89415-54-3|5-Bromo-N2-methylpyridine-2,3-diamine| Ambeed

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Quality Control of [ 89415-54-3 ] Purity: 95% SDS Specification

COA

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Product Details of [ 89415-54-3 ]

CAS No. :	89415-54-3
Formula :	C₆H₈BrN₃
M.W :	202.05
SMILES Code :	NC1=CC(Br)=CN=C1NC
MDL No. :	MFCD07375019
InChI Key :	BKWVCWSASGSHSS-UHFFFAOYSA-N
Pubchem ID :	15194032

Safety of [ 89415-54-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 89415-54-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	2.0
Molar Refractivity	45.65
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	50.94 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.53
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	1.18
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.29
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.	0.72
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	0.99
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.14

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.21
Solubility	1.23 mg/ml ; 0.00611 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.85
Solubility	2.88 mg/ml ; 0.0143 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	-2.96
Solubility	0.221 mg/ml ; 0.00109 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.	-6.69 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)	2.04

Application In Synthesis of [ 89415-54-3 ]

* 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 [ 89415-54-3 ]
Downstream synthetic route of [ 89415-54-3 ]

[ 89415-54-3 ] Synthesis Path-Upstream 1~2

1
[ 89415-54-3 ]
[ 149-73-5 ]
[ 37805-78-0 ]

References: [1] Patent: WO2011/15343, 2011, A1, . Location in patent: Page/Page column 43.

2
[ 64-18-6 ]
[ 89415-54-3 ]
[ 37805-78-0 ]

References: [1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 467 - 471.

[ 89415-54-3 ] Synthesis Path-Downstream 1~35

1
[ 43229-87-4 ]
[ 89415-54-3 ]
4-[(7-bromo-4-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]-pyrazin-2-yl)methyl]-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.2%	In ethanol;	e. 4-[(7-bromo-4-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]-pyrazin-2-yl)methyl]-benzonitrile Prepared analogously to Example 7f from <strong>[89415-54-3]3-amino-5-bromo-2-methylamino-pyridine</strong> and 3-(4-cyano-phenyl)-2-oxo-propionic acid in ethanol. Yield: 26.2% of theory, Rf value: 0.68 (silica gel; methylene chloride/ethanol/glacial acetic acid=4:1:0,01).

References: [1]Patent: US6200976,2001,B1 .

2
[ 70232-59-6 ]
[ 89415-54-3 ]

Yield	Reaction Conditions	Operation in experiment
~ 100%		Step 2. 5-bromo-N2-methylpyridine-2,3-diamine; The crude material was dissolved in acetic acid (10 ml) and water (2.5 ml) and iron (445 mg, 7.97 mmol) was added. The reaction was stirred at room temperature for 40 minutes and then poured into 5 N NaOH (40 ml), and the suspension was cooled briefly in an ice water bath. Then, the suspension was filtered through a Celite (diatomaceous earth), pad, which was washed with water, EtOAC, and 10: 1 DCM / MeOH. The biphasic solution was separated, and the aqueous phase was extracted with 10: 1 DCM / MeOH. The Celite (diatomaceous earth), pads were washed again with MeOH, and this filtrate was combined with the organic extracts, concentrated, and dried under high vacuum in water bath (~ 60 C) to afford 5-bromo-N2-methylpyridine-2,3-diamine (427 mg, ~ 100%). LCMS supports structure of compound (peak at 0.7 minutes with m/e of 202 and 204). Compound isolated in ~ 100% yield over 2 steps. MS (ESI pos. ion) m/z: 202 (MH+, 79Br), 204 (MH+, 81Br). Calculated exact mass for C6H8BrN3 201 (79Br), 203 (81Br).
92.5%	With hydrogen;aluminum nickel; In ethyl acetate;	d. 3-amino-5-bromo-2-methylamino-pyridine Prepared analogously to Example 3d from 5-bromo-3-nitro-2-methylamino-pyridine and Raney nickel/hydrogen in ethyl acetate. Yield: 92.5% of theory, Rf value: 0.18 (silica gel; methylene chloride/ethanol=19:1).
77%		63b (2.95 g, 1 eq) is dissolved in THF (51 mL) and 1N aq HCl (50 mL, 3.9 eq) and tin powder (2.57 g, 1.70 eq) are added and stirred at RT for 3 h. 1N NaOH (50 mL) is added, followed by brine. The mixture is extracted with EtOAc (3×). The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The obtained 63c is dried under high vacuum and used in the subsequent step without further purification (1.98 g, 77%).

		A suspension of (5-brorno-3-nitro-py?din-2-yl)-methylamine (Stage 67.1.5, 4.58 g, 19.75 mmol) and tin dichloride dihydrate (Acros, Basel, Switzerland, 13.38 g, 59 3 mmol) in 200 ml of THF was heated at 7OC for 220 mialpha The solvent was removed by evaporation and the residue taken in CH2CI2 (100 ml) and 5 M aqueous NaOH (50 ml) and stirred until all the solid was dissolved. The organic layer was separted and the aqueous layer was extracted with CH2CI2 The combined organic layers were washed with brine, dried over Na?SO4l ftltered and evaporated to give the tie compound as a brown solid. (HPLC tR 1 69 min (Method A), M+H = 202, 204 MS-ES)
	With tin(II) chloride dihdyrate; In ethyl acetate; for 3.5h;Reflux;	[00134] SnCI22H2O (4.71 g, 20.9 mmol) is added to a solution of (5-bromo-3-nitro- pyridin-2-yl)-methyl-amine (0.97 g, 4.2 mmol) in EtOAc and the mixture is heated to reflux for 3.5 h. The mixture is then cooled, diluted with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic phase is dried over anhydrous Na2SO4 and evaporated to dryness to give sufficiently pure 5-Bromo-N2*-methyl-pyridine-2,3- diamine.
	With iron; ammonium chloride; In ethanol; water; for 2h;Reflux;	A mixture of the 5-bromo-/V-methyl-3-nitro-2-pyridinamine (1.14 g, 4.21 mmol assumed). and ammonium chloride (1.103 g, 20.62 mmol) in EtOH^O (8.5 mL of a 1 :1 solution) was stirred as iron (1 .152 g, 20.62 mmol) was added. The mixture was heated to reflux for ~ 2 hours. The mixture was allowed to cool to room temperature then diluted with EtOH and filtered through Celite. The filtrate was concentrated to yield a black tar which was diluted with EtOH then concentrated three times. The residue was slurried in EtOH then filtered. The filtrate was concentrated to yield a black solid which was dissolved in pyridine (15.1 mL). N, N dimethylaminopyridine (0.060 g, 0.49 mmoL) was added followed bybenzenesulfonylchlonde (0.63 mL, 4.91 mmol). The resulting mixture was stirred for one hour under a nitrogen atmosphere. The mixture was then concentrated. The residue diluted with EtOAc, washed with water two times, then saturated NaHC03 followed by brine, dried(Na2S0 ) and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes). Fractions containing the product were combined and concentrated to yield A/-[5-bromo-2-(methylamino)-3-pyridinyl]benzenesulfonamide (0.859 g, 2.51 mmol 60% over 3 steps) as a grey solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.58 (br. s., 1 H) 7.94 (br. s., 1 H) 7.75 - 7.64 (m, 3 H) 7.62 - 7.55 (m, 2 H) 6.92 (d, J=2.3 Hz, 1 H) 6.25 (br. s., 1 H) 2.68 (d, J=4.5 Hz, 3 H) LCMS: m/z 344 (M+1 ).
	With tin(II) chloride dihdyrate; In ethanol; at 20 - 80℃; for 4h;	5-Bromo-N2-methylpyridine-2,3-diamineTo a solution of 5-bromo-N-methyl-3-nitropyridin-2-amine (800 mg, 3.45 mmol) in EtOH (20 ml_) at RT, SnCI2-2 H20 (31 12 mg, 13.79 mmol) was added. The reaction mixture was stirred for the 4 h at 80 C. The solvent was evaporated under reduce pressure and saturated NaHC03solution was added to pH=7 then was extracted with EtOAc (2x), and the combined organic layers were washed once with brine. The organic layer was concentrated to give 720 mg (103%) of the title compound. LC-MS m/z 202.1 , 203.9 (M+H)+, 0.33 (ret. time).
	With ammonium metavanadate; platinum on carbon; hydrogen; hypophosphorous acid; In tetrahydrofuran; ethanol; water; at 20 - 45℃; under 15201.0 Torr; for 1.5h;	Into a pressure reactor was charged with Pt/C (5% wt, 78.7 g, 10.6% w/w), aq. H3PO2 (50 % wt, 5.8 g), NH4VO3 (2.1 g), THF/EtOH (V/V = 1/1, 12.1 L) and 5-bromo-N-methyl-3-nitropyridin-2-amine (740 g, 3.19 mol). The reactor was purged with hydrogen and pressurized to 20 atm followed by stirring at 20 to 30 C for about 0.5 h. Then the mixture was re-pressurized to 20 atm with hydrogen and stirred at 30 to 45 C for 1 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite followed by washing the cake with THF (1 L). The combined filtrate was concentrated at 40 to 45 C under vacuum. Solvent chasing distillation by n-heptane (1 L × 2) and dilution with ACN (3 L) afforded a dark solution of the title compound in ACN which was used in the next step without further purification

References: [1]Patent: WO2009/17822,2009,A2 .Location in patent: Page/Page column 79; 80.
[2]Patent: US6200976,2001,B1 .
[3]Patent: US2010/261714,2010,A1 .Location in patent: Page/Page column 89.
[4]Patent: WO2010/139731,2010,A1 .Location in patent: Page/Page column 174-175.
[5]Patent: WO2011/15343,2011,A1 .Location in patent: Page/Page column 43.
[6]Patent: WO2012/37108,2012,A1 .Location in patent: Page/Page column 245-246.
[7]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 204; 205.
[8]Patent: WO2018/67786,2018,A1 .Location in patent: Page/Page column 107; 108; 109.

3
[ 108-21-4 ]
[ 89415-54-3 ]
[ 67-64-1 ]
[ 1112982-74-7 ]
[ 1112982-75-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3. 5-bromo-N3-isopropyl-N2-methylpyridine-2.3-diamine and 6-bromo-2,2,3-trimethyl-2.3-dihydro- 1H-imidazor4.5-blpyridine; <strong>[89415-54-3]5-bromo-N2-methylpyridine-2,3-diamine</strong> (54.4 mg, 0.269 mmol) was dissolved in isopropyl acetate (1.5 ml) and acetone (23 mul, 0.31 mmol), trifluoroacetic acid (0.045 ml, 0.58 mmol), and sodium triacetoxyborohydride (64 mg, 0.30 mmol) were added. The reaction was stirred under nitrogen at room temperature for 4 hours, and then more acetone was added (0.040 ml) along with TFA (0.090 ml) and isopropyl acetate (0.5 ml). The reaction was then stirred overnight. This reaction was repeated on a larger scale using <strong>[89415-54-3]5-bromo-N2-methylpyridine-2,3-diamine</strong> (288 mg, 1.43 mmol), 2,2,2-trifluoroacetic acid (0.30 ml, 3.9 mmol), acetone (0.13 ml, 1.8 mmol), and sodium triacetoxyborohydride (352 mg, 1.66 mmol). Then, both reactions were poured into water (25 ml), and solid sodium hydroxide was added to raise the pH to about 10. The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum. To afford 5-bromo-N3-isopropyl-N2-methylpyridine-2,3-diamine and 6-bromo-2,2,3- trimethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridine (399 mg, 97% combined yield). 5-bromo-N3-isopropyl-N2-methylpyridine-2,3-diamine: MS (ESI pos. ion) m/z: 244 (MH+, 79Br), 246 (MH+, 81Br). Calculated exact mass for C9H14BrN3 243 (79Br), 245 (81Br). 6-bromo-2,2,3-trimethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridine: MS (ESI pos. ion) m/z: 242 (MH+, 79Br), 244 (MH+, 81Br). Calculated exact mass for C9H12BrN3 241 (79Br), 243 (81Br).

References: [1]Patent: WO2009/17822,2009,A2 .Location in patent: Page/Page column 79; 80.

4
[ 1445-45-0 ]
[ 89415-54-3 ]
[ 92260-32-7 ]

Yield	Reaction Conditions	Operation in experiment
84%		63c (1.00 g, 1 eq) is dissolved in DMF (2.8 mL) and trimethyl orthoacetate (2.87 mL, 3.5 eq). Reaction mixture is stirred at 100 C. for 1 h, then acetic acid (570 muL, 2 eq) is added and heating is pursued for 16 h. After cooling, the reaction mixture is diluted with EtOAc and the resulting solution is washed with a 1:1 brine:sat aq sodium bicarbonate. The aqueous layer is re-extracted with EtOAc (3×), and the combined organic extracts are evaporated under reduced pressure to obtain 63d, used without further purification in the following step (944 mg, 84%).

References: [1]Patent: US2010/261714,2010,A1 .Location in patent: Page/Page column 89.

5
[ 89415-54-3 ]
[ 78-39-7 ]
[ 92260-32-7 ]

Yield	Reaction Conditions	Operation in experiment
	at 140℃; for 38.5h;	A solution of 5-bromo-N2-methyl-pyridine-2 3-diamine (Stage 67.1.4, 960 mg, 4 75 mmol) in triethylorthoacetate (Aldrich, Buchs, Switzerland, 25 ml) was stirred for 38 5 h at 140C. The reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over Na2SO4, filtered and evaprated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0% - 4%) to give the title compound as a brown solid (HPLC. tR 1 95 mm (Method A); M+H = 226, 228 MS-ES).
	With acetic acid; at 80℃; for 2h;	To a suspension of <strong>[89415-54-3]5-bromo-N2-methylpyridine-2,3-diamine</strong> (510 mg, 2.51 mmol) in AcOH (20 mL) was added MeC(OEt)3 (1 mL) and the solution was warmed to 80 C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-25% THF/CH2Cl2 gradient) to afford the desired product. 1H NMR (400 MHz, CDCl3) delta 8.36 (d, J=1.8 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 3.80 (s, 3H), 2.65 (s, 3H).

References: [1]Patent: WO2010/139731,2010,A1 .Location in patent: Page/Page column 181-182.
[2]Patent: US2013/281433,2013,A1 .Location in patent: Paragraph 1373.

6
[ 89415-54-3 ]
[ 1257554-00-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sulfuric acid; sodium nitrite; at 20℃; for 1h;	6-Bromo-3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridineTo a solution of <strong>[89415-54-3]5-bromo-N2-methylpyridine-2,3-diamine</strong> (720 mg, 3.56 mmol) inH2S04(1.90 muIota_, 35.6 mmol) at RT, NaN02(246 mg, 3.56 mmol) was added. The reaction mixture was stirred for 1 h after which time water was added to quench the reaction. EtOAc was added, and the layers were separated. The aqueous layer was extracted once with EtOAc, and the combined organic layers were washed once with brine. The organic layer was concentrated to give 694 mg (91 %) of the title compound. LC-MS m/z 212.8, 214.8 (M+H)+, 0.66 (ret. time).
		To a solution of 5-brom?-N2-methyl-pyridine-2,3-diamine (Stage 67.1.4, 1 2 g, 5.94 mmol) in 2 M aqueous HCI (70 ml) cooled with an ice-bath was added a solution of sodium nitrite (Fluka, Buchs, Switzerland, 492 mg, 7 13 mmol) in water (10 ml) The reaction mixture was stirred at 0C for 1 h and at rt for 75 mm then basifed with 2 M aqueous NaOH (75 ml) and extracted with EtOAc The organic layer was washed with brine, dried over NaaSO,., filtered and evaprated The crude product was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0% - 30%) to give the title compound as a blue solid (HPLC tR 2 46 min (Method A), M+H = 213, 215 MS-ES),

References: [1]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 205.
[2]Patent: WO2010/139731,2010,A1 .Location in patent: Page/Page column 180-181.

7
[ 1850-14-2 ]
[ 89415-54-3 ]
6-bromo-2-methoxy-3-methylimidazo<4,5-b>pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; at 100℃; for 1.5h;	A solution of 5-bromo-N2-methylpyridine-2,3-diamine (Stage 67.1.4, 960 mg, 4 75 mmo.) and tetramethyl orthocarbonate (Aki?ch, Buchs, Switzerland, 2 ml, 14 7 mmol) and acetic acid (0 273 ml, 4 75 mmol) was stirred for 90 min at 100 C The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated aqueous NaHCO3 and with brine, then dried over Na2SO4, filtered and evaprated The crude product was dry loaded on silica gel and purifted by MPLC (DCM/MeOH 0% - 4%) to g>;ve the title compound as a green solid. (HPLC tR 2.83 mm (Method A), M+H - 242, 244 MS-ES).

References: [1]Patent: WO2010/139731,2010,A1 .Location in patent: Page/Page column 179.

8
[ 89415-54-3 ]
[ 33842-02-3 ]
[ 1257553-97-1 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one; at 20℃; for 17h;	A solution of 5-bromo-N2-methyl-pyridine-2,3-diamine (Stage 67,1.4, 2 09 g 10 34 mrnol) and dichloromethylene-dimethyliminium chloride (Aldrich, Buchs, Switzerland 5 04 g, 31 0 mmol) in NMP (60 ml) was stirred for 17 h at rt The reaction mixture was quenched with saturated aqueous NaHCO3 and EtOAc The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated aqueous NaHCO3 and with brine, then dned over Na2SO4, filtered and evaporated The crude product was dry loaded on silica gel and pu?fied by MPLC (DCM/MeOH 0% ? 5%) to give the title compound as a red solid (HPLC t« 2 13 mm (Method A). M+H - 255, 257 MS-ES)

References: [1]Patent: WO2010/139731,2010,A1 .Location in patent: Page/Page column 178.

9
[ 89415-54-3 ]
[ 149-73-5 ]
[ 37805-78-0 ]

Yield	Reaction Conditions	Operation in experiment
	for 3h;Reflux;	[00135] 5-Bromo-N2-methyl-pyridine-2,3-diamine (0.85 g, 4.55 mmol) is dissolved in trimethylorthoformate (12 mL) and the solution is heated to reflux for 3h, then cooled and evaporated to dryness. The solid residue is purified by flash column chromatography to give the title compound as a yellow oil.

References: [1]Patent: WO2011/15343,2011,A1 .Location in patent: Page/Page column 43.

10
[ 67443-38-3 ]
[ 89415-54-3 ]

References: [1]Patent: WO2011/15343,2011,A1 .
[2]Patent: WO2012/37108,2012,A1 .
[3]Patent: WO2018/67786,2018,A1 .
[4]Patent: US2010/261714,2010,A1 .

11
[ 89415-54-3 ]
[ 98-09-9 ]
[ 1366131-89-6 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; for 1h;Inert atmosphere;	A mixture of the 5-bromo-/V-methyl-3-nitro-2-pyridinamine (1.14 g, 4.21 mmol assumed). and ammonium chloride (1.103 g, 20.62 mmol) in EtOH^O (8.5 mL of a 1 :1 solution) was stirred as iron (1 .152 g, 20.62 mmol) was added. The mixture was heated to reflux for ~ 2 hours. The mixture was allowed to cool to room temperature then diluted with EtOH and filtered through Celite. The filtrate was concentrated to yield a black tar which was diluted with EtOH then concentrated three times. The residue was slurried in EtOH then filtered. The filtrate was concentrated to yield a black solid which was dissolved in pyridine (15.1 mL). N, N dimethylaminopyridine (0.060 g, 0.49 mmoL) was added followed bybenzenesulfonylchlonde (0.63 mL, 4.91 mmol). The resulting mixture was stirred for one hour under a nitrogen atmosphere. The mixture was then concentrated. The residue diluted with EtOAc, washed with water two times, then saturated NaHC03 followed by brine, dried(Na2S0 ) and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes). Fractions containing the product were combined and concentrated to yield A/-[5-bromo-2-(methylamino)-3-pyridinyl]benzenesulfonamide (0.859 g, 2.51 mmol 60% over 3 steps) as a grey solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.58 (br. s., 1 H) 7.94 (br. s., 1 H) 7.75 - 7.64 (m, 3 H) 7.62 - 7.55 (m, 2 H) 6.92 (d, J=2.3 Hz, 1 H) 6.25 (br. s., 1 H) 2.68 (d, J=4.5 Hz, 3 H) LCMS: m/z 344 (M+1 ).

References: [1]Patent: WO2012/37108,2012,A1 .Location in patent: Page/Page column 245-246.

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References: [1]Patent: WO2012/37108,2012,A1 .

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References: [1]Patent: WO2012/37108,2012,A1 .

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