116026-98-3|tert-Butyl (2-bromopyridin-3-yl)carbamate| Ambeed

Structure of 116026-98-3

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Quality Control of [ 116026-98-3 ] Purity: 98% SDS Specification

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Product Details of [ 116026-98-3 ]

CAS No. :	116026-98-3
Formula :	C₁₀H₁₃BrN₂O₂
M.W :	273.13
SMILES Code :	CC(C)(C)OC(=O)NC1=CC=CN=C1Br
MDL No. :	MFCD07367911
InChI Key :	QYWNZOFKKFIZAL-UHFFFAOYSA-N
Pubchem ID :	14177127

Safety of [ 116026-98-3 ]

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

Computational Chemistry of [ 116026-98-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.4
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	62.18
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	51.22 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.61
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	2.44
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.0
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.	1.54
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	1.82
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.28

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.1
Solubility	0.216 mg/ml ; 0.00079 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.	-3.16
Solubility	0.189 mg/ml ; 0.000694 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	-3.83
Solubility	0.0406 mg/ml ; 0.000149 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	Yes
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	Yes
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.	-6.23 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	1.0 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<0.0
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)	2.46

Application In Synthesis of [ 116026-98-3 ]

* 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 [ 116026-98-3 ]
Downstream synthetic route of [ 116026-98-3 ]

[ 116026-98-3 ] Synthesis Path-Upstream 1~5

1
[ 39856-58-1 ]
[ 24424-99-5 ]
[ 116026-98-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: at 20℃; for 1.5 h;	Step 1 : fert-Butyl 2-bromopyridin-3-ylcarbamate (10a)To a solution of 2-bromopyridin-3-amine (3.0 g, 17.3 mmol) in THF (30 mL) was added lithium bis(trimethylsilyl)amide (1 M, 35 mL, 35 mmol) slowly at 0°C and the mixture was stirred at this temperature for 30 min. (Boc)₂0 (3.9 g, 17.3 mmol) in THF (20 mL) was added and the mixture was stirred at rt for 1.5 h. The reaction mixture was poured into 0.1 M of HCI and extracted with EA. The combined organic layers were extracted with brine, dried and concentrated under reduced pressure. The crude product was purified by CC (PE/EA = 5/1) to give compound 10a (2.9 g, 62percent) as a white solid.
50.7%	Stage #1: With dmap In tetrahydrofuran for 3 h; Reflux Stage #2: With potassium carbonate In tetrahydrofuran; methanol at 20℃; for 3 h; Reflux	Example 120A tert-butyl 2-bromopyridin-3-ylcarbamate To a solution of 2-bromopyridin-3-amine (5.0 g, 28.9 mmol) in THF (50 mL) was added Boc₂O (18.92 g, 87 mmol) and DMAP (0.353 g, 2.89 mmol). The resulting mixture was refluxed for about 3 hours, cooled to room temperature and K₂CO₃ (11.98 g, 87 mmol) and 50 mL of MeOH were added respectively. The resulting mixture was stirred at reflux for about 3 hours, then cooled to room temperature, filtrated, and concentrated to give the crude product. The residue was chromatographed on silica gel column (50:1 Hexanes/EtOAc) to afford the product as a white solid (4.0 g, yield: 50.7percent). ¹H NMR (400 MHz, CDCl₃): δ 8.45-8.47 (d, 1H, J=8 Hz), 7.02-8.03 (d, 1H, J=4.4 Hz), 7.23-7.26 (m, 1H), 7.05 (s, 1H), 1.55 (s, 9H).
50.7%	Stage #1: With dmap In tetrahydrofuran for 3 h; Reflux Stage #2: With methanol; potassium carbonate In tetrahydrofuran for 3 h; Reflux	tert-butyl 2-bromopyridin-3-ylcarbamate[204] To a solution of 2-bromopyridin-3-amine (5.0 g, 28.9 mmol) in THF (50 mL) was added Boc₂0 (18.92 g, 87 mmol) and DMAP (0.353 g, 2.89 mmol). The resulting mixture was refluxed for about 3 hours, cooled to room temperature and K₂CO₃ (1 1.98 g, 87 mmol) and 50 mL of MeOH were added respectively. The resulting mixture was stirred at reflux for about 3 hours, then cooled to room temperature, filtrated, and concentrated to give the crude product. The residue was chromatographed on silica gel column (50: 1 Hexanes/EtOAc) to afford the product as a white solid (4.0 g, yield: 50.7 percent). *H NMR (400 MHz, CDCI₃): ? 8.45-8.47 (d, IH, J= 8 Hz), 7.02-8.03 (d, IH, J= 4.4 Hz), 7.23-7.26 (m, IH), 7.05 (s, IH), 1.55 (s, 9H).

References: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5032 - 5043.
[2] Patent: WO2013/64231, 2013, A1, . Location in patent: Page/Page column 51.
[3] Patent: US2013/131036, 2013, A1, . Location in patent: Paragraph 1676; 1677.
[4] Patent: WO2013/62966, 2013, A2, . Location in patent: Paragraph 203; 204.
[5] Patent: WO2005/21529, 2005, A1, . Location in patent: Page/Page column 31.
[6] Patent: WO2019/16269, 2019, A1, . Location in patent: Page/Page column 84.

2
[ 35905-85-2 ]
[ 75-65-0 ]
[ 116026-98-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 80℃; for 3 h;	Intermediate 28:; (2-Bromo-pyridin-3-vl)-carbamic acid tert-butyl ester:; To the known starting material 2-bromo-nicotinic acid (J. Org. Chem.; 14; 1949; 509, 513) (3.0 g, 13.0 mmol) in 26 ml of t-BuOH was added diphenylphosporyl azide (3.9 g, 14.3 mmol). The resulting solution was heated in an oil bath at 80°C for 3 h. Upon cooling, the reaction solution was then concentrated and rediluted in EtOAc and washed with H₂O (50 ml_), followed by saturated aqueous NaHCO₃ (30 ml) and brine (30 ml_). Combined organics were then dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification was accomplished by flash chromatography on a 35L Biotage silica gel column eluting with 20percent EtOAc/Hexanes and collecting 18 mL fractions. Product containing fractions (19-29) were combined and concentrated under reduced pressure to give colorless oil (3.5 g, 12.8 mmol, 99percent yield); Rf 0.75 (20percent EtOAc/Hexanes); LRMS m/z (APCI*) 274/275 [M+ H]; 400 MHz ¹HNMR (CDCI₃) 6 8.44 (dd, J= 7.9, 1.5 Hz, 1H); 8.02 (dd, J=4.6, 1.7 Hz, 1H); 7.23 (dd, J=8.3, 4.6 Hz, 1 H); 7.03 (bs, 1 H); 1.53 (s, 9H).
76%	for 2 h; Heating / reflux	2-bromo-3-methylpyridine (25.0 mL, 213 mmol) was added to a solution of potassium permanganate (87.7 g, 555 mmol) in 800 ML of water and the mixture was stirred under reflux. After 5 hours, 600 mL of water was distilled off and the remaining suspension was filtered. The residue was washed with two 50 mL portions of hot water and the combined filtrates were acidified with concentrated HC1. The white precipitate was filtered and dried in a vacuum oven to give 26.8 g of 2-bromonicotinic acid (62percent yield). DIPHENYLPHOSPHORYLAZIDE was added to a solution of 2-bromonicotinic acid (15.0 g, 74.0 mmol) and triethylamine (11.4 mL, 81. 4 mmol) in 140 mL of anhydrous tert-butanol. The reaction mixture was stirred under reflux for 2 hours, cooled to room temperature, and concentrated in VACUO. The residue was dissolved in 150 ML of ethyl acetate and washed with three 50 mL portions of water, three 50 mL portions of saturated aqueous sodium bicarbonate, and with two 50 mL portions of brine. The organic layer was dried over magnesium sulfate (MGS04), filtered, and concentrated in vacuo. The residue crystallized upon standing to give 15.3 g of the title product (76percent yield).

References: [1] Patent: WO2004/110996, 2004, A1, . Location in patent: Page/Page column 28.
[2] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145.
[3] Patent: WO2005/30213, 2005, A1, . Location in patent: Page/Page column 165.

3
[ 462-08-8 ]
[ 24424-99-5 ]
[ 116026-98-3 ]

References: [1] Patent: EP1300464, 2003, A1, .

4
[ 39856-58-1 ]
[ 1538-75-6 ]
[ 116026-98-3 ]

References: [1] Patent: WO2009/140642, 2009, A2, . Location in patent: Page/Page column 85.

5
[ 39856-58-1 ]
[ 24424-99-5 ]
[ 7440-44-0 ]
[ 116026-98-3 ]

References: [1] Patent: US6281227, 2001, B1, .

[ 116026-98-3 ] Synthesis Path-Downstream 1~35

1
[ 2591-86-8 ]
[ 116026-98-3 ]
[ 116026-99-4 ]

Yield	Reaction Conditions	Operation in experiment
65%		Step 2: fert-Butyl 2-formylpyridin-3-ylcarbamate (10b)To a solution of compound 10a (2.9 g, 10.7 mmol) in THF (30 mL) was added n-BuLi (2.5M, 8.5 mL, 21.4 mmol) at -78C under N2 atmosphere and the resulting mixture was stirred for 1 h at this temperature. /V-Formylpiperidine (1.3 mL, 11.8 mmol) was added with rapid stirring. The mixture was stirred at 0C for 1 h and then partitioned with 1.5M HCI solution. The pH was adjusted to 7 by the addition of solid Na2C03. The aqueous layer was extracted with EA twice and the combined organic layers were dried over Na2S04, concentrated under reduced pressure and purified by CC (PE/EA = 3/1) to give compound 10b (1.5 g, 65%) as a white solid.
64.9%		Add the compound (2-bromopyridin-3-yl) tert-butyl carbamate (20.1 g, 73.3 mmol), 200 mL of dry tetrahydrofuran to a 500 mL three-necked flask, and then N2 replacement protection after the temperature in the reaction flask drops to Slowly add n-BuLi (2.4 M, 73 mL) dropwise after -75C, keep the temperature in the reaction flask not to exceed -65C during the dropwise addition, continue to keep the temperature after the drop, and react for 1 h before adding 4-piperidinaldehyde (9.1 g, 80 mmol), stir for about 10 min after the addition, and then raise the temperature to 0C to react for 1 h. After the reaction was monitored by TLC, saturated ammonium chloride solution was added to quench the reaction, the reaction solution was extracted with ethyl acetate, the organic phases were combined, dried and purified by column chromatography (eluent: ethyl acetate-petroleum ether 1:9) to obtain the compound (2-Formylpyridin-3-yl) tert-butyl carbamate (10.6 g, 64.9%).

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 2136 - 2145.
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 5032 - 5043.
[3]Patent: WO2013/64231,2013,A1 .Location in patent: Page/Page column 51.
[4]Patent: CN112375032,2021,A .Location in patent: Paragraph 0015; 0017-0018.

2
[ 35905-85-2 ]
[ 75-65-0 ]
[ 116026-98-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With diphenyl phosphoryl azide; at 80℃; for 3h;	Intermediate 28:; (2-Bromo-pyridin-3-vl)-carbamic acid tert-butyl ester:; To the known starting material 2-bromo-nicotinic acid (J. Org. Chem.; 14; 1949; 509, 513) (3.0 g, 13.0 mmol) in 26 ml of t-BuOH was added diphenylphosporyl azide (3.9 g, 14.3 mmol). The resulting solution was heated in an oil bath at 80C for 3 h. Upon cooling, the reaction solution was then concentrated and rediluted in EtOAc and washed with H2O (50 ml_), followed by saturated aqueous NaHCO3 (30 ml) and brine (30 ml_). Combined organics were then dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was accomplished by flash chromatography on a 35L Biotage silica gel column eluting with 20% EtOAc/Hexanes and collecting 18 mL fractions. Product containing fractions (19-29) were combined and concentrated under reduced pressure to give colorless oil (3.5 g, 12.8 mmol, 99% yield); Rf 0.75 (20% EtOAc/Hexanes); LRMS m/z (APCI*) 274/275 [M+ H]; 400 MHz 1HNMR (CDCI3) 6 8.44 (dd, J= 7.9, 1.5 Hz, 1H); 8.02 (dd, J=4.6, 1.7 Hz, 1H); 7.23 (dd, J=8.3, 4.6 Hz, 1 H); 7.03 (bs, 1 H); 1.53 (s, 9H).
76%	With diphenylphosphoryl azide; triethylamine; for 2h;Heating / reflux;	2-bromo-3-methylpyridine (25.0 mL, 213 mmol) was added to a solution of potassium permanganate (87.7 g, 555 mmol) in 800 ML of water and the mixture was stirred under reflux. After 5 hours, 600 mL of water was distilled off and the remaining suspension was filtered. The residue was washed with two 50 mL portions of hot water and the combined filtrates were acidified with concentrated HC1. The white precipitate was filtered and dried in a vacuum oven to give 26.8 g of 2-bromonicotinic acid (62% yield). DIPHENYLPHOSPHORYLAZIDE was added to a solution of 2-bromonicotinic acid (15.0 g, 74.0 mmol) and triethylamine (11.4 mL, 81. 4 mmol) in 140 mL of anhydrous tert-butanol. The reaction mixture was stirred under reflux for 2 hours, cooled to room temperature, and concentrated in VACUO. The residue was dissolved in 150 ML of ethyl acetate and washed with three 50 mL portions of water, three 50 mL portions of saturated aqueous sodium bicarbonate, and with two 50 mL portions of brine. The organic layer was dried over magnesium sulfate (MGS04), filtered, and concentrated in vacuo. The residue crystallized upon standing to give 15.3 g of the title product (76% yield).
50%	With diphenyl phosphoryl azide; triethylamine; at 80℃; for 2h;Inert atmosphere;	Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromopyridine-3-carboxylic acid (10 g, 49.5 mmol, 1.0 equiv), TEA (5.5 g, 54.5 mmol, 1.1 equiv), and t-BuOH (150 mL). The flask was evacuated and flushed three times with nitrogen. This was followed by the addition of DPPA (14.3 g, 52.0 mmol, 1.05 equiv). The mixture was stirred for 2 hr at 80 C. in an oil bath. The reaction mixture was cooled to room temperature, quenched with H2O (100 mL), extracted with 3100 mL of ethyl acetate, and the organic phase was washed with 225 ml of Na2CO3 and 2*25 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column with ethyl acetate/petroleum ether (3:1). 6.7 g (50%) of tert-butyl N-(2-bromopyridin-3-yl)carbamate was obtained as a white solid. LCMS (ES) [M+1]+ m/z: 273.

39.8%

Add the compound 2-bromonicotinic acid (50 g, 0.25 mol) and 350 mL of tert-butanol to a 1000 mL single-neck flask,Add TEA (50 mL) with stirring,After stirring for about 30 minutes, add DPPA (63 mL, 0.3 mol), continue to stir for about 10 minutes, and then heat to 95C for 2 hours. After the reaction was monitored by TLC, the reaction was cooled to room temperature, and most of the tert-butanol solvent was removed by rotary evaporation, diluted with ethyl acetate and washed with water. The organic phase was separated, and the combined organic phase was dried and purified by column chromatography (eluent: ethyl acetate Ester-petroleum ether 1:4) to obtain the compound (2-bromopyridin-3-yl) tert-butyl carbamate (27g, 39.8%).

References: [1]Patent: WO2004/110996,2004,A1 .Location in patent: Page/Page column 28.
[2]Journal of Medicinal Chemistry,1988,vol. 31,p. 2136 - 2145.
[3]Patent: WO2005/30213,2005,A1 .Location in patent: Page/Page column 165.
[4]Patent: US2020/190045,2020,A1 .Location in patent: Paragraph 0354; 0355.
[5]Patent: CN112375032,2021,A .Location in patent: Paragraph 0015-0017.

3
[ 627-19-0 ]
[ 116026-98-3 ]
(2-pent-1-ynyl-pyridin-3-yl)-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

References: [1]Synlett,2005,p. 3121 - 3125.

4
[ 116026-98-3 ]
[ 882881-05-2 ]

References: [1]Synlett,2005,p. 3121 - 3125.

5
[ 116026-98-3 ]
[ 116027-00-0 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 2136 - 2145.

6
[ 116026-98-3 ]
[ 116027-01-1 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 2136 - 2145.

7
[ 116026-98-3 ]
[ 116027-03-3 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 2136 - 2145.

8
[ 116026-98-3 ]
[ 1066-54-2 ]
[ 849353-49-7 ]

Yield	Reaction Conditions	Operation in experiment
43%	bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In DMF (N,N-dimethyl-formamide); triethylamine; at 20℃;	A mixture of (2-bromopyridin-3-yl) carbamic acid tert-butyl ester (1.09 mg, 4.00 mmol), (trimethylsilyl) acetylene (2.83 mL, 20.0 mmol), Cul (75.8 mg, 0.400 MMOL), and dichlorobis (triphenylphosphine) palladium (II) (141 mg, 0.200 mmol) in a mixture of 12 mL of triethylamine and 3.0 ML of anhydrous DMF were stirred at room temperature overnight. The reaction was diluted with 50 ML OF diethyl ether and quenched with 50 mL of saturated aqueous ammonium chloride solution. The organic layer was washed with 20 mL of saturated aqueous ammonium chloride solution and the combined aqueous layers were extracted with three 20 mL portions of diethyl ether. The combined organic layers were then washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SI02 (20% to 30% ethyl acetate in hexanes, gradient) gave 500 mg of (2- trimethylsilanylethynylpyridin-3-yl) carbamic acid ter-butyl ester (43% yield). A mixture of (2-TRIMETHYLSILANYLETHYNYLPYRIDIN-3-YL) carbamic acid tert-butyl ester (500 mg, 1.72 mmol) in 5 mL of THF was treated with TBAF (1 M in THF, 10.3 mL) at room temperature. The mixture was heated at reflux for 8 hours, cooled to room temperature, diluted with 100 mL of diethyl ether, and quenched with 100 mL of water. The aqueous layer was extracted with three 50 mL portions of diethyl ether, and the combined organic layers were washed with 500 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SI02 (100% CH2CI2 to 10% MeOH in CH2C12, gradient) gave 160 mg of the title product as tan solid (79% yield).

References: [1]Patent: WO2005/30213,2005,A1 .Location in patent: Page/Page column 190-191.

9
[ 75-03-6 ]
[ 116026-98-3 ]
[ 917868-24-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 80℃; for 18h;	A mixture of tert-butyl (2-BROMOPYRIDIN-3-YL) carbamate (300 mg, 1.1 MMOL), EtI (0.14 ML, 1. 65 mmol), and NaH (32 mg, 1.32 MMOL) IN DMF (10 ML) was heated to 80 C for 18 hr. The solvent was then removed in vacuo and the residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine (2X), dried (NA2SO4) and concentrated. The crude residue was purified by silica gel chromatography (ethyl ACETATE/HEXANES) to afford tert-butyl (2-BROMOPYRIDIN-3- yl) ETHYLCARBAMATE. 1H NMR (CDC13, 500 MHz) 8 8.30 (d, 1H), 7.49 (d, 1H), 7.29 (t, 1H), 3.83 (m, 1H), 3.46 (m, 1H), 1.48 (s, 2H), 1.35 (s, 7H), 1.13 (t, 3H).

References: [1]Patent: WO2005/21529,2005,A1 .Location in patent: Page/Page column 31-32.

10
[ 39856-58-1 ]
[ 24424-99-5 ]
[ 116026-98-3 ]

Yield	Reaction Conditions	Operation in experiment
62%		Step 1 : fert-Butyl 2-bromopyridin-3-ylcarbamate (10a)To a solution of 2-bromopyridin-3-amine (3.0 g, 17.3 mmol) in THF (30 mL) was added lithium bis(trimethylsilyl)amide (1 M, 35 mL, 35 mmol) slowly at 0C and the mixture was stirred at this temperature for 30 min. (Boc)20 (3.9 g, 17.3 mmol) in THF (20 mL) was added and the mixture was stirred at rt for 1.5 h. The reaction mixture was poured into 0.1 M of HCI and extracted with EA. The combined organic layers were extracted with brine, dried and concentrated under reduced pressure. The crude product was purified by CC (PE/EA = 5/1) to give compound 10a (2.9 g, 62%) as a white solid.
50.7%		Example 120A tert-butyl 2-bromopyridin-3-ylcarbamate To a solution of 2-bromopyridin-3-amine (5.0 g, 28.9 mmol) in THF (50 mL) was added Boc2O (18.92 g, 87 mmol) and DMAP (0.353 g, 2.89 mmol). The resulting mixture was refluxed for about 3 hours, cooled to room temperature and K2CO3 (11.98 g, 87 mmol) and 50 mL of MeOH were added respectively. The resulting mixture was stirred at reflux for about 3 hours, then cooled to room temperature, filtrated, and concentrated to give the crude product. The residue was chromatographed on silica gel column (50:1 Hexanes/EtOAc) to afford the product as a white solid (4.0 g, yield: 50.7%). 1H NMR (400 MHz, CDCl3): δ 8.45-8.47 (d, 1H, J=8 Hz), 7.02-8.03 (d, 1H, J=4.4 Hz), 7.23-7.26 (m, 1H), 7.05 (s, 1H), 1.55 (s, 9H).
50.7%		tert-butyl 2-bromopyridin-3-ylcarbamate[204] To a solution of 2-bromopyridin-3-amine (5.0 g, 28.9 mmol) in THF (50 mL) was added Boc20 (18.92 g, 87 mmol) and DMAP (0.353 g, 2.89 mmol). The resulting mixture was refluxed for about 3 hours, cooled to room temperature and K2CO3 (1 1.98 g, 87 mmol) and 50 mL of MeOH were added respectively. The resulting mixture was stirred at reflux for about 3 hours, then cooled to room temperature, filtrated, and concentrated to give the crude product. The residue was chromatographed on silica gel column (50: 1 Hexanes/EtOAc) to afford the product as a white solid (4.0 g, yield: 50.7 %). *H NMR (400 MHz, CDCI3): ? 8.45-8.47 (d, IH, J= 8 Hz), 7.02-8.03 (d, IH, J= 4.4 Hz), 7.23-7.26 (m, IH), 7.05 (s, IH), 1.55 (s, 9H).

	With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;	A mixture of 2-BROMOPYRIDIN-3-AMINE (1 g, 5.8 mmol), di-tert-butyl dicarbonate (1.76 g, 8 mmol), DMAP (141 mg, 1.16 MMOL), and ethyl (diisopropyl) amine (2 mL, 11.6 mmol) in CTI2C12 (40 mL) was stirred at room temperature for 18 hr. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford tel-t-butyl (2- bromopyridin-3-yl) carbamate).'H NMR (CDC13, 500 MHZ) 8 8.40 (d, 1H), 8.02 (d, 1H), 7.13 (t, 1H), 7.08 (bs, 1H), 1.54 (s, 9H).
	at 100℃;	A solution of 2-bromopyridin-3-amine (10 g. 58 mmol) in Boc20 (100 mL) was stirred at 100C overnight, cooled to rt, diluted with water (20 mL) and extracted with EA (3 x 15 mL). The combined organic layer was dried over Na2S04, concentrated and purified by FCC (PE:EA = 20: 1 ) to give compound P28a as a white solid.

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 5032 - 5043.
[2]Journal of the American Chemical Society,2022,vol. 144,p. 3776 - 3781.
[3]Patent: WO2013/64231,2013,A1 .Location in patent: Page/Page column 51.
[4]Patent: US2013/131036,2013,A1 .Location in patent: Paragraph 1676; 1677.
[5]Patent: WO2013/62966,2013,A2 .Location in patent: Paragraph 203; 204.
[6]Patent: WO2005/21529,2005,A1 .Location in patent: Page/Page column 31.
[7]Patent: WO2019/16269,2019,A1 .Location in patent: Page/Page column 84.

11
[ 462-08-8 ]
[ 24424-99-5 ]
[ 116026-98-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; triethylamine;2-(Dimethylamino)pyridine; In N-methyl-acetamide; dichloromethane; ethyl acetate;	Example B234 tert-Butyl N-(2-bromo-3-pyridyl) carbamate N-bromosuccinimide (7.51 g, 42.2 mmol) was added to an ice-cooled mixed solution of 3-aminopyridine (3:97 g, 42.2 mmol) in dimethylformamide (25 ml), and this reaction mixture was stirred at that temperature for 30 minutes. After ethyl acetate was added, the reaction mixture was washed with saturated brine and concentrated under reduced pressure. A solution of the residue in methylene chloride (20 ml) was cooled on ice, then triethylamine (3.74 ml, 26.8 mmol), a catalytic amount of dimethylaminopyridine, and di-t-butyl dicarbonate (3.08 ml, 13.4 mmol) were added to the solution, and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (344 mg). 1H-NMR(CDCl3) δ (ppm): 1.55(9H, s), 7.03(1H, brs), 7.25(1H, dd), 8.03(1H, dd), 8.46(1H, d)

References: [1]Patent: EP1300464,2003,A1 .

12
[ 39856-58-1 ]
[ 24424-99-5 ]
[ 7440-44-0 ]
[ 116026-98-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hexamethyldisilazane; In tetrahydrofuran;	A. (2-Bromo-pyridin-3-yl)-carbamic acid tert-butyl ester To a solution of 3-amino-2-bromopyridine (1.5 g, 8.7 mmol) and di-tert-butyl dicarbonate (2.0 g, 9.2 mmol) in THF (15 ml) is added 1.0 M sodium bis(trimethylsilyl)amide in THF (18 ml, 18 mmol) at 0 C. The mixture is stirred at r.t. for 4 h, and then concentrated, quenched with saturated NH4Cl, diluted with EtOAc, and washed with water. The organic layer is dried over MgSO4, treated with charcoal, filtered and concentrated to dryness. Title compound is obtained as a light yellow solid (2.1 g, 7.7 mmol). 1H NMR (CDCl3, 300 MHz) δ8.44 (d, 1H), 8.03 (d, 1H), 7.20 (m, 1H), 7.02 (bs, 1H), 1.50 (s, 9H). EI MS [M+H]+=273, 275.

References: [1]Patent: US6281227,2001,B1 .

13
[ 251936-15-9 ]
[ 116026-98-3 ]
[ 251936-35-3 ]

Yield	Reaction Conditions	Operation in experiment
		B. 2-(3-(S)-Amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester The title compound is prepared from <strong>[116026-98-3](2-bromo-pyridin-3-yl)-carbamic acid tert-butyl ester</strong> (1.6 g, 5.9 mmol) and (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl carbamic acid benzyl ester (1.6 g, 5.9 mmol) according to the methods described in EXAMPLE 59, Parts C,D and E. The title compound was obtained as a white solid (0.29 g, 0.88 mmol). 1H NMR (CDCl3, 300 MHz) δ8.45 (d, 1H), 8.27 (d, 1H), 7.18 (dd, 1H), 6.50 (s, 1H), 4.90 (AB, 2H), 3.64 (m, 1H), 3.45 (m, 2H), 2.52 (m, 1H), 1.85 (m, 1H), 1.70 (s, 9H). EI MS [M+H]+=331.

References: [1]Patent: US6281227,2001,B1 .

14
[ 106-96-7 ]
[ 116026-98-3 ]
[ 1133976-04-1 ]

References: [1]Tetrahedron,2008,vol. 64,p. 8182 - 8187.

15
[ 61362-77-4 ]
[ 116026-98-3 ]
C₂₁H₃₄N₂O₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Step 3: 2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-lfl-pyrrolo[3,2-A]pyridine [00401] (2-Bromo-pyridin-3-yl)-carbamic acid tert-buty ester (12.74g, 46.6mmol) and tert-butyl- dimethyl-pent-4-ynyloxy-silane (9.19g, 46.3mmol) were combined in DMF (20OmL). Triethylamine (26mL, 186mmol) was added, and the mixture was purged with N2 for 20 minutes. Bis(triphenylphosphine)palladium(II) dichloride (3.2g, 4.63mmol) and copper iodide (0.88g, 4.63mmol) were added, and the reaction was stirred at room temperature overnight. Analytical LCMS indicated that the coupled product was the major product, so the reaction was heated to 5OC, and 1,8-diazabicyclo[5.4.0]undec-7-ene (14mL, 93mmol) was added. After stirring at 50C for 3 hours, the mixture was diluted with EtOAc and washed twice with saturated aqueous NH4Cl and twice with H2O. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was loaded onto silica gel (10 eq. w/w) and stirred at 8OC under vacuum for 12 hours, and then purified by silica gel chromatography to give the title compound.

References: [1]Patent: WO2009/140642,2009,A2 .Location in patent: Page/Page column 85.

16
[ 39856-58-1 ]
[ 1538-75-6 ]
[ 116026-98-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: (2-Bromo-pyridin-3-yl)-carbamic acid fert-butyl ester[00400] 3-Amino-2-bromopyridine (25.8 Ig, 149.2mmol) was dissolved in THF (40OmL) and cooled to OC. Sodium hexamethyldisilazide (2M in THF; 15OmL, 300.0mmol) was added drop-wise over 15 minutes, and the mixture was allowed to warm to room temperature. Di-tert-butyl dicarbonate (34.2g, 156.6mmol) in THF (5OmL) was added drop-wise, and the reaction was stirred overnight at room temperature. The mixture was diluted with EtOAc and H2O, and the organic layer was washed, dried, and purified by silica gel chromatography to give the title compound

References: [1]Patent: WO2009/140642,2009,A2 .Location in patent: Page/Page column 85.

17
[ 815631-56-2 ]
[ 116026-98-3 ]
[ 815631-72-2 ]

Yield	Reaction Conditions	Operation in experiment
77%		Intermediate 29:F2-(4-Fluoro-2-methvl-phenvl)-pyridin-3-vl1-carbamic acid tert-butyl ester:Intermediate 28 (1.67 g, 6.13 mmol) was dissolved in 15 mL of anhydrous DME under N2. Pd(Ph3P)4 (0.08 g, 5% by weight) catalyst was then added and the reaction was stirred for Vz h at rt. The colorless solution turns from yellow to orange and back to yellow. Intermediate 1-(1.59 g, 6.74 mmol) was then added, followed by 18.5 mL of 1M K2CO3 and the biphasic solution was heated to reflux for 2 h. The resulting green suspension was cooled to rt, diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3. Combined' organics were then washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to give a pale green solid (2.51 g). Purification was accomplished by flash chromatography on a 40M Biotage silica gel column using a gradient of 10%, 20%, 30% EtOAc/Hexanes and collecting 18 mL factions. Product containing fractions (31-50) werecombined and concentrated under reduced pressure to give a colorless crystalline solid (1.42 g, 4.70 mmol, 77% yield); Rf 0.5 (25% EtOAc/Hexanes); LRMS m/z (APCI*) 301/303 [M-/+ H]; 400 MHz 1HNMR (CDCI3) 6 8.59 (d, J=8.3 Hz, 1H); 8.34 (dd, J=5.0, 1.7 Hz, 1H); 7.30-7.22 (m, 2H); 7.04 (ddd, J=17.4, 9.5, 2.5 Hz, 2H); 6.14 (bs); 2.13 (s, 3H); 1.46 (s, 9H); 100 MHz 13C NMR (CDCI3) 8 192.9, 162.0, 152.8, 143.7, 133.5, 131.4, 131.3, 126.6, 123.3, 118.0, 117.8,113.9,113.7,81.6,45.2,28.4,19.7.

References: [1]Patent: WO2004/110996,2004,A1 .Location in patent: Page/Page column 28-29.

18
[ 116026-98-3 ]
[ 184370-68-1 ]
C₂₄H₄₀N₂O₃Si [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4647 - 4651.

19
[ 609849-80-1 ]
[ 116026-98-3 ]
[ 1260092-57-6 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 6681 - 6698.

20
[ 95-92-1 ]
[ 116026-98-3 ]
[ 1312606-05-5 ]

Yield	Reaction Conditions	Operation in experiment
		Ethyl 2-(3-(tert-butoxycarbonylamino)pyridin-2-yl)-2-oxoacetate; A solution of tert-butyl 2-bromopyridin-3-ylcarbamate (3.85 g, 14 mmol) (prepared from the procedure used by Kowol etc, J. Med. Chem., 2009, 52, 5032-5043) in dry THF (20 mL) was cooled to -78 C. and was treated drop-wise with n-butyllithium (11.2 mL of 2.5M solution in hexane, 2.0 eq) such that the temperature never exceeded -65 C., and the resulting mixture was stirred at -78 C. for an additional hour. After drop-wise addition of diethyl oxalate (4 mL, 29 mmol, 2.1 eq), the reaction mixture was allowed to warm to 0 C., maintained there for 1 h, and then quenched by the addition of NH4Cl (40 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (3×20 mL) and brine (20 mL). After drying, filtration, and evaporation, the residue was purified by column chromatography on silica gel with dichloromethane as eluant to afford ethyl 2-(3-(tert-butoxycarbonylamino)pyridin-2-yl)-2-oxoacetate as a white solid. Mass Spectrum (ESI) m/e=295 (M+1).
		To a solution of compound P28a (8.0 g, 29 mmol) in dry THF (60 mL) was added dropwise n- BuLi (29 mL of 2.5M solution in hexane) at -78C. The mixture was allowed to warm to -20C for 2 h. After diethyl oxalate (8.5 mL, 62 mmol) was added dropwise to the mixture at -78C, the mixture was stirred at rt for 2 h, quenched by NH4CI (50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine (2 x 20 mL), dried over Na2S04, filtered, concentrated and purified by FCC (PE:EA = 20: 1 ) to give compound P28b as a white solid.S
		To a solution of <strong>[116026-98-3]tert-butyl (2-bromopyridin-3-yl)carbamate</strong> (8.00 g, 29.4 mmol) in dry THF (60 mL) was added dropwise with n-BuLi (29 mL of a 2.5M solution in hexane) at-78C, then the mixture was allowed to warm to-20C for 2 h. Then diethyl oxalate (8.5 mL, 62 mmol) was added dropwise to the mixture at-78C and the mixture was stirred at rt for 2 h, quenched with aq. NH4Cl (50 mL) and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL), dried over Na2SO4, concentrated and purified by FCC (PE:EA = 20:1) to give compound 6a as a white solid.

References: [1]Patent: US2011/152296,2011,A1 .Location in patent: Page/Page column 31.
[2]Patent: WO2019/16269,2019,A1 .Location in patent: Page/Page column 84; 85.
[3]Patent: WO2020/148325,2020,A1 .Location in patent: Page/Page column 49.

21
[ 116026-98-3 ]
[ 1312606-06-6 ]