89466-16-0|6-Bromo-3-methylpyridin-2-amine| Ambeed

Structure of 89466-16-0

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Quality Control of [ 89466-16-0 ] Purity: 97% SDS Specification

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Product Details of [ 89466-16-0 ]

CAS No. :	89466-16-0
Formula :	C₆H₇BrN₂
M.W :	187.04
SMILES Code :	NC1=NC(Br)=CC=C1C
MDL No. :	MFCD17014961
InChI Key :	ANDWKDRELVPNDM-UHFFFAOYSA-N
Pubchem ID :	59605384

Safety of [ 89466-16-0 ]

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

Computational Chemistry of [ 89466-16-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
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	41.31
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.71
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	1.89
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.74
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.	1.33
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	1.78
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.69

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.68
Solubility	0.387 mg/ml ; 0.00207 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.	-2.33
Solubility	0.876 mg/ml ; 0.00468 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	-2.91
Solubility	0.232 mg/ml ; 0.00124 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.	-6.1 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	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<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)	1.87

Application In Synthesis of [ 89466-16-0 ]

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

Downstream synthetic route of [ 89466-16-0 ]

[ 89466-16-0 ] Synthesis Path-Downstream 1~35

3
[ 13922-41-3 ]
[ 89466-16-0 ]
3-methyl-6-(naphthalen-1-ylmethyl)pyridin-2-amine [ No CAS ]

References: [1]Journal of Organic Chemistry,2012,vol. 77,p. 2729 - 2742.

4
[ 1306734-44-0 ]
[ 89466-16-0 ]
tert-butyl (1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In toluene; at 60℃; for 20h;	(1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (1 equiv), <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (1.2 equiv), EEDQ (1.2 equiv) in toluene (10 vol) was stirred for 20h at 60 °C. The solvent was removed under reduced pressure and the remaining residue was dissolved in DCM ,Washed with IN HCl and washed with aq NaHCCb and dried over Na2S04. The solvent was removed and the residue was added to DCM/heptane (1 :3, 8 vol ) and stirred 10 min at RT and cooled to 5 °C. The precipitated solid was then filtered and directly used in the next reaction.

References: [1]Patent: WO2017/35351,2017,A1 .Location in patent: Paragraph 0596; 0597.

5
[ 89466-16-0 ]
(2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride [ No CAS ]

References: [1]Patent: WO2017/35355,2017,A1 .

6
[ 89466-16-0 ]
(2S,4R)-1-(2-(3-acetyl-5-((5-methyipyrimidin-2-yl)oxy)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]

References: [1]Patent: WO2017/35355,2017,A1 .

7
[ 89466-16-0 ]
(2S,4R)-1-(2-(3-acetyl-5-((5-methylpyrazin-2-yl)oxy)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]

References: [1]Patent: WO2017/35355,2017,A1 .

8
[ 89466-16-0 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-50° C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-50° C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5° C. Then <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (200 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 430 mg (quantitative yield) of titled compound was obtained.
		Step 1: terf-Butyl (2S,4R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyI)-4- fluoropyrrolidine-l-carboxylate (209) [0696] To an ice cold solution of (2S,4R)-l -(feri-butoxycarbonyl)-4-fluoropyrrolidine-2- carbox lic acid (1 equiv) in DCM (10 vol) was added l-chloro-N,N,2-trimethyl-l-propenylamine ( 1 , 1 equiv) dropwise with stirring. Stirring was continued for 3 h at this temperature, and then 6- bromo-3-methylpyridin-2-amine (1.1 equiv) was added, followed by DIEA (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water and extracted with DCM. The organic layer was washed successively with an aqueous solution of NaHCCb, water and brine, then dried over Na2SO<i and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (DCM EtOAc) to give compound 209.

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1460.
[2]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0696.

9
[ 334769-80-1 ]
[ 89466-16-0 ]
tert-butyl (2S,5S)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
310 mg	With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 4h;	In a pre-dried flask, (2S,5 S)? 1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (purchased from Aldrich) (230 mg, 1.0 mmol), <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (188 mg, 1.0 mmol) are placed, and then anhydrous DCM (15 mL) was added. The flask was placed in an ice bath. To the solution, dry pyridine (0.25 mL, 3.0 mmol) was added in one portion, followed by addition of POCl3(100 muL, 1.0 mmol). After completion of addition, the mixture was stirred for 4 hours at 0° C., and then the reaction was quenched with water (15 mL). The DCM layer was collected and the aqueous phase was extracted with DCM (15 mL×2). The combined DCM solution was washed with brine, and dried over MgSO4. The solution was filtered and concentrated; the resulting residue was purified to give 310.0 mg pure product.1H NMR (400 MHz, DMSO-d6): (major rotamer) delta 1.21 (d, J=6.4 Hz, 3H), 1.37 (s, 9H), 1.97-2.00 (m, 2H), 1.57 (s, 1H), 2.11 (s, 3H), 2.15-2.22 (m, 1H), 3.88 (s, 1H), 4.35 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 10.23 ppm. LC (method A): tR=2.11 min. LC/MS (EI) m/z: [M+H]398.25

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1146.

10
[ 364750-81-2 ]
[ 89466-16-0 ]
tert-butyl (2S,4S)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
194 mg	With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 4h;	In a pre-dried flask, (2 S,4 S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (purchased from Aldrich) (230 mg, 1.0 mmol), <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (188 mg, 1.0 mmol) are placed, and then anhydrous DCM (15 mL) was added. The flask was placed in an ice bath. To the solution, dry pyridine (0.25 mL, 3.0 mmol) was added in one portion, followed by addition of POCl3(100 muL, 1.0 mmol). After completion of addition, the mixture was stirred for 4 hours at 0° C., and then the reaction was quenched with water (15 mL). The DCM layer was collected and the aqueous phase was extracted with DCM (15 mL×2). The combined DCM solution was washed with brine, and dried over MgSO4. The solution was filtered and concentrated; the resulting residue was purified to give 194 mg pure product.1H NMR (400 MHz, DMSO-d6): (major rotamer) delta 1.06 (d, J=6.4 Hz, 3H), 1.35 (s, 9H), 1.38-1.49 (m, 1H), 2.11 (s, 3H), 2.15-2.25 (m, 1H), 2.42-2.50 (m, 1H), 2.84-2.90 (m, 1H), 3.61-3.65 (m, 1H), 4.28 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 10.25 ppm. LC (method A): tR=2.00 min. LC/MS (EI) m/z: [M+H]398.25

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1140.

11
[ 89466-16-0 ]
[ 364750-80-1 ]
tert-butyl (2S,4R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
227 mg	With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 4h;	In a pre-dried flask, (2S,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (purchased from Synthonix) (230 mg, 1.0 mmol), <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (188 mg, 1.0 mmol) are placed, and then anhydrous DCM (15 mL) was added. The flask was placed in an ice bath. To the solution, dry pyridine (0.25 mL, 3.0 mmol) was added in one portion, followed by addition of POCl3(100 muL, 1.0 mmol). After completion of addition, the mixture was stirred for 4 hours at 0 C., and then the reaction was quenched with water (15 mL). The DCM layer was collected and the aqueous phase was extracted with DCM (15 mL×2). The combined DCM solution was washed with brine, and dried over MgSO4. The solution was filtered and concentrated; the resulting residue was purified to give 227 mg of pure product.1HNMR (400 MHz, DMSO-d6): (major rotamer) delta 0.99 (d, J=6.4 Hz, 3H), 1.36 (s, 9H), 1.82-1.93 (m, 1H), 2.02-2.06 (m, 1H), 2.11 (s, 3H), 2.30-2.37 (m, 1H), 2.86 (t, J=8.0 Hz, 1H), 3.57-3.61 (m, 1H), 4.35 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 10.25 ppm. LC (method A): tR=2.04 min. LC/MS (EI) m/z: [M+H]398.25

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1143.

12
[ 89466-16-0 ]
[ 197142-36-2 ]
tert-butyl (1S,3S,5S)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
302 mg	With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 4h;	In a pre-dried flask, (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (228 mg, 1.0 mmol), <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (188 mg, 1.0 mmol) are placed, and then anhydrous DCM (15 mL) was added. The flask was placed in an ice bath. To the solution, dry pyridine (0.25 mL, 3.0 mmol) was added in one portion, followed by addition of POCl3(100 muL, 1.0 mmol). After completion of addition, the mixture was stirred for 4 hours at 0° C., and then the reaction was quenched with water (15 mL). The DCM layer was collected and the aqueous phase was extracted with DCM (15 mL×2). The combined DCM solution was washed with brine, and dried over MgSO4. The solution was filtered and concentrated; the resulting residue was purified to give 302.0 mg pure product.1H NMR (400 MHz, DMSO-d6): (major rotamer) delta 0.62-0.64 (m, 1H), 0.97 (s, br, 1H), 1.34 (s, 9H), 1.49-1.58 (m, 1H), 1.90-1.96 (m, 1H), 2.10 (s, 3H), 2.54-2.69 (m, 1H), 3.37-3.41 (m, 1H), 4.66 (t, J=11.2 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 10.31 ppm. LC (method A): tR=2.01 min. LC/MS (EI) m/z: [M+H]396.15, 398.25

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1149.

13
[ 89466-16-0 ]
[ 160033-52-3 ]
tert-butyl (2S,5R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
188 mg	With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 4h;	In a pre-dried flask, (2S,5 S)? 1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (230 mg, 1.0 mmol), <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (188 mg, 1.0 mmol) are placed, and then anhydrous DCM (15 mL) was added. The flask was placed in an ice bath. To the solution, dry pyridine (0.25 mL, 3.0 mmol) was added in one portion, followed by addition of POCl3(100 muL, 1.0 mmol). After completion of addition, the mixture was stirred for 4 hours at 0° C., and then the reaction was quenched with water (15 mL). The DCM layer was collected and the aqueous phase was extracted with DCM (15 mL×2). The combined DCM solution was washed with brine, and dried over MgSO4. The solution was filtered and concentrated; the resulting residue was purified to give 188 mg pure product.1H NMR (400 MHz, DMSO-d6): (major rotamer) delta 1.12 (t, J=8.8 Hz, 3H), 1.34 (s, 9H), 1.46-1.55 (m, 1H), 1.84-1.91 (m, 1H), 2.02-2.08 (m, 1H), 2.11 (s, 3H), 2.28-2.37 (m, 1H), 3.95-4.02 (m, 1H), 4.35 (t, J=8.8 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 10.26 ppm. LC (method A): tR=2.10 min. LC/MS (EI) m/z: [M+H]398.25

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1152.

14
[ 400720-05-0 ]
[ 89466-16-0 ]
tert-butyl (1S,2S,5R)-2-((6-bromopyridin-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To an ice cold solution of (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (103 mg, 0.45 mmole) in 6 mL of CH2Cl2, 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.07 mL, 1.1 equiv) was added drop-wise with stirring. The stirring was continued for 3 hours at the same temperature. Then <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (93 mg, 1.0 equiv) was added, followed by 0.23 mL (3 equiv) Hunig's base. The cooling bath was removed and the reaction mixture was stirred at room temperature for overnight. The solvent was co-evaporated with 5 mL of MeOH, and the residue was purified by ISCO (eluted 5percent MeOH in DCM, gradient) to obtain 160 mg (90percent) of title compound as yellow oil.

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1560.

15
[ 89466-16-0 ]
(1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester [ No CAS ]
tert-butyl (3S,4S)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; trichlorophosphate; In dichloromethane; at 20℃;Cooling with ice;	In a pre-dried flask, (3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (48 mg, 0.2 mmol), <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (37 mg, 0.2 mmol) are placed, and then anhydrous DCM (5 mL) was added. The flask was placed in an ice bath. To the solution, dry pyridine (50 muL, 0.6 mmol) was added in one portion, followed by addition of POCl3(20 muL, 0.2 mmol). After completion of addition, the mixture was stirred overnight at room temperature, and then the reaction was quenched with water (5 mL). The DCM layer was collected and the aqueous phase was extracted with DCM (10 mL×2). The combined DCM solution was washed with brine, and dried over MgSO4. The solution was filtered and concentrated; the resulting residue was used for next step without further purification.

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1125.

16
(3S)-2-(tert-butoxycarbonyl)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid [ No CAS ]
[ 89466-16-0 ]
(3S)-tert-butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 90℃;	To a solution of scheme 8-38 compound S1 (1 g, 3.89 mmol) and <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (870 mg, 4.67 mmol) in DCE (10 ml) was added DIPEA (2.56 mL, 15.56 mmol) and EEDQ (1.92 g, 7.78 mmol). The reaction was stirred at 90 C. overnight. The solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to afford compound 2 (710 mg, 43.0% yield) as a white solid. LC/MS (ESI) m/z: 426 (M+H)+.
43.0%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 90℃;	To a solution of scheme 8-38 compound S1 (1 g, 3.89 mmol) and <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (870 mg, 4.67 mmol) in DCE (10 ml) was added DIPEA (2.56 mL, 15.56 mmol) and EEDQ (1.92 g, 7.78 mmol). The reaction was stirred at 90 oC overnight. The solvent was removed under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate =2: 1) to afford scheme 8-38 compound S2 (710 mg, 43.0% yield) as a white solid. LC/MS (ESI) m/z: 426 (M+H)+.

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1671.
[2]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0743.

17
[ 89466-16-0 ]
[ 197142-34-0 ]
tert-butyl (1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (261 mg, 1.16 mmole) in 15 mL of CH2Cl2, was added 1-methyl imidazole (0.23 mL, 2.5 equiv.) at 0-5° C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5° C. and then added methane sulfonyl chloride (0.11 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50° C. Then <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (217 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 371 mg (94percent yield) of titled compound was obtained.

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1542.

18
(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoro-4-(fluoromethyl)pyrrolidine-2-carboxylic acid [ No CAS ]
[ 89466-16-0 ]
C₁₇H₂₂BrF₂N₃O₃ [ No CAS ]

References: [1]Patent: WO2017/35353,2017,A1 .Location in patent: Page/Page column 312.

19
(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoro-4-(fluoromethyl)pyrrolidine-2-carboxylic acid [ No CAS ]
[ 89466-16-0 ]
(x)C₂HF₃O₂*C₁₂H₁₄BrF₂N₃O [ No CAS ]