709652-82-4|2-Amino-5-bromonicotinonitrile| Ambeed

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Quality Control of [ 709652-82-4 ] Purity: 98% SDS Specification

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Product Details of [ 709652-82-4 ]

CAS No. :	709652-82-4
Formula :	C₆H₄BrN₃
M.W :	198.02
SMILES Code :	N#CC1=C(N)N=CC(Br)=C1
MDL No. :	MFCD08688591
InChI Key :	UJKZMLZIIIGCMI-UHFFFAOYSA-N
Pubchem ID :	24229199

Safety of [ 709652-82-4 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301-H315-H318-H335
Precautionary Statements:	P261-P280-P301+P310-P305+P351+P338
Class:	6.1
UN#:	2811
Packing Group:	Ⅲ

Computational Chemistry of [ 709652-82-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	41.06
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	62.7 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.29
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	1.47
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.31
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.	0.36
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	1.29
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.	-2.44
Solubility	0.723 mg/ml ; 0.00365 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.	-2.39
Solubility	0.801 mg/ml ; 0.00404 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-2.61
Solubility	0.487 mg/ml ; 0.00246 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.	-6.46 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	1.0
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)	1.85

Application In Synthesis of [ 709652-82-4 ]

* 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 [ 709652-82-4 ]

[ 709652-82-4 ] Synthesis Path-Downstream 1~35

1
[ 709652-82-4 ]
[ 37904-72-6 ]
C₁₆H₁₃BrN₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		6-bromo-2-(4-(dimethyIamino)phenyl)indolizine-8-carbonitrile (L14).; 2-Bromo-l-(4-(dimethylamino)phenylethanone (11) (1.21 g; 5.00 mmol) and 2-amino-5- bromonicotinonitrile (7j) (1.03 g; 5.2 mmol) were used to give 12j (0.77 g; yield 45 %); mp: 240-246 0C; 1H NMR (400 MHz, DMSO-J6) delta 9.12 (d, 4JHH = 1.8 Hz, IH, Ar-H), 8.32 (s, IH, Ar-H), 8.13 (d, 4JHH = 1.8 Hz, IH, Ar-H), 7.81 (d, 3JHH= 8.9 Hz, 2H, Ar-H), 6.79 (d, 3JHH = 8.9 Hz, 2H, Ar-H), 2.96 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-J6) delta 150.6, 147.4, 141.3, 133.6, 131.1, 127.0 (s, 2C, Ar), 119.9, 114.8, 112.1 (s, 2C, Ar), 109.0, 103.5, 99.9, 39.9 (s, 2C, NCH3). m/z (ES-MS): 443.9 (4%), 441.9 (3%), 344.0 (11%), 343.0 (98%), 342.0 (11%), 341.0 (100%, [M+H]+). HRMS m/z (TOF+): CaIc. C16Hi4N4Br = 341.0402. Found: 341.0389. Error (ppm): - 3.8.

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 4746 - 4758.
[2]Patent: WO2007/124345,2007,A2 .Location in patent: Page/Page column 15.

2
[ 709652-82-4 ]
[ 335033-27-7 ]
[ 709652-81-3 ]

Yield	Reaction Conditions	Operation in experiment
43%		A propionitrile (15 mL) solution of <strong>[709652-82-4]2-amino-5-bromo-nicotinonitrile</strong> (198 mg, 1 mmol), N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-acrylamide (457 mg, 2 mmol) and DIISOPROPYL-ETHYLAMINE (523 UL, 3 mmol) was purged with Argon for 10 min. Pd (OAc) 2 (23 mg, 0.1 mmol) and P (o-Tol) 3 (61 mg, 0.2 mmol) was added and the Argon purge was repeated. The mixture was heated to 100 C and stirred for 6 hr under Argon. Upon cooling, solvents were removed under vacuo and the residue was purified by Flash chromatography (silica, 2% MEOH in CH2CL2). The purified free base was converted to its HCl salt by addition of HCl (1 mL, 1 mmol, 1M in ether). The salt was washed with ether and dried to afford 162 mg (43%) of the title COMPOUND. LH NMR (300 MHz, DMSO-D6) 8 8.50 (m, 2H), 7.55-6. 95 (m, 4H), 6.40 and 6.17 (rotamers, 2s, 1H), 5.03 and 4.83 (rotamers, 2s, 2H), 3.71 and 3.67 (rotamers, 2s, 3H), 3.09 and 2.96 (rotamers, 2s, 3H). MS (ESI) INULE : 346.1662 (M+H) +.

References: [1]Patent: WO2004/52890,2004,A1 .Location in patent: Page 189.

3
[ 24517-64-4 ]
[ 709652-82-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With bromine; sodium carbonate; acetic acid; at 20℃; for 0.5h;	Example 1; 2-amino-5-bromopyridine-3--carbonitrile (2); [00140] 2-aminopyridine-3-carbonitrile 1 (0.56g, 4.6 mmol) was dissolved in 10 mL HOAc, to which one equivalent of Na2CO3 was added. Then, 1.1 equivalent of Br2 was added dropwise and reaction mixture was stirred at room temperature for 30 minutes. Orange precipitation was formed and filtered off to obtain the desired compound 2 in quantitative yield. The compound was carried on without further purification.
98%	With N-Bromosuccinimide; ammonium acetate; In acetonitrile; at 0℃; for 12h;	To a solution of 2-aminonicotinonitrile (10 g, 84 mmol) in dry MeCN (200 ml) NH4Ac (0.64 g, 8.2 mmol) was added. The reaction was cooled to 0 C and NBS (16.44 g,92.4 mmol) was added all at once. After 12 h, solvent was removed under the reduced pressure and 5% hydrochloric acid (360 ml) was added until most of product was redissolved. Resulting solution was filtered, cooled to 0 C, and basified to pH > 10 with 6 M NaOH (200 ml).In 20 min, crystals were collected, washed on the filter with large amount of water and dried in vacuo affording 2-amino-5-bromo-3-pyridinecarbonitrile (Lacbay et al.2014). White crystal; yield 98%; 193-194 C; 1H NMR (400 MHz, DMSO-d6) delta 8.27 (d, J = 2.5 Hz, 1H, H-4),8.14 (d, J = 2.5 Hz, 1H, H-6), 7.13 (s, 2H, NH2); 13C NMR(100 MHz, DMSO-d6) delta 159.22 (C-2), 154.16 (C-6), 144.01(C-4), 116.19 (C?N), 104.28 (C-3), 91.39 (C-5); HRMS(ESI) m/z: calculated for C6H5BrN3+ [M + H]+: 197.9667; found: 197.9670.
96%	With bromine; sodium carbonate; In acetic acid; at 20℃; for 0.833333h;	8.1 Compound 9: 2-Aminonicotinonitrile 8 (100 g, 0.839 mol) was dissolved in HOAc (800 mL) . To the solution was added Na2C03 (88.97 g, 0.839 mol). Then, Br2 (46.4 mL, 0.923 mol) was added dropwise. The reaction mixture was stirred at room temperature for 50 min. To the mixture was added water (600 mL) . The mixture was cooled to about 5C. The precipitate thus formed was collected by filtration and dried to give compound 9 (207 g, 96%) .

96%	With bromine; sodium carbonate; acetic acid; at 20℃; for 0.833333h;	Compound 9: 2-Aminonicotinonitrile 8 (100 g, 0.839 mol) was dissolved in HOAc (800 mL). To the solution was added Na2CO3 (88.97 g, 0.839 mol). Then, Br2 (46.4 mL, 0.923 mol) was added dropwise. The reaction mixture was stirred at room temperature for 50 min. To the mixture was added water (600 mL). The mixture was cooled to about 5 C. The precipitate thus formed was collected by filtration and dried to give compound 9 (207 g, 96%).
94.6%	With bromine; sodium carbonate; acetic acid; at 20℃; for 18h;Inert atmosphere;	Step 1: Preparation of 2-amino-5-bromonicotinonitrile (42) 2-Aminonicotinonitrile (95.0 g, 0.80 mol, 1.0 eq) was dissolved in HOAc (2 L) and then Na2CO3 (93.1 g, 0.88 mol, 1.1 eq) was added. Then Br2 (142.6 g, 0.88 mol, 1.1 eq) in HOAc (2 L) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 18 hours, which was then poured into ice water (10 L), filtered, washed with water (2 L×2) and dried to give the pure intermediate 42 (150.0 g, 0.75 mol, 94.6%). 1H NMR (400 MHz, DMSO-d6) delta 8.28-8.27 (d, J=2.4 Hz, 1H), 8.15-8.14 (d, J=2.4 Hz, 1H), 7.13 (s, 2H).
80%	With bromine; sodium carbonate; acetic acid; at 20℃; for 1h;	To a solution of 2-aminonicotinonitrile (1.5 g, 12.5 mmol, 1.0 eq.) in AcOH (30 mL) was added Na2003 (1.3 g, 12.5 mmol). Bromine (0.7 ml, 13.8 mmol) was added drop wise to the resulting suspension and reaction mixture was stirred at rt for 1 h. The orange precipitate formed was collected by filtration, washed with water and dried to afford 2.0 g (80%) of 1-34 as a yellow solid. NMR (400 MHz, DMSO) 6 8.27 (5, 1 H), 8.15 (5, 1 H), 7.12 (brs, 2H).
78%	With bromine; In acetic acid; at 10 - 20℃; for 22h;	Bromine (1.1 mL, 21 mmol) in ACOH (3 mL) was added dropwise to a solution of 2-AMINO-NICOTINONITRILE (1.00 g, 8.4 mmol) in ACOH (20 mL) at 10 C. The orange mixture was stirred for 22 hours at ambient temperature then diluted with ether (100 mL). The resultant precipitated salt was filtered, washed with ether and dried on air. The precipitate was suspended in water (100 mL), neutralized with 1N NAOH, filtered, washed with water and dried on air to give 1.29 g (78%) title COMPOUND. LH NMR (300 MHz, DMSO-d6) 8 8.27 (d, J= 2. 5HZ, 1H), 8. 14 (d, J= 2. 5HZ, 1H), 7.13 (s, br, 2H). MS (ESI) INULE : 197.9655 (M+H) +.
73%	With bromine; sodium carbonate; acetic acid; at 0 - 20℃; for 2h;	1.1 2-Amino-5-bromo-nicotinonitrile To a solution of 2-amino-nicotinonitrile (0.50 g; 4.11 mmol) in acetic acid (10 mL) was added sodium carbonate (0.48 g; 4.52 mmol) at 0 C followed by the dropwise addition of bromine (0.74 g; 4.52 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The solvent was evaporated under vacuum, the residue was suspended in water (50 mL), filtered by suction and dried to afford the title compound (0.60 g; 73%). The product was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) delta 8.26 (d, J = 2.5 Hz, 1 H), 8.14 (d, J = 2.5 Hz, 1H), 7. 3 (brs, 2H); LC/MS (B), Rt: 2.59 min; (M+2H) 200.
69%	With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid; In 1,2-dimethoxyethane; at 80℃; for 24h;Schlenk technique; Inert atmosphere; Green chemistry;	General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
	With bromine; sodium carbonate; acetic acid; at 20℃; for 2h;	To a stirred solution of compound 1 (560 mg) in HOAc (14 mL) was added sodium carbonate (487 mg, ) and bromine (808 mg)at room temperature. The reaction mixture was stirred at room temperature for 2h. The resulting solids were collected by filtration and dried in vacuum to give compound 2
	With bromine; sodium carbonate; acetic acid; at 20℃; for 2h;	Step-1 [0068] To a stirred solution of compound 1 (560 mg) in HOAc (14 mL) was added sodium carbonate (487 mg,) and bromine (808 mg) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The resulting solids were collected by filtration and dried in vacuum to give compound 2

References: [1]Patent: WO2007/59219,2007,A1 .Location in patent: Page/Page column 54.
[2]Chemical Papers,2018,vol. 72,p. 2965 - 2972.
[3]Patent: WO2013/29548,2013,A1 .Location in patent: Page/Page column 87.
[4]Patent: US2014/179675,2014,A1 .Location in patent: Paragraph 0841.
[5]Patent: US2016/311772,2016,A1 .Location in patent: Paragraph 1260-1263.
[6]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 710 - 714.
[7]Patent: US2015/368241,2015,A1 .Location in patent: Paragraph 0116.
[8]Patent: WO2014/78802,2014,A1 .Location in patent: Page/Page column 92; 93.
[9]Patent: WO2004/52890,2004,A1 .Location in patent: Page 188.
[10]Patent: WO2015/14442,2015,A1 .Location in patent: Page/Page column 54.
[11]Tetrahedron Letters,2014,vol. 55,p. 5058 - 5061.
[12]Patent: WO2013/42035,2013,A1 .Location in patent: Page/Page column 17.
[13]Patent: US2014/249170,2014,A1 .Location in patent: Paragraph 0067; 0068.
[14]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 507 - 512.

4
[ 709652-82-4 ]
[ 75-36-5 ]
[ 941604-21-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium hexamethylsilazane; In tetrahydrofuran; at -78 - 20℃; for 4h;	Potassium bis(trimethylsilyl)amide (25 mL, 12.5 mmol, 0.5M in toluene) was added to a solution of <strong>[709652-82-4]2-amino-5-bromo-nicotinonitrile</strong> (496 mg, 2.5 mmol) in THF (10 mL) at -78 0C which was followed by a dropwise addition of acetyl chloride (533 muL, 7.5 mmol). The reaction was stirred at ambient temperature for 4 h then quenched with ammonium chloride (10 mL, sat). The resulting mixture was extracted with methylene chloride; the organic layer was washed with water and dried over MgSO_j. The volatiles were removed under vacuum to give the title compound (420 mg, 70%). 1H NMR (300 MHz, DMSO-4 delta): 10.92 (s, IH), 8.82 (d, J = 2.3Hz, IH), 8.66 (d, J= 2.3Hz, IH), 2.12 (s, 3H). MS (ESI) m/e: 240 and 242 (M+H)+.

References: [1]Patent: WO2007/67416,2007,A2 .Location in patent: Page/Page column 109.

5
[ 709652-82-4 ]
[ 405224-23-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrogenchloride; sodium nitrite; In water; at -5 - 20℃;	To a stirred solution of compound 2 (4.6 g) in HC1 (48.4 mL ) was added sodium nitrite ( 5.3 mL ) dropwise at-5 C. The reaction mixture was stirred at room temperature for 2h. The resulting solids were collected by filtration and dried in vacuum to give compound 3 (4.4 g, 88%).
88%	With hydrogenchloride; sodium nitrite; In water; at -5 - 20℃; for 2h;	Step-2 [0069] To a stirred solution of compound 2 (4.6 g) in HCl (48.4 mL) was added sodium nitrite (5.3 mL) dropwise at -5 C. The reaction mixture was stirred at room temperature for 2 h. The resulting solids were collected by filtration and dried in vacuum to give compound 3 (4.4 g, 88%).
70%	With hydrogenchloride; sodium nitrite; In water; at 0℃;	Example 2; 5-bromo-2-chloropyridine-3-carbonitrile (3) ; [00141] Compound 2 was dissolved in cone. HCl at O2C, to which 1.1 equivalent of NaNO2 in H2O was added dropwise. Precipitation was formed. The white solid was filtered off, which gave the title compound 3. Overall yield was 70%.

References: [1]Patent: WO2013/42035,2013,A1 .Location in patent: Page/Page column 17.
[2]Patent: US2014/249170,2014,A1 .Location in patent: Paragraph 0067; 0069.
[3]Patent: WO2007/59219,2007,A1 .Location in patent: Page/Page column 54.

6
[ 709652-82-4 ]
[ 1246362-00-4 ]
[ 1246362-01-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 0.166667h;Inert atmosphere; Microwave irradiation;	Int-136 (0.058 mmols, 0.040 g) and <strong>[709652-82-4]2-amino-5-bromonicotinonitrile</strong> (0.098 mmols, 0.020 g) were added to a 5mL microwave vessel equipped with a magnetic stir bar. Dioxane (2 mL) and saturated NaHC03(aq) (1 mL) were then added and the reaction vessel was flushed with nitrogen gas. PdC12(dppf) (0.023 mmols, 0.017 g) was added, the reaction vessel was sealed and placed in a microwave reactor and heated to 110 oC for 10 minutes. The reaction solution was then poured into water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo. This crude material was then purified by preparative LC/MS: (Water/Acetonitrile; 55-80%). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (2R)-1-(4-(6-amino-5- cyanopyridin-3 -yl)phenyl)-4-(3 -(7-fluoro- 1 -(3 -methoxypropyl)-3 -methyl- 1 H-indol-2- yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (Int-137) as a clear oil (0.040 mmols, 0.027 g, 69% yield). ESI-MS: m/z 683.4 (M+H)+.

References: [1]Patent: WO2010/111634,2010,A2 .Location in patent: Page/Page column 216.

7
[ 709652-82-4 ]
[ 380430-49-9 ]
[ 1267853-94-0 ]

Yield	Reaction Conditions	Operation in experiment
71%		To a microwave reaction vessel were added 4-(tert- butoxycarbonylamino)phenylboronic acid (180 mg, 0.759 mmol), 5-bromo-3-cyano- 2-aminopyridine (170.0 mg, 0.858 mmol), 1,4-dioxane (3.5 mL) and 2M aqueous sodium carbonate (0.94 mL, 1.88 mmol). Argon gas was bubbled through the solution for 5 min, then tetrakis(triphenylphosphine) palladium(O) (40.0 mg, 0.035 mmol) was <n="120"/>added and the vial was sealed and heated in a microwave reactor for 20 min at 170 C. The mixture was partitioned between EtOAc (10 mL) and saturated sodium bicarbonate (10 mL) The aqueous layer was separated and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered and concentrated under reduced pressure to give an oil which was purified by silica gel flash chromatography, eluting with 25-100% EtOAc in hexanes. The purified material was dissolved in DCM (4 mL), excess TFA (2 mL) added and the mixture was stirred at rt for 4 h. The mixture was concentrated to dryness, then EtOAc (8 mL), saturated NaHC03 (8 mL) and 1 M aqueous NaOH (1 mL) were added. After confirming basic pH, the layers were shaken and separated and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined extracts were dried over MgS04, filtered and concentrated under reduced pressure to give 2- amino-5-(4-aminophenyl)nicotinonitrile (113.9 mg, 71%) as a solid, which was sufficiently pure for the next step. LC-MS (ESI) m/z 2 (M +H)+.

References: [1]Patent: WO2011/22473,2011,A1 .Location in patent: Page/Page column 118-119.

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[ 1267849-53-5 ]

References: [1]Patent: WO2011/22473,2011,A1 .

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[ 1354691-58-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine;dmap; In dichloromethane; at 20℃; for 18h;	Imidodicarbonic acid, 2-[5-bromo-3-(cyano)-2-pyridinyl]-, 1 ,3-bis(1 , 1 -dimethylethyl) ester To <strong>[709652-82-4]2-amino-5-bromonicotinonitrile</strong> (0.785 g, 3.96 mmol), triethylamine (0.553 mL, 3.96 mmol) and 4-dimethylaminoyridine (20 mg, 0.164 mmol) in CH2CI2 (25 mL) was added di-ferf-butyl- dicarbonate (2.16 g, 9.91 mmol) and the resulting mixture stirred at room temperature for 18h. Evaporated to dryness in vacuo and triturated in heptane (25 mL) for 72h. The resulting precipitate was filtered and washed with heptane (10 mL) to give imidodicarbonic acid, 2-[5- bromo-3-(cyano)-2-pyridinyl]-, 1 ,3-bis(1 , 1-dimethylethyl) ester as a beige solid (1.1 g, 70% yield). 1H N MR (400 Mhz, CDCI3, 298K) 1 .51 (s, 181-1) 8.16 (d, 1 1-1) 8.77 (d, 1 H). LCMS: [M+H]+=398/400.1 , Rt (4)= 1.43 min.
70%	With dmap; triethylamine; In dichloromethane; at 20℃; for 18h;	To <strong>[709652-82-4]2-amino-5-bromonicotinonitrile</strong> (0.785 g, 3.96 mmol), triethylamine (0.553 mL, 3.96 mmol) and 4-dimethylaminoyridine (20 mg, 0.164 mmol) in CH2CI2 (25 mL) was added di-fe f-butyl- dicarbonate (2.16 g, 9.91 mmol) and the resulting mixture stirred at room temperature for 18h. Evaporated to dryness in vacuo and triturated in heptane (25 mL) for 72h. The resulting precipitate was filtered and washed with heptane (10 mL) to give imidodicarbonic acid, 2-[5- bromo-3-(cyano)-2-pyridinyl]-, 1 ,3-bis(1 , -dimethylethyl) ester as a beige solid (1.1 g, 70% yield). 1 H NMR (400 Mhz, CDCI3, 298K) 1.51 (s, 18H) 8.16 (d, 1 H) 8.77 (d, 1 H). LCMS: [M+H]+=398/400.1 , Rt (4)= 1.43 min.
70%	With dmap; triethylamine; In dichloromethane; at 20℃; for 18h;	Imidodicarbonic acid, 2-[5-bromo-3-(cyano)-2-pyridinyl]-,1,3-bis(1,1-dimethylethyl)ester To <strong>[709652-82-4]2-amino-5-bromonicotinonitrile</strong> (0.785 g, 3.96 mmol), triethylamine (0.553 mL, 3.96 mmol) and 4-dimethylaminoyridine (20 mg, 0.164 mmol) in CH2Cl2 (25 mL) was added di-tert-butyl-dicarbonate (2.16 g, 9.91 mmol) and the resulting mixture stirred at room temperature for 18 h. Evaporated to dryness in vacuo and triturated in heptane (25 mL) for 72 h. The resulting precipitate was filtered and washed with heptane (10 mL) to give imidodicarbonic acid, 2-[5-bromo-3-(cyano)-2-pyridinyl]-,1,3-bis(1,1-dimethylethyl)ester as a beige solid (1.1 g, 70% yield). 1H NMR (400 Mhz, CDCl3, 298K) 1.51 (s, 18H) 8.16 (d, 1H) 8.77 (d, 1H). LCMS: [M+H]+=398/400.1, Rt(4)=1.43 min.

References: [1]Patent: WO2012/4299,2012,A1 .Location in patent: Page/Page column 73-74.
[2]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 80; 81.
[3]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 0818.

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References: [1]Patent: WO2013/88404,2013,A1 .
[2]Patent: US2015/342951,2015,A1 .
[3]Patent: WO2012/4299,2012,A1 .

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[ 1354691-57-8 ]

References: [1]Patent: US2015/342951,2015,A1 .

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[ 108-94-1 ]
[ 1315209-36-9 ]

References: [1]Green Chemistry,2012,vol. 14,p. 945 - 951.

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