[ CAS No. 1563-56-0 ] {[proInfo.proName]}

Name: 1563-56-0|(2-Amino-5-bromophenyl)(pyridin-2-yl)methanone|98%
Brand: Ambeed
SKU: A217026
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Quality Control of [ 1563-56-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1563-56-0 ]

Product Details of [ 1563-56-0 ]

CAS No. :	1563-56-0	MDL No. :	MFCD07780283
Formula :	C₁₂H₉BrN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KHVZPFKJBLTYCC-UHFFFAOYSA-N
M.W :	277.12	Pubchem ID :	73807
Synonyms :		Chemical Name :	(2-Amino-5-bromophenyl)(pyridin-2-yl)methanone

Calculated chemistry of [ 1563-56-0 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	66.22
TPSA :	55.98 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.8 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.01
Log Po/w (XLOGP3) :	3.09
Log Po/w (WLOGP) :	2.67
Log Po/w (MLOGP) :	1.47
Log Po/w (SILICOS-IT) :	2.79
Consensus Log Po/w :	2.4

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.93
Solubility :	0.0327 mg/ml ; 0.000118 mol/l
Class :	Soluble
Log S (Ali) :	-3.93
Solubility :	0.0323 mg/ml ; 0.000117 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.98
Solubility :	0.00289 mg/ml ; 0.0000104 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.96

Safety of [ 1563-56-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P301+P312+P330-P302+P352	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1563-56-0 ]

* 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 [ 1563-56-0 ]
Downstream synthetic route of [ 1563-56-0 ]

[ 1563-56-0 ] Synthesis Path-Upstream 1~4

1
[ 109-04-6 ]
[ 5794-88-7 ]
[ 1563-56-0 ]

Yield	Reaction Conditions	Operation in experiment
89.3%	Stage #1: at -40℃; for 1.5 h; Stage #2: at 0℃; for 2 h;	To a -40°C solution of 2.5 M n-butyllithium in hexane (400 mL, 1000 mmol, 4 eq) and diethyl ether (1 L) was added 2-bromopyridine (173.93 g, 1101 mmol, 4.4 eq) over approximately 30 min. The reaction was stirred for 1 h at -40°C, and then treated with 5-bromoanthranilic acid (54.14 g, 250.6 mmol, 1 eq) in THF (1 L). The reaction was warmed to 0°C and stirred 2 h at 0°C, then quenched with chlorotrimethylsilane (625 mL, 4924 mmol, 20 eq). The reaction was stirred 30 min at ambient temperature, then cooled to 0°C and quenched with 3N HCI (625 mL). The aqueous layer was separated, and the organic layer was extracted once with 3N HCl. The combined aqueous layers were neutralized with solid sodium hydroxide pellets, with cooling via ice bath. The resulting mixture was extracted with diethyl ether (3 .x. 1 L). The combined ether layers were dried over sodium sulfate, filtered and concentrated to a black oil, which was subsequently purified by flash chromatography (1 L silica gel, 20-30percent ethyl acetate/hexane) to give the required compound as a brown solid (62 g, 224 mmol, 89.3percent).
62.7%	Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; Stage #2: at -40 - 0℃; for 2 h; Stage #3: With chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 0.5 h;	To a -40 °C solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2- bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40 °C, and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0 °C and stirred for 2 h then quenched with TMSC1 (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0 °C and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na₂S0₄, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7percent) HPLC-MS: M+H=277/279; t_Ret =3.16 min; AM6
62.7%	Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; for 1.25 h; Stage #2: at 0℃; for 2 h;	To a -40° C. solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2-bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40° C., and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0° C. and stirred for 2 h then quenched with TMSCl (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0° C. and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na₂SO₄, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7percent) HPLC-MS: M+H=277/279; t_Ret=3.16 min; AM6

50.7%

Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; for 1 h; Inert atmosphere
Stage #2: at 0 - 10℃; for 3 h; Inert atmosphere

Add tetrahydrofuran (44 mL) to the reaction flask, protect with nitrogen, add n-butyl lithium (51 mL) at -40 ° C, control the internal temperature not to exceed -20 ° C, lower the temperature to -40 ° C, and slowly add 2-bromopyridine ( 15.8g), the reaction was incubated for 1 hour, the temperature was controlled below -40 ° C, and a solution of 2-amino-5-bromo-benzoic acid (6.7 g) dissolved in (44 mL) tetrahydrofuran was added dropwise.After the dropwise addition, the temperature was naturally raised to about 0 ° C for 3 hours.The internal temperature was kept below 10 °C, and a saturated ammonium chloride solution (11 mL) was slowly added dropwise to terminate the reaction. Water (50 mL) was added thereto, and the mixture was partitioned. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50mL) The organic layers were combined and washed with saturated aqueous sodium chloride (40 mL×2).Drying over anhydrous sodium sulfate, filtration, and concentrated under reduced pressure to give an oily substance, purified by column chromatography (eluent PE: EA = 3:1 to 1:1, volume ratio), and the positive component was collected and concentrated to give a solid product ( 4.37 g, yield 50.7percent).

Reference： [1] Patent: EP1183243, 2006, B1, . Location in patent: Page/Page column 11
[2] Patent: WO2014/154762, 2014, A1, . Location in patent: Page/Page column 62
[3] Patent: US2014/296230, 2014, A1, . Location in patent: Paragraph 0303-0306
[4] Patent: CN108264499, 2018, A, . Location in patent: Paragraph 0050-0051; 0075; 0076; 0077-0079

2
[ 5794-88-7 ]
[ 1563-56-0 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; Stage #2: at 0℃;	(2-Amino-5-bromo-phenyl)-pyridin-2-yl-methanone 123; The anion of 2-bromo-pyridine 121 and 2-amino-5-bromobenzoic acid 122 were condensed to provide the 2'-pyridylketone 123.

Reference： [1] Patent: US2006/3995, 2006, A1, . Location in patent: Page/Page column 60-61

3
[ 1812-30-2 ]
[ 1563-56-0 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1987, vol. 35, # 10, p. 4338 - 4341
[2] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 12, p. 3678 - 3681

4
[ 1812-30-2 ]
[ 1563-56-0 ]
[ 56-40-6 ]

Reference： [1] Journal of Pharmaceutical Sciences, 1991, vol. 80, # 5, p. 459 - 468

[ 1563-56-0 ] Synthesis Path-Downstream 1~75

1
[ 1142-20-7 ]
[ 1563-56-0 ]
[ 136295-72-2 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

2
[ 1161-13-3 ]
[ 1563-56-0 ]
[ 136295-73-3 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

3
[ 1563-56-0 ]
[ 74405-07-5 ]
[ 82562-61-6 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 559 - 563

4
[ 1812-30-2 ]
[ 1563-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; water; for 3h;Darkness; Reflux;	As reported elsewhere [39], pure BMZ (1 g) was dissolved into theleast amount of methanol. This was followed by the addition of 1 NHCl (50 mL). The mixed solution was then kept away from light andrefluxed for 3 h. TLC was used to monitor the reaction, with a 4:1chloroform-acetone mixture as the development solvent. The completefading of the drug spot (BMZ) and the appearance of a new spot (ABP)on the TLC plate was an indication of BMZ transformation into ABP. Theacid degradation reaction was neutralized by the dropwise addition of2 N NaOH solution till the formation of a yellowish precipitate of degradationproduct ABP, and then refrigerated overnight. The ABP precipitatewas filtered and washed several times with distilled water andthen oven-dried at 70 C. Confirmation was obtained by the used of infraredand mass spectrometry.

Reference： [1]Chemical and Pharmaceutical Bulletin,1987,vol. 35,p. 4338 - 4341
[2]Chemical and Pharmaceutical Bulletin,1980,vol. 28,p. 3678 - 3681
[3]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2020,vol. 238

5
[ 1812-30-2 ]
[ 1563-56-0 ]
[ 56-40-6 ]

Reference： [1]Journal of Pharmaceutical Sciences,1991,vol. 80,p. 459 - 468

6
[ 1563-56-0 ]
[ 79-04-9 ]
[ 41526-21-0 ]

Reference： [1]Journal of Chemical Research, Miniprint,1980,p. 4762 - 4776

9
C₂₄H₁₇Br₂N₅ [ No CAS ]
[ 1563-56-0 ]

Reference： [1]European Journal of Organic Chemistry,2006,p. 2987 - 2990

10
[ 1563-56-0 ]
[ 76895-76-6 ]

Reference： [1]Journal of Chemical Research, Miniprint,1980,p. 4762 - 4776

11
[ 1563-56-0 ]
[ 76895-81-3 ]

Reference： [1]Journal of Chemical Research, Miniprint,1980,p. 4762 - 4776

12
[ 1563-56-0 ]
[ 1812-30-2 ]

Reference： [1]Journal of Chemical Research, Miniprint,1980,p. 4762 - 4776
[2]Synthesis,2018,vol. 50,p. 4124 - 4132
[3]Patent: US2018/312511,2018,A1

13
[ 1563-56-0 ]
2-acetamido-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine [ No CAS ]

Reference： [1]Journal of Chemical Research, Miniprint,1980,p. 4762 - 4776

14
[ 1563-56-0 ]
2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine hydrochloride [ No CAS ]

Reference： [1]Journal of Chemical Research, Miniprint,1980,p. 4762 - 4776

15
[ 1563-56-0 ]
[ 82562-62-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 559 - 563

16
[ 1563-56-0 ]
[ 136295-75-5 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308
[2]Tetrahedron,1991,vol. 47,p. 5295 - 5308

17
[ 1563-56-0 ]
(S)-2-Amino-N-[4-bromo-2-(pyridine-2-carbonyl)-phenyl]-propionamide [ No CAS ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

18
[ 1563-56-0 ]
1,3-dihydro-3(S)-benzyl-5-(pyrid-2'-yl)-2H-1,4-benzodiazepin-2-one [ No CAS ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

19
[ 1563-56-0 ]
[ 136295-76-6 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

20
[ 1563-56-0 ]
(S)-2-Amino-N-[4-bromo-2-(pyridine-2-carbonyl)-phenyl]-3-phenyl-propionamide [ No CAS ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

21
[ 1563-56-0 ]
1-benzyl-7-bromo-1,3-dihydro-3(S)-benzyl-5-(pyrid-2'-yl)-2H-1,4-benzodiazepin-2-one [ No CAS ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

22
[ 1563-56-0 ]
2-(N-carbobenzoxy-S-alanyl)-amino-5-bromophenyl-pyrid-2'-yl carbinol [ No CAS ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5295 - 5308

23
[ 5794-88-7 ]
[ 1563-56-0 ]

Yield	Reaction Conditions	Operation in experiment
58%		(2-Amino-5-bromo-phenyl)-pyridin-2-yl-methanone 123; The anion of 2-bromo-pyridine 121 and 2-amino-5-bromobenzoic acid 122 were condensed to provide the 2'-pyridylketone 123.

Reference： [1]Patent: US2006/3995,2006,A1 .Location in patent: Page/Page column 60-61

24
[ 15761-38-3 ]
[ 1563-56-0 ]
(S)-{1-[4-bromo-2-(pyridine-2-carbonyl)-phenylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
[ 2387-23-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 8.5h;	{1-[4-Bromo-2-(pyridine-2-carbonyl)-phenylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester 124; To a stirred solution of (2-amino-5-bromophenyl)-pyridin-2-yl-methanone 123 (16 g, 57.33 mmol) and the N-Boc-L-alanine 107 (10.92 g, 57.73 mmol) in CH2Cl2 (100 mL) was added dicyclohexylcarbodiimide (DCC) (11.91 g, 57.73 mmol) in CH2Cl2 (60 mL) dropwise, over a 30 min period at 0 C. The reaction mixture was allowed to stir an additional 8 h at rt. The dicyclohexyl urea which formed was filtered off and the filtrate concentrated under reduced pressure. The crude solid 124 was purified by recrystallization from hexane and EtOAc to afford 124 (7.88 g, 81%). mp 208-210 C.; IR (KBr, cm-1) 3332, 2931, 1694, 1507, 1287, 1163; 1H NMR (CDCl3) delta 11.68 (s, 1H), 8.71 (d, J=9.0 Hz, 1H), 7.69 (dd, J=9.0, 2.3 Hz, 1H), 7.55-7.62 (m, 2H), 7.46 (td, J=7.6, 1.4 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.21 (t, J=9.1 Hz, 1H), 5.13 (b, 1H), 4.37 (b, 1H), 1.51 (d, J=7.2 Hz, 3H), 1.45 (S, 9H). MS (EI) m/e (relative intensity) 449 (M++1, 5), 448 (M+, 5), 376 (10), 329 (20), 304 (100), 228 (25); [alpha]26D=-36.1 (c 0.61, EtOAc).

Reference： [1]Patent: US2006/3995,2006,A1 .Location in patent: Page/Page column 60-61

25
[ 109-04-6 ]
[ 5794-88-7 ]
[ 1563-56-0 ]

Yield	Reaction Conditions	Operation in experiment
89.3%		To a -40C solution of 2.5 M n-butyllithium in hexane (400 mL, 1000 mmol, 4 eq) and diethyl ether (1 L) was added 2-bromopyridine (173.93 g, 1101 mmol, 4.4 eq) over approximately 30 min. The reaction was stirred for 1 h at -40C, and then treated with 5-bromoanthranilic acid (54.14 g, 250.6 mmol, 1 eq) in THF (1 L). The reaction was warmed to 0C and stirred 2 h at 0C, then quenched with chlorotrimethylsilane (625 mL, 4924 mmol, 20 eq). The reaction was stirred 30 min at ambient temperature, then cooled to 0C and quenched with 3N HCI (625 mL). The aqueous layer was separated, and the organic layer was extracted once with 3N HCl. The combined aqueous layers were neutralized with solid sodium hydroxide pellets, with cooling via ice bath. The resulting mixture was extracted with diethyl ether (3 × 1 L). The combined ether layers were dried over sodium sulfate, filtered and concentrated to a black oil, which was subsequently purified by flash chromatography (1 L silica gel, 20-30% ethyl acetate/hexane) to give the required compound as a brown solid (62 g, 224 mmol, 89.3%).
62.7%		To a -40 C solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2- bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40 C, and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0 C and stirred for 2 h then quenched with TMSC1 (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0 C and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na2S04, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7%) HPLC-MS: M+H=277/279; tRet =3.16 min; AM6
62.7%		To a -40 C. solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2-bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40 C., and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0 C. and stirred for 2 h then quenched with TMSCl (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0 C. and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7%) HPLC-MS: M+H=277/279; tRet=3.16 min; AM6

50.7%

Add tetrahydrofuran (44 mL) to the reaction flask, protect with nitrogen, add n-butyl lithium (51 mL) at -40 C, control the internal temperature not to exceed -20 C, lower the temperature to -40 C, and slowly add 2-bromopyridine ( 15.8g), the reaction was incubated for 1 hour, the temperature was controlled below -40 C, and a solution of 2-amino-5-bromo-benzoic acid (6.7 g) dissolved in (44 mL) tetrahydrofuran was added dropwise.After the dropwise addition, the temperature was naturally raised to about 0 C for 3 hours.The internal temperature was kept below 10 C, and a saturated ammonium chloride solution (11 mL) was slowly added dropwise to terminate the reaction. Water (50 mL) was added thereto, and the mixture was partitioned. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50mL) The organic layers were combined and washed with saturated aqueous sodium chloride (40 mL×2).Drying over anhydrous sodium sulfate, filtration, and concentrated under reduced pressure to give an oily substance, purified by column chromatography (eluent PE: EA = 3:1 to 1:1, volume ratio), and the positive component was collected and concentrated to give a solid product ( 4.37 g, yield 50.7%).

Reference： [1]Patent: EP1183243,2006,B1 .Location in patent: Page/Page column 11
[2]Patent: WO2014/154762,2014,A1 .Location in patent: Page/Page column 62
[3]Patent: US2014/296230,2014,A1 .Location in patent: Paragraph 0303-0306
[4]Patent: CN108264499,2018,A .Location in patent: Paragraph 0050-0051; 0075; 0076; 0077-0079

26
[ 79-20-9 ]
[ 1563-56-0 ]
2-[2-(1-methoxyethylideneamino)-5-bromobenzoyl]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In benzene;	a. A mixture of 8.7 g. of 2-(2-amino-5-bromobenzoyl)-pyridine, 5.7 g. of ortho-methyl acetate, 2.8 ml. of acetic acid and 100 ml. of benzene is refluxed, while removing alcohol produced by azeotropic distillation, for 1.5 hours and then cooled. The resultant mixture is washed with saturated aqueous sodium hydrogen carbonate solution, then with water, and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gives 2-[2-(1-methoxyethylideneamino)-5-bromobenzoyl]pyridine as an oily product.

Reference： [1]Patent: US4013763,1977,A

27
[ 1563-56-0 ]
[ 58765-74-5 ]

Yield	Reaction Conditions	Operation in experiment
	With formic acid;	a. A mixture of 14 g. of 2-(2-amino-5-bromobenzoyl)-pyridine and 42 ml. of formic acid (99%) is refluxed for one hour and then the solvent is evaporated. The residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and the precipitated crystals of 2-(5-bromo-2-formamidobenzoyl)pyridine are collected by filtration, followed by washing with water. Recrystallization from methanol gives yellow needles melting at 116 to 117 C. Elemental analysis for C13 H9 BrN2 O: Calculated: C 51.17, H 2.97, N 9.18 Found: C 51.12, H 2.75, N 9.14

Reference： [1]Patent: US4013763,1977,A

28
[ 1563-56-0 ]
[ 68235-85-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium borohydrid; sodium hydrogencarbonate; In methanol;	(1) 2-Amino-5-bromo-alpha-(2-pyridyl)benzyl alcohol In 100 ml of methanol was dissolved 10 g of 2-amino-5-bromophenyl-2-pyridylketone. To the solution was added 1.7 g of sodium borohydride and stirred for 30 minutes. The solvent methanol was evaporated off under reduced pressure. The residue was treated with an aqueous solution of hydrochloric acid. The decomposed residue was then neutralized with 200 ml of a sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 2-amino-5-bromo-alpha-(2-pyridyl)benzyl alcohol (9.0 g) as prisms, m.p. 104-105 C. Elementary analysis for C12 H11 BrN2 O Calcd.: C 51.64; H 3.97; N 10.04 Found: C 51.61; H 3.93; N 10.04

Reference： [1]Patent: US5726306,1998,A

29
[ 1563-56-0 ]
[ 308242-62-8 ]

Reference： [1]Patent: WO2011/32692,2011,A1
[2]Patent: WO2011/32692,2011,A1
[3]Patent: EP2305647,2011,A1
[4]Patent: EP2305647,2011,A1

30
[ 1563-56-0 ]
[ 308242-23-1 ]

Reference： [1]Patent: WO2011/32692,2011,A1
[2]Patent: EP2305647,2011,A1
[3]Patent: CN108264499,2018,A
[4]Patent: US2018/312511,2018,A1

31
[ 1563-56-0 ]
[ 1275616-61-9 ]

Reference： [1]Patent: WO2011/32692,2011,A1
[2]Patent: EP2305647,2011,A1

32
[ 1563-56-0 ]
[ 1275616-58-4 ]

Reference： [1]Patent: EP2305647,2011,A1

33
[ 1563-56-0 ]
[ 1275616-60-8 ]

Reference： [1]Patent: WO2011/32692,2011,A1
[2]Patent: EP2305647,2011,A1
[3]Patent: CN108264499,2018,A
[4]Patent: US2018/312511,2018,A1

34
[ 1563-56-0 ]
3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester benzene sulfonate [ No CAS ]

Reference： [1]Patent: WO2011/32692,2011,A1
[2]Patent: WO2011/32692,2011,A1
[3]Patent: WO2011/32692,2011,A1
[4]Patent: EP2305647,2011,A1
[5]Patent: EP2305647,2011,A1
[6]Patent: EP2305647,2011,A1

35
[ 1563-56-0 ]
[ 1275616-59-5 ]

Reference： [1]Patent: WO2011/32692,2011,A1
[2]Patent: EP2305647,2011,A1

36
[ 1563-56-0 ]
C₁₈H₁₇BrN₂O₅*ClH [ No CAS ]

Reference： [1]Patent: WO2011/32692,2011,A1

37
[ 45214-91-3 ]
[ 1563-56-0 ]
C₂₃H₂₅BrN₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In dichloromethane; at -10 - 0℃; for 41h;	Example A1 :Preparation of the compound of formula (B)222g (801 mmol) <strong>[1563-56-0](2-amino-5-bromo-phenyl)-pyridin-2-yl-methanone</strong> of formula (A)(A) (prepared as described in European Journal of Organic Chemistry, 2006, 13, 2987- 2990) and 230g (881 mmol) 'Boc-Glu DMeJ-OH were mixed as solids and dissolved in 1200 ml dichloromethane and the solution was cooled to a temperature of - 10C. A solution of coupling reagent dicyclohexylcarbodiimide DCC (165 g, 801 mmol) in 400 ml dichloromethane was added dropwise over a period of 1 hour while the internal temperature was kept at a temperature from - 10C to - 5C, then the solution was stirred for 40 hours at a temperature of - 5C to 0 C. The suspension was filtered, the filter cake was washed with 1000 ml dichloromethane and the filtrate was evaporated to a yellow residue, showing for the main product the following NMR data:1 H-NMR (CDCI3, 300 MHz) 11.29 (brs, 1 H); 8.65(dt, 1 H, J= 4.8, 1.4); 8.50 (d, 1 H, J= 9.0); 7.91(d, 1 H, J= 2.3); 7.86 (m, 2H); 7.59 (dd, 1 H, J= 9.0, 2.3) 7.45 (ddd, 1 H, J= 6.4, 4.0, 2.3); 5.27 (brd, 1 H, J=6.4); 4.27 (brm, 1 H); 3.60 (s, 3H); 2.52-2.14 (m, 2H); 2.04-1.82 (m, 2H); 1.36 (s, 9H), corresponding to the compound of formula (B).

Reference： [1]Patent: WO2011/32692,2011,A1 .Location in patent: Page/Page column 15-16

38
[ 45214-91-3 ]
[ 1563-56-0 ]
[ 1275616-57-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In dichloromethane; at -10 - 0℃;	222g (801 mmol) <strong>[1563-56-0](2-amino-5-bromo-phenyl)-pyridin-2-yl-methanone</strong> of formula (A) (prepared as described in European Journal of Organic Chemistry, 2006, 13, 2987-2990) and 230g (881 mmol)'Boc-Glu(OMe)-OH were mixed as solids and dissolved in 1200 ml dichloromethane and the solution was cooled to a temperature of - 10C. A solution of coupling reagent dicyclohexylcarbodiimide DCC (165 g, 801 mmol) in 400 ml dichloromethane was added dropwise over a period of 1 hour while the internal temperature was kept at a temperature from - 10C to - 5C, then the solution was stirred for 40 hours at a temperature of - 5C to 0 C. The suspension was filtered, the filter cake was washed with 1000 ml dichloromethane and the filtrate was evaporated to a yellow residue, showing for the main product the following NMR data: 1H-NMR (CDCl3, 300 MHz) 11.29 (brs, 1H); 8.65(dt, 1H, J= 4.8, 1.4); 8.50 (d. 1H, J= 9.0); 7.91 (d, 1H, J= 2.3); 7.86 (m, 2H); 7.59 (dd, 1H, J= 9.0, 2.3) 7.45 (ddd, 1H. J= 6.4, 4.0, 2.3); 5.27 (brd, 1H. J=6.4); 4.27 (brm, 1H): 3.60 (s, 3H); 2.52-2.14 (m, 2H); 2.04-1.82 (m, 2H); 1.36 (s, 9H), corresponding to the compound of formula (B).

Reference： [1]Patent: EP2305647,2011,A1 .Location in patent: Page/Page column 9

39
[ 1563-56-0 ]
6-bromo-3-methyl-4-pyridin-2-yl-3,4-dihydro-1H-quinazolin-2-one [ No CAS ]

Reference： [1]Patent: WO2014/154762,2014,A1
[2]Patent: US2014/296230,2014,A1

40
[ 1563-56-0 ]
6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-pyridin-2-yl-3,4-dihydro-1H-quinazolin-2-one [ No CAS ]

Reference： [1]Patent: WO2014/154762,2014,A1
[2]Patent: US2014/296230,2014,A1

41
[ 1563-56-0 ]
[ 74-89-5 ]
4-bromo-2-(methylaminopyridin-2-yl-methyl)phenylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (2-Amino-5-bromo-phenyl)-pyridin-2-yl-methanone (500 mg, 1.8 mmol) in MeOH (20 mL) is added Ti(i-OPr)4 (1.0 g, 3.6 mmol) and methylamine (2M in THF, 4.5 mL). Then the mixture is stirred at room temperature for 6 h. Sodium borohydride (137 mg, 3.6 mmol) is added in one portion. The mixture is stirred at room temperature for 2 h. Water (10 mL) is added and the mixture is filtered and washed with EtOAc. The filtrate is washed with brine, the organic layer is concentrated in vacuum to give the desired product as a crude mixture. This is used in next step with no further purification. Yield: 500 mg HPLC-MS: M+H=292/294; tRet =0.96 min; AM12
		To a solution of (2-Amino-5-bromo-phenyl)-pyridin-2-yl-methanone (500 mg, 1.8 mmol) in MeOH (20 mL) is added Ti(i-OPr)4 (1.0 g, 3.6 mmol) and methylamine (2M in THF, 4.5 mL). Then the mixture is stirred at room temperature for 6 h. Sodium borohydride (137 mg, 3.6 mmol) is added in one portion. The mixture is stirred at room temperature for 2 h. Water (10 mL) is added and the mixture is filtered and washed with EtOAc. The filtrate is washed with brine, the organic layer is concentrated in vacuum to give the desired product as a crude mixture. This is used in next step with no further purification. Yield: 500 mg HPLC-MS: M+H=292/294; tRet=0.96 min; AM12

Reference： [1]Patent: WO2014/154762,2014,A1 .Location in patent: Page/Page column 63
[2]Patent: US2014/296230,2014,A1 .Location in patent: Paragraph 0307-0310

42
[ 1563-56-0 ]
(R) 6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-pyridin-2-yl-3,4-dihydrobenzo[e][1,3]oxazin-2-one [ No CAS ]

Reference： [1]Patent: US2014/296230,2014,A1

43
[ 1563-56-0 ]
3-[(S)-7-bromo-2-(2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid methyl ester [ No CAS ]

Reference： [1]Patent: CN108264499,2018,A

44
[ 1563-56-0 ]
methyl (S)-3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine -4-yl)propionate tosylate [ No CAS ]

Reference： [1]Patent: CN108264499,2018,A

45
[ 1563-56-0 ]
(S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acid [ No CAS ]
methyl (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-[4-bromo-2-(pyridine-2-carbonyl)phenyl]carbamoyl}butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In dichloromethane; at -10 - 0℃; for 48h;	(2-Amino-5-bromophenyl)(pyridin-2-yl)methanone (4 g) was added to the methyl ester reaction flask.Fmoc-L-glutamic acid methyl ester (6.2g)Dissolved in dichloromethane (50 mL), cooled to -10 C, and dropwisely added a solution of 1,3-dicyclohexylcarbodiimide (3.0 g) in dichloromethane (8 mL), temperature -10 C -5 The mixture was reacted for 48 hours at -5 C to 0 C, filtered, and the filtrate was concentrated under reduced pressure to an oily material to afford crude product.

Reference： [1]Patent: CN108264499,2018,A .Location in patent: Paragraph 0050-0051; 0075-0076; 0080-0083

46
[ 1563-56-0 ]
[ 69585-94-0 ]

Reference： [1]Synthesis,2018,vol. 50,p. 4124 - 4132

47
[ 1563-56-0 ]
[ 612527-54-5 ]

Reference： [1]Synthesis,2018,vol. 50,p. 4124 - 4132

48
[ 1563-56-0 ]
C₁₉H₁₄N₄O [ No CAS ]

Reference： [1]Synthesis,2018,vol. 50,p. 4124 - 4132

49
[ 1563-56-0 ]
[ 612527-56-7 ]

Reference： [1]Synthesis,2018,vol. 50,p. 4124 - 4132

50
[ 1563-56-0 ]
3-ethyl-5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)-1,2,4-oxadiazole [ No CAS ]

Reference： [1]Synthesis,2018,vol. 50,p. 4124 - 4132

51
[ 1563-56-0 ]
8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carbaldehyde [ No CAS ]

Reference： [1]Synthesis,2018,vol. 50,p. 4124 - 4132
[2]Synthesis,2018,vol. 50,p. 4124 - 4132

52
[ 1563-56-0 ]
5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole [ No CAS ]

Reference： [1]Synthesis,2018,vol. 50,p. 4124 - 4132
[2]Synthesis,2018,vol. 50,p. 4124 - 4132

53
[ 1563-56-0 ]
[ 598-21-0 ]
[ 1694-64-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydrogencarbonate; In dichloromethane; at 0℃; for 2h;	2-(2-Amino-5-bromobenzoyl)pyridine (compound 1a, 60 g, 0.22 mol) was dissolved in DCM (3 L), and NaHCO3 (36.9 g, 0.44 mol) was added. The mixture was cooled to 0 C., and 2-bromoacetyl bromide (52.4 g, 0.26 mol) was added dropwise slowly. The reaction mixture was stirred at 0 C. for 2 h until TLC indicated that the reaction was completed. The reaction mixture was concentrated to obtain 2-bromo-N-(4-bromo-2-(pyridin-2-ylcarbonyl)phenyl)acetamide (compound 1b, 88 g, yield: 100.0%).
	With sodium hydrogencarbonate; In dichloromethane; at 0 - 20℃;	The 2?-pyridyl ketone 5 (120 g, 433.2 mmol) was dissolved in anhydDCM (1.4 L) in a 3-necked round-bottom flask and stirred with anoverhead mechanical stirrer for 15 min to obtain a homogenous solution.Then solid NaHCO3 (72.8 g, 866.4 mmol) was added to the solutionwith vigorous stirring to avoid clogging of the stirrer, and themixture was cooled to 0 C using an ice bath. A solution of bromoacetylbromide (144.9 g, 714.8 mmol) in anhyd DCM (200 mL) was thenadded dropwise at 0 C with an addition funnel. The reaction mixturewas allowed to warm to r.t. and stirred overnight until the startingmaterial was consumed as monitored on analysis by TLC (silica gel,EtOAc/hexanes 1:1). The mixture was quenched with ice-water (500mL) and stirred at r.t. for 30 min. The organic layer was then separated,and the aqueous layer was extracted with DCM (3 × 250 mL). Theorganic layers were combined, washed (200 mL each) sequentiallywith sat. aq NaHCO3, H2O, 10% HCl, brine, and then dried (Na2SO4).The solvent was then concentrated to one quarter of its original volumeunder reduced pressure. The intermediate 6, which was prepared,was used in the next step without further purification.MeOH (1.4 L) was cooled to 0 C using an ice-water cooling bath andsaturated with anhyd ammonia gas. The DCM solution of the aboveprepared intermediate 6 was added to the solution of saturatedMeOH/NH3 at 0 C. The mixture was allowed to warm to r.t. and slowlyheated to reflux (Caution mild exotherm observed) until the startingmaterial was consumed on analysis by TLC (silica gel) in 12 h. Themixture was then cooled to r.t. and the solvent was removed underreduced pressure. The solid which remained was filtered and washedwith H2O (3 × 150 mL), cold EtOAc (3 × 50 mL), and DCM (3 × 50 mL).The crude solid was dissolved in MeOH (600 mL) and DCM (100 mL)at 60 C, and the solution was concentrated to one quarter of its originalvolume. The amide 7 was recrystallized from MeOH and DCM atr.t. and filtered, after which it was washed with DCM to obtain themajority of the pure amide 7 as white crystals. The filtrates werecombined and concentrated under reduced pressure to an oily residue,which was further purified by flash chromatography on silica gel(EtOAc/hexanes 1:1 and 1% of Et3N) to afford additional amide 7;yield: 108.6 g (78% over the two steps); mp 228-229 C; Rf = 0.4 (EtOAc/hexanes 1:1 and 1% of Et3N).1H NMR (300 MHz, DMSO-d6): delta = 10.63 (s, 1 H), 8.55 (d, J = 4.1 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1 H), 7.93 (d, J = 7.4 Hz, 1 H), 7.69 (d, J = 8.6 Hz,1 H), 7.54-7.44 (m, 1 H), 7.42 (s, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 4.23 (s,2 H).13C NMR (75 MHz, DMSO-d6): delta = 170.3, 168.1, 156.3, 148.9, 139.3,137.5, 134.4, 134.1, 127.9, 125.4, 123.9, 123.6, 114.5, 57.6.HRMS (ESI/IT-TOF): m/z [M + H]+ calcd for C14H11BrN3O: 316.0080;found: 316.0076.

Reference： [1]Patent: US2018/312511,2018,A1 .Location in patent: Paragraph 0239-0240
[2]Synthesis,2018,vol. 50,p. 4124 - 4132

54
[ 1563-56-0 ]
methyl 3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)-2-methylpropanoate [ No CAS ]