[ CAS No. 917882-64-5 ] {[proInfo.proName]}

Name: 917882-64-5|(S)-(1,4-Dioxan-2-yl)methyl 4-methylbenzenesulfonate|95%
Brand: Ambeed
SKU: A706926
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Quality Control of [ 917882-64-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 917882-64-5 ]

SDS Specification

Alternatived Products of [ 917882-64-5 ]

Product Details of [ 917882-64-5 ]

CAS No. :	917882-64-5	MDL No. :	MFCD18711703
Formula :	C₁₂H₁₆O₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JOMHMWCSNNGYNP-NSHDSACASA-N
M.W :	272.32	Pubchem ID :	57722840
Synonyms :

Calculated chemistry of [ 917882-64-5 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	64.87
TPSA :	70.21 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.66
Log Po/w (XLOGP3) :	1.12
Log Po/w (WLOGP) :	2.2
Log Po/w (MLOGP) :	0.9
Log Po/w (SILICOS-IT) :	1.55
Consensus Log Po/w :	1.69

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.22
Solubility :	1.65 mg/ml ; 0.00607 mol/l
Class :	Soluble
Log S (Ali) :	-2.19
Solubility :	1.77 mg/ml ; 0.00649 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.21
Solubility :	0.166 mg/ml ; 0.000611 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.64

Safety of [ 917882-64-5 ]

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

Application In Synthesis of [ 917882-64-5 ]

* 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 [ 917882-64-5 ]
Downstream synthetic route of [ 917882-64-5 ]

[ 917882-64-5 ] Synthesis Path-Upstream 1~6

1
[ 98-59-9 ]
[ 917882-64-5 ]

Reference： [1] Patent: US2006/293358, 2006, A1, . Location in patent: Page/Page column 51

2
[ 1170702-79-0 ]
[ 98-59-9 ]
[ 917882-64-5 ]

Reference： [1] Patent: US2009/182002, 2009, A1, . Location in patent: Page/Page column 16

3
[ 67843-74-7 ]
[ 98-59-9 ]
[ 107-07-3 ]
[ 917882-64-5 ]

Reference： [1] Patent: US2014/275082, 2014, A1, . Location in patent: Paragraph 0231

4
[ 861852-08-6 ]
[ 917882-64-5 ]

Reference： [1] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858

5
[ 861852-07-5 ]
[ 917882-64-5 ]

Reference： [1] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858

6
[ 98-59-9 ]
[ 406913-88-0 ]
[ 917882-64-5 ]

Reference： [1] Organic Process Research and Development, 2010, vol. 14, # 4, p. 849 - 858

[ 917882-64-5 ] Synthesis Path-Downstream 1~43

1
[ 98-59-9 ]
[ 917882-64-5 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: Tosylate 22B-2; A solution of conc. aqueous NaOH solution (26.1 L) and water (31.3 L) was heated to 87 C. Crude epoxide 22B-1 (prepared as above; 5.24 kg, 38.4 mol) was added and the reaction aged at 90 C. for 30 min. The reaction was cooled to 22 C. and then diluted with DCM (21 L). p-Toluenesulfonyl chloride (7.46 kg, 38.36 mol) was added and the mixture was aged at 22 C. for 16 h. Water (21 L) was added and the phases separated. The aqueous layer was extracted with DCM (2×21 L). The combined organic layers were washed with a 5% brine solution (21 L). The organic layer was concentrated in vacuo and the residue dissolved in toluene (32 L). Heptane (7 L) was added followed by 22B-2 as seed (100 g) and the mixture cooled to 4 C. After ageing for 16 h, the mixture was filtered and the solids washed with 8:1 heptane/toluene (4 L). Tosylate 22B-2 was isolated as a white solid: 1H NMR (CDCl3) delta 2.47 (3H, s), 3.37 (1H, dd, J=9.6, 11.2 Hz), 3.70 (6H, m), 3.97 (1H, dd, J=4.8, 10.4 Hz), 4.03 (1H, dd, J=5.4, 10.6 Hz), 7.37 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz).

Reference： [1]Patent: US2006/293358,2006,A1 .Location in patent: Page/Page column 51

2
[ 917882-64-5 ]
[ 74-89-5 ]
[ 917882-58-7 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of tosylate 1B-2 (7.76 kg), methylamine in ethanol (62 L of a 33 wt % solution) and ethanol (62 L) was heated to an internal temperature of 65 C. for 20 h. The resulting solution was then concentrated via atmospheric distillation to a volume of 15 L. This solution was held at 50 C. while NaOEt (9.2 L of a 21 wt % solution in ethanol; 1.05 equiv) was added, along with MTBE (47 L) each in two alternating portions. The slurry was then cooled to room temperature and filtered to remove sodium tosylate. The solids were washed with MTBE (15.5 L). The combined filtrates were solvent switched to isopropanol via atmospheric distillation. The final volume was 30 L. Conc. HCl (2.1 L of S.G. 1.18, 1.05 equiv) was added whilst keeping the temperature <60 C. Isopropanol (116 L) was added, and the batch was concentrated via atmospheric distillation to a total volume of 30 L. This mixture was held at 50 C. until a slurry formed, then cooled to room temperature overnight. The solids were filtered, washed with 1:1 heptane:isopropanol (15 L) and dried to give 1B-3 as a white solid.1H NMR (400 MHz, MeOD): delta 3.90 (m, 2H), 3.77 (m, 3H), 3.62 (tr d, J=12 Hz, J=2.5 Hz, 1H), 3.36 (m, 1H), 3.06 (m, 2H), 2.73 (s, 3H)
		Step 3: 1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride; A solution of tosylate 22B-2 (7.76 kg), methylamine in ethanol (62 L of a 33 wt % solution) and ethanol (62 L) was heated to an internal temperature of 65 C. for 20 h. The resulting solution was then concentrated via atmospheric distillation to a volume of -15 L. This solution was held at 50 C. while NaOEt (9.2 L of a 21 wt % solution in ethanol; 1.05 equiv) was added, along with MTBE (47 L) each in two alternating portions. The slurry was then cooled to room temperature and filtered to remove sodium tosylate. The solids were washed with MTBE (15.5 L). The combined filtrates were solvent switched to isopropanol via atmospheric distillation. The final volume was 30 L. Conc. HCl (2.1 L of S.G. 1.18, 1.05 equiv) was added whilst keeping the temperature <60 C. Isopropanol (116 L) was added, and the batch was concentrated via atmospheric distillation to a total volume of -30 L. This mixture was held at 50 C. until a slurry formed, then cooled to room temperature overnight. The solids were filtered, washed with 1:1 heptane:isopropanol (15 L) and dried to give 22B-3 as a white solid. 1H NMR (400 MHz, MeOD): delta 3.90 (m, 2H), 3.77 (m, 3H), 3.62 (tr d, J=12 Hz, J=2.5 Hz, 1H), 3.36 (m, 1H), 3.06 (m, 2H), 2.73 (s, 3H)

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858
[2]Patent: US2009/182002,2009,A1 .Location in patent: Page/Page column 17
[3]Patent: US2006/293358,2006,A1 .Location in patent: Page/Page column 51

3
[ 917882-64-5 ]
[ 1112178-37-6 ]
[ 1112169-39-7 ]

Yield	Reaction Conditions	Operation in experiment
30%	With triethylamine; In N,N-dimethyl acetamide; at 85℃; for 18h;	Step 3 Preparation of 6-(2-(((ff)-1 ,4-diotaoxan-2-yl)methyl)-2H-tetrazol-5-yl)-lambda/-(3-methoxybenzyl)-2- methylpyriotamiotadiotane-4-carboxamiotadeA mixture of lambda/-(3-methoxybenzyl)-2-methyl-6-(2/-/-tetrazol-5-yl)py?miotadiotane-4-carboxamiotade (prepared as described in step 6 of the synthesis of lambda/-(3-Methoxybenzyl)-6-(2-(((frans)-4- aminocyclohexyOmethyO^H-tetrazol-S-yO^-methylpyrimidine^-carboxamide, Example 5) (100 mg, O 307 mmol), (S)-(1 , 4-diotaoxan-2-yl)methyl 4-methylbenzenesulfonate (167 mg, 0 615 mmol), t?ethylamine (0 17 mL, 1 23 mmol) and dimethylacetamide (0 3 mL) was stirred at 85 0C for 18 hours The mixture was purified by reverse phase preparative HPLC Fractions containing the desired product were combined, isolated and concentrated to afford the title compound as a white solid (39 mg, 30%) LC/MS (5%-95% CH3CN/H2O, 4 mm , 95% CH3CN, 1 mm ) 2 75, m/z 426 (M+H) 1H NMR (400 MHz, DMSO-d6) delta ppm 2 83 (s, 3 H), 3 38 - 3 58 (m, 3 H), 3 64 (d, J=10 8 Hz, 1 H), 3 70 - 3 77 (m, 4 H), 3 92 (dd, J=1 1 4, 2 4 Hz, 1 H), 4 10 - 4 19 (m, 1 H), 4 51 (d, J=6 5 Hz, 2 H), 4 92 (d, J=1 6 Hz, 2 H), 6 83 (dd, J=9 0, 1 6 Hz, 1 H), 6 90 - 6 95 (m, 2 H), 7 24 (t, J=8 1 Hz, 1 H), 8 42 (s, 1 H), 9 54 (t, J=6 4 Hz, 1 H)

Reference： [1]Patent: WO2009/16498,2009,A1 .Location in patent: Page/Page column 143

4
[ 917882-64-5 ]
[ 1112178-44-5 ]
[ 1112169-41-1 ]

Yield	Reaction Conditions	Operation in experiment
39%	With triethylamine; In N,N-dimethyl acetamide; at 85℃; for 18h;	Example 546-(2-(((R)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(4-fluoro-3-methoxybenzyl)-2- methylpyrimidine-4-carboxamideA mixture of lambda/-(4-fluoro-3-methoxybenzyi)-2-methyl-6-(2H-tetrazol-5-yl)pyriotamiotadiotane-4- carboxamide (prepared as described in step 2 of the synthesis of lambda/-(4-fluoro-3-methoxybenzyl)-6-(2- (frans-4-amiotanocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyriotamiotadiotane-4-carboxamiotade, Example 9) (100 mg, 0 291 mmol), (S)-(1 , 4-diotaoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((R)-1 ,4-diotaoxan-2-yl)methy.)-2H-tetrazol-5-yl)-lambda/-(3-methoxybenzyl)- 2-methylpy?miotadiotane-4-carboxamiotade, Example 53) (159 mg, 0 583 mmol), triethylamine (0 16 mL, 1 17 mmol) and dimethylacetamide (0 3 mL) was stirred at 85 0C for 18 hours The mixture was purified by reverse phase preparative HPLC Fractions containing the desired product were isolated and concentrated to afford the title compound as a white solid (51 mg, 39%) LC/MS (5%-95% CH3CN/H2O, 4 mm , 95% CH3CN, 1 mm ) 2 78 mm, m/z 444 (M+H) 1H NMR (400 MHz, DMSO-Cf6) delta ppm 2 83 (s, 3 H), 3 38 - 3 58 (m, 3 H), 3 65 (d, J=10 6 Hz, 1 H), 3 73 (d, J=11 4 Hz, 1 H), 3 83 (s, 3 H), 3 91 (dd, J= 1 1 5, 2 4 Hz, 1 H), 4 1 1 - 4 19 (m, 1 H), 4 51 (d, J=6 2 Hz, 2 H), 4 93 (d, J=6 2 Hz, 2 H), 6 88 - 6 94 (m, 1 H), 7 09 - 7 22 (m, 2 H), 8 42 (s, 1 H), 9 51 (t, J=6 4 Hz, 1 H)

Reference： [1]Patent: WO2009/16498,2009,A1 .Location in patent: Page/Page column 143

5
[ 917882-64-5 ]
[ 1112178-79-6 ]
[ 1112169-45-5 ]

Yield	Reaction Conditions	Operation in experiment
18%	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 15h;	Example 566-(2-(((/?)-1 ,4-Dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-W-(4-fluoro-3-(2-hydroxyethoxy)benzyl)-2- methylpyrimidine-4-carboxamidelambda/-(4-Fluoro-3-(2-hydroxyethoxy)benzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyriotamiotadiotane-4- carboxamide (prepared as described in step 2 of the synthesis of lambda/-(4-fluoro-3-(2- hydroxyethoxy)benzyl)-6-(2-(((<rans-4-cyanocyclohexyl)methyl)-2/-/-tetrazol-5-yl)-2-methylpyrimidme-4- carboxamide, Example 27) (45 mg, 0 20 mmol) and (S)-(1 ,4-diotaoxan-2-yl)methyl 4- methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6-(2-(((R)-1 ,4-diotaoxan-2- yl)methyl)-2/-/-tetrazol-5-yl)-lambda/-(3-methoxybenzyl)-2-methylpyriotamiotadiotane-4-carboxamiotade, Example 53) (60 mg, 0 22 mmo.) were taken up in triethylamine (1 00 mL) and dimethylformamide (0 12 mL) The reaction was heated at 90 0C while shaking on a reactor block for 15 h The mixture was concentrated and the residue was purified by reverse phase chromatography to afford the title compound as an oil (17 mg, 18%) LC/MS (5%-95% CH3CN/H2O, 6 mm) 3 43 mm, m/z 474 (M+H) 1H NMR (400 MHz, DMSO-CZ6) delta ppm 2 81 (3 H, s), 3 35 - 3 57 (3 H, m), 3 62 (1 H, d, J=10 8 Hz), 3 67 - 3 75 (3 H, m), <n="146"/>3 89 (1 H, dd, J=11 6, 2 5 Hz), 4 02 (2 H, t, J=5 0 Hz), 4 06 - 4 18 (1 H, m), 4 47 (2 H, d, J=6 2 Hz),4 81 (1 H, t, J=5 4 Hz)1 4 90 (2 H, d, J=6 6 Hz), 6 81 - 6 94 (1 H, m), 7 08 - 7 20 (2 H, m), 8 40 (1 H, s) 9 48 (1 H, t, J=6 3 Hz)

Reference： [1]Patent: WO2009/16498,2009,A1 .Location in patent: Page/Page column 144-145

6
[ 917882-64-5 ]
[ 1112178-97-8 ]
[ 1112169-43-3 ]

Yield	Reaction Conditions	Operation in experiment
15%	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 15h;	Example 556-(2-(((/?)-1 ,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-/V-(3-chloro-4-fluorobenzyl)-2- methylpyrimidine-4-carboxamidelambda/-(3-Chloro-4-fluorobenzyl)-2-methyl-6-(2H-tetrazol-5-yl)pyriotamiotadiotane-4-carboxamiotade (prepared as described in step 1 of the synthesis of lambda/-(3-chloro-4-fluorobenzyl)-2-methyl-6-(2-((S)-morpholiotan-2- ylmethyl)-2H-tetrazol-5-yl)pyriotamiotadiotane-4-carboxamiotade, Example 47) (150 mg, 0 43 mmol) and (S)-(1 , 4- diotaoxan-2-yl)methyl 4-methylbenzenesulfonate (prepared as described in step 2 of the synthesis of 6- (2-(((f?)-1 ,4-diotaoxan-2-yl)methyl)-2/-/-tetrazol-5-yl)-lambda/-(3-methoxybenzyl)-2-methylpyriotamiotadiotane-4- carboxamide, Example 53) (129 mg, 0 47 mmol) were taken up in triethylamine (2 00 mL) and dimethylformamide (0 033 mL) The reaction was heated at 90 0C while shaking on a reactor block for 15 h The mixture was concentrated and the residue was purified by reverse phase chromatography to afford the title compound as an oil (29 mg, 15%) LC/MS (5%-95% CH3CN/H2O, 6 mm) 4 25 mm, m/z 448 (M+H) 1H NMR (400 MHz, DMSO-d6) ppm 2 81 (3 H, s), 3 35 - 3 57 (3 H, m), 3 62 (1 H, d, J=10 6 Hz), 3 71 (1 H, d, J=1 1 2 Hz), 3 89 (1 H, dd, J=11 53, 2 4 Hz), 4 06 - 4 20 (1 H, m), 4 49 (2 H, d, J=6 4 Hz), 4 90 (2 H, d, J=6 4 Hz), 7 35 (2 H, d, J=7 1 Hz), 7 54 (1 H, d, J=7 3 Hz), 8 39 (1 H, s), 9 59 (1 H, t, J=6 2 Hz)

Reference： [1]Patent: WO2009/16498,2009,A1 .Location in patent: Page/Page column 144

7
[ 1170702-79-0 ]
[ 98-59-9 ]
[ 917882-64-5 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of conc. aqueous NaOH solution (26.1 L) and water (31.3 L) was heated to 87 C. Crude epoxide 1B-1 (prepared as above; 5.24 kg, 38.4 mol) was added and the reaction aged at 90 C. for 30 min. The reaction was cooled to 22 C. and then diluted with DCM (21 L). p-Toluenesulfonyl chloride (7.46 kg, 38.36 mol) was added and the mixture was aged at 22 C. for 16 h. Water (21 L) was added and the phases separated. The aqueous layer was extracted with DCM (2×21 L). The combined organic layers were washed with a 5% brine solution (21 L). The organic layer was concentrated in vacuo and the residue dissolved in toluene (32 L). Heptane (7 L) was added followed by 22B-2 as seed (100 g) and the mixture cooled to 4 C. After ageing for 16 h, the mixture was filtered and the solids washed with 8:1 heptane/toluene (4 L). Tosylate 1B-2 was isolated as a white solid:1H NMR (CDCl3) delta 2.47 (3H, s), 3.37 (1H, dd, J=9.6, 11.2 Hz), 3.70 (6H, m), 3.97 (1H, dd, J=4.8, 10.4 Hz), 4.03 (1H, dd, J=5.4, 10.6 Hz), 7.37 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz).

Reference： [1]Patent: US2009/182002,2009,A1 .Location in patent: Page/Page column 16

9
[ 861852-08-6 ]
[ 917882-64-5 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

10
[ 861852-07-5 ]
[ 917882-64-5 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

11
[ 917882-64-5 ]
[ 917879-37-9 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

12
[ 917882-64-5 ]
MK-2461 [ No CAS ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

13
[ 917882-64-5 ]
[ 917882-59-8 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

14
[ 917882-64-5 ]
[ 917882-61-2 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

15
[ 917882-64-5 ]
[ 1233483-72-1 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

16
[ 917882-64-5 ]
[ 917882-60-1 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

17
[ 98-59-9 ]
[ 406913-88-0 ]
[ 917882-64-5 ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 849 - 858

18
[ 67843-74-7 ]
[ 98-59-9 ]
[ 107-07-3 ]
[ 917882-64-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1K (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate To 2-chloroethanol (9.1 mL) in toluene (17 mL) was added Et2O.BF3 (0.30 mL), and a warm water bath was used to warm the mixture to 38 C. S-(+)-epichlorohydrin (3.4 mL) was added dropwise, keeping the temperature <45 C. The reaction was stirred at ?35 C. for 20 minutes, cooled to 15 C., and 20% NaOH (21 mL) was added dropwise, keeping the temperature <18 C. The reaction was then allowed to warm to room temperature for 1 hour. Water was added (10 mL), the layers were separated, the aqueous layer was extracted with toluene, the combined toluene layers washed with water, and the organic layer was concentrated down to an oil. NaOH (20% (wt) aqueous, 50 g) was heated to 90 C., then the above oil was added, and the mixture was heated for 1 hour, and cooled to room temperature. Then dichloromethane (12 mL) was added, followed by p-toluenesulfonyl chloride (8.0 g). The biphasic reaction was stirred at room temperature overnight. Water was added (10 mL), and the aqueous layer was extracted twice with dichloromethane (10 mL). The combined dichloromethane layers were washed with 1/1 water/brine and dried over Na2SO4. After filtration and concentration, the crude material was chromatographed on silica gel with 65/35 heptanes/ethyl acetate to afford the title compound.

Reference： [1]Patent: US2014/275082,2014,A1 .Location in patent: Paragraph 0231

19
[ 917882-64-5 ]
(R)-2-(azidomethyl)-1,4-dioxane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; In N,N-dimethyl-formamide; at 80℃; for 3h;	(R)-2-(azidomethyl)-1,4-dioxane EXAMPLE 1K (2.5 g) was dissolved in N,N-dimethylformamide (12 mL), then sodium azide (1.0 g) was added and the reaction was heated at 80 C. for 3 hours. The reaction was then cooled and diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. After filtration and concentration, the crude material was chromatographed on silica gel with 3/1 heptanes/ethyl acetate to afford the title compound.

Reference： [1]Patent: US2014/275082,2014,A1 .Location in patent: Paragraph 0232

20
[ 917882-64-5 ]
4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide [ No CAS ]

Reference： [1]Patent: US2014/275082,2014,A1

21
[ 917882-64-5 ]
(R)-(1,4-dioxan-2-yl)methanamine [ No CAS ]

Reference： [1]Patent: US2014/275082,2014,A1

22
[ 917882-64-5 ]
4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide [ No CAS ]

Reference： [1]Patent: US2014/275082,2014,A1

23
[ 917882-64-5 ]
N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide [ No CAS ]
N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(2S)-1,4-dioxan-2-ylmethyl]ethanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium carbonate; In N,N-dimethyl acetamide; N,N-dimethyl-formamide; at 100℃;	A stock solution of Example 72A (0.16 M in DMF, 200 iL, 0.03 mmol Example 72A (1.0 equivalent)), K2C03 (13.4 mg, 0.096 mmol, 3.2 equivalents) and (25)-4-(i,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (0.04 M in DMA, 89 iL, 0.036 mmol, 1.2 equivalents), were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100 C, and passed through the reactor at 180 iL min1 (10 minute residencetime). Upon exiting the reactor, the reaction was loaded directly into an injection loop andpurified by preparative HPLC on a Phenomenex Luna C8(2) 5 tm boA AXL& column (50mm x 21.2 mm). A gradient of acetonitrile (A) and 0.1 % ammonium acetate in water (B)was used, at a flow rate of 30 mL/min (0-0.5 mm 5 % A, 0.5-6.5 mm linear gradient 5-60 %A, 6.5-7.0 mm linear gradient 60-100 % A, 7.0-8.9 mm 100 % A, 8.9-9.0 mm linear gradient100-5 % A, 9.0-10 mm 5 % A) to yield the title compound (6.39 mg, 32 % yield). ?H NMR(400 MHz, DMSO-d6/D20) oe 7.56 (m, 1H), 7.44-7.38 (m, 2H), 7.29 (m, 1H), 7.15-7.03 (m,2H), 6.96 (m, 1H), 5.87 (s, 1H), 4.02 (q, J= 7.0 Hz, 2H), 3.80 (m, 1H),3.77-3.72 (m, 2H),3.70 - 3.62 (m, 2H), 3.61 - 3.49 (m, 4H), 3.44 (s, 3H), 3.20 (m, 2H), 1.31 (t, J = 7.4 Hz, 3H),1.24 (t, J = 7.0 Hz, 3H). MS (ESI+) mlz 565.1 (M+H).

Reference： [1]Patent: WO2015/89075,2015,A1 .Location in patent: Page/Page column 91

24
[ 917882-64-5 ]
[ 1256545-97-7 ]
(S)-8-(((1,4-dioxan-2-yl)methoxy)methyl)-8-fluoro-1,4-dioxaspiro[4.5]decane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of Example 39D (1.7 g) in dimethylformamide (20 mL) was added sodiumhydride (1.1 g, 60% oil dispersion) at 0C under nitrogen. After 10 minutes, a solution of<strong>[917882-64-5](S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate</strong> (3.8 g) in dimethylformamide (20 mL) was added to thereaction. The reaction was stirred at 50 C for 12 hours. Two additional reactions were set up as above.All three reactions were combined. The reaction was poured into ice water and exacted with ethylacetate twice, The combined organic layers were dried over anhydrous sodium sulfate, filtered andconcentrated to give a residue which was purified by column chromatography on silica gel (eluting withpetroleum ether: ethyl acetate = 100:1 to 20:3) to give the title compound. ?H NMR (400 MHz, CDCI3) 6ppm 4.03-3.87 (m, 4H), 3.85-3.66 (m, 5H), 3.65-3.37 (m, 6H), 2.02-1.80 (m, 4H), 1.79-1.55 (m, 4H).

Reference： [1]Patent: WO2019/35911,2019,A1 .Location in patent: Paragraph 00351

25
[ 917882-64-5 ]
methyl 3-hydroxy-6-(2-methoxyphenyl)picolinate [ No CAS ]
methyl (S)-3-((1,4-dioxan-2-yl)methoxy)-6-(2-methoxyphenyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 25℃;	Example 53B (150 mg) and cesium carbonate (566 mg) were suspended in N, N-dimethylformamide (5.0 mL). <strong>[917882-64-5](S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate</strong> (284 mg) was added. The reaction mixture was stirred at 25 C for 2 days. Additional (S)-(l,4-dioxan-2-yl)methyl 4- methylbenzenesulfonate (284 mg) and cesium carbonate (566 mg) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and the phases were separated. The aqueous layer was extracted with dichloromethane (three times) and ethyl acetate(three times). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. Purification was performed on a silica gel column (4 g, 0-23% methanol in dichloromethane), followed by a second purification (4 g, 0-50% ethyl acetate in n-heptane). The desired fractions were combined and the solvents were removed under reduced pressure to provide the title compound. MS (APCI) m/z 360.2 (M+H).

Reference： [1]Patent: WO2019/35911,2019,A1 .Location in patent: Paragraph 00482

26
[ 614730-97-1 ]
[ 917882-64-5 ]
(S)-tert-butyl 4-(((1,4-dioxan-2-yl)methoxy)methyl)-4-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine- 1 -carboxylate (200 mg) indimethylformamide (2.8 mL) at 0 C was added sodium hydride (43 mg, 60% oil dispersion), and the reaction was allowed to stir for 15 minutes. (S)-( I ,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (410 mg) was added, and the reaction was allowed to warm to room temperature ovemight. The reaction was diluted with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filteredand concentrated. The residue was purified by normal phase MPLC on a Teledyne Isco Combiflash Rf+ 24 g gold silica gel column eluting with 0-45% ethyl acetate in heptanes to give the title compound. ?H NMR (500 MHz, dimethylsulfoxide-d6) 6 ppm 3.82-3.36 (m, 12H), 3.26 (dd, 1H), 2.99 (br s, 2H), 1.78-1.66 (m, 2H), 1.63-1.46 (m, 2H), 1.39 (s, 9H).

Reference： [1]Patent: WO2019/35911,2019,A1 .Location in patent: Paragraph 00223

27
[ 917882-64-5 ]
[ 142253-56-3 ]
tert-butyl (S)-3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidine-1-carboxylate [ No CAS ]