sodium triacetoxyborohydride (0.63 g, 2.97 mmol) was added, the reaction allowed to warm to room temperature and stirred overnight. The reaction was then heated to 800C for 4 hours. The reaction mixture was allowed to cool and saturated aqueous sodium bicarbonate was added until gas evolution stopped. The organic layer was separated and the aqueous layer extracted with dichloromethane. The organic layers were separated using a hydrophobic frit and concentrated in vacuo. The residue was purified by flash-silica gel chromatography, eluting with a 10-100% gradient if ethyl acetate in isohexane to give 1-[3-bromo-2-(methyloxy)phenyl]-4-[(2- chloro-4-fluorophenyl)methyl]-2,3-piperazinedione (0.28 g) as a light brown solid. LC/MS [M+H]+ = 440.97, retention time = 2.86 minutes.

Reference： [1]Patent: WO2010/125103,2010,A1 .Location in patent: Page/Page column 76-77

9
[ 1304581-32-5 ]
[ 116557-46-1 ]
C₁₉H₂₂BrNO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; for 16h;	General Procedure: Methyl 2-[4-(chlorosulfonyl)-2,3-dimethylphenyl]oxy}propanoate (7) (4 g, 13.0 mmol) was dissolved in pyridine (10 mL). After 5 min, 3-bromo-2-chloroaniline (3.22 g, 15.6 mmol) was added. The reaction was complete within a few hours. The reaction mixture was then extracted using diethyl ether. The combined organic phases were washed with 1N HCl and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound which was used without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2345 - 2350

10
[ 116557-46-1 ]
C₂₃H₃₀BrNO₆S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2345 - 2350

11
[ 116557-46-1 ]
C₂₂H₂₈BrNO₆S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2345 - 2350

12
[ 116557-46-1 ]
[ 1304581-92-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2345 - 2350

13
[ 116557-46-1 ]
[ 1261448-77-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 603 - 607

14
[ 116557-46-1 ]
C₁₇H₂₈N₂O₄S [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 603 - 607

15
[ 116557-46-1 ]
[ 1261794-09-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 603 - 607

16
[ 529-28-2 ]
[ 116557-46-1 ]
[ 1449428-31-2 ]

Reference： [1]Dalton Transactions,2013,vol. 42,p. 11824 - 11830

17
[ 529-28-2 ]
[ 116557-46-1 ]
[ 1449428-28-7 ]

Reference： [1]Dalton Transactions,2013,vol. 42,p. 11824 - 11830

18
[ 13073-25-1 ]
[ 74-88-4 ]
[ 116557-46-1 ]

Yield	Reaction Conditions	Operation in experiment
97%		[00162] Intermediate 9A. 3-Bromo-2-methoxyaniline: Potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (2.86 mL, 46.8 mmol) were added to a solution of 2- bromo-6-nitrophenol (5.10 g, 23.4 mmol) in DMF (100 mL) at room temperature and the resulting reaction mixture was stirred for 16 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (500 mL). The aqueous layer was extracted with EtOAc. The combined organics were washed with saturated aHC03 solution and brine, dried over MgS04, filtered, and evaporated. The crude was dissolved in EtOH (100 mL) and zinc (15.30 g, 233.9 mmol) and ammonium chloride (12.52 g, 233.9 mmol) were added. The reaction mixture was stirred at room temperature for 6 h. The reaction was diluted with EtOAc, filtered through CELITE, and evaporated. The crude was purified by flash chromatography (10-20% EtOAc/hexanes) to give Intermediate 9A (4.6 g, 97%) as a yellow oil. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 1.38 min (Method A).

Reference： [1]Patent: WO2014/22343,2014,A1 .Location in patent: Paragraph 00162

19
[ 116557-46-1 ]
[ 1555699-65-4 ]

Reference： [1]Patent: WO2014/22343,2014,A1

20
[ 116557-46-1 ]
[ 1388032-47-0 ]

Yield	Reaction Conditions	Operation in experiment
95.28%		To compound 54.1 (6.35g, 31.7mmol, 1.Oeq) in 6NHC1 (l2OmL) at 0 C, sodium nitrite (2.4g, 34.9mmol, 1.leq) in water was added. Reaction mixture was stirred at 0C for 30mm. Then tin chloride (21.45g, 95mmol, 3.Oeq) in conc. HC1 (31.75mL) was added to the reaction mixture and stirred at 0 C for further 2h. After completion of the reaction, solid obtained in the reaction mixture was filtered, washed with conc. HC1 and dried to obtain 54.2 (6.5g, 95.28%). MS (ES): m/z 252.47 [M+H]t
42%		[00163] Intermediate 9B. (3-Bromo-2-methoxyphenyl)hydrazine: A suspension of Intermediate 9A (4.0 g, 20 mmol) in 6 M HC1 was cooled to -10 C and a solution of sodium nitrite (1.41 g, 20.8 mmol) in water (5 mL) was added slowly to keep the temperature below 0 C. After the addition, the reaction was stirred for additional 20 min at -10 C. A solution of tin (II) chloride (11.26 g, 59.39 mmol) in cone. HC1 (20 mL) was added slowly, resulting in precipitation. After 30 min, the precipitate was filtered, washed with cone. HC1 and then water, suspended in 10% NaOH solution, and extracted with EtOAc. The combined organics were dried over MgS04, filtered, and evaporated to give Intermediate 9B (1.8 g, 42%), which was used directly in the next step. LCMS (ESI) m/z 200, 202 (M-NH3+H, M-NH3+2+H)+, RT = 1.09 min (Method A).

Reference： [1]Patent: WO2018/75937,2018,A1 .Location in patent: Paragraph 00486; 00488
[2]Patent: WO2014/22343,2014,A1 .Location in patent: Paragraph 00163

21
[ 116557-46-1 ]
[ 1555699-62-1 ]

Reference： [1]Patent: WO2014/22343,2014,A1

22
[ 67-56-1 ]
[ 28165-50-6 ]
[ 116557-46-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; for 1.08333h;	Preparation 22Stepl[00236j To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at room temperature was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, diisopropylazodicarboxylate (DIAD, 12.41 mL, 63.8 mmol) was then added dropwise via syringe over 5 minutes. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluent. Fractions containing the major UV-active productwere combined and concentrated under vacuum to afford 2.35 g (55%) of a dark brown oil as the desired product. HPLC (Method N) RT = 1.33 minutes. LCMS MH+ 202/204 (observed bromide isotope pattern).
55%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h;	Step 4 To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, DIAD (12.41 mL, 63.8 mmol) was then added dropwise via syringe over ~5 min. (exothermic). After the addition was complete, the reaction which had warmed due to the exothermic reaction was allowed to stir at rt for ~1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluant. Fractions containing the major uv active product were combined and concentrated under vacuum to afford 2.35 g (55%) of a dark brown oil as the desired product. HPLC (method N) RT = 1.33 min. LCMS MH+ 202/204 (observed bromide isotope pattern).
55%		To a slurry of 2-amine-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 Mmol).After stirring for several minutes, DIAD (12.41 mL, 63.8 mmol) (exotherm) was added dropwise via the syringe over about 5 minutes. After the addition was complete, the reaction, which had been heated by the exothermic reaction, was stirred for about 1 h at rt. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by flash chromatography on silica gel using hexane / ethyl acetate as the eluent. The fractions containing the major product of uv activity were combined and concentrated in vacuo to afford 2.35 g (55%) of the desired product as a dark brown oil.

Reference： [1]Patent: WO2014/74660,2014,A1 .Location in patent: Paragraph 00236
[2]Patent: WO2015/69310,2015,A1 .Location in patent: Paragraph 00176
[3]Patent: TWI582077,2017,B .Location in patent: Page/Page column 82; 83

23
[ 116557-46-1 ]
[ 761446-44-0 ]
[ 1609531-35-2 ]

Yield	Reaction Conditions	Operation in experiment
77%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;	[00238j To a reaction vial charged with <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (1.12 g, 5.54mmol), 1 -methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (1.499 g,7.21 mmol) in dioxane (6 mL) was added aqueous potassium phosphate (2.0 M) (5.54 ml,11.09 mmol). The resulting mixture was deoxygenated by bubbling argon through themixture for 5 minutes. [1,1 ?-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)(PdC12(dppf), 0.122 g, 0.166 mmol) was then added and the mixture was heated at 110 Cfor 2 hours. The reaction was cooled, diluted with ethyl acetate (200 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford tan oil as the crude product mixture. This material was purified by silica gel flash chromatography using hexanes/ethyl acetate mixtures as the eluent. Fractions containingthe desired product were collected, combined, and concentrated under vacuum to afford0.87 g (77%) of the desired product as an oil which solidified upon standing. HPLC (Method N) = 0.89 minutes. LCMS MH+ 204.1.
77%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;	Preparation 10 To a reaction vial charged with <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (from Step 4 of Preparation 9, 1.12 g, 5.54 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (1.499 g, 7.21 mmol) in dioxane (6 mL) was added aqueous potassium phosphate (2.0 M) (5.54 ml, 11.09 mmol). The resulting mixture was deoxygenated by bubbling argon through the mixture for ~5 min. PdCl2(dppf) (0.122 g, 0.166 mmol) was then added and the mixture was heated at 110 C for 2h. The reaction was cooled, diluted with EtOAc (200 mL), washed with water, brine, dried over anhyd sodium sulfate, filtered and concentrated to afford tan oil as the crude product mixture. This material was purified by silica gel flash chromatography using hexanes/ethyl acetate mixtures as the eluant. Fractions containing the desired product were collected, combined, and concentrated under vacuum to afford 0.87 g (77%) of the desired product (Preparation 10) as an oil which solidified upon standing. HPLC (method N) = 0.89 min. LCMS MH+ 204.1.
77%	In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere;	To a solution containing dioxane (6 mL)<strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (from Step 4 of Preparation 9, 1.12 g, 5.54 mmol), 1-methyl-4- (4,4,5,5-tetramethyl- ,2-Dioxaborolan-2-yl) -lH-pyrazole (1.499 g, 7.21 mmol)(2.0 M) (5.54 ml, 11.09 mmol) was added to the reaction vial.The mixture was removed by bubbling argon through the resulting mixture for about 5 min.PdCl2 (dppf) (0.122 g, 0.166 mmol) was then added and the mixture was heated at 110 & lt; 0 & gt; C for 2 h.The reaction was cooled, diluted with EtOAc (200 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a crude product mixture as a tan oil. The material was purified by flash chromatography using silica gel using a hexane / ethyl acetate mixture as a solvate. The fractions containing the desired product were collected, combined and concentrated in vacuo to afford 0.87 g (77%) of the desired product in the form of an oil (Preparation 10)It solidifies after standing.

Reference： [1]Patent: WO2014/74660,2014,A1 .Location in patent: Paragraph 00238
[2]Patent: WO2015/69310,2015,A1 .Location in patent: Paragraph 00178
[3]Patent: TWI582077,2017,B .Location in patent: Page/Page column 84

24
[ 1029716-44-6 ]
[ 116557-46-1 ]
[ 1609394-38-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere;	Step 4[00252j To a reaction vial charged with 3-bromo-2-methoxyaniline (0.30 g, 1.485 mmol) and 1 -(1 -ethoxyethyl)-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (0.43 5 g, 1.633 mmol) in dioxane (2 ml) was added 2 M aqueous potassium phosphate (1.485 ml, 2.97 mmol) and the resulting mixture was deoxygenated by bubbling argon through the mixture for 5 mi PdC12(dppf) (0.033 g, 0.045 mmol) was then added and the mixture was heated at 110 C for 3h. The reaction was cooled, dilutedwith EtOAc (100 mL), washed with water then brine and dried over sodium sulfate. The resulting dried solution was filtered and concentrated to afford a black oil which was purified via silica gel flash column chromatography using a gradient elution of ethyl acetate in hexanes. Fractions containing the desired product were concentrated under vacuum to afford 3 -(1 -(1 -ethoxyethyl)- 1 H-pyrazol-4-yl)-2-methoxyaniline (355 mg,1.358 mmol, 91% yield) as an oil which solidified upon standing. HPLC Peak RT = 1.58 mm. and MS (m+1) = 262.1.
91%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere;	Step 5 To a reaction vial charged with 3-bromo-2-methoxyaniline from Step 4 (0.30 g, 1.485 mmol) and l-(l-ethoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole from Step 3 (0.435 g, 1.633 mmol) in dioxane (2 ml) was added aqueous potassium phosphate (2.0 M) (1.485 ml, 2.97 mmol). The resulting mixture was deoxygenated by bubbling argon through the mixture for ~5 min. PdCl2(dppf) (0.033 g, 0.045 mmol) was then added and the mixture was heated at 110 C for 3h then cooled to rt. The resulting mixture was diluted with EtOAc (100 mL), washed with water, brine, dried over anhyd sodium sulfate, filtered and concentrated to afford a black oil as the crude product mixture. This material was purified by silica gel flash chromatography using hexanes/ethyl acetate solvent mixtures as the eluant. Fractions containing the major uv active component were collected and combined then concentrated under vacuum to afford the desired product, Preparation 9 (355 mg, 1.358 mmol, 91%> yield) as an oil which solidified upon standing. HPLC (method N) RT = 1.58 min. LCMS (m+1) = 262.1.
91%	With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); tripotassium phosphate; In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere;	To a solution of 3-bromo-2-methoxyaniline (0.30 g, 1.485 mmol) from step 4 in dioxane (2 mL)And from the steps(1-ethoxyethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- Pyrazole (0.435 g, 1.633 mmol)(2.0 M) (1.485 ml, 2.97 mmol) was added to the reaction vial.The mixture was removed by bubbling argon through the resulting mixture for about 5 min. PdCl2 (dppf) (0.033 g, 0.045 mmol) was then added and the mixture was heated at 110 & lt; 0 & gt; C for 3 h and then cooled to rt. The resulting mixture was diluted with EtOAc (100 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a black oil as a crude product mixture. The material was purified by silica gel flash chromatography using a hexane / ethyl acetate solvent mixture as a resolver. The fractions containing the major components of the uv activity were collected and combined and then concentrated in vacuo to afford the desired product in the form of an oil (Preparation 9) (355 mg, 1.358 mmol, 91% yield) which solidified upon standing.

Reference： [1]Patent: WO2014/74661,2014,A1 .Location in patent: Paragraph 00252
[2]Patent: WO2015/69310,2015,A1 .Location in patent: Paragraph 00177
[3]Patent: TWI582077,2017,B .Location in patent: Page/Page column 83; 84

25
[ 116557-46-1 ]
[ 1609393-91-0 ]

Reference： [1]Patent: WO2014/74661,2014,A1

26
[ 116557-46-1 ]
[ 73183-34-3 ]
[ 1609393-90-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	Step 3[00174j IntlO (2.0 g, 9.9 mmol) was dissolved in dioxane (40 mL) and the vessel purged with nitrogen for 5 minutes. Next bis(pinacolato)diborone (3.77 g, 14.85 mmol), [1,1 ?-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (404 mg, 0.49 mmol) and potassium acetate (2.91 g, 29.7 mmol) were added. The flask was evacuated and backfilled with nitrogen, and then heated to 100 Cfor 15 hours. Water was added to quench the reaction and the product was then extracted with EtOAc. The combined organic layers were washed with brine (x3), dried over sodium sulfate, filtered, concentrated and purified using automated chromatography (elutes at 40% ethyl acetate) to provide Intl 1 (2.0 g, 8 1%). ?H NMR (400MHz, chloroform-d) oe 7.12 (dd,J=7.3, 1.8 Hz, 1H), 6.96-6.89 (m, 1H), 6.88-6.83 (m, 1H),3.82 (s, 3H), 1.37 (s, 12H). LC retention time 0.65 [J]. m/z: 250 (MHj.
60.2%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;	Step 3 A solution of <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> from Step 2 (1.94 g, 9.60 mmol), 4,4,445,5,55'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.66 g, 14.40 mmol), PdCl2(dppf)-CH2Cl2 complex (0.392 g, 0.480 mmol) and potassium acetate (2.83 g, 28.8 mmol) in dioxane (32 mL) in a flask was heated to reflux (-100 C) overnight then cooled to room temperature, concentrated in vacuo on CELITE. This crude product was purified by flash chromatography using a 120g silica gel column (solid loading) eluting with 0-50% ethyl acetate/hexanes. Appropriate fractions (eluted near 25% EtOAc/hexanes) were collected and concentrated in vacuo to give 2-methoxy-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.47 g, 5.78 mmol, 60.2% yield) as a crystalline off-white solid. LCMS MH+ 250.1.
60.2%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;	In the flask will come from step 2<strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (1.94 g, 9.60 mmol)4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)(3.66 g, 14.40 mmol),PdCl2 (dppf) -CH2Cl2 (0.392 g, 0.480 mmol) and potassium acetate (2.83 g, 28.8 mmol) in dioxane (32 mL)The solution was heated to reflux (about 100 & lt; 0 & gt; C) overnight,Then cooled to room temperature,Concentrated on diatomaceous earth in a vacuum.The crude product was purified by flash chromatography using 120 g of a silica gel column (solid loading) with 0-50% ethyl acetate / hexane. The appropriate fractions were collected (eluted with nearly 25% EtOAc / hexanes) and concentrated in vacuo,To give 2-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline in an off-white crystalline solid form (1.47 g , 5.78 mmol, 60.2% yield).

58%		A suspension of <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (500 mg, 2.47 mmol), bis(pinacolato)diboron (755 mg, 2.97 mmol) and potassium acetate (729 mg, 7.42 mmol) in 1,4-dioxane (8 mL) was sparged with nitrogen for 5 min. Pd(dppf)Cl2·DCM (173 mg, 0.21 mmol) was added and the mixture was heated under reflux for 2.5 h then cooled to room temperature. The reaction was diluted with DCM (35 mL) and washed with water (35 mL). The organic phase was concentrated under reduced pressure then purified by flash column chromatography, eluting with 0-100% EtOAc in isohexane, to return 49h (358 mg, 58%) an off-white solid. 1H NMR (300 MHz, DMSO-d6) delta 6.72-6.83 (m, 3H), 4.80 (s, 2H), 3.64 (s, 3H), 1.28 (s, 12H).
47%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere;	A 500 ml round-bottomed flask was charged with SI (6.61 g, 32.7 mmol), S2 (12.46 g, 49.1 mmol), Pd(dppfkCl2(l.05 g, 1.1 mmol), KOAc (9.62 g, 98.2 mmol) and l,4-dioxane (200 ml), degassed and refilled with N2. The resulting solution was heated to l00C under an N2 atmosphere and then stirred overnight. After cooled to room temperature, the solution was quenched with water (10 ml) and diluted with ethyl acetate (150 ml). The resulting mixture was washed with brine (3x100 ml), dried with Na2S04. After the solvent was removed in vacuo, the residue was subjected to flash column over silica gel eluting with ethyl acetate/hexane (1:3, v/v) to obtain compound S3 (3.83 g, 47%) as off-white solid. 1 H NMR (400 MHz, CDCb, ppm): d 7.11 (d, J = 7.1 Hz, 1H, ArH), 6.93 (t, J = 6.9 Hz, 1H, ArH), 6.86 (d, J = 6.9 Hz, 1H, ArH), 3.82 (br? 2H, NH2), 3.81 (s, 3H, OMe), 1.36 (s, 12H, Me); 13C NMR (lOOMHz, CDCb, ppm): d 152.7, 139.6, 126.1, 124.3, 119.1, 83.6, 24.9. The carbon directly attached to the boron atom was not detected, likely due to quadrapolar relaxation; HRMS (ESI) m/z 250.1614 [M + H]+calcd for C13H21BNO3, found 250.1609.
358 mg	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; for 2.5h;Inert atmosphere; Reflux;	[00239] 3-Bromo-2-methoxyaniline (500 mg, 2.47 mmol), bis(pinacolato)diboron (755 mg,2.97 mmol) and potassium acetate (728 mg, 7.42 mmol) were mixed in 1,4-dioxane (8 mL) and nitrogen gas was blown through for 5 minutes. 1,1-Bis(diphenyl-phosphino)ferrocene- palladium(ll)dichloride DCM adduct (173 mg, 0.21 mmol) was added and nitrogen blown through again. The mixture was heated under reflux conditions for 2.5 hours then allowed to cool (black mixture). Dl water and DCM were added (35mls of each) and the mixture wasstirred vigourously for 30 minutes then passed through a hydrophobic frit. The DCM phase was concentrated down to remove excess Dioxane then redissolved in minimum DCM and was purified by flash chromatography eluting with 0-100% ethyl acetate/isohexane over 40 minutes. Product containing fractions were concentrated down to give 2-methoxy-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)aniline as an off-white solid 358mg. [00240] 1H NMR (DMSO-d6): O 6.88 (m, 3H), 4.80 (bs, 2H), 3.64 (5, 3H), 1.29 (5, 12H).

Reference： [1]Patent: WO2014/74661,2014,A1 .Location in patent: Paragraph 00174
[2]Patent: WO2015/69310,2015,A1 .Location in patent: Paragraph 00186
[3]Patent: TWI582077,2017,B .Location in patent: Page/Page column 87; 88
[4]European Journal of Medicinal Chemistry,2016,vol. 112,p. 20 - 32
[5]Angewandte Chemie - International Edition,2018,vol. 57,p. 11924 - 11928
Angew. Chem.,2018,vol. 130,p. 12100 - 12104,5
[6]Patent: WO2019/226863,2019,A1 .Location in patent: Paragraph 39; 40; 41
[7]Patent: WO2015/79251,2015,A1 .Location in patent: Paragraph 00239; 00240

27
[ 116557-46-1 ]
6-bromo-7-methoxy-1H-indole-2,3-dione [ No CAS ]

Reference： [1]Patent: US2014/296229,2014,A1
[2]Patent: WO2014/154760,2014,A1

28
[ 116557-46-1 ]
2-amino-4-bromo-3-methoxybenzoic acid [ No CAS ]

Reference： [1]Patent: US2014/296229,2014,A1
[2]Patent: WO2014/154760,2014,A1

29
[ 116557-46-1 ]
4-bromo-2-iodo-3-methoxybenzoic acid [ No CAS ]

Reference： [1]Patent: US2014/296229,2014,A1
[2]Patent: WO2014/154760,2014,A1

30
[ 116557-46-1 ]
4-bromo-2-iodo-3-methoxybenzoic acid ethyl ester [ No CAS ]

Reference： [1]Patent: US2014/296229,2014,A1
[2]Patent: WO2014/154760,2014,A1

31
[ 116557-46-1 ]
5-bromo-4-methoxy-3-phenyl-3H-isobenzofuran-1-one [ No CAS ]

Reference： [1]Patent: US2014/296229,2014,A1
[2]Patent: WO2014/154760,2014,A1

32
[ 116557-46-1 ]
5-(dimethyl-1,2-oxazol-4-yl)-4-methoxy-3-phenyl-1,3-dihydro-2-benzofuran-1-one [ No CAS ]

Reference： [1]Patent: US2014/296229,2014,A1
[2]Patent: WO2014/154760,2014,A1

33
[ 302-17-0 ]
[ 116557-46-1 ]
N-(3-bromo-2-methoxyphenyl)-2-hydroxyiminoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogenchloride; hydroxylamine sulfate; sodium sulfate; In water; at 35 - 75℃; for 3.5h;	A mixture of 3-Bromo-2-methoxy-phenylamine (10 g, 0.05 mol), NH2OH*H2SO4 (48.73 g, 0.3 mol), conc. HCl (5 mL) in H2O (50 mL) is slowly added to the solution of chloral hydrate (9 g, 0.05 mol), Na2SO4 (42.18 g, 0.3 mol) in H2O (200 mL) then stirred at 35 C. for 1 h, 52 C. for 1.5 h, 75 C. for 1 h. After the reaction, the mixture is filtered and the solid is dried under vacuum to give the desired compound. Yield: 12.7 g (94%) HPLC-MS: M+H=273/275; tRet=1.65 min; AM12
94%	With hydrogenchloride; hydroxyammonium sulfate; sodium sulfate; In water; at 35 - 75℃; for 3.5h;	N-(3-Bromo-2-methoxy-phen l)-2-hydroxyimino-acetamide A mixture of 3-Bromo-2-methoxy-phenylamine (10 g, 0.05 mol), NH2OH H2S04 (48.73 g, 0.3 mol), cone. HC1 (5 mL) in H20 (50 mL) is slowly added to the solution of chloral hydrate (9 g, 0.05 mol), Na2S04 (42.18 g ,0.3 mol) in H20 (200 mL) then stirred at 35 C for lh, 52 C for 1.5h, 75 C for lh. After the reaction, the mixture is filtered and thesolid is dried under vacuum to give the desired compound. Yield: 12.7 g (94%) HPLC-MS: M+H=273/275; tRet =1.65 min; AM 12

Reference： [1]Patent: US2014/296229,2014,A1 .Location in patent: Paragraph 0261; 0262; 0263
[2]Patent: WO2014/154760,2014,A1 .Location in patent: Page/Page column 56

34
[ 25487-66-5 ]
[ 116557-46-1 ]
[ 1176777-76-6 ]

Yield	Reaction Conditions	Operation in experiment
1.8 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In ethanol; water; for 28h;Reflux;	A mixture of <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (3 g), 3-carboxyphenylboronic acid (2.94 g), bis(triphenylphosphine)palladium(II)chloride [PdCl2(PPh3)2] (0.30 g) and potassium carbonate (5.2 g) in ethanol (100 mL) and water (20 mL) was heated to about reflux temperature and stirred for about 28 hours. The hot mixture was filtered to remove the catalyst. The clear filtrate was concentrated under vacuum. To the residue, water (50 mL) and methanol (50 mL) was added, acidified to pH 3-5 using hydrochloric acid and stirred for about 30 minutes at about room temperature. The slurry was filtered, washed with n-hexane (50 mL) and dried in an oven at about 55 C. to about 60 C. for about 12 hours. Yield: 1.8 g 1H NMR (300 MHz in DMSO-d6): delta 8.08 (s, 1H), 7.89-7.92 (d, 1H), 7.73-7.75 (d, 1H), 7.51-7.56 (t, 1H), 6.87-6.92 (t, 1H), 6.72-6.74 (d, 1H), 6.50-6.53 (d, 1H), 3.27 (s, 3H)

Reference： [1]Patent: US2015/87845,2015,A1 .Location in patent: Paragraph 0192; 0193

35
[ 116557-46-1 ]
[ 376591-99-0 ]

Reference： [1]Patent: US2015/87845,2015,A1
[2]Patent: US2015/87845,2015,A1
[3]Patent: US2015/87845,2015,A1
[4]Patent: US2015/87845,2015,A1

36
[ 116557-46-1 ]
eltrombopag olamine [ No CAS ]

Reference： [1]Patent: US2015/87845,2015,A1
[2]Patent: US2015/87845,2015,A1
[3]Patent: US2015/87845,2015,A1
[4]Patent: US2015/87845,2015,A1

37
[ 116557-46-1 ]
3'-{2-[1-(ethoxycarbonyl)-2-oxopropylidene]hydrazino}-2'-methoxybiphenyl-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2015/87845,2015,A1
[2]Patent: US2015/87845,2015,A1

38
[ 116557-46-1 ]
(Z)-1-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-methoxyphenyl)hydrazono-5-pyrazolone [ No CAS ]

Reference： [1]Patent: US2015/87845,2015,A1

39
[ 116557-46-1 ]
(Z)-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2'-methoxybiphenyl-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2015/87845,2015,A1
[2]Patent: US2015/87845,2015,A1
[3]Patent: US2015/87845,2015,A1

40
[ 116557-46-1 ]
1-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-hydroxyphenyl)hydrazono-5-pyrazolone [ No CAS ]

Reference： [1]Patent: US2015/87845,2015,A1

41
[ 116557-46-1 ]
[ 141-97-9 ]
ethyl 2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33 g		To a solution of <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (20 g) in 1N hydrochloric acid (400 mL) was added a solution of sodium nitrite (7.2 g in 720 mL of water) at about 0 C. to about 5 C. under stirring. The reaction mixture was stirred for about 15 minutes at about 5 C. Then ethyladetoacetate (12.9 g) was added to the reaction mixture and stirred for about 15 minutes at about 0 C. to about 5 C. Sodium bicarbonate solution (27.5 g in 300 mL water) and ethanol (400 mL) was then added to the reaction mixture. The reaction mixture was allowed to warm to about room temperature and stirred for about 2 hours. The mixture was filtered, washed with water (200 mL) and dried to get yellowish solid. Yield: 33 g; Melting point: 75.9-77.1 C.; Purity (HPLC): 99.12% IR: 3421, 1706, 1684, 1517, 1215, 1093, 980 cm-1; Mass: m/z 342.88 [M+] and 344.86 [M+2] 1H NMR (300 MHz in CDCl3): delta 12.86 (s, 1H), 7.58-7.61 (d, 1H), 7.30-7.33 (d, 1H), 7.02-7.07 (m, 1H), 4.31-4.43 (q, 2H), 3.95 (s, 3H), 2.5 (s, 3H), 1.38-1.43 (t, 3H)

Reference： [1]Patent: US2015/87845,2015,A1 .Location in patent: Paragraph 0176; 0177

42
[ 116557-46-1 ]
2-methoxy-3-(2-methylthiazol-4-yl)aniline [ No CAS ]

Reference： [1]Patent: WO2015/69310,2015,A1
[2]Patent: TWI582077,2017,B

43
[ 116557-46-1 ]
C₂₁H₂₁⁽²⁾H₃ClN₅O₃ [ No CAS ]

Reference： [1]Patent: WO2015/69310,2015,A1

44
[ 116557-46-1 ]
C₁₈H₁₈ClN₅O₂ [ No CAS ]

Reference： [1]Patent: WO2015/69310,2015,A1
[2]Patent: TWI582077,2017,B

45
[ 116557-46-1 ]
C₂₂H₂₄N₆O₃ [ No CAS ]

Reference： [1]Patent: WO2015/69310,2015,A1
[2]Patent: TWI582077,2017,B

46
[ 116557-46-1 ]
[ 125708-66-9 ]

Reference： [1]Patent: WO2015/79251,2015,A1
[2]European Journal of Medicinal Chemistry,2016,vol. 112,p. 20 - 32

47
[ 116557-46-1 ]
3-((6,7-dimethoxyquinazolin-4-yl)amino)-2-methoxyphenol [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 112,p. 20 - 32

48
[ 116557-46-1 ]
7-bromo-8-methoxy-4-methylhydroquinolin-2-one [ No CAS ]

Reference： [1]Patent: EP2987787,2016,A1

49
[ 116557-46-1 ]
7-bromo-1-cyclopropyl-8-methoxy-4-methylhydroquinolin-2-one [ No CAS ]

Reference： [1]Patent: EP2987787,2016,A1

50
[ 116557-46-1 ]
7-bromo-1-cyclopropyl-8-methoxy-2-oxohydroquinoline-4-carboaldehyde [ No CAS ]

Reference： [1]Patent: EP2987787,2016,A1

51
[ 116557-46-1 ]
7-bromo-1-cyclopropyl-4-(hydroxymethyl)-8-methoxyhydroquinolin-2-one [ No CAS ]

Reference： [1]Patent: EP2987787,2016,A1

52
[ 116557-46-1 ]
1-cyclopropyl-8-methoxyl-4-(hydroxymethyl)-7-(4-hydroxyphenyl)hydroquinolin-2-one [ No CAS ]

Reference： [1]Patent: EP2987787,2016,A1

53
[ 116557-46-1 ]
2-oxetanone [ No CAS ]
N-(3-bromo-2-methoxyphenyl)-3-oxobutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	In toluene; at 140℃; for 6h;	A solution of <strong>[116557-46-1]3-bromo-2-methoxyphenylamine</strong> (16.8 g, 83.2 mmol) and 2-oxetanone (8.40 g, 99.8 mmol) in toluene was stirred at 140C for 6 hours. The solution was cooled to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give N-(3-bromo-2-methoxyphenyl)-3-oxobutanamide as white solid (15.6 g, yield 66%).1H-NMR Spectrum (300MHz, DMSO-d6):delta (ppm): 2.20 (s, 3H), 3.72 (s, 2H), 3.74 (s, 3H), 7.05 (d, 1H, J=8.1Hz), 7.35 (dd, 1H, J=8.1, 1.5Hz), 8.05 (dd, 1H,J=8.4, 1.8Hz), 9.77 (s, 1H)

Reference： [1]Patent: EP2987787,2016,A1 .Location in patent: Paragraph 0132

54
[ 116557-46-1 ]
3,6-dibromo-5-methoxy-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide [ No CAS ]

Reference： [1]Patent: WO2017/98421,2017,A1

55
[ 116557-46-1 ]
3,6-dibromo-5-hydroxy-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide [ No CAS ]

Reference： [1]Patent: WO2017/98421,2017,A1

56
[ 116557-46-1 ]
6-bromo-3-((2-fluorophenyl)amino)-5-hydroxy-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide [ No CAS ]

Reference： [1]Patent: WO2017/98421,2017,A1

57
[ 1189-71-5 ]
[ 116557-46-1 ]
6-bromo-5-methoxy-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.6 g		6-Bromo-5-methoxy-2H-benzorein ,2.41thiadiazin-3(4H)-one 1.1 -dioxide (lnt-14) (2156) A 250 mL round-bottomed flask was charged with chlorosulfonyl isocyanate (2.57 ml) in nitropropane (40.2 ml) to give a colorless solution at -40 C under nitrogen. After 10 min, a solution of <strong>[116557-46-1]3-bromo-2-methoxyaniline</strong> (4.87 g) in nitropropane (10 ml) was added to the reaction mixture. After 10 min, the reaction was warmed to 0 C. After 1 h, aluminum chloride (4.02 g) was added to the reaction mixture. After 5 min, the reaction mixture was warmed to 1 10 C. After 30 min, the reaction mixture was poured into ice/ water (400 mL) and stirred. The reaction mixture was extracted with DCM (3x). The dichloromethane layers were dried over Na2S04, filtered, and concentrated. The crude solid was stirred with EtOAc (10 mL). The solids were filtered and washed with hexanes to obtain the titled compound (1 .6 g), which was used without further purification. LCMS m/z 306.9 (M+H).

Reference： [1]Patent: WO2017/98421,2017,A1 .Location in patent: Page/Page column 142

58
[ 116557-46-1 ]
C₁₁H₁₂BrN₃O*ClH [ No CAS ]

Reference： [1]Patent: WO2018/75937,2018,A1

59
[ 116557-46-1 ]
C₂₄H₂₂N₄O [ No CAS ]

Reference： [1]Patent: WO2018/75937,2018,A1

60
[ 116557-46-1 ]
C₁₁H₁₄N₄O [ No CAS ]

Reference： [1]Patent: WO2018/75937,2018,A1

61
[ 116557-46-1 ]
C₇H₉BrN₂O*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.45%		To a suspension of compound 55.1 (8g, 39.6mmol, 1.Oeq) in water (8OmL) at 0 C, sodium nitrite (3.27g, 47.5mmol, 1.2eq) was added. Reaction mixture was stirred at 0C for 30mm followed by addition of tin chloride (14.96g, 79.6mmol, 2.Oeq) at 0C and stirred for 3h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. Organic layer combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 55.2 (7g, 8 1.45%). MS(ES): m/z 218.34 [M+H]t

Reference： [1]Patent: WO2018/75937,2018,A1 .Location in patent: Paragraph 00495; 00497

62
[ 116557-46-1 ]
C₁₀H₁₀BrN₃O [ No CAS ]

Reference： [1]Patent: WO2018/75937,2018,A1

63
[ 116557-46-1 ]
C₂₃H₂₀N₄O [ No CAS ]

Reference： [1]Patent: WO2018/75937,2018,A1

64
[ 116557-46-1 ]
C₁₀H₁₂N₄O [ No CAS ]

Reference： [1]Patent: WO2018/75937,2018,A1

65
[ 116557-46-1 ]
3, 3'-(pyridine-2,6-diyl)bis(2-methoxyaniline) [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 11924 - 11928
Angew. Chem.,2018,vol. 130,p. 12100 - 12104,5
[2]Patent: WO2019/226863,2019,A1

66
[ 116557-46-1 ]
C₄₅H₄₇N₇O₄ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 11924 - 11928
Angew. Chem.,2018,vol. 130,p. 12100 - 12104,5
[2]Patent: WO2019/226863,2019,A1

67
[ 116557-46-1 ]
C₅₁H₅₅N₇O₄ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 11924 - 11928
Angew. Chem.,2018,vol. 130,p. 12100 - 12104,5
[2]Patent: WO2019/226863,2019,A1

68
[ 116557-46-1 ]
[ 928627-15-0 ]