[ CAS No. 886365-46-4 ] {[proInfo.proName]}

Name: 886365-46-4|5-Chloro-3-methylpyridine-2-carboxylic acid|95%
Brand: Ambeed
SKU: A225570
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Quality Control of [ 886365-46-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 886365-46-4 ]

SDS Specification

Alternatived Products of [ 886365-46-4 ]

Product Details of [ 886365-46-4 ]

CAS No. :	886365-46-4	MDL No. :	MFCD07375127
Formula :	C₇H₆ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QQNDJNHLMAFNJI-UHFFFAOYSA-N
M.W :	171.58	Pubchem ID :	22392009
Synonyms :

Calculated chemistry of [ 886365-46-4 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.17
TPSA :	50.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.25
Log Po/w (XLOGP3) :	1.7
Log Po/w (WLOGP) :	1.74
Log Po/w (MLOGP) :	-0.18
Log Po/w (SILICOS-IT) :	1.82
Consensus Log Po/w :	1.27

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.31
Solubility :	0.836 mg/ml ; 0.00487 mol/l
Class :	Soluble
Log S (Ali) :	-2.37
Solubility :	0.733 mg/ml ; 0.00427 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.4
Solubility :	0.688 mg/ml ; 0.00401 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 886365-46-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 886365-46-4 ]

* 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.

Upstream synthesis route of [ 886365-46-4 ]
Downstream synthetic route of [ 886365-46-4 ]

[ 886365-46-4 ] Synthesis Path-Upstream 1~3

1
[ 16110-09-1 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 886365-46-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1,1'-bis-(diphenylphosphino)ferrocene; triethylamine In methanol at 100℃; for 11 h;	A 10 L bottle was charged with dichloropyridine, palladium acetate, dppf (1,1'-Bis(diphenylphosphino)ferrocene), and TEA in methanol 6 L. The bottle was stirred then contents transferred to an 5 gallon stainless steel stirred reaction vessel (Kla=1.42 (at) 40percent fill and 1000 rpm) via vacuum. The bottle was rinsed with another 2 L methanol, and the rinse was added to reaction vessel by the same method. The vessel was tested for leaks using nitrogen, then purged with nitrogen three times and carbon monoxide three times with the final carbon monoxide charge to be 50 psig of Carbon monoxide. The pressurized vessel was heated to a temperature of 100° C. The agitation rate was 1000 rpm. The reaction was allowed to progress for eleven hours, then allowed to cool to room temperature and sampled. Reaction was judged to be complete when 3percent LCAP or less of starting material remained. Batch was transferred to a 50 L r.b. flask equipped with a thermocouple and stir paddle. Flask was connected to a batch concentrator and concentration begun at approximately 25-30 in Hg of applied vacuum. Intermittent heating of batch was applied to maintain temp at approximately 30-35° C. Concentration was discontinued when copious precipitate was noted. Saturated brine 20 L was added via addition funnel over one hour. Batch was aged with gentle stirring overnight. In morning, a methanol/ice bath was applied to cool batch to -5° C. for 1.5 hours. Solids were collected by filtration and rinsed with 5 L brine twice, then dried under nitrogen tent overnight to give 3.47 Kg of product intimately mixed with sodium chloride: 57 wt percent, 1.98 Kg of product in the isolated solids, 99percent yield, ML losses 0.41percent. The product can be stored at this point if desired. NMR 1H δ: 3.87 (s, 3H), 7.69 (dd, J=8.4, 2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H). NMR 13C δ: 52.8, 125.8, 135.7, 136.6, 145.7, 148.6, 164.6. Solids and tetrahydrofuran were charged to a 50 L r.b. flask equipped with stir paddle. The batch was stirred for one hour, at which point the water content (Kf) of the batch was less than 1000 ug/0.5 mL. The batch was concentrated with incremental tetrahydrofuran addition to azeotropically dry to Kf of 780 ug/0.5 mL. HPLC assay was 122 mg/g of THF solution, 1.97 Kg product in 16.06 Kg of solution.

Reference： [1] Patent: US2004/102472, 2004, A1, . Location in patent: Page 49; 50

2
[ 156072-84-3 ]
[ 886365-46-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: With sodium hydroxide In ethanol at 90℃; for 18 h; Stage #2: With hydrogenchloride In water	To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH 5. ON (110 ml, 550 mmol). The resulting mixture was refluxed at 90 °C for 18 h. After cooling to RT, the reaction mixture was conentrated, diluted with water and the pH of the solution was adjusted to 4 by addition of 5N HC1. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2X). The aqueous layer was again acidified with 5N HC1 to pH 4 and extracted with EtOAc (2X). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40 °C for 12 h to give the title compound 5-chloro-3-methylpicolinic acid (24.1 g, 140 mmol, 89 percent yield). LC/MS (ESf ) m/z = 172.0 (M+H)⁺; H NMR (400 MHz, CHLOROFORM -J) δ ppm 11.29 (br. s., 1 H), 8.41 (d, J=1.76 Hz, 1 H), 7.73 (d, J=1.76 Hz, 1 H), 2.75 (s, 3 H)
89%	With sodium hydroxide In ethanol at 90℃; for 18 h;	To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH (110 mL of 5 N solution, 550 mmol). The resulting mixture was refluxed at 90° C. for 18 h. After cooling to RT, the reaction mixture was concentrated. The residue was diluted with water and the pH of the solution was adjusted to 4 by addition of 5 N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2×). The aqueous layer was again acidified with 5 N HCl to pH 4 and extracted with EtOAc (2×). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40° C. for 12 h to give 5-chloro-3-methylpicolinic acid (268) (24.1 g, 140 mmol, 89percent yield). LC/MS (ESI⁺) m/z=172.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.29 (br. s., 1H), 8.41 (d, J=1.76 Hz, 1H), 7.73 (d, J=1.76 Hz, 1H), 2.75 (s, 3H).
89%	Stage #1: With sodium hydroxide In ethanol at 90℃; for 18 h; Stage #2: With hydrogenchloride In water	A mixture of 2-bromo-5-chloro-3-methylpyridine (45 g, 218 mmol), zinc cyanide (8.30 mL, 131 mmol), tris(dibenzylideneacetone) dipalladium (0) (4.99 g, 5.45 mmol), and 1 ,1’-bis(diphenylphosphino)ferrocene (6.04 g, 10.90 mmol) in dimethylacetamide (40 mL) was heated to 110 °C for 4 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic phase obtained was concentrated under reduced pressure and residue purified by chromatography on silica gel using ISCO eluting with 0-60percent EtOAc/hexanes to afford 5-chloro-3-methylpicolinonitrile (25.4 g, 166 mmol, 76 percent yield). LC/MS (ESI⁺) m/z = 153.1 (M+H) . To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH (110 mL of 5 N solution, 550 mmol). The resulting mixture was refluxed at 90 °C for 18 h. After cooling to RT, the reaction mixture was concentrated. The residue was diluted with water and the pH of the solution was adjusted to 4 by addition of 5 N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2 x). The aqueous layer was again acidified with 5 N HCl to pH 4 and extracted with EtOAc (2 x). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a vacuum oven at 40 °C for 12 h to give 5-chloro-3-methylpicolinic acid (268) (24.1 g, 140 mmol, 89percent yield). LC/MS (ESI⁺) m/z = 172.0 (M+H) ⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.29 (br. s., 1 H), 8.41 (d, J=1.76 Hz, 1 H), 7.73 (d, J=1.76 Hz, 1 H), 2.75 (s, 3 H).

Reference： [1] Patent: US2014/249104, 2014, A1, . Location in patent: Page/Page column
[2] Patent: WO2014/138484, 2014, A1, . Location in patent: Page/Page column 143
[3] Patent: US2015/38497, 2015, A1, . Location in patent: Paragraph 0992; 0994
[4] Patent: WO2016/22724, 2016, A1, . Location in patent: Page/Page column 294; 295

3
[ 65550-77-8 ]
[ 886365-46-4 ]

Reference： [1] Patent: US2014/249104, 2014, A1,
[2] Patent: WO2014/138484, 2014, A1,
[3] Patent: US2015/38497, 2015, A1,
[4] Patent: WO2016/22724, 2016, A1,

[ 886365-46-4 ] Synthesis Path-Downstream 1~34

1
[ 16110-09-1 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 886365-46-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1,1'-bis-(diphenylphosphino)ferrocene; triethylamine;palladium diacetate; In methanol; at 100℃; under 2585.81 Torr; for 11h;	A 10 L bottle was charged with dichloropyridine, palladium acetate, dppf (1,1'-Bis(diphenylphosphino)ferrocene), and TEA in methanol 6 L. The bottle was stirred then contents transferred to an 5 gallon stainless steel stirred reaction vessel (Kla=1.42 (at) 40% fill and 1000 rpm) via vacuum. The bottle was rinsed with another 2 L methanol, and the rinse was added to reaction vessel by the same method. The vessel was tested for leaks using nitrogen, then purged with nitrogen three times and carbon monoxide three times with the final carbon monoxide charge to be 50 psig of Carbon monoxide. The pressurized vessel was heated to a temperature of 100 C. The agitation rate was 1000 rpm. The reaction was allowed to progress for eleven hours, then allowed to cool to room temperature and sampled. Reaction was judged to be complete when 3% LCAP or less of starting material remained. Batch was transferred to a 50 L r.b. flask equipped with a thermocouple and stir paddle. Flask was connected to a batch concentrator and concentration begun at approximately 25-30 in Hg of applied vacuum. Intermittent heating of batch was applied to maintain temp at approximately 30-35 C. Concentration was discontinued when copious precipitate was noted. Saturated brine 20 L was added via addition funnel over one hour. Batch was aged with gentle stirring overnight. In morning, a methanol/ice bath was applied to cool batch to -5 C. for 1.5 hours. Solids were collected by filtration and rinsed with 5 L brine twice, then dried under nitrogen tent overnight to give 3.47 Kg of product intimately mixed with sodium chloride: 57 wt %, 1.98 Kg of product in the isolated solids, 99% yield, ML losses 0.41%. The product can be stored at this point if desired. NMR 1H delta: 3.87 (s, 3H), 7.69 (dd, J=8.4, 2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H). NMR 13C delta: 52.8, 125.8, 135.7, 136.6, 145.7, 148.6, 164.6. Solids and tetrahydrofuran were charged to a 50 L r.b. flask equipped with stir paddle. The batch was stirred for one hour, at which point the water content (Kf) of the batch was less than 1000 ug/0.5 mL. The batch was concentrated with incremental tetrahydrofuran addition to azeotropically dry to Kf of 780 ug/0.5 mL. HPLC assay was 122 mg/g of THF solution, 1.97 Kg product in 16.06 Kg of solution.

Reference： [1]Patent: US2004/102472,2004,A1 .Location in patent: Page 49; 50

2
[ 886365-46-4 ]
[ 676-58-4 ]
[ 40472-78-4 ]

Yield	Reaction Conditions	Operation in experiment
		A 100 L r.b. flask was flushed with nitrogen, fitted with thermocouple, overhead stir paddle, and dropping funnel. The flask was charged with a 3M solution of methylmagnesium chloride and stirring begun. The flask was packed in an ice bath. When the temperature reached 5 C., a solution of chloro-ester was added by dropping funnel. The rate of addition was controlled to keep temperature below 30 C., and generally between 20-25 C. After addition was complete, the reaction was aged for 30-45 minutes longer and assayed. The reaction was quenched by addition of ethyl acetate 800 mL followed by methanol 800 mL, again not allowing temperature to rise above 30 C. pH was adjusted with 2N hydrochloric acid solution to pH=4. The acidic reaction solution was extracted with ethyl acetate 9 L. The organic layer was extracted once with 1N hydrochloric acid solution 40 L, and again with 1N hydrochloric acid solution 20 L. The combined aqueous layers were adjusted with 10 N sodium hydroxide to pH=8 (4 L) (Note: an oily layer was noted to separate out on top). The basic aqueous layer was extracted once with ethyl acetate 10 L, dried and concentrated to a solution of 200 mg/mL concentration of product. An aliquot of product solution was concentrated to an oil and purified further by column chromatography on a silica gel 5-10% ethyl acetate in hexanes gradient for characterization purposes. NMR 1H delta: 1.53 (s, 6H), 4.44 (br s, 1H), 7.35 (dd, J=8.4, 0.7 Hz, 1H), 7.66 (dd, J=8.4, 2.4 Hz, 1H), 8.46 (dd, J=2.3, 0.6 Hz, 1H). NMR 13C delta: 30.5, 71.9, 119.5, 130.1, 136.6, 146.4, 164.4.

Reference： [1]Patent: US2004/102472,2004,A1 .Location in patent: Page 50

3
[ 886365-46-4 ]
N-(3-tert-butylphenyl)-2-phenylpiperidine-3-carboxamide [ No CAS ]
N-(3-tert-butylphenyl)-1-(5-chloro-3-methylpicolinoyl)-2-phenylpiperidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	d) <strong>[886365-46-4]5-Chloro-3-methylpicolinic acid</strong> (30 mg, 0.16 mmol) and N-(3-tert-butylphenyl)-2-phenylpiperidine-3-carboxamide (50 mg, 0.15 mmol, prepared in step c above) were dissolved in anhydrous DMF (1 mL). N,N-Diisopropylethylamine (0.15 mL) was added at room temperature followed by HCTU (67 mg, 0.16 mmol). After stirring 2 h at ambient temperature, LC-MS and TLC indicated the completion of the reaction. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1 N HCl (20 mL), saturated NaHCO3 (30 mL), and brine (30 mL) and the resulting solution was concentrated under reduced pressure.The residue was purified by preparative HPLC (20?95% gradient of MeCN-H2O with 0.1% TFA) and the pure fractions were lyophilized to afford the title compound (50 mg, 67% yield). HPLC retention time=2.88 minutes. 1H NMR (400 MHz, CDCl3) delta 8.42 (d, 1H, J=0.8 Hz), 7.97 (br, 1H), 7.59 (d, 1H, J=0.8 Hz), 7.56 (d, 1H, J=7.6 Hz), 7.34 (m, 3H), 7.20 (m, 3H), 7.10 (d, 1H, J=7.6 Hz), 6.61 (two sets of br, 1H), 3.12 (two sets of m, 2H), 2.94 (three sets of m, 1H), 2.36 (s, 3H), 2.20 (two sets of br, 2H), 1.74 (br complex, 2H), 1.29 (s, 9H). MS: (ES) m/z 490.2 (M+H+).

Reference： [1]Patent: US2010/160320,2010,A1 .Location in patent: Page/Page column 20

4
[ 886365-46-4 ]
[ 1383985-65-6 ]
[ 1383982-87-3 ]

Yield	Reaction Conditions	Operation in experiment
18%		Example 20wN-[(1r,4r)-4''-Amino-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-6'-yl]-5-chloro-3-methylpyridine-2-carboxamide; To a slurry of <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (37.6 mg, 0.22 mmol) in a mixture of DCM/DMF/THF (2.0:2.0:0.5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45.5 mg, 0.24 mmol). The mixture containing the activated acid was stirred for 20 min. under argon before it was added to a cold (0 C., external temp.) stirred solution of (1r,4r)-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4'',6'-diamine (Example 20j, step 1, 57.0 mg, 0.18 mmol), hydrochloric acid (3 M) (0.3 mL, 0.90 mmol) and triethylamine (0.099 mL, 0.71 mmol) in DMF (2.0 mL). After 2 h, another portion of activated acid, prepared as above, was added at 0 C. The mixture was stirred at 0 C. for 5 min. and then at r.t. for -1 h before raising the temperature to 30 C. for 30 min. The reaction was quenched by addition of MeOH (1.5 mL) and the mixture was concentrated at reduced pressure to give a crude product that was purified by preparative chromatography. The isolated material was treated with 1.25M HCl in MeOH (1.5 mL) to give the title compound as the hydrochloride salt (15 mg, 18% yield). 1H NMR (500 MHz, CDCl3) delta ppm 1.14 (m, 1H), 1.28-1.44 (m, 3H), 1.64-1.78 (m, 2H), 1.96-2.10 (m, 2H), 2.46 (s, 3H), 2.77 (s, 3H), 3.05-3.16 (m, 2H), 3.22 (m, 1 H), 3.35 (s, 3H), 7.32-7.36 (m, 2H), 7.62-7.66 (m, 2H), 8.37 (d, 1H), 10.05 (s, 1H); MS (ES+) m/z 466 [M+H]+.

Reference： [1]Patent: US2012/165347,2012,A1 .Location in patent: Page/Page column 66

5
[ 886365-46-4 ]
[ 1262860-48-9 ]

Yield	Reaction Conditions	Operation in experiment
		Acid-16: 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid; A suspension of 500 mg (2.91 mmol) <strong>[886365-46-4]5-chloro-3-methyl-pyridine-2-carboxylic acid</strong> (CAS Nr.: 886365-46-4) in 9 ml of D20 (99,96% D) was treated with 1 ml of a 40% solution of NaOD in D20. The homogeneous solution was heated in a 100 ml Teflon vessel with a Synthos 3000 Microwave apparatus. The mixture was heated at 160 C for 5 h and cooled down. 1 H-NMR and MS analyses of the product showed that deuteration had progressed to a high degree. Only minor amounts of tetradeutero derivatives were present. The reaction mixture was acidified to pH3 with 2N HCI and extracted with EtOAc. The org. phase was dried with MgS04.H20 and evaporated to give the title compound as a white solid, pure enough for further transformations.HPLC: Rtm= 2.820 min; ESIMS [M+H]+ = 177 (5D);1H-NMR (360 MHz, D20): delta non deuterated impurities.
	With [D]-sodium hydroxide; In water-d2; at 160℃; for 5h;Microwave irradiation;	Acid 2: 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acidA suspension of 500 mg (2.91 mmol) <strong>[886365-46-4]5-chloro-3-methyl-pyridine-2-carboxylic acid</strong> (CAS Nr.: 886365-46-4) in 9 ml of D2O (99,96% D) was treated with 1 ml of a 40% solution of NaOD in D2O. The homogeneous solution was heated in a 100 ml Teflon vessel with a Synthos 3000 Microwave apparatus. The mixture was heated at 160 C. for 5 h and cooled down. 1H-NMR and MS analyses of the product showed that deuteration had progressed to a high degree. Only minor amounts of tetradeutero derivatives were present. The reaction mixture was acidified to pH3 with 2N HCl and extracted with EtOAc. The org. phase was dried with MgSO4.H2O and evaporated to give the title compound as a white solid, pure enough for further transformations.HPLC: RtH1=2.820 min; ESIMS [M+H]+=177 (5D); 1H-NMR (360 MHz, D2O): delta non deuterated impurities.

Reference： [1]Patent: WO2012/95463,2012,A1 .Location in patent: Page/Page column 90
[2]Patent: US2012/184539,2012,A1 .Location in patent: Page/Page column 54

6
[ 886365-46-4 ]
5-chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid [4-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-2-yl]-amide [ No CAS ]

Reference： [1]Patent: US2012/184539,2012,A1

7
[ 886365-46-4 ]
[ 1387560-81-7 ]

Reference： [1]Patent: US2012/184539,2012,A1

8
[ 886365-46-4 ]
[ 1387559-75-2 ]

Reference： [1]Patent: US2012/184539,2012,A1

9
[ 886365-46-4 ]
[ 1310350-45-8 ]
[ 1310347-54-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 3980 - 3995

10
[ 886365-46-4 ]
[ 1600513-04-9 ]
[ 144-55-8 ]
[ 68957-94-8 ]
[ 1600508-79-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: (R)-N-(3-(8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide To a stirred mixture of (R)-8-amino-6-(5-amino-2-fluorophenyl)-6-(fluoromethyl)-4-thia-7-azaspiro[2.5]oct-7-ene 4,4-dioxide (0.0625 g, 0.198 mmol) and 5-chloro-3-methylpicolinic acid (0.036 g, 0.208 mmol) in DCM (3 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.378 g, 0.595 mmol). After the addition, the mixture was stirred at RT for 16 h, saturated aqueous NaHCO3 was added, layers were separated, organic phase dried over Na2SO4, concentrated and purified by silica gel chromatography (30% EtOAc/DCM) to give the title compound as an off white solid (51 mg, 55%). LC/MS (ESI+) m/z: 469 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) ppm 10.01 (1H, s), 8.35-8.43 (1H, m), 7.96 (1H, ddd, J=8.8, 4.3, 2.8 Hz), 7.63-7.68 (2H, m), 7.09 (1H, dd, J=11.7, 8.8 Hz), 4.82 (1H, dd, J=14.7, 8.8 Hz), 4.55 (1H, dd, J=14.7, 8.8 Hz), 4.45 (2H, br. s.), 3.77 (2H, dd, J=14.5, 8.8 Hz), 2.79 (3H, s), 1.73-1.86 (2H, m), 1.56 (2H, m).

Reference： [1]Patent: US2014/107109,2014,A1 .Location in patent: Page/Page column

11
[ 886365-46-4 ]
tert-butyl ((11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate [ No CAS ]
[ 1620981-59-0 ]
[ 1620981-60-3 ]

Yield	Reaction Conditions	Operation in experiment
110 mg; 70 mg	With pyridine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;	To the crude tert-butyl ((11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4-a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (190 mg, 0.449 mmol) from Step 4 (-2:1 trans/cis mixture) dissolved in DMF (2 ml), was added <strong>[886365-46-4]5-chloro-3-methylpyridine-2-carboxylic acid</strong> (92 mg, 0.538 mmol), pyridine (0.109 ml, 1.346 mmol) and HATU (256 mg, 0.673 mmol) and resulting solution was stirred for 1 hr at RT. The mixture was diluted with EtOAc (8 ml) and saturated NaHCO3 solution (3 ml). Water was added to dissolve precipitated solids. The organic layer was separated, washed with water, brine and concentrated. The residue was and purified by silica gel chromatography on 12 g RediSep Gold column using 10-70% EtOAc in heptane to afford major less polar trans-isomer tert-butyl ((4aR,11bR)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4-a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (110 mg, 0.191 mmol, 42.5% yield and more polar minor cis-isomer tert-butyl ((4aS,11bR)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4-a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (70 mg, 0.121 mmol, 27% yield).

Reference： [1]Patent: US2014/213581,2014,A1 .Location in patent: Paragraph 0590; 0595; 0880

12
[ 886365-46-4 ]
tert-butyl ((4aRS,11bRS)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b] [1,4]thiazin-2-yl)carbamate [ No CAS ]
tert-butyl ((4aRS,11bRS)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76 mg	With pyridine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 0.75h;	Crude tert-butyl ((4aRS,11bRS)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4-a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (70 mg, 0.165 mmol) was suspended in DMF (2 ml) and sonicated for 1 min. 5-Chloro-3-methylpyridine-2-carboxylic acid (34.0 mg, 0.198 mmol), pyridine (0.04 ml, 0.496 mmol) and HATU (94 mg, 0.248 mmol) were added and resulting suspension was stirred for 45 min at RT. The mixture was diluted with EtOAc (8 ml) and saturated NaHCO3 solution (3 ml). Water was added to dissolve precipitated solids. The organic layer was separated, washed with water and concentrated, and the resulting concentrate/residue was purified by FC on 12 g RediSep Gold column using 10-80% EtOAc in heptane to afford tert-butyl ((4aRS,11bRS)-10-(5-chloro-3-methylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4-a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (76 mg, 0.132 mmol, 80% yield) as white solid.

Reference： [1]Patent: US2014/213581,2014,A1 .Location in patent: Paragraph 0576; 0584

13
[ 886365-46-4 ]
tert-butyl ((11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate [ No CAS ]
[ 1620977-77-6 ]

Reference： [1]Patent: US2014/213581,2014,A1

14
[ 65550-77-8 ]
[ 886365-46-4 ]

Reference： [1]Patent: US2014/249104,2014,A1
[2]Patent: WO2014/138484,2014,A1
[3]Patent: US2015/38497,2015,A1
[4]Patent: WO2016/22724,2016,A1

15
[ 156072-84-3 ]
[ 886365-46-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	In ethanol;	Step 2: Synthesis of 5-chloro-3-methylpicolinic acid To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH 5.0N (110 ml, 550 mmol). The resulting mixture was refluxed at 90 C. for 18 h. After cooling to RT, the reaction mixture was concentrated, diluted with water and the pH of the solution was adjusted to 4 by addition of 5N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2). The aqueous layer was again acidified with 5N HCl to pH 4 and extracted with EtOAc (2). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40 C. for 12 h to give the title compound 5-chloro-3-methylpicolinic acid (24.1 g, 140 mmol, 89% yield). LC/MS (ESI+) m/z=172.0 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 11.29 (br. s., 1H), 8.41 (d, J=1.76 Hz, 1H), 7.73 (d, J=1.76 Hz, 1H), 2.75 (s, 3H).
89%		To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH 5. ON (110 ml, 550 mmol). The resulting mixture was refluxed at 90 C for 18 h. After cooling to RT, the reaction mixture was conentrated, diluted with water and the pH of the solution was adjusted to 4 by addition of 5N HC1. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2X). The aqueous layer was again acidified with 5N HC1 to pH 4 and extracted with EtOAc (2X). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40 C for 12 h to give the title compound 5-chloro-3-methylpicolinic acid (24.1 g, 140 mmol, 89 % yield). LC/MS (ESf ) m/z = 172.0 (M+H)+; H NMR (400 MHz, CHLOROFORM -J) delta ppm 11.29 (br. s., 1 H), 8.41 (d, J=1.76 Hz, 1 H), 7.73 (d, J=1.76 Hz, 1 H), 2.75 (s, 3 H)
89%	With sodium hydroxide; In ethanol; at 90℃; for 18h;	To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH (110 mL of 5 N solution, 550 mmol). The resulting mixture was refluxed at 90 C. for 18 h. After cooling to RT, the reaction mixture was concentrated. The residue was diluted with water and the pH of the solution was adjusted to 4 by addition of 5 N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2×). The aqueous layer was again acidified with 5 N HCl to pH 4 and extracted with EtOAc (2×). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40 C. for 12 h to give 5-chloro-3-methylpicolinic acid (268) (24.1 g, 140 mmol, 89% yield). LC/MS (ESI+) m/z=172.0 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 11.29 (br. s., 1H), 8.41 (d, J=1.76 Hz, 1H), 7.73 (d, J=1.76 Hz, 1H), 2.75 (s, 3H).

89%

A mixture of 2-bromo-5-chloro-3-methylpyridine (45 g, 218 mmol), zinc cyanide (8.30 mL, 131 mmol), tris(dibenzylideneacetone) dipalladium (0) (4.99 g, 5.45 mmol), and 1 ,1?-bis(diphenylphosphino)ferrocene (6.04 g, 10.90 mmol) in dimethylacetamide (40 mL) was heated to 110 C for 4 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic phase obtained was concentrated under reduced pressure and residue purified by chromatography on silica gel using ISCO eluting with 0-60% EtOAc/hexanes to afford 5-chloro-3-methylpicolinonitrile (25.4 g, 166 mmol, 76 % yield). LC/MS (ESI+) m/z = 153.1 (M+H) . To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH (110 mL of 5 N solution, 550 mmol). The resulting mixture was refluxed at 90 C for 18 h. After cooling to RT, the reaction mixture was concentrated. The residue was diluted with water and the pH of the solution was adjusted to 4 by addition of 5 N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2 x). The aqueous layer was again acidified with 5 N HCl to pH 4 and extracted with EtOAc (2 x). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a vacuum oven at 40 C for 12 h to give 5-chloro-3-methylpicolinic acid (268) (24.1 g, 140 mmol, 89% yield). LC/MS (ESI+) m/z = 172.0 (M+H) +. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 11.29 (br. s., 1 H), 8.41 (d, J=1.76 Hz, 1 H), 7.73 (d, J=1.76 Hz, 1 H), 2.75 (s, 3 H).

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column
[2]Patent: WO2014/138484,2014,A1 .Location in patent: Page/Page column 143
[3]Patent: US2015/38497,2015,A1 .Location in patent: Paragraph 0992; 0994
[4]Patent: WO2016/22724,2016,A1 .Location in patent: Page/Page column 294; 295

16
[ 886365-46-4 ]
[ 1624605-58-8 ]
[ 96042-30-7 ]
N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethyl acetate;	Step 2: N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide (rac-4-n) A round-bottomed flask was charged with N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (rac-4l, 0.233 g, 0.589 mmol), DCM (8 mL), N,N-diisopropylethylamine (0.133 mL, 0.766 mmol), <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (intermediate 6) 0.131 g, 0.766 mmol) and finally with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate; 0.347 mL, 0.589 mmol). The reaction mixture was stirred at room temperature for 15 min. The Reaction mixture was poured into aqueous saturated NaHCO3 (50 mL) and then extracted with EtOAc (2*50 mL). The combined extracts were washed with brine, dried over Na2SO4 and loaded onto silica gel. Purification by silica gel chromatography (gradient 0 to 30% EtOAc/hexane) gave the title compound (50 mg). MS m/z=549.1 [M+H]+. Calculated for C26H21ClF4N4O3: 548.9

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

17
[ 886365-46-4 ]
[ 1624605-58-8 ]
N-(3-((4SR,6SR)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide [ No CAS ]

Reference： [1]Patent: US2014/249104,2014,A1

18
[ 886365-46-4 ]
[ 1624603-63-9 ]

Reference： [1]Patent: US2014/249104,2014,A1

19
[ 886365-46-4 ]
[ 1256790-98-3 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of 5-chloro-3-methylpicolinamide The title compound was synthesized according to Method AA starting from <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (intermediate 6). MS m/z=171.1 [M+H]+. Calculated for C7H7ClN2O: 170

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

20
[ 886365-46-4 ]
[ 1624603-92-4 ]

Reference： [1]Patent: US2014/249104,2014,A1

21
[ 886365-46-4 ]
[ 1624603-18-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4 Synthesis of N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide The title compound was synthesized by procedures and steps analogous to those described in Method A in Example 2 above, but using <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (Intermediate 6) in step 1. MS m/z=463.0 [M+H]+. Calculated for C19H16ClF5N4O2: 462.801 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 2.22 (t, J=13.20 Hz, 1H) 2.73 (dd, J=13.60, 2.64 Hz, 1H) 2.79 (s, 3H) 4.14-4.22 (m, 1H) 4.41-4.58 (m, 1H) 4.63-4.79 (m, 1H) 7.11 (dd, J=11.54, 9.00 Hz, 1H) 7.47 (dd, J=6.94, 2.84 Hz, 1H) 7.65 (d, J=1.76 Hz, 1H) 8.08 (ddd, J=8.85, 4.16, 2.84 Hz, 1H) 8.39 (d, J=1.76 Hz, 1H) 10.04 (s, 1H).

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

22
[ 886365-46-4 ]
[ 1624604-70-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 170 Synthesis of N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-chloro-3-methylpicolinamide The titled compound was synthesized by procedure and steps analogous to those described in Method Y, Example 163 above, but using <strong>[886365-46-4]5-chloro-3-methyl-pyridine-2-carboxylic acid</strong> (Frontier Scientific, Inc) in step 10. MS m/z=463.0 [M+H]+. Calculated for C19H16ClF5N4O2: 462.8 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.68 (br. s., 3H) 1.94 (t, J=12.52 Hz, 1H) 2.78 (br. s., 4H) 3.99-4.15 (m, 1H) 7.03 (br. s., 1H) 7.66 (br. s., 1H) 8.11 (br. s., 1H) 8.39 (br. s., 1H) 10.06 (br. s., 1H)

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

23
[ 886365-46-4 ]
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide [ No CAS ]

Reference： [1]Patent: US2015/38497,2015,A1

24
[ 886365-46-4 ]
5-chloro-3-methylpyridine-2-carbonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 17h;	<strong>[886365-46-4]5-Chloro-3-methylpicolinic acid</strong> (42.1 mg, 240 muiotaetaomicron) was suspended in dichloromethane (3 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (42.6 mg, 29.4 muL·, 336 mupiiotaomicron) as well as dimethylformamide (0.137 M in toluene, 43.8 mu, 6 mupiiotaomicron) were added. The mixture was stirred for 17 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) to afford 5-chloro-3-methylpicolinoyl chloride as brown oil (48 mg, quant.). After that, tert-butyl ((4aR,5R,9R)-5-(6-amino-3-fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido- 2,3,4,4a,5,8-hexahydro-[l,4]thiazino[2, l-f][l,2]thiazin-7-yl)carbamate (Int-51AAp, 80 mg, 168 mumol) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5C (ice bath) and N,N-diisopropylethylamine (41.3 mg, 55.8 muL·, 320 muiotaetaomicron) was added, followed by a solution of 5-chloro-3-methylpicolinoyl chloride (vide supra, 50.6 mg, 240 mupiiotaomicron) in dichloromethane (3 mL). The reaction mixture was stirred for 15 min at 0-5C, followed by 90 min at room temperature. Then, an aqueous solution of sodium carbonate (10%, 15 mL) was added, the mixture was stirred for 10 min at room temperature. After phase separation, the aqueous layer was extracted the dichloromethane (2 x 10 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 10:90 to 40:60) to yield, after drying in vacuo (40C, 5 mbar), the title compound as an off-white solid (61 mg, 58%). HPLC (method LCMS_gradient) tR = 3.86 min. MS (ES+) m/z 629.2 [M+H] .
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 60℃; for 1h;	Thionyl chloride (71 mul, 962 mumol) is added to a mixture of <strong>[886365-46-4]5-chloro-3-methyl-pyridine-2-carboxylic acid</strong> (150 mg, 874 mumol), toluene (1 ml) and DMF (20 mul). The mixture is heated to 60 C. for 1 hour. The mixture is concentrated in vacuo and the crude product used directly without further purification.
	With thionyl chloride; In N,N-dimethyl-formamide; at 60℃; for 1h;	Thionyl chloride (71 mu, 962 muiotaetaomicron) is added to a mixture of 5-chloro-3-methyl-pyridine-2- carboxylic acid (150 mg, 874 muiotaetaomicron), toluene (1 ml) and DMF (20 mu). The mixture is heated to 60C for 1 hour. The mixture is concentrated in vacuo and the crude product used directly without further purification.

Reference： [1]Patent: WO2016/55496,2016,A1 .Location in patent: Page/Page column 183; 184
[2]Patent: US2015/57286,2015,A1 .Location in patent: Paragraph 0192-0193
[3]Patent: WO2015/25018,2015,A1 .Location in patent: Page/Page column 59

25
[ 886365-46-4 ]
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide [ No CAS ]

Reference： [1]Patent: US2015/38497,2015,A1

26
[ 886365-46-4 ]
imidodicarbonic acid 2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-2-en-2-yl]-1,3-bis(1,1-dimethylethyl)ester [ No CAS ]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide [ No CAS ]

Reference： [1]Patent: US2015/38497,2015,A1

27
[ 886365-46-4 ]
imidodicarbonic acid 2-[(4R)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-2-en-2-yl]-1,3-bis(1,1-dimethylethyl)ester [ No CAS ]
C₃₂H₄₀ClFN₄O₇S [ No CAS ]
C₃₂H₄₀ClFN₄O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 1.5h;	To a solution of Intermediates 14A and 14B (0.218 g, 0.415 mmol) in dicholomethane (4 mL) were added <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (0.075 g, 0.435 mmol), triethylamine (0.115 mL, 0.829 mmol) and (O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate) (0.173 g, 0.456 mmol). The mixture was stirred at room temperature for 90 minutes and then concentrated. The crude product was purified by silica-gel column chromatography, eluting with 5% to 40% ethyl acetate in heptanes, to provide two diastereomeric intermediates. The major diastereomer was redissolved in DCM (1.0 mL), and trifluoroacetic acid (0.39 mL, 5.3 mmol) was added. The reaction was stirred at ambient temperature for 30 minutes, concentrated, and partitioned between saturated aqueous sodium bicarbonate and DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (48 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) delta 10.67 (s, 1H), 8.60 (d, J=1.86 Hz, 1H), 8.03 (d, J=1.66 Hz, 1H), 7.90 (d, J=8.41 Hz, 1H), 7.64 (br. s., 1H), 7.06-7.25 (m, 1H), 6.01 (br. s., 2H), 2.56 (s, 3H), 2.25-2.42 (m, 1H), 1.83 (br. s., 3H), 1.71 (t, J=7.19 Hz, 2H), 1.56 (d, J=10.37 Hz, 1H), 1.50 (s, 3H), 1.41 (br. s., 3H). LC/MS (ESI+) m/z=479.0 (M+H).

Reference： [1]Patent: US2015/38497,2015,A1 .Location in patent: Paragraph 0880; 0881

28
[ 886365-46-4 ]
tert-butyl N-[2-(5-amino-2-fluorophenyl)-2-(fluoromethyl)-5-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonylcarbamate [ No CAS ]
C₃₁H₃₆ClF₂N₃O₈S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; methanol; for 0.166667h;	General procedure: To a solution of the aniline (1 equivalent) and the carboxylic acid (1.1 equivalent) in 2:1 tetrahydrofuran/methanol is added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 1.5 equivalents). After about ten minutes, water and saturated aqueous sodium bicarbonate is added, and the mixture is extracted with DCM. The organic extract is washed with brine and concentrated. The residue is redissolved in DCM, and TFA (up to 10 equivalents) is added. The reaction is stirred at RT for 1 hour, diluted with dichloromethane, and washed with saturated aqueous sodium bicarbonate and brine, and concentrated. The crude product is purified by silica-gel chromatography to provide the title compound.

Reference： [1]Patent: US2015/38497,2015,A1 .Location in patent: Paragraph 0816; 0817; 1008

29
[ 886365-46-4 ]
imidodicarbonic acid 2-[4-(5-amino-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3.1]non-2-en-2-yl]-1,3-bis(1,1-dimethylethyl)ester [ No CAS ]
C₃₂H₄₀ClFN₄O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; methanol; at 20℃; for 3h;	General procedure: To a solution of Intermediates 2A and 2B (150 mg, 0.285 mmol) and <strong>[886365-46-4]5-chloro-3-methylpyridine-2-carboxylic acid</strong> (49 mg, 0.285 mmol) in methanol (1 mL) and THF (2 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (88 mg, 0.300 mmol). The reaction was stirred at RT. After 3 hours, the reaction mixture was partitioned between water and ethyl acetate; the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was redissolved in DCM (5 mL), and TFA (0.44 mL, 5.71 mmol) was added. The reaction was stirred at RT for 2.5 hours, washed with saturated aqueous sodium bicarbonate and brine, and concentrated. The crude product was purified by silica-gel column chromatography, eluting with 2-10% methanol in DCM, to provide the title compound (56 mg, 41% yield). 1H-NMR (400 MHz, DMSO-d6): delta ppm 10.54 (s, 1H), 8.57 (d, J=2.3 Hz, 1H), 8.02-8.06 (m, 2H), 7.85-7.89 (m, 1H), 7.16 (dd, J=11.7, 8.8 Hz, 1H), 5.96 (s, 2H), 3.57 (s, 1H), 2.57 (s, 3H), 2.03-2.14 (m, 1H), 1.89-1.96 (m, 2H), 1.70 (s, 3H), 1.50-1.53 (m, 1H), 1.48 (s, 3H), 1.21-1.35 (m, 2H). LC/MS (ESI+) m/z=479.1 D (M+H).

Reference： [1]Patent: US2015/38497,2015,A1 .Location in patent: Paragraph 0823; 0824

30
[ 886365-46-4 ]
imidodicarbonic acid 2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-2-en-2-yl]-1,3-bis(1,1-dimethylethyl)ester [ No CAS ]
C₃₁H₃₈ClFN₄O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of Intermediate 12 (100 mg, 0.195 mmol) in N,N-dimethylformamide (1.0 mL) was added <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (43.6 mg, 0.254 mmol), (O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate) (111 mg, 0.293 mmol), and pyridine (0.047 mL, 0.586 mmol). The reaction was stirred at ambient temperature for 2 hours, and then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was redissolved in DCM (0.5 mL) and TFA (0.301 mL, 3.91 mmol) was added. The reaction was stirred at RT for an hour. The reaction was quenched with saturated aqueous sodium carbonate, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica-gel column chromatography, eluting with 0-50% (3:1 ethyl acetate:ethanol, 2% ammonium hydroxide) in heptanes, to provide the title compound (62 mg, 68.2% yield). 1H NMR (400 MHz, DMSO-d6) ppm 1.28-1.34 (m, 1H) 1.46 (s, 3H) 1.68-1.72 (m, 1H) 1.74 (s, 3H) 1.87-2.09 (m, 2H) 2.57 (s, 3H) 3.68 (d, J=5.77 Hz, 1H) 6.03 (br. s., 2H) 7.17 (dd, J=11.74, 8.90 Hz, 1H) 7.72-7.81 (m, 1H) 7.81-7.89 (m, 1H) 8.03 (dd, J=2.25, 0.68 Hz, 1H) 8.52-8.61 (m, 1H) 10.54 (s, 1H). LC/MS (ESI+) m/z=465.1 (M+H).

Reference： [1]Patent: US2015/38497,2015,A1 .Location in patent: Paragraph 0861; 0862

31
[ 886365-46-4 ]
N-(6-((4aR,5R,9R)-7-amino-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[1,4]thiazino[2,1-f][1,2]thiazin-5-yl)-5-fluoropyridin-2-yl)-5-chloro-3-methylpicolinamide [ No CAS ]

Reference： [1]Patent: WO2016/55496,2016,A1

32
[ 886365-46-4 ]
tert-butyl ((4aR,5R,9R)-5-(6-(5-chloro-3-methylpicolinamido)-3-fluoropyridin-2-yl)-3,3-difluoro-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[1,4]thiazino[2,1-f][1,2]thiazin-7-yl)carbamate [ No CAS ]

Reference： [1]Patent: WO2016/55496,2016,A1

33
[ 886365-46-4 ]
tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-6-yl)carbamate [ No CAS ]
tert-butyl ((3aS,4R,8R)-4-(3-fluoro-6-(5-chloro-3-methylpicolinamido)pyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-6-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 70℃; for 4h;	To a solution of tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int- 39AB, 150 mg, 0.35 mmol) in THF (20 mL) was added <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (92.8 mg, 0.53 mmol), followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). MS (ES+) m/z 579.2 [M+H].

Reference： [1]Patent: WO2016/55496,2016,A1 .Location in patent: Page/Page column 147; 148

34
[ 886365-46-4 ]
tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-6-yl)carbamate [ No CAS ]
tert-butyl ((3aR,4R,8S)-4-(3-fluoro-6-(5-chloro-3-methylpicolinamido)pyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-6-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 70℃; for 4h;	To a solution of tert-butyl ((3aR,4R,8S)-4-(6-amino-3-fluoropyridin-2-yl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int- 39BA, 150 mg, 0.35 mmol) in THF (20 mL) was added <strong>[886365-46-4]5-chloro-3-methylpicolinic acid</strong> (92.4 mg, 0.53 mmol) followed by T3P (1.1 g, 1.75 mmol, 50% in ethyl acetate), and diisopropylethylamine (267 mg, 2.1 mmol). The reaction was stirred at 70 C for 4 h. After that, the reaction mixture was diluted with aqueous saturated sodium hydrogencarbonate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude product. The crude was purified by preparative TLC (silica gel, dichloromethane / ethyl acetate 1: 1, UV) to yield, after drying in vacuo, the title compound as a yellow solid (100 mg, 50% yield). MS (ES+) m/z 579.2 [M+H].

Reference： [1]Patent: WO2016/55496,2016,A1 .Location in patent: Page/Page column 148; 149

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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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[ 886365-46-4 ] Synthesis Path-Upstream 1~3

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Chlorides

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Pyridines

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