910543-72-5|3-Amino-5-bromo-1-methylpyridin-2(1H)-one| Ambeed

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Quality Control of [ 910543-72-5 ] Purity: 95% SDS Specification

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Structure-Guided Design and Synthesis of Pyridinone-Based Selective Bromodomain and Extra-Terminal Domain (BET)-First Bromodomain (BD1) Inhibitors

Yangfeng Li ; Zhengnan Shen ; Kiira Ratia ; Jiong Zhao ; Fei Huang ; Oleksii Dubrovyskyii , et al.

DOI: 10.1021/acs.jmedchem.3c01837 JMC,2024,67(4):2712-2731.

Abstract: The bromodomain and extra-terminal domain (BET) proteins are epigenetic readers, regulating transcription via two highly homologous tandem bromodomains, BD1 and BD2. Clinical development of nonselective pan-BD BET inhibitors has been challenging, partly due to dose-limiting side effects such as thrombocytopenia. This has prompted the push for domain-selective BET inhibitors to achieve a more favorable therapeutic window. We report a structure-guided drug design campaign that led to the development of a potent BD1-selective BET inhibitor, 33 (XL-126), with a Kd of 8.9 nM and 185-fold BD1/BD2 selectivity. The high selectivity was first assayed by SPR, validated by a secondary time-resolved fluorescence energy transfer assay, and further corroborated by BROMOscan (∼57–373 fold selectivity). The cocrystal of 33 with BRD4 BD1 and BD2 demonstrates the source of selectivity: repulsion with His437 and lost binding with the leucine clamp. Notably, the BD1 selectivity of BET inhibitor 33 leads to both the preservation of platelets and potent anti-inflammatory efficacy.

Purchased from AmBeed: 910543-72-5 ; 56-84-8 ; 71-00-1 ; 944937-53-5 ; 1793016-39-3 ; 50618-82-1

Product Details of [ 910543-72-5 ]

CAS No. :	910543-72-5
Formula :	C₆H₇BrN₂O
M.W :	203.04
SMILES Code :	O=C1C(N)=CC(Br)=CN1C
MDL No. :	MFCD09835082
InChI Key :	KRUDZWOELKQDJW-UHFFFAOYSA-N
Pubchem ID :	52911268

Safety of [ 910543-72-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 910543-72-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	44.07
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	48.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.6
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.33
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.74
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.76
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.87
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.86

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.75
Solubility	3.6 mg/ml ; 0.0178 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.9
Solubility	25.4 mg/ml ; 0.125 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.99
Solubility	2.06 mg/ml ; 0.0102 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.3 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.86

Application In Synthesis of [ 910543-72-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 910543-72-5 ]

[ 910543-72-5 ] Synthesis Path-Downstream 1~35

1
[ 14529-54-5 ]
[ 910543-72-5 ]

Yield	Reaction Conditions	Operation in experiment
54%		Example 2N-{3-[5-(4-Amino-pyridin-2-ylamino)-l-methyl-6-oxo-l,6-dihydro-pyridin-3-yl]- 2-methyl-phenyl}-4-ter/-butyl-benzamide (7); 3-Amino-5-bromo-l-methyl-lH-pyridin-2-one (4)[00186] A 48-mL sealed tube equipped with a magnetic stirring bar was charged with benzophenone imine (0.43 g, 2.4 mmol), 3,5-dibromo-l-methyl-lH- pyridin-2-one (1) (0.51 g, 2.0 mmol), Pd(OAc)2 (0.025 g, 0.040 mmol), rac-BINAP (0.082 g, 0.13 mmol), and Cs2CO3 (0.92 g, 2.8 mmol) in dioxane (15 mL). After the mixture was degassed for 15 min., it was heated at 95 0C for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane (3 x 10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude product was dissolved in 1 N HCl/MeOH (3 mL) and stirred for 1 h at room temperature. Then, to the reaction mixture was added sat. NaHCO3 (10 mL) and dichloromethane (10 mL), and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10 % MeOH in dichloromethane/ether (1/1), to afford 0.22 g (54 %) of 3-amino-5-bromo-l-methyl- lH-pyridin-2-one (4) as a solid.

References: [1]Advanced Synthesis and Catalysis,2010,vol. 352,p. 1677 - 1687.
[2]Patent: WO2008/33854,2008,A1 .Location in patent: Page/Page column 66.

2
[ 910543-72-5 ]
[ 910235-65-3 ]
[ 1011797-06-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 170℃; for 0.5h;Microwave irradiation;	A mixture of 46 (0.248 g, 1.22 mmol, CASRN 910543-72-5), A-6 (0.574 g, 1.46 mmol), Na2CO3 (0.388 g, 3.66 mmol), and Pd(0)(PPh3)4 (0.141 g, 0.122 mmol) in DME (10 mL) and H2O (5 mL) was stirred and heated at 170 C. for 30 min in a microwave synthesizer. The mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was extracted with two 100 mL portions of EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 4% MeOH) to afford 0.341 g (72%) of 48 as a yellow solid. The material was not completely pure but was used as is in the next step.
68%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 16.25h;	N-[3-(5-Amino-l-methyl-6-oxo-l,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-4- terf-butyl-benzamide (5); <n="68"/>[00187] A 48-mL sealed tube equipped with a magnetic stirring bar was charged with 3-amino-5-bromo-l -methyl- lH-pyridin-2-one (4) (0.10 g, 0.50 mmol), 4-tert-butyl-iV-[2-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- benzamide (0.24 g, 0.70 mmol), and Pd(PPh3)4 (0.030 g, 0.025 mmol) in DME (10 mL) and IN Na2CO3 (5 mL). After the mixture was degassed for 15 min., it was heated at 95 0C for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10 % MeOH in dichloromethane/ether (1/1), to afford 0.14 g (68 %) of iV-[3-(5-amino-l-methyl-6-oxo-l,6-dihydro-pyridin-3-yl)-2-methyl- phenyl]-4-te/t-butyl-benzamide (5) as a solid.
68%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 16h;	N-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (3) A 48-mL seal tube equipped with a magnetic stirring bar was charged with <strong>[910543-72-5]3-amino-5-bromo-1-methyl-1H-pyridin-2-one</strong> (2) (0.10 g, 0.50 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.24 g, 0.70 mmol), and Pd(PPh3)4 (0.030 g, 0.025 mmol) in DME (10 mL) and 1N Na2CO3 (5 mL). After the mixture was degassed for 15 min., it was heated at 95 C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10% MeOH in dichloromethane/ether (1/1), to afford 0.14 g (68%) of N-[3-(5-amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (3) as a solid.

References: [1]Patent: US2009/105209,2009,A1 .Location in patent: Page/Page column 53.
[2]Patent: WO2008/33854,2008,A1 .Location in patent: Page/Page column 67.
[3]Patent: US2008/153834,2008,A1 .Location in patent: Page/Page column 22.

3
[ 75-44-5 ]
[ 910543-72-5 ]
C₇H₆BrClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; toluene; at 0℃; for 1h;	Triethylamine (21 muL, 0.15 mmol) was added to a solution of 3-amino-5-bromo-l- methylpyridin-2(lH)-one (30.0 mg, 0.15 mmol) and phosgene (20% wt. in toluene; 16.0 muL, 0.15 mmol) in tetrahydrofuran (1 mL) at 0 0C. After 1 h, l-piperidin-4-yl-l,3-dihydro-2H-imidazo[4,5-delta]pyridin-2- one (32 mg, 0.15 mmol) and triethylamine (62 muL, 0.44 mmol) were sequentially added. The reaction mixture was allowed to warm to ambient temperature. After 18 h, the reaction mixture was filtered and concentrated. Purification by reverse phase EtaPLC (C- 18, 95% water/ acetonitrile ? 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (26 mg). MS 447.1 (M).

References: [1]Patent: WO2006/99268,2006,A2 .Location in patent: Page/Page column 69.
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 512 - 516.

4
[ 153888-45-0 ]
[ 910543-72-5 ]

Yield	Reaction Conditions	Operation in experiment
77%		3-Amino-5-bromo-1-methylpyridin-2-one (42); A 1-L three-neck round-bottomed flask equipped with a mechanical stirrer and reflux condenser was purged with nitrogen and charged with 41 (21.7 g, 93.3 mmol), ethanol (305 mL), iron powder (-325 mesh, 52.1 g, 933 mmol) and 2N hydrochloric acid (50 mL, 100 mmol), and the mixture was heated for 2 h at 60 C. After this time, the reaction was cooled to room temperature, and potassium carbonate was added to pH 8 as determined by a pH paper. The resulting suspension was filtered and the filter cake washed with ethanol (4×100 mL). The filtrate was concentrated under reduced pressure to yield a brown solid. This solid was purified by column chromatography on silica gel to afford 42 in 77% yield (14.5 g) as an off-white powder: mp 104-105 C.; 1H NMR (500 MHz, DMSO-d6) delta 7.15 (d, 1H, J=2.5 Hz), 6.46 (d, 1H, J=2.5 Hz), 5.45 (bs, 2H), 3.40 (s, 3H); MS (ESI+) m/z 203 (M+H).
34%	With iron; ammonium chloride; In ethanol; water-d2; at 95℃; for 3h;Inert atmosphere;	Iron powder (1 g, 18 mmol, 4.2 equivalents) and ammonium chloride (0.964 g, 18 mmol, 4.2 equivalents) were added to a solution of 1-methyl-3-nitro-5-bromo-pyridin-2-one (1 g, 4.3 mmol, 1 equivalent) in ethanol (8 mL) and water (6 mL) and stirred at 95 C for 3 hours. The solution was then filtered through a pad of celite and concentrated. The residue was then taken up in water (20 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were dried over magnesium sulfate and concentrated to give a brown oil that solidified upon standing. The residue was purified by SCX to give the desired product as a dark red solid (300 mg, 34%).
	With tin(ll) chloride; In N,N-dimethyl-formamide; at 80℃; for 1.5h;	Tin(?) chloride dihydrate (53.3 g, 236 mmol) was added to a solution of 5-bromo-l- methyl-3-nitropyridin-2(lH)-one (11.0 g, 47.2 mmol) in ethyl acetate (400 mL) at 80 0C. After 1.5 h, the reaction mixture was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (3x), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 203.1 (M).

With iron; ammonium chloride; In ethanol; water; at 60℃; for 2h;

3-Amino-5-bromo-1-methyl-1H-pyridin-2-one C-12 Iron powder (21.6 g; 0.39 mol) is added to a suspension of 5-bromo-1-methyl-3-nitro-1H-pyridin-2-one H (18.0 g; 0.08 mol) in EtOH (120.0 mL) and saturated aqueous NH4Cl (60.0 mL) at 60 C. The reaction is stirred at 60 C. for 2 h. The reaction mixture is then filtered and the solid residue on the filter is washed with EtOAc. The filtrate is concentrated under reduced pressure and extracted with EtOAc (3*100.0 mL). The combined extracts are washed with brine, dried with Na2SO4, filtered and concentrated. The residue is purified by column chromatography to afford the desired compound. HPLC-MS: (M+H)+=203/205; tRet=1.248 min; method M11

References: [1]Organic Process Research and Development,2014,vol. 18,p. 228 - 238.
[2]Patent: US2009/82330,2009,A1 .Location in patent: Page/Page column 39-41.
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3021 - 3029.
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 755 - 758.
[5]Patent: WO2006/99268,2006,A2 .Location in patent: Page/Page column 69.
[6]Patent: US2018/44335,2018,A1 .Location in patent: Paragraph 0446-0447.

5
[ 185961-99-3 ]
[ 75-44-5 ]
[ 910543-72-5 ]
[ 910543-73-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 755 - 758.

6
[ 1013-88-3 ]
[ 14529-54-5 ]
[ 910543-72-5 ]

Yield	Reaction Conditions	Operation in experiment
54%		3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (2) A 48-mL seal tube equipped with a magnetic stirring bar was charged with benzophenone imine (0.43 g, 2.4 mmol), 3,5-dibromo-1-methyl-1H-pyridin-2-one (1) (0.51 g, 2.0 mmol), Pd(OAc)2 (0.025 g, 0.040 mmol), rac-BINAP (0.082 g, 0.13 mmol), and Cs2CO3 (0.92 g, 2.8 mmol) in dioxane (15 mL). After the mixture was degassed for 15 min., it was heated at 95 C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane (3*10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude product was dissolved in 1 N HCl/MeOH (3 mL) and stirred for 1 h at room temperature. Then, to the reaction mixture was added sat. NaHCO3 (10 mL) and dichloromethane (10 mL), and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10% MeOH in dichloromethane/ether (1/1), to afford 0.22 g (54%) of 3-amino-5-bromo-1-methyl-1H-pyridin-2-one (2) as a solid.

References: [1]Patent: US2008/153834,2008,A1 .Location in patent: Page/Page column 21-22.

7
[ 75-44-5 ]
[ 910543-72-5 ]
[ 74-89-5 ]
[ 1147531-83-6 ]

Yield	Reaction Conditions	Operation in experiment
99%		To a solution of 46 (0.5 g, 2.46 mmol), DIPEA (0.952 g; 7.38 mmol) and DCM (40 mL) cooled to 0 C. under a nitrogen atmosphere was added phosgene (1.8 mL, 3.69 mmol, 20% in toluene). The reaction mixture was stirred for 20 min then methylamine (12 mL, 24.6 mmol, 2M solution in THF) was added slowly. The mixture warmed to RT and stirred for 5 h. The product was filtered, washed with DCM and dried in vacuo to afford 0.8 g (99%, 80% pure) of 62 which was used in the following step without further purification.

References: [1]Patent: US2009/105209,2009,A1 .Location in patent: Page/Page column 56-57.

8
[ 64614-49-9 ]
[ 910543-72-5 ]
[ 1147530-81-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a 0 C. solution of 66 (14.00 g, 61.77 mmol) and 46 (12.54 g, 61.77 mmol DMF (160 mL) was added sodium hydride (95%, 3.12 g, 123.5 mmol). This solution was slowly warmed to RT, stirred for 18 h then poured into 1.3 L cold water. EtOAc (3mL) was added and the resulting precipitate was filtered, washed with water, and air dried for 3 d to afford 18.84 g (47.91 mmol) of 68: MS (ESI) 393.1 (M+H)+.

References: [1]Patent: US2009/105209,2009,A1 .Location in patent: Page/Page column 58.
[2]Organic Process Research and Development,2014,vol. 18,p. 228 - 238.

9
[ 910543-72-5 ]
[ 27464-17-1 ]
[ 1147531-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 95℃; for 18h;	A heterogeneous mixture of 46 (0.1 g, 0.49 mmol), 158 (0.16 g, 1.5 eq), Pd2(dba)3 (32 mg, 0.07 eq), xantphos (31 mg, 0.1 eq), and Cs2CO3 (0.32 g, 2 eq) in dioxane (1.5 mL) was purged with argon. The mixture was sealed and heated for 18 h in a sand bath at 95 C. The cooled mixture was partitioned between EtOAc and H2O, concentrated, and purified on a preparative SiO2 plate developed with 6% MeOH/DCM to afford 39 mg of 160 as a dark green solid.

References: [1]Patent: US2009/105209,2009,A1 .Location in patent: Page/Page column 67.

10
[ 910543-72-5 ]
[ 64614-50-2 ]
[ 1178884-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; for 18h;	To a solution of (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-l-yl)-methanone (2.0Og, 7.46 mmol) in 10 mL dimethylformamide was added 3-Amino-5-bromo-l -methyl- lH-pyridin-2-one (1.8Og, 8.95mmol) and sodium hydiride (537mg, 22.4mmol). After stirring for 18 hours, this was quenched with water. This was extracted with ethylacetate. The ethylacetate layer was dired over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% methanol/DCM) to yield 5-Bromo-l-methyl-3-[5-(4-methyl- piperazine-l-carbonyl)-pyridin-2-ylamino]-lH-pyridin-2-one (900mg, 1.94mmol). MS (ESI) 406.0 (M+H)+.
	With sodium hydride; In N,N-dimethyl-formamide;	To a solution of (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.00 g, 7.46 mmol) in 10 mL dimethylformamide was added 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (1.80 g, 8.95 mmol) and sodium hydiride (537 mg, 22.4 mmol). After stirring for 18 hours, this was quenched with water. This was extracted with ethylacetate. The ethylacetate layer was dired over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (900 mg, 1.94 mmol). MS (ESI) 406.0 (M+H)+.

References: [1]Patent: WO2009/98144,2009,A1 .Location in patent: Page/Page column 67-68.
[2]Patent: US2010/222325,2010,A1 .Location in patent: Page/Page column 89.

11
[ 910543-72-5 ]
[ 333-20-0 ]
[ 1885-14-9 ]
[ 1198765-36-4 ]

Yield	Reaction Conditions	Operation in experiment
		Phenyl chloroformate (2.32 mL, 3 equiv) in acetone (3 mL) is added dropwise to a suspension of potassium thiocyanate (1.79 g, 3 equiv) in acetone (12 mL) over 5 min. After stirring for 10 min, the slurry is heated to 60 C. for 10 min after which it is cooled to ambient temperature. To this slurry is added aminopyridone (1.25 g, 6.15 mmol) in acetone (5 mL) and the mixture is stirred overnight. The mixture is then filtered, washed with dichloromethane, concentrated in vacuo, and chromatographed (50% to 100% EtOAc/Hexanes) to give slightly impure bromo phenyl carbamate (1.80 g, ~77%)

References: [1]Patent: US2010/222325,2010,A1 .Location in patent: Page/Page column 130.

12
[ 910543-72-5 ]
[ 463-71-8 ]
C₇H₆BrClN₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In chloroform; water;	Preparation of 1-(5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-3-(2-hydroxy-ethyl)-thiourea To a solution of 5-bromo-3-amino-1-methyl-2-pyridone (500 mg, 2.46 mmol) in chloroform (12 mL) was added a solution of saturated aqueous sodium bicarbonate (12 mL). To the vigorously stirred mixture was added thiophosgene (0.2 mL, 2.7 mmol) via drop-wise addition. The mixture was stirred for 1 hour and then transferred to a separatory funnel. The chloroform phase was collected and the aqueous phase was back extracted with methylene chloride (10 mL). The organic phases were combined in a 100 mL round bottom flask. To the rapidly stirred solution was added ethanolamine (0.16 mL, 2.7 mmol) via slow drop-wise addition. The material was stirred for 1.5 hours and the precipitated product was collected by filtration. The solid was dried in a vacuum oven providing the desired product as a light white-yellow solid (515 mg). (M-H)-=304/306 m/e.

References: [1]Patent: US2010/222325,2010,A1 .Location in patent: Page/Page column 70-71.

13
[ 910543-72-5 ]
[ 1178884-44-0 ]
[ 1198765-39-7 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium phosphate; XPhos;bis(dibenzylideneacetone)-palladium(0); In water; butan-1-ol; at 100 - 110℃; for 0.75h;Inert atmosphere of argon;	3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (392 mg, 1.93 mmol) was placed into 13 ml n-butanol. To this mixture under argon was added: Pddba2 (55.2 mg, 0.096 mmol), XPhos (91.2 mg, 0.191 mmol), acetic acid 2-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (900 mg, 1.93 mmol), potassium phosphate (814 mg, 3.84 mmol) and 4 ml water. The mixture was heated under argon in a sealed flask for 45 minutes at 100-110 C. After cooling, the mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromathography using 5% methanol in dichloromethylene to afford 450 mg of Acetic acid 245-amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (49% yield).

References: [1]Patent: US2010/222325,2010,A1 .Location in patent: Page/Page column 131.

14
[ 910543-72-5 ]
[ 1242156-74-6 ]
[ 1242156-75-7 ]

Yield	Reaction Conditions	Operation in experiment
40%		To a solution of 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine (0.327 g, 1.32 mmol) and 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (0.321 g, 1.58 mmol) in dioxane (5.5 mL) add Cs2CO3 (0.645 g, 1.98 mmol), xantphos (0.153 g, 0.264 mmol) and bubbled argon through reaction mixture for 15 min. Add Pd (OAc)2 (0.03 g, 0.132 mmol) in the end. The reaction was heated at 100 C. under argon for 3 h. TLC shows 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine was gone. The reaction mixture was treated with water (30 mL) and extracted with dichloromethane (3*20 mL). Organic phase was concentrated and loaded onto silica gel column separation. Using 3-5% MeOH in DCM gave 5-bromo-1-methyl-3-[5-(1-methyl-azetidin-3-yloxy)-pyridin-2-ylamino]-1H-pyridin-2-one as green solid (200 mg, 40% yield).

References: [1]Patent: US2010/222325,2010,A1 .Location in patent: Page/Page column 69.

15
[ 910543-72-5 ]
[ 1198765-41-1 ]
[ 1198765-42-2 ]

Yield	Reaction Conditions	Operation in experiment
		Combined in a sealable tube was 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (0.38 g, 1.9 mmol), 2-bromo-5-(tert-butyl-dimethyl-silanyloxy)-pyridine (0.54 g, 1.9 mmol), and Cs2CO3 (0.85 g, 2.6 mmol) in 5 mL of dry 1,4-dioxane. The mixture was bubbled with argon for 10 minutes. To the suspension was added Pd2(dba)3 (0.12 g, 0.13 mmol) and xantphos (0.15 g, 0.26 mmol). The vessel was sealed and heated over night at 85 C. The cooled mixture was filtered over celite, concentrated and purified on a prep plate with 1:1 ethyl acetate/hexanes to give 0.46 g (1.1 mmol) of the desired product as a light yellow solid.

References: [1]Patent: US2010/222325,2010,A1 .Location in patent: Page/Page column 133.

16
[ 910543-72-5 ]
[ 1198765-48-8 ]
[ 1242157-05-6 ]

Yield	Reaction Conditions	Operation in experiment
		Combined in a sealable vial was <strong>[910543-72-5]3-amino-5-bromo-1-methyl-1H-pyridin-2-one</strong> (0.18 g, 0.86 mmol), tert-Butyl-{2-[4-iodo-2-(2-methoxy-ethoxy)-phenoxy]-ethoxy}-dimethyl-silane (0.47 g, 1.04 mmol), and Cs2CO3 (0.42 g, 1.3 mmol) in 10 mL of dry 1,4-dioxane. The mixture was bubbled with argon for 10 minutes. Added to this mixture was Pd(OAc)2 (19 mg, 0.09 mmol) and xantphos (10 mg, 0.17 mmol). The reaction was sealed and heated to 100 C. for 3 hrs. Material was filtered over celite, dry loaded onto granular silica, and chromatographed with a gradient of 30-75% ethyl acetate/hexanes to give 0.19 g (0.35 mmol) of the desired product.

References: [1]Patent: US2010/222325,2010,A1 .Location in patent: Page/Page column 135.

17
[ 15862-34-7 ]
[ 910543-72-5 ]

References: [1]Organic Process Research and Development,2014,vol. 18,p. 228 - 238.
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3021 - 3029.

18
[ 910543-72-5 ]
[ 1178884-09-7 ]

References: [1]Organic Process Research and Development,2014,vol. 18,p. 228 - 238.
[2]Organic Process Research and Development,2014,vol. 18,p. 228 - 238.

19
[ 910543-72-5 ]
[ 1178884-30-4 ]