[ CAS No. 123-90-0 ] {[proInfo.proName]}

Name: 123-90-0|Thiomorpholine|98%
Brand: Ambeed
SKU: A603893
Price: 9.0 USD
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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 123-90-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 123-90-0 ]

CAS No. :	123-90-0	MDL No. :	MFCD00005974
Formula :	C₄H₉NS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BRNULMACUQOKMR-UHFFFAOYSA-N
M.W :	103.19	Pubchem ID :	67164
Synonyms :

Calculated chemistry of [ 123-90-0 ]

Physicochemical Properties

Num. heavy atoms :	6
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.54
TPSA :	37.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.49
Log Po/w (XLOGP3) :	0.22
Log Po/w (WLOGP) :	-0.06
Log Po/w (MLOGP) :	0.35
Log Po/w (SILICOS-IT) :	1.8
Consensus Log Po/w :	0.76

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.62
Solubility :	24.8 mg/ml ; 0.241 mol/l
Class :	Very soluble
Log S (Ali) :	-0.56
Solubility :	28.2 mg/ml ; 0.273 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.08
Solubility :	8.64 mg/ml ; 0.0838 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.6

Safety of [ 123-90-0 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3267
Hazard Statements:	H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 123-90-0 ]

* 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.

Upstream synthesis route of [ 123-90-0 ]
Downstream synthetic route of [ 123-90-0 ]

[ 123-90-0 ] Synthesis Path-Upstream 1~11

1
[ 60-23-1 ]
[ 123-90-0 ]

Reference： [1] Angewandte Chemie - International Edition, 2008, vol. 47, # 20, p. 3784 - 3786

2
[ 111-42-2 ]
[ 123-90-0 ]

Reference： [1] Patent: CN105906582, 2016, A, . Location in patent: Paragraph 0011; 0012; 0013

3
[ 124-02-7 ]
[ 123-90-0 ]
[ 23265-01-2 ]

Reference： [1] Russian Journal of General Chemistry, 1995, vol. 65, # 2.2, p. 300[2] Zhurnal Obshchei Khimii, 1995, vol. 65, # 2, p. 347

4
[ 1217491-78-5 ]
[ 123-90-0 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 12, p. 1415 - 1420

5
[ 20196-21-8 ]
[ 123-90-0 ]

Reference： [1] Journal of the American Chemical Society, 1954, vol. 76, p. 1187

6
[ 1217491-62-7 ]
[ 123-90-0 ]
[ 1217491-78-5 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 12, p. 1415 - 1420

7
[ 505-60-2 ]
[ 123-90-0 ]

Reference： [1] Journal of the Chemical Society, 1920, vol. 117, p. 299
[2] Archiv der Pharmazie (Weinheim, Germany), 1958, vol. 291, p. 3,5

8
[ 45695-98-5 ]
[ 123-90-0 ]
[ 75-15-0 ]

Reference： [1] Journal of Organic Chemistry, 2008, vol. 73, # 18, p. 7189 - 7196

9
[ 123-90-0 ]
[ 540-51-2 ]
[ 6007-64-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 15, p. 3865 - 3868
[2] Archiv der Pharmazie, 1995, vol. 328, # 7-8, p. 585 - 594
[3] Patent: WO2015/43688, 2015, A1, . Location in patent: Page/Page column 14-15

10
[ 123-90-0 ]
[ 39093-93-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydroxide; oxone In HOCH₃; water	Example 11 Synthesis of 1-amino-3-(1,1-dioxo-λ⁶-thiomorpholin-4-yl)-propan-2-ol To the solution of thiomorpholine (5.0 g, 48.7 mmol) in HOCH₃ (200 mL) was added the solution of oxone (36.0 g, 58.5 mmol) in H₂O (100 mL). The mixture was well stirred at 40° C. for 48 h and then cooled to 0° C. Aqueous NaOH was added dropwise to adjust pH=12. Solid was filtered out and washed with HOCH₃ (3*40 mL). The combined liquid was condensed and purified by flash chromatograph on silica gel (CHCl₃/CH₃₀H/NH₃.H₂O=3/1/0.1-2/1/0.1) to give thiomorpholine 1,1-dioxide (6.2 g)in 93percent yield. ¹H NMR (DMSO-d₆) δ 2.97 (m, 4H), 3.07 (m, 4H), 3.42 (brs, 1H), MS (m/z) 136 (M+1).

Reference： [1] Patent: US2003/92917, 2003, A1,
[2] Tetrahedron Letters, 1995, vol. 36, # 6, p. 833 - 836
[3] Patent: WO2004/104001, 2004, A2, . Location in patent: Page 59
[4] Patent: WO2005/89771, 2005, A1, . Location in patent: Page/Page column 37

11
[ 123-90-0 ]
[ 39213-13-3 ]
[ 39093-93-1 ]

Reference： [1] Catalysis Letters, 2017, vol. 147, # 9, p. 2313 - 2318

[ 123-90-0 ] Synthesis Path-Downstream 1~87

1
[ 123-90-0 ]
[ 39186-58-8 ]
2,2-diphenyl-4-thiomorpholino-butyronitrile [ No CAS ]

Reference： [1]Archives Internationales de Pharmacodynamie et de Therapie,1955,vol. 103,p. 82,86

2
[ 20196-21-8 ]
[ 123-90-0 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 1187

3
[ 123-90-0 ]
[ 39093-93-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydroxide; oxone; In HOCH3; water;	Example 11 Synthesis of 1-amino-3-(1,1-dioxo-lambda6-thiomorpholin-4-yl)-propan-2-ol To the solution of thiomorpholine (5.0 g, 48.7 mmol) in HOCH3 (200 mL) was added the solution of oxone (36.0 g, 58.5 mmol) in H2O (100 mL). The mixture was well stirred at 40° C. for 48 h and then cooled to 0° C. Aqueous NaOH was added dropwise to adjust pH=12. Solid was filtered out and washed with HOCH3 (3*40 mL). The combined liquid was condensed and purified by flash chromatograph on silica gel (CHCl3/CH30H/NH3.H2O=3/1/0.1-2/1/0.1) to give thiomorpholine 1,1-dioxide (6.2 g)in 93percent yield. 1H NMR (DMSO-d6) delta 2.97 (m, 4H), 3.07 (m, 4H), 3.42 (brs, 1H), MS (m/z) 136 (M+1).
	With dihydrogen peroxide; acetic acid; In water; at 0 - 100℃; for 16h;	To a solution of thiomorpholine (1.0g, 9. 69MMOL) in acetic acid (11.5mL) cooled to 0°C (ice bath) was added aqueous hydrogen peroxide solution (30percent w/v, 4mL) and the reaction heated to 100°C for 16H. The mixture was cooled and solvent removed in vacuo before trituration of the residue with methanol gave a white precipitate. The solid was filtered and washed with methanol to give the title compound as an off-white powder. m/z (ES+) = 136. 06 [M+ H] +.
		9.98 g of thiomorpholine and 14.8 g of triflic anhydride were stirred together in DCM at room temperature for 2 hours. The reaction was then partitioned between 1 M K2C03 (aq) and DCM. The organic layer was separated and dried by passing through a hydrophobic frit, then concentrated in vacuo. 13.82 g of the resultant oil was stirred with 85.2 g of oxone in 50 mL of methanol and 50 mL of water for 18 h at room temperature. The reaction was then filtered and washed with methanol and the filtrate concentrated. This was then partitioned between water and EtOAc and the aqueous layer washed 3 times with EtOAc. The combined organic extracts were then dried (MgS04) and concentrated to produce a white solid. This was then stirred at room temperature with 40 g of K2C03 in 80 mL of methanol for 18 h. The methanol was then removed in vacuo and the remains partitioned between DCM and sat. K2CO3 (aq). The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo to produce the title compound, 3.51 g.

Reference： [1]Patent: US2003/92917,2003,A1
[2]Tetrahedron Letters,1995,vol. 36,p. 833 - 836
[3]Patent: WO2004/104001,2004,A2 .Location in patent: Page 59
[4]Patent: WO2005/89771,2005,A1 .Location in patent: Page/Page column 37

4
[ 123-90-0 ]
[ 540-51-2 ]
[ 6007-64-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; for 16h;Reflux;	To a solution of thiomorpholine (3 g; 29.1 mmol) in acetonitrile (40 mL) were added potassium carbonate (12 g, 87.2 mmol) and 2-bromoethanol (6.18 ml, 87.2 mmol) and the suspension stirred under reflux for 16 h. After complete conversion dichloromethane (150 mL) was added to this suspension, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The colorless oil was directly used for step 2 without purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3865 - 3868
[2]Archiv der Pharmazie,1995,vol. 328,p. 585 - 594
[3]Patent: WO2015/43688,2015,A1 .Location in patent: Page/Page column 14-15

5
[ 123-90-0 ]
[ 369-34-6 ]
[ 168828-70-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.25h;Microwave irradiation;	To a solution of 1 ,2-difluoro-4-nitrobenzene (5.00 g, 31.43 mmol) in acetonitrile (10 mL), thiomorpholine (3.57 g, 34.57 mmol) was added followed by lambda/-ethyl-lambda/-(1- methylethyl)-2-propanamine (6.09 g, 47.14 mmol). The reaction was heated in the microwave to 14O0C for 15 min. The solvent was removed in vacuo, and the residue was dissolved in EtOAc and washed with NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvent was removed to give 7.56 g, 99% yield, of the title compound of Step A. ES-LCMS m/z 243 (M+H).
98%	With triethylamine; In methanol; at 50 - 60℃; for 24h;	3-3-1: Preparation of 3-fluoro-4-thiomorpholinonitrobenzene To 100 ml of methanol were sequentially added 3 g (18.9 mmol) of 3,4-difluoronitrobenzene, 3.15 ml (22.6 mmol) of triethylamine and 2.15 ml (20.8 mmol) of thiomorpholine, followed by reaction at a temperature of 50 to 60 for 24 hours. After the reaction was complete, the reaction liquid was cooled to room temperature, followed by removal of the solvent, extracted with ethyl acetate, purified by column chromatography with a 6:1 (v/v) solution of n-hexane and ethyl acetate as a developing solvent and then dried under vacuum at about 40 to afford 4.48 g (yield: 98%) of the desired compound. Mass (M+): 243.0 1H-NMR (DMSO-d6): 2.80(m, 4H), 3.53(m, 4H), 6.97(d, 1H), 7.88(dd, 1H), 8.01(s, 1H).
98%	With triethylamine; In methanol; at 50 - 60℃; for 24h;	Example 3-3-1 Preparation of 3-fluoro-4-thiomorpholinonitrobenzene To 100ml of methanol were sequentially added 3g (18.9mmol) of 3,4-difluoronitrobenzene, 3.15ml (22.6mmol) of triethylamine and 2.15ml (20.8mmol) of thiomorpholine, followed by reaction at a temperature of 50 to 60C for 24 hours. After the reaction was complete, the reaction liquid was cooled to room temperature, followed by removal of the solvent, extracted with ethyl acetate, purified by column chromatography with a 6:1 (v/v) solution of n-hexane and ethyl acetate as a developing solvent and then dried under vacuum at about 40C to afford 4.48g (yield: 98%) of the desired compound. Mass (M+): 243.0 1H-NMR (DMSO-d6): 2.80(m, 4H), 3.53(m, 4H), 6.97(d, 1H), 7.88(dd, 1H), 8.01(s, 1H).

72%	With triethylamine; In ethyl acetate; for 0.5h;	To a solution of thiomorpholine (3.57 g, 34.56 mmol) and Et3N (3.50 g, 34.56 mmol) in EtOAc was added 3,4-difluoronitrobenzene (5.00 g, 31.43 mmol) dropwise over a period of 30 mm in an ice bath. Upon the end of addition the reaction mixture was warmed to rt slowly, and solid was precipitated out. The mixture was filtered. The filter cake was washed with an appropriate amount of water, dried in vacuo to obtain the 1st crop of product. The filtrate was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (5.50 g, 72%).
72%	With triethylamine; In ethyl acetate; at 20℃;Cooling with ice;	To a solution of thiomorpholine (3.57 g, 34.56 mmol) and Et3N (3.50 g, 34.56 mmol) in EtOAc was added 3,4-difluoronitrobenzene (5.00 g, 31.43 mmol) dropwise over a period of 30 min in an ice bath. Upon the end of addition the reaction mixture was warmed to rt slowly, and solid was precipitated out. The mixture was filtered. The filter cake was washed with an appropriate amount of water, dried in vacuo to obtain the 1st crop of product. The filtrate was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (5.50 g, 72%).
72%	With triethylamine; In ethyl acetate; for 0.5h;Cooling with ice;	3,4-Difluoronitrobenzene (5.00 g, 31.43 mmol) was slowly added dropwise to thiomorpholine (3.57 g, 34.56 mmol) under ice-cooling.In a solution of triethylamine (3.50 g, 34.56 mmol) in ethyl acetate, the addition was continued for about 30 minutes.After the drop was slowly warmed to room temperature, a solid precipitated.Filter and filter cake with a suitable amount of water and dry to give a yellow solid.The filtrate was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and the ethyl acetate was evaporated to dryness to give a yellow solid.The above two-part solids gave a yellow solid (5.50 g, 72%).
61%	In acetonitrile; at 0 - 110℃; for 0.25h;Microwave irradiation; Sealed tube;	3,4-difluoronitrobenzene (10 mmol) was added dropwise to a mixture of thiomorpholine (10 mmol) in dry acetonitrile at 0-5 C for 5 min and then irradiated in a monomode microwave reactor in a closed vessel under pressure controlat 110 C for 15 min (hold time) at 200 W maximum power. The salt formed was removed by filtration, and the resulting solution was evaporated to dryness under reduced pressure. The yellow solid obtained was recrystallized from ethanol:ethyl acetate (2:1) to afford the desired product. Yield: 61%, mp. 80 C. FT IR (upsilonmax, cm-1): 2960 (ar-CH), 1323 and 1494 (NO2). 1H NMR (DMSO-d6, delta ppm): 2.72-2.75 (m, 4H,2CH2), 3.54-3.57 (m, 4H, 2CH2), 7.18 (t, 1H, ar-H, J=8.8Hz), 7.96 (bs, 1H, ar-H,), 7.99 (bs, 1H, ar-H). 13C NMR(DMSO-d6, delta ppm): 27.05 (2CH2), 52.40 (2CH2), arC:[112.66 and 112.92 (d, CH, J=10.4 Hz), 119.02 (CH), 121.69(CH), 139.70 and 139.78 (d, C, J=8.0 Hz), 145.83 (C),151.14 and 153.60 (d, C, JHF=246.0 Hz). LC MS m/z: 242.28([M]+ 45), 128.10 (100). Elemental analysis for C10H11FN2O2S, Calculated: C: 49.58; H: 4.58; N: 11.56%. Found: C:49.56; H: 4.59; N: 11.51.

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 680 - 685
[2]Patent: WO2009/32667,2009,A1 .Location in patent: Page/Page column 109
[3]Patent: US2011/306606,2011,A1 .Location in patent: Page/Page column 14
[4]Patent: EP2394993,2011,A2 .Location in patent: Page/Page column 22
[5]Medicinal Chemistry Research,1999,vol. 9,p. 149 - 161
[6]Patent: WO2014/12360,2014,A1 .Location in patent: Paragraph 00279
[7]Patent: US2015/87639,2015,A1 .Location in patent: Paragraph 0531
[8]Patent: TWI607995,2017,B .Location in patent: Paragraph 125; 126
[9]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1302 - 1305
[10]Letters in drug design and discovery,2017,vol. 14,p. 444 - 463
[11]Medicinal Chemistry Research,2015,vol. 24,p. 2986 - 2992
[12]Chemical Papers,2018,vol. 72,p. 457 - 468
[13]Journal of Molecular Structure,2020,vol. 1217

6
[ 123-90-0 ]
[ 30169-25-6 ]
[ 67-51-6 ]
[ 270588-65-3 ]

Reference： [1]Russian Journal of Organic Chemistry,1999,vol. 35,p. 1363 - 1371

7
[ 123-90-0 ]
[ 55676-22-7 ]
[ 727381-90-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2071 - 2074

8
[ 123-90-0 ]
[ 350-46-9 ]
[ 90254-22-1 ]

Yield	Reaction Conditions	Operation in experiment
88.6%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;	To a stirred mixture of 4-fluoronitrobenzene (5.0 g, 1.0 eq) and thiomorpholine (3.65 g, 1.0 eq) in DMF (50 mL) in a vial, K2C03 (14.6 g, 3.0 eq) was added and the mixture was heated to 90C for 4 h while monitoring by TLC. After completion of the reaction, the mixture was cooled to rt, poured into ice water and extracted with EtOAc (3 x 100 ml). The organic layer was washed with brine, cold water, dried over anhydrous sodium sulphate, and concentrated to obtain crude a yellow solid which was washed with n-hexane to obtain 4-(4-nitrophenyl)thiomorpholine as yellow solid (7.0 g, 88.6%). 1H NMR (400 MHz, DMSO-d6): delta 8.060 (d, 2H), 7.025 (d, 2H), 3.886 (t, 4H), 2.645 (t, 4H), LCMS calculated for (M) 224.06 found (M+H) 224.97.
72.3%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;	Step: 3A-1Synthesis of 4-(4-Nitro-phenyl)-thiomorpholine.Procedure:K2C03 (2.15g, 0.0155mol) followed by 1 -Fluoro-4-nitro-benzene (2g, 0.0141mol) was added to a solution of thiomorpholine (1.46g, 0.0141mol) in DMF (10ml) and stirred for 2- 3hrs at 80C. The reaction was monitored by the TLC (30% EtOAc: hexane). The resultant was cooled to RT and precipitated using ice. The precipitate was collected, dried under reduced pressure to afford 2.3g (72.3% yield) of 4-(4-Nitro-phenyl)-thiomoipholine.
	In toluene;	4-(4-Nitro-phenyl)-thiomorpholine 4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in toluene (25 mL). <strong>[123-90-0]Thiomorpholin</strong>e (2.4 mL, 23.4 mmol) was added and the mixture stirred overnight at 100 C. At 17 h, the mixture was distributed between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid.

	In dichloromethane; water;	(ab) 23 ml of thiomorpholine are slowly added dropwise at about 80 to 17.17 g of p-fluoronitrobenzene in such a manner that the internal temperature does not rise above 110. The mixture is then stirred at 120 for an additional 1 hour, whereupon it is extracted three times with 1 l of dichloromethane each time and the organic phases are washed three times with 500 ml of water each time, dried over sodium sulfate and evaporated. By recrystallization of the crude product from dichloromethane/ether, there is obtained 4-(p-nitrophenyl)-tetrahydro-4-H-1,4-thiazine of melting point 142-144.
	In toluene;	4-(4-Nitro-phenyl)-thiomorpholine. 4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in toluene (25 mL). <strong>[123-90-0]Thiomorpholin</strong>e (2.4 mL, 23.4 mmol) was added and the mixture stirred overnight at 100 C. At 17 h, the mixture was distributed between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid.
	In toluene;	4-(4-Nitro-phenyl)-thiomorpholine 4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in toluene (25 mL). <strong>[123-90-0]Thiomorpholin</strong>e (2.4 mL, 23.4 mmol) was added and the mixture stirred overnight at 100 C. At 17 h, the mixture was distributed between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated; dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid.
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 48h;Heating / reflux;	Step 1.Preparation of 4-(4-nitrophenyl)thiomorpholine. thiomorpholine (6.0 ML, 6.2 g, 60 mmol) is added to a solution of 1-fluoro-4-nitro-benzene (7.1 g, 50 mmol) and diisopropylethylamine (13 ML, 9.6 g, 75 mmol) in acetonitrile (90 ML).The solution is heated at reflux for 2 days, concentrated, and dissolved in ethyl acetate.The solution is washed with 100 ML each of 1 M HCl, sat. aq. NaHCO3, and brine.The solution is dried (MgSO4), filtered and concentrated to provide the title compound as solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 40℃;	General procedure: Substituted amine (1.2 equiv) was added to a mixture of 4-fluoronitrobenzene (1 equiv) and K2CO3 (2.0 equiv) in DMF (7mL/g). The reaction mixture was stirred at 40C and followed by TLC. After completion of the reaction, the mixture was poured into stirring ice-water. The resulting precipitate was filtered and dried to obtain compounds 11 as a yellow solid.
	With triethylamine; In acetonitrile; for 3h;Reflux;	General procedure: To a stirred solution of 1-fluoro-4-nitrobenzene 7 (2.0 g, 14.2 mmol) in 20 mL acetonitrilewas added morpholine (1.9 g, 21.3 mmol) followed by triethylamine(4.3 g, 5.9 mL, 42.5 mmol). The mixture was stirred at reflux for 3 h.After the reaction was cooled to room temperature, it was pouredinto 80 mL water and extracted with ethyl acetate (2 x 80 mL). Thecombined organic layers were washed with brine (60 mL), driedover sodium sulfate, concentrated in vacuo, then dried under vacuumto obtain 2.7 g of 8a as yellow solid; yield: 92%; 8a was usedwithout further purification.

Reference： [1]Patent: WO2015/38417,2015,A1 .Location in patent: Page/Page column 102
[2]Medicinal Chemistry Research,1999,vol. 9,p. 149 - 161
[3]Patent: WO2012/59932,2012,A1 .Location in patent: Page/Page column 109
[4]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 353 - 360
[5]Patent: US2003/13708,2003,A1
[6]Patent: US4640918,1987,A
[7]Patent: US2004/87575,2004,A1
[8]Patent: US2004/110745,2004,A1
[9]Patent: US2003/232812,2003,A1 .Location in patent: Page 21
[10]European Journal of Medicinal Chemistry,2019,vol. 163,p. 690 - 709
[11]New Journal of Chemistry,2019,vol. 43,p. 10190 - 10202
[12]European Journal of Medicinal Chemistry,2019,vol. 181

9
[ 123-90-0 ]
[ 64248-62-0 ]
[ 872843-87-3 ]

Yield	Reaction Conditions	Operation in experiment
8.74 g	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;	Thiomorpholine (4.9 mL, 48.5 mmol) and potassium carbonate (13.4 g, 96.9 mmol) was dissolved in 50 mL DMF and the <strong>[64248-62-0]3,4-difluorobenzenenitrile</strong> (6.7 g, 48.5 mmol) was added. Reaction heated to 100C overnight. Reaction was blown to dryness and residue was taken up in EtOAc and washed with water (2x), brine and then dried over sodium sulfate. Drying agent removed by filtration and then organics concentrated down and residue was recrystallized from hot isopropanol to give 8.74 g of 3-fluoro-4- thiomorpholinobenzonitrile as a light yellow solid. Residue can also be purified through silica gel.

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 8261 - 8269
[2]Patent: WO2017/49321,2017,A1 .Location in patent: Page/Page column 54-55

10
[ 123-90-0 ]
[ 214045-84-8 ]
[ 888226-99-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2584 - 2589

11
[ 123-90-0 ]
[ 75-15-0 ]
potassium thiomorpholine-4-carbodithiolate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		A solution of thiomorpholine (1.002mL, 10mmol) in methanol (5mL) was cooled in an ice bath. A cold solution of potassium hydroxide (0.561g, 10mmol) in H2O-MeOH (10mL, 1:1) was added to it. After stirring 15min, an ice cold solution of carbon disulfide (0.604mL, 10mmol) in methanol (5mL) was added maintaining the reaction temperature below 10C. A solid did appear which was stirred for 2h, filtered and washed with cold methanol followed by drying in vacuum. The ligand was air stable and soluble in methanol at room temperature (25C). Yield (89%, 1.934g): IR (ATR, cm-1) nu=1450 (C-N), 993 (C-S). 1H NMR (DMSO, 400MHz): delta=2.52 (4H, t, S-CH2), 4.59 (4H, t, N-CH2) ppm. 13C{1H} NMR (100MHz, DMSO): delta=26.5 (C-S), 51.7 (C-N), 213.8 (CS2) ppm.
		A mixture of 3-acetylquinoline (0.34g, 2mmol), paraformaldehyde (0.24g, 8mmol) and dimethylamine hydrochloride (0.33g, 4mmol) in acetic acid (5mL) was heated under reflux for12h. The reaction mixture was concentrated under vacuum to afford the intermediate 13m which was used directly without further purification. A mixture of secondary amine (4mmol), potassium carbonate (1.11g, 8mmol) and acetone (10mL) was stirred for 15min, and CS2 (0.37g, 4.8mmol) was added dropwise. After stirring 1h, the reaction mixture was concentrated to give the intermediate (24a-24g). The intermediate (24a-24g) was dissolved in water (5ml) and the DMF (5ml) solution of 13m was added. The reaction mixture was stirred at room temperature for 12h. Water (50mL) was added and the mixture was extracted with ethyl acetate (15mL×3), the combined organic phase was washed with water (20mL×2), dried over anhydrous Na2SO4 and concentrated under vacuum to afford the crude product. The crude product was purified by column chromatography to obtain the pure product (25a-25g).

Reference： [1]Journal of Organometallic Chemistry,2017,vol. 853,p. 27 - 34
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2005,vol. 180,p. 2717 - 2724
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 7310 - 7314
[4]Polyhedron,2014,vol. 79,p. 324 - 329
[5]Inorganica Chimica Acta,2014,vol. 421,p. 210 - 217
[6]European Journal of Medicinal Chemistry,2015,vol. 93,p. 381 - 391

12
[ 123-90-0 ]
[ 1635-61-6 ]
[ 404009-18-3 ]

Yield	Reaction Conditions	Operation in experiment
91.5%	With potassium carbonate; In ISOPROPYLAMIDE; at 135℃; for 24h;Inert atmosphere;	A mixture of 5-chloro-2-nitroaniline (5.6 g, 32 mmol), Ihiomorpholine (10.0 g, 97 mmol) and anhydrous potassium carbonate (4.98 g, 36 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 135 C under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 3 hours. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting brown solid was washed with diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-NitGammaO-5-thiomo holin-4-yl- phenylamine (7.0 g, 91.5 %) as a brown powder, and used in the next step without further purification. NMR (400 MHz, CDC13) delta 2.6, m, 4H; 3.75 m, 4H; 5.95, d, (J=2.34 Hz), 1H; 6.1 , s (broad), 2H; 6.18, dd (J=2.3, 7.3 Hz), 1H; 7.98, d (J=9.6 Hz)

Reference： [1]Patent: WO2011/123890,2011,A1 .Location in patent: Page/Page column 136
[2]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4490 - 4518

13
[ 123-90-0 ]
[ 2155-96-6 ]
[ 912803-22-6 ]

Reference： [1]Dalton Transactions,2006,p. 4134 - 4145

14
[ 123-90-0 ]
[ 5728-20-1 ]
C₆H₈ClN₃S₂ [ No CAS ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 8285 - 8288

15
[ 123-90-0 ]
[ 3744-87-4 ]
[ 1000587-56-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0℃;	Step 1 (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomorpholine (2.29 g, 22.2 mmol) at 0 C. The reaction mixture was stirred at 0 C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0℃;	Preparation 6: (S) -2-( 1,1 -Dioxo-llambda>f6>f-thiomorpholin-4-yl)-l -methyl-ethylamine; The synthetic procedure used in this preparation is outlined below in Scheme H. Step 1 (l-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester; To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomor- pholine (2.29 g, 22.2 mmol) at 00C. The reaction mixture was stirred at 00C overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO/t. The solvent was removed under vacuum to give ( l-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carb- amic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H) = 275.
98%	With 1-methyl-pyrrolidin-2-one; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃;	Step 1 (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic Acid Tert-Butyl Ester; To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomorpholine (2.29 g, 22.2 mmol) at 0 C. The reaction mixture was stirred at 0 C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.

98%	With 1-methyl-pyrrolidin-2-one; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃;	Step 1 (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic Acid Tert-Butyl Ester; To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomorpholine (2.29 g, 22.2 mmol) at 0 C. The reaction mixture was stirred at 0 C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.
98%	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0℃;	Step 1 (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic Acid Tert-Butyl Ester To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomorpholine (2.29 g, 22.2 mmol) at 0 C. The reaction mixture was stirred at 0 C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0℃;	Step 1 (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomorpholine (2.29 g, 22.2 mmol) at 0 C. The reaction mixture was stirred at 0 C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.

Reference： [1]Patent: US2008/4442,2008,A1 .Location in patent: Page/Page column 198
[2]Patent: WO2008/55840,2008,A1 .Location in patent: Page/Page column 60
[3]Patent: US2009/163502,2009,A1 .Location in patent: Page/Page column 41
[4]Patent: US2009/163499,2009,A1 .Location in patent: Page/Page column 29
[5]Patent: US2009/170873,2009,A1 .Location in patent: Page/Page column 43
[6]Patent: US2009/170874,2009,A1 .Location in patent: Page/Page column 59

16
[ 123-90-0 ]
[ 106614-28-2 ]
[ 553672-28-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate; In dimethyl sulfoxide; at 80℃;	Production Example 58 methyl 2-fluoro-4-(4-thiomorpholinyl)benzoate To a 30 ml dimethyl sulfoxide solution of 3.44 g (20 mmol) of <strong>[106614-28-2]methyl 2,4-difluorobenzoate</strong>, 1.9 ml (20 mmol) of thiomorpholine and 2.76 g (20 mmol) of potassium carbonate were added, and the mixture was stirred at 80C. Then, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.. The organic layer was washed with water and a saturated aqueous solution of sodium chloride.. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off.. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 5/1) to obtain 2.96 g (58%) of the captioned compound.

Reference： [1]Patent: EP1454897,2004,A1 .Location in patent: Page 29

17
[ 123-90-0 ]
[ 66684-58-0 ]
[ 383199-85-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 24h;	[0778] A solution of <strong>[66684-58-0]3,4,5-trifluoronitrobenzene</strong> (5.00 g, 28.24 mmol) in acetonitrile (60 mL) was cooled to 0° C. and treated with N,N-diisopropylethylamine (7.38 mL, 42.35 mmol) followed by thiomorpholine (2.98 mL, 29.65 mmol). The ice bath was removed and the reaction mixture stirred at room temperature under nitrogen for approximately 24 hrs, during which additional thiomorpholine (0.1 eq) was added. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid (until the washings were acidic), saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, mp 104-105° C.
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 24h;	A solution of 3, 4, 5-trifluoronitrobenzene (5.00 g, 28.24 mmol) in acetonitrile (60 mL) is cooled to 0°C and treated with N, N-diisopropylethylamine (7. 38 mL, 42.35 mmol) followed by thiomorpholine (2.98 mL, 29.65 mmol). The ice bath is removed and the reaction mixture stirred at room temperature under nitrogen for approximately 24 h, during which additional thiomorpholine (0.1 eq) is added. The solvent is removed under reduced pressure, and the residue is diluted with ethyl acetate, washed with 1N hydrochloric acid (until the washings are acidic), saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, mp 104-105°C.
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 24h;	Step 1: Preparation of 4-(2,6-Difluoro-4-nitrophenyl)thiomorpholine A solution of <strong>[66684-58-0]3,4,5-trifluoronitrobenzene</strong> (5.00 g, 28.24 mmol) in acetonitrile (60 ML) is cooled to 0° C. and treated with N,N-diisopropylethylamine (7.38 ML, 42.35 mmol) followed by thiomorpholine (2.98 ML, 29.65 mmol).The ice bath is removed and the reaction mixture stirred at room temperature under nitrogen for approximately 24 h, during which additional thiomorpholine (0.1 eq) is added.The solvent is removed under reduced pressure, and the residue is diluted with ethyl acetate, washed with 1N hydrochloric acid (until the washings are acidic), saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, mp 104-105° C.

Reference： [1]Patent: US2004/14967,2004,A1 .Location in patent: Page 66-67
[2]Patent: WO2003/72553,2003,A1 .Location in patent: Page/Page column 98-99
[3]Patent: US2004/147760,2004,A1 .Location in patent: Page 50 - 51

18
[ 123-90-0 ]
[ 24424-99-5 ]
[ 220655-09-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane;	A solution of BOC-O-BOC (28.34 g, 0.13 Mole) in dichloromethane (100 ml) was added over 15 minutes to a solution thiomorpholine (13.05 ml, 0.13 Mole) and triethylamine (20.87 ml, 0.15 Mole) in dichloromethane (600 ml). The mixture was stirred for 1 hour. Vigorous evolution of carbon dioxide occurred. Ether (600 ml) was added and the organic solution was washed with citric acid (3300 ml 1M), water (3300 ml), brine (300 ml), dried over magnesium sulphate, and evaporated in vacuo to give N-tert-butyloxycarbonyl thiomorpholine as a colourless solid (26.5 g, 100%). NMR (300 MHz,CDCl3) 1.4(s,9H); 2.5-2.6(m,4H); 3.6-3.65(m,4H). MS ESP+ (mH)+ 204.
100%	With triethylamine; In dichloromethane; at 20℃;Inert atmosphere;	Preparation 1 tert-Butyl thiomorpholine-4-carboxylate To a solution of thiomorpholine (4.84 mL, 50 mmol, 1 eq) in DCM (200 mL) was added Et3N (14.6 mL, 2.1 eq) and di-tert-butyldicarbonate (12.0 g, 1.1 eq) with stirring under nitrogen atmosphere. The resulting clear solution was stirred at RT for an overnight. The reaction solution was washed with H2O (1), aqueous NH4Cl (1), brine (1*) and dried over anhydrous MgSO4. The organic solution was filtered through a pad of celite and the filtrate concentrated. The white solid residue was treated with EtOAc-hexane (1:25) with stirring and then cooled in fridge for 30 min. The white solid which formed was collected to give the title compound as a white crystalline solid (10.1 g, quantitative). 1H NMR (DMSO-d6) delta: 3.54-3.59 (m, 4H), 2.48-2.54 (m, 4H), 1.40 (s, 9H)
88%	With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 5h;	To the mixture of 18 thiomorpholine (5.8g, 0.055mol) and 76 TEA (6.8g, 0.067mol) in 77 THF (60mL), 78 dibutyldicarbonate (12.8g, 0.058mol) was added dropwise while maintaining the temperature below 0C. After the addition was completed, the resulted mixture was stirred for 5hat 25C. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure. Then 79 ethyl acetate (50mL) was added and the misture was washed with saturated citric acid aqueous solution and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to yield 40 1 as yellow oil in 88% yield.

67%	In dichloromethane; at 0 - 20℃; for 22h;	Example 22; Preparation of 1-(3-fluoro-4-(2-(3-(S-oxo-4-thiapiperidin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea; Step A: Preparation of tert-butyl thiomorpholine-4-carboxylate; A stirred solution of thiomorpholine (194 g, 1.87 mol) in CH2Cl2 (1 L) was cooled to 0 C. under N2. A solution of tert-butyl tert-butyloxycarbonylcarbonate (389 g, 1.78 mol) in CH2Cl2 (800 mL) was added over a 4 hour period via addition funnel. The reaction was allowed to warm to room temperature, and stirring was continued for 18 hours. The reaction mixture was washed with a saturated aqueous solution of NH4Cl (2×500 mL), 1M aqueous HCl (500 mL), and brine (500 mL). The organic phase was dried (MgSO4), filtered, and concentrated. The crude was stirred with diethyl ether (400 mL) for 18 hours and then filtered to obtain a white powder (243 g, 67%).
	With triethylamine; In tetrahydrofuran; at 20℃; for 10h;	<strong>[123-90-0]Thiomorpholin</strong>e (5.0 ml, 53 mmol) was dissolved in tetrahydrofuran (200 ml); triethylamine (8.1 ml, 58 mmol) was added thereto; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the residue was purified by silica gel column (eluent; hexane: ethyl acetate = from 80: 20, 75: 25 to 70: 30) to yield the title compound as colorless crystals (10.4 g, 51 mmol). 1H-NMR Spectrum (CDCl3) delta (ppm): 1.46 (9H, s), 2.57 (4H, m), 3.69 (4H, m).
	In methanol;	<strong>[123-90-0]Thiomorpholin</strong>e-1,1-dioxide was prepared from thiomorpholine by protection of the secondary amine to N-Boc thiomorpholine ((Boc)2O, MeOH), oxidation to sulfone (mCPBA, CH2Cl2, 0 C.), and deprotection of the N-Boc group to provide the free amine (CF3CO2H, CH2Cl2). (m/z): [M+H]+ calcd for C4H9NO2S, 136.04; found, 135.9.
	In methanol;	<strong>[123-90-0]Thiomorpholin</strong>e-1,1-dioxide was prepared from thiomorpholine by protection of the secondary amine to N-Boc thiomorpholine ((Boc)2O, MeOH), oxidation to sulfone (mCPBA, CH2Cl2, 0 C.), and deprotection of the N-Boc group to provide the free amine (CF3CO2H, CH2Cl2). (m/z): [M+H]+ calcd for C4H9NO2S, 136.04; found, 135.9.
	In methanol;	<strong>[123-90-0]Thiomorpholin</strong>e-1,1-dioxide was prepared from thiomorpholine by protection of the secondary amine to N-Boc thiomorpholine ((Boc)2O, MeOH), oxidation to sulfone (mCPBA, CH2Cl2, 0 C.), and deprotection of the N-Boc group to provide the free amine (CF3CO2H, CH2Cl2). (m/z): [M+H]+ calcd for C4H9NO2S, 136.04; found, 135.9.
	In methanol;	<strong>[123-90-0]Thiomorpholin</strong>e-1,1-dioxide was prepared from thiomorpholine by protection of the secondary amine to N-Boc thiomorpholine ((Boc)2O, MeOH), oxidation to sulfone (mCPBA, CH2Cl2, 0 C.), and deprotection of the N-Boc group to provide the free amine (CF3CO2H, CH2Cl2). (m/z): [M+H]+calcd for C4H9NO2S, 136.04; found, 135.9.
	In dichloromethane; at 0℃; for 4h;	PREPARATIVE EXAMPLE 10; STEP A; <strong>[123-90-0]Thiomorpholin</strong>e (6 gm, 58 mmol) was dissolved in CH2Cl2 (200 mL) under a dry nitrogen atmosphere and the reaction mixture cooled in an ice bath. A solution of di-tert.butyl-dicarbonate (15.3 gm, 70 mmol) in CH2Cl2 (50 mL) was added dropwise and the reaction mixture stirred for 4 hours. The reaction mixture was washed with brine, followed by saturated NaHCO3, dried over MgSO4, filtered, and evaporated to obtain 14.37 gm of title product as a crystalline solid. mp= 72.9-78.9C.
	In methanol;	Preparation of secondary amines; <strong>[123-90-0]Thiomorpholin</strong>e-1, 1-dioxide was prepared from thiomorpholine by protection of the secondary amine to N-Boc thiomorpholine ((Boc)2O, MeOH), oxidation to sulfone (mCPBA, CH2C12, 0C), and deprotection of the N-Boc group to provide the free amine (CF3CO2H, CH2C12). (m/z) : [M+H] + calcd for C4H9N02S, 136.04 ; found, 135.9.
		2.50 parts of the compound represented by the formula (I1-a), 2.94 parts of triethylamine and 12.50 parts of tetrahydrofuran, and the mixture was stirred at 23 C. for 30 minutes. To the resulting mixed solution, a mixed solution of 5.29 parts of the compound represented by the formula (I1-b) and 5.29 parts of tetrahydrofuran was added dropwise at 23 C. over 10 minutes and further stirred at 23 C. for 12 hours did. The resulting reaction mass was concentrated and 25 parts of ethyl acetate and 8.33 parts of ion-exchanged water were added to the obtained residue, and the mixture was stirred at 23 C. for 30 minutes, separated, and the organic layer was taken out. This operation was repeated 4 times. The collected organic layer was concentrated to obtain 4.42 parts of the compound represented by the formula (I1-c).
3.9 g	With triethylamine; In dichloromethane; at 20℃;Cooling with ice;	In the ice bath,Di-tert-butyl dicarbonate (4.23 g) was slowly added dropwise to a solution of thiomorpholine (2 g) and triethylamine (3.1 mL) in dichloromethane.After joining,Warming to room temperature,The reaction was overnight.Add appropriate amount of water,Extract with dichloromethane,The combined organic phases are washed with saturated brine,Dried over anhydrous sodium sulfate,Filtration and concentration of the filtrate in vacuo gave tert-butyl hydrinomorpholine-4-carboxylate (3.9 g).
	With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	To a stirred solution of thiomorpholine (700 mg, 6.78 mmol) in dry DCM (7 mL), TEA (1.1 mL, 8.13 mmol) was added at R, followed by boc anhydride (1.7 mL, 7.46 mmol) at 0 C. The resulting mixture was stirred 3 h at RT. It was diluted with DCM (10 mL) and washed with water (20 mL), brine (5 mL), dried over Na2S04 and concentrated under vacuum to get the title compound. It was used in the next step without further purification. Yield: 91 % (1 .25 g, white solid). LCMS: (Method A) 104.2 (M+H), Rt. 2.15 min, 97.12% (Max).

Reference： [1]Patent: US6486154,2002,B1
[2]Patent: US2015/166518,2015,A1 .Location in patent: Paragraph 0068; 0069
[3]European Journal of Medicinal Chemistry,2018,vol. 158,p. 247 - 258
[4]Patent: US2007/197537,2007,A1 .Location in patent: Page/Page column 59
[5]Patent: EP1522540,2005,A1 .Location in patent: Page/Page column 69
[6]Patent: US2006/100426,2006,A1 .Location in patent: Page/Page column 17
[7]Patent: US2006/135764,2006,A1 .Location in patent: Page/Page column 21
[8]Patent: US2006/100236,2006,A1 .Location in patent: Page/Page column 19
[9]Patent: US2006/199839,2006,A1 .Location in patent: Page/Page column 21
[10]Patent: EP1140904,2005,B1 .Location in patent: Page/Page column 37
[11]Patent: WO2005/80389,2005,A1 .Location in patent: Page/Page column 35
[12]Journal of Medicinal Chemistry,2016,vol. 59,p. 9541 - 9559
[13]Patent: JP5977543,2016,B2 .Location in patent: Paragraph 0228
[14]Patent: CN108003161,2018,A .Location in patent: Paragraph 0678; 0680-0682
[15]European Journal of Medicinal Chemistry,2020,vol. 185
[16]Patent: WO2020/39027,2020,A1 .Location in patent: Page/Page column 183

19
[ 123-90-0 ]
[ 112108-73-3 ]
[ 864272-43-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 2.0h;	1.0 g (5.27 mmol) 27 are dissolved in 500 pi THF, treated with 612 ul (5.81 mmol) thiomorpholine and 808 pi (4.75 mmol) N-ethyl-N, N-diisopropyl amine and stirred for 2 h at 50C. After customary workup, 1.4 g (87%) 37 (Rt. = 2.93 min (method E) ) is obtained as a brown oil.

Reference： [1]Patent: WO2005/82853,2005,A1 .Location in patent: Page/Page column 217

20
[ 123-90-0 ]
[ 5580-79-0 ]
[ 870447-55-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; acetonitrile; at 20℃; for 8.0h;	EXAMPLE 1; Preparation of (S)-N-[[3-[2,3,5-trifluoro-4-(thiomorpholin-4- yl)phenyl]-2-oxo-5-oxazolidinonyl]methyl]acetamide.; Step 1:; Preparation of 4-(2,3,6-trifluoro-4-nitrophenyl)thiomorpholine; A solution of <strong>[5580-79-0]2,3,4,5-tetrafluoronitrobenzene</strong> (61.0 mmol) in DMSO (150 mL) is treated with NN-diisopropylethylamine (61.0 mmol) and then thiomorpholine (61.0 mmol) in acetonitrile (40 mL) is added dropwise at room temperature. After stirring 8 hours at room temperature the mixture is diluted with H20 and extracted with EtOAc. The combined organic extracts are washed with H20, brine, dried over Mg2S04, filtered and concentrated under reduced pressure. The residue is triturated with Et20. The solid is collected by filtration and chromatographed over silica gel (Biotage 40M column), eluting with 1:1 dichlormethane /10% EtOAc/hexane. Appropriate fractions are combined and concentrated under reduced pressure to give the title compound.

Reference： [1]Patent: WO2005/113520,2005,A1 .Location in patent: Page/Page column 11-12

21
[ 123-90-0 ]
[ 75-44-5 ]
[ 383865-57-4 ]
thiomorpholine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In toluene;	EXAMPLE 135 Thiomorpholine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide Conversion of <strong>[383865-57-4]2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol</strong> (100 mg, 0.377 mg) with phosgene (20% in toluene, 0.2 ml) and thiomorpholine (0.045 ml, 0.47 mmol) using the general procedure D affords the product as white solid in 73% yield. MS: m/e=395 (M+H+).

Reference： [1]Patent: US2002/45615,2002,A1

22
[ 123-90-0 ]
[ 499-80-9 ]
2,4-Di-[(thiomorpholin-1-yl)-carbonyl]-pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; triethylamine; In N-methyl-acetamide; toluene;	EXAMPLE 1 2,4-Di-[(thiomorpholin-1-yl)-carbonyl]-pyridine 5 g (0.03 mol) of <strong>[499-80-9]pyridine-2,4-dicarboxylic acid</strong> are suspended in 100 ml of toluene. 4.4 ml (0.06 mol) of thionyl chloride +1 ml of dimethylformamide are added dropwise at room temperature. The mixture is boiled under reflux for 2 hours until the resulting evolution of gas has ended and the solution has become clear. It is cooled to 0° C. and a solution of 60 ml (0.06 mol) of thiomorpholine and 10.4 ml (0.075 mol) of triethylamine in 20 ml of toluene is added dropwise. The mixture is stirred at room temperature for 12 hours and washed once with saturated sodium bicarbonate solution. The aqueous phase is extracted twice more by shaking with toluene and the combined organic phases are dried over magnesium sulfate and evaporated. The residue is triturated with diethylether and filtered off with suction. Yield: 5.2 g Melting point: 117°-119° C. 1 H-NMR: delta=2.47-2.93 (m, 8 H); 3.53-4.15 (m, 8 H); 7.25 (m, 1 H); 7.60 (m, 1 H); 8.70 (m, 1 H);

Reference： [1]Patent: US5240921,1993,A

23
[ 123-90-0 ]
[ 124072-61-3 ]
4-(N-t-Butoxycarbonyl-N-methyl-β-alanyl)thiomorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(1) 4-(N-t-Butoxycarbonyl-N-methyl-beta-alanyl)thiomorpholine (798 mg) was obtained from N-t-butoxycarbonyl-N-methyl-beta-alanine (610 mg) and thiomorpholine (372 mg). Rf: 0.79 (chloroform:methanol, 9:1, V/V)

Reference： [1]Patent: US4921855,1990,A

24
[ 123-90-0 ]
ethereal hydrogen chloride [ No CAS ]
[ 66575-29-9 ]
[ 598-21-0 ]
[ 122431-87-2 ]

Yield	Reaction Conditions	Operation in experiment
69.1 mg (47.8%)	In dichloromethane; ethyl acetate; N,N-dimethyl-aniline;	EXAMPLE 8 7beta-Acetoxy-8,13-epoxy-1alpha-[(thiomorpholin-4-yl)acetoxy]-6beta,9alpha-dihydroxylabd-14-en-11-one To a stirred solution of 104 mg of 7beta-acetoxy-8,13-epoxy-1alpha,6beta,9alpha-trihydroxylabd-14-en-11-one containing 0.037 ml of N,N-dimethylaniline in 1 ml of dry dichloromethane at 0 under nitrogen was added dropwise a solution of 0.026 ml of bromoacetyl bromide. The mixture was stirred 1 hr at 0, allowed to warm to room temperature, poured onto ice, extracted with ethyl acetate, washed with anhydrous sodium sulfate, filtered, and the filtrate concentrated to an oil. The oil was dissolved in 1 ml of dry dichloromethane and the solution was added dropwise to a solution of 0.1 g of thiomorpholine in 1 ml of ethyl acetate. The mixture was stirred 1.5 hr, poured onto ice, diluted with ethyl acetate, washed with water, saturated sodium chloride and dride over anhydrous sodium sulfate. Filtration followed by evaporation of solvent and purification by flash chromatography to yield an oil. The oil was dissolved in ether and ethereal hydrogen chloride was added to provide 69.1 mg (47.8%) of product, as the hydrochloride, mp 161-171.

Reference： [1]Patent: US4639446,1987,A

25
[ 123-90-0 ]
[ 1005-38-5 ]
[ 96225-88-6 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 36 Using the method of Example 35, thiomorpholine was reacted with <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> to provide 4-amino-2-methylthio-6-(4-thiomorpholino)pyrimidine as a yellow solid, m.p. 144°-145° C. The structural assignment was supported by nuclear magnetic resonance spectral analysis.

Reference： [1]Patent: US4503050,1985,A

26
[ 123-90-0 ]
[ 82419-35-0 ]
9-Fluoro-2,3-dihydro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine;	EXAMPLE 6 9-Fluoro-2,3-dihydro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A mixture of 0.18 g (0.6 mmol) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 0.3 ml (3.0 mmol) of thiomorpholine and 20 ml of pyridine was heated under reflux for 21 hours. The solution was evaporated to dryness, the residue was triturated with hot methanol, and filtered to give 0.05 g of the title compound, mp>300.

Reference： [1]Patent: US4473568,1984,A

27
[ 123-90-0 ]
[ 56035-28-0 ]
[ 108-91-8 ]
[ 1979-96-0 ]
[ 56032-04-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triethylamine; In methanol; chloroform; water; acetone;	EXAMPLE F 2-Methylmercapto-4-thiomorpholino-5-nitro-6-cyclohexylaminopyrimidine 14.0 gm of 2-methylmercapto-4,6 -dichloro-5-nitropyrimidine (Brown and Jacobsen, J. Chem. Soc. 1963, 3776) were dissolved in 200 ml of methanol, the solution was cooled to -60C, and 6.0 gm of triethylamine were added. Over a period of 1 hour 4.0 gm of cyclohexylamine were added dropwise, while stirring, without exceeding the temperature of -60C. Afterwards, the methanol was distilled off, the residue was taken up in chloroform, and the solution was washed 5 times with water. After distilling off the chloroform, the residue was recrystallized from isopropanol, and pure 2-methyl-mercapto-4-chloro-5-nitro-6-cyclohexylamino-pyrimidine was obtained. Yield: 11.2 gm (62% of theory), m.p. 98-104C. 3.0 gm of 2-methylmercapto-4-chloro-5-nitro-6-cyclohexylamino-pyrimidine were dissolved in 30 ml of acetone, a solution of 1.38 gm of potassium carbonate in 1.5 ml of water was added, and the mixture was admixed with a solution of 1.2 gm of thiomorpholine in 10 ml of acetone. The resulting mixture was stirred at room temperature, whereby after a short time a voluminous, crystalline precipitate was formed which was further increased by addition of water. The mixture was suction-filtered and the filter cake, 2-methylmercapto-4-thiomorpholino-5-nitro-6-cyclohexylamino-pyrimidine, was recrystallized from isopropanol. Yield: 2.3 gm (62% of theory), m.p. 145-146C.

Reference： [1]Patent: US3975384,1976,A

28
[ 123-90-0 ]
[ 3029-64-9 ]
[ 56032-13-4 ]

Yield	Reaction Conditions	Operation in experiment
4.5%		5-Cyano-4,6 -dichloro-2-thiomorpholino-pyrimidine (m.p. 99°C, yield: 4.5percent of theory) from 5-cyano-2,4,6 -trichloro-pyrimidine and thiomorpholine.

Reference： [1]Patent: US3975384,1976,A

29
[ 123-90-0 ]
[ 21902-40-9 ]
[ 60691-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane;	EXAMPLE B 1-Thiomorpholino-3-chloro-5-methyl-isoquinoline A mixture of 23.3 gm (0.11 mol) of <strong>[21902-40-9]1,3-dichloro-5-methyl-isoquinoline</strong> [prepared according to G. Simchen et al, Chem. Ber. 102, 3666 (1969); m.p. 120C], 28.3 gm (0.275 mol) of thiomorpholine and 110 ml of dry dioxane was refluxed for 4 hours. The mixture was then evaporated, the residue was taken up with a mixture of tolune and water, and the toluene phase was isolated, dried and evaporated. The residue was recrystallized from 100 ml of ethyl acetate, yielding 22.7 gm (72% of theory) of the desired compound, m.p. 134-136C. The following starting compounds were prepared in analogous manner:

Reference： [1]Patent: US3975524,1976,A

30
[ 123-90-0 ]
[ 79562-49-5 ]
6-amino-1-cyclopropyl-8-methyl-7-(1-thiomorpholinyl)-1,4-dihydro-4-oxo-quinoline carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 14 By working according to the operative conditions described by example 12, starting from <strong>[79562-49-5]2,6-difluoro-3-nitrotoluene</strong> and using thiomorpholine as the amine, it is possible to obtain the 6-amino-1-cyclopropyl-8-methyl-7-(1-thiomorpholinyl)-1,4-dihydro-4-oxo-quinoline carboxylic acid (35). 1H-NMR (DMSO-d6) delta: 0.8-1.4 (4H, m, cyclopropylic CH2), 2.65 (3H, s, CH3), 2.8-3.4 (8H, m, thiomorpholinic H), 3.7-3.9 (1H, m, cyclopropylic CH), 4.8 (2H, br s, NH2), 7.6 (1H, s, H-5), 8.60 (1H, s, H-2).

Reference： [1]Patent: EP531958,1993,A1

31
[ 123-90-0 ]
[ 502767-50-2 ]
[ 676360-95-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydroxide; In 1,4-dioxane; water;	Example 116 Synthesis of N2-(3-chloro-4-methoxyphenyl)-N4-cycloheptyl-6-(1, 4-thiazinan-4-yl)-1,3,5-triazine-4,2-diamine (E27) A mixture of thiomorpholine (97 mg, 0.942 mmol), sodium hydroxide (31.4 mg, 0.785 mmol) and water (0.5 mL) in 1,4-dioxane (15 mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to 25 C. followed by the addition of compound 133 (0.30 g, 0.785 mmol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (220 mL). The combined organic layers were washed with water (210 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E27 as a pale yellow solid (0.26 g, 74%). mp 78-80 C.; HPLC: Inertsil ODS 3V (250*4.6 mm) 5 microns [solvent A=0.01 M KH2PO4; solvent B=CH3CN], A:B=20:80; 220 nm, Rt 20.36 min, 97.15% purity; MS (CI): m/z 449 (M+H, 100).
74%		Example 116 Synthesis of N2-(3-chloro-4-methoxyphenyl)-N4-cycloheptyl-6-(1,4-thiazinan-4-yl)-1,3,5-triazine-4,2-diamine (E27) A mixture of thiomorpholine (97 mg, 0.942 mmol), sodium hydroxide (31.4 mg, 0.785 mmol) and water (0.5 mL) in 1,4-dioxane (15 mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to 25 C. followed by the addition of compound 133 (0.30 g, 0.785 mmol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (220 mL). The combined organic layers were washed with water (210 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E27 as a pale yellow solid (0.26 g, 74%). mp 78-80 C.; HPLC: Inertsil ODS 3V (250*4.6 mm) 5 microns [solvent A=0.01 M KH2PO4; solvent B=CH3CN], A:B=20:80; 220 nm, Rt 20.36 min, 97.15% purity; MS (CI): m/z 449 (M+H, 100).
74%		A mixture of thiomorpholine (97 mg, 0.942 mmol), sodium hydroxide (31.4 mg, 0.785 mmol) and water (0.5 mL) in 1,4-dioxane (15 mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to 25 C. followed by the addition of compound 133 (0.30 g, 0.785 mmol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (220 mL). The combined organic layers were washed with water (210 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E27 as a pale yellow solid (0.26 g, 74%). mp 78-80 C.; HPLC: Inertsil ODS 3V (250*4.6 mm) 5 microns [solvent A=0.01 M KH2PO4; solvent B=CH3CN], A:B=20:80; 220 nm, Rt 20.36 min, 97.15% purity; MS (CI): m/z 449 (M+H, 100).

74%

A mixture of thiomorpholine (97 mg, 0.942 mmol), sodium hydroxide (31.4 mg, 0. 785 mmol) and water (0.5mL) in 1,4-dioxane (15mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to25 C followed by the addition of compound 133 (0.30 g, 0.785 mmol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrousNa2S04 and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20 % EtOAc-Hexane) to afford the title compound E27 as a pale yellow solid (0.26 g, 74 %). mp78-80 C ; HPLC: Inertsil ODS 3V (250 x 4. 6 mm) 5 microns [solvent A = 0.01 MKH2PO4 ; solvent B =CH3CN], A: B = 20: 80; 220nm, Rt 20.36 min, 97.15 % purity ; MS (CI):only 449 (M+H, 100).

Reference： [1]Patent: US2004/224950,2004,A1
[2]Patent: US2004/209880,2004,A1 .Location in patent: Page/Page column 111
[3]Patent: US2004/209881,2004,A1 .Location in patent: Page/Page column 129
[4]Patent: WO2004/26844,2004,A1 .Location in patent: Page 384

32
[ 123-90-0 ]
[ 1193-54-0 ]
[ 1083410-52-9 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2007,vol. 43,p. 1197 - 1201

33
[ 123-90-0 ]
[ 69321-60-4 ]
[ 1020180-12-4 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 2938 - 2950

34
[ 123-90-0 ]
[ 100986-89-8 ]
C₁₇H₁₇FN₂O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1229 - 1236

35
[ 123-90-0 ]
[ 112811-72-0 ]
[ 114213-99-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 2558 - 2569

36
[ 123-90-0 ]
[ 5728-20-1 ]
[ 173053-53-7 ]

Yield	Reaction Conditions	Operation in experiment
	at 109℃; for 2.08333h;	Step 1: To 21.0 g of thiamorpholine in flask at 109 0C, 7.8 g of 3,4-dichloro-l,2,5- thiadiazole was added dropwise over 5 min. The mixture was kept stirring at 109 0C for 2 hrs. After the mixture was cooled down to room temperature the reaction was quenched by addition of 50 mL of water. It was extracted with EtOAc (3x100 mL). The organic phase was washed with IN HCl (2x30 mL). The brown oil was purified by column chromatography after work up. 11.6 g of 3-chloro-4-thiamorpholin-yl-l,2,5-thiadiazole was obtained.
	In water; at 109℃; for 2.08333h;	To 21.0 g of thiamorpholine in flask at 109 C., 7.8 g of <strong>[5728-20-1]<strong>[5728-20-1]3,4-dichloro-1,2,5-thiadiazol</strong>e</strong> was added dropwise over 5 min. The mixture was kept stirring at 109 C. for 2 hrs. After the mixture was cooled down to room temperature the reaction was quenched by addition of 50 mL of water. It was extracted with EtOAc (3100 mL). The organic phase was washed with 1N HCl (230 mL). The brown oil was purified by column chromatography after work up. 11.6 g of 3-chloro-4-thiamorpholin-yl-1,2,5-thiadiazole was obtained.

Reference： [1]Patent: WO2008/103613,2008,A2 .Location in patent: Page/Page column 89
[2]Patent: US2008/200405,2008,A1 .Location in patent: Page/Page column 40

37
[ 123-90-0 ]
[ 68641-49-6 ]
[ 1093952-56-7 ]

Reference： [1]South African Journal of Chemistry,2008,vol. 61,p. 43 - 46

38
[ 123-90-0 ]
[ 1159600-11-9 ]
[ 1159600-20-0 ]

Yield	Reaction Conditions	Operation in experiment
100%		A solution of trimethylaluminium (2 M in toluene, 600 muL, 1.2 mmol) was added dropwise (exothermic) to a solution of thiomorpholine (124 mg, 120 muL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95 C. for 4 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:3) afforded the title compound (124 mg, 100%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.
100%		Example 22 {6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone A solution of trimethylaluminium (2 M in toluene, 600 muL, 1.2 mmol) was added dropwise (exothermic) to a solution of thiomorpholine (124 mg, 120 muL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95 C. for 4 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:3) afforded the title compound (124 mg, 100%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.
100%		Example 22 {6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl- methanone A solution of trimethylaluminium (2 M in toluene, 600 mu?, 1.2 mmol) was added dropwise (exothermic) to a solution of thiomorpholine (124 mg, 120 mu?^, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3- fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85 - 95 C for 4 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1:3) afforded the title compound (124 mg, 100%) which was obtained as a light yellow gum. MS: m/e = 414.4 [M+H]+.

Reference： [1]Patent: US2009/143371,2009,A1 .Location in patent: Page/Page column 32
[2]Patent: US2013/102778,2013,A1 .Location in patent: Paragraph 0272; 0273
[3]Patent: WO2013/57123,2013,A1 .Location in patent: Page/Page column 48; 49

39
[ 123-90-0 ]
[ 1197164-41-2 ]
[ 1197164-42-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium carbonate; In water; acetone; at 60℃; for 2.5h;	A solution of 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.450 g, 1.29 mmol) in acetone (5 mL) and water (10 mL) was prepared. To this was added sodium carbonate (0.274 g, 2.59 mmoles), followed by thiomorpholine (0.134 ml, 1.42 mmol). The resulting light tan suspension was allowed to stir at 60 C. for 2.5 hours. The suspension was filtered and the solid was washed with water and dried in vacuo to provide 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.455 g, 85%) as a white solid. HRMS 415.1546 (M+H, calc.), 415.1526 (M+H, obs.).

Reference： [1]Patent: US2017/119778,2017,A1 .Location in patent: Paragraph 1608-1609
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2648 - 2653

40
[ 123-90-0 ]
[ 132898-96-5 ]
[ 1144853-48-4 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 2188 - 2191

41
[ 123-90-0 ]
[ 71406-74-1 ]
[ 1236138-74-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	In butan-1-ol; at 145 - 150℃;	General procedure: To a solution of 7, 8 or 9 (0.74-0.91 mmol) in 3 mL of n-BuOH kept in a PV with stirring, cyclic amines (1.12 mmol) was added. The sealed PV was placed in an oil bath at 145-150 C and stirred for 30-40 min. n-BuOH was evaporated in vacuo and the residue was re-dissolved in 3:1 EtOAc/DCM and washed successively with saturated NaHCO3 and NaCl solution (1 × 15 mL), respectively. The aqueous layer was washed with EtOAc (3 × 5 mL) and the organic layer was dried over anhydrous MgSO4 then filtered. The solution was evaporated in vacuo to afford either solid or semisolid product. Some physical and spectroscopy data are provided below for 7a-r, 8a-f, 9a-e.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3606 - 3609
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2269 - 2281

42
[ 123-90-0 ]
[ 50-00-0 ]
[ 632-85-9 ]
5,7-dihydroxy-8-methoxy-2-phenyl-6-(thiomorpholinomethyl)-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 55℃; for 4h;	Examples 13; Preparation of 5,7-dihydroxy-8-methoxy-2-phenyl-6-(thiomorpholinomethyl)-4H-chromen-4-one [Sulfurmorpholine <strong>[632-85-9]Wogonin</strong>]; The mixture of <strong>[632-85-9]Wogonin</strong> (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.1 ml), sulfurmorpholine (10.3 g) was stirred under for 4 hours at 55 C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65 C. to get the product as yellow solid 37.6 g of purity 99.2%. MS: (API-ES) m/z 400.5[M+H]+, 422.5[M+Na]+; 1H NMR (DMSO-d6, 400 MHz)delta: 8.068.08 (m, 2H, Ar-2',6'-H), 7.617.63 (m, 3H, Ar-3',4',5'-H), 6.99 (s, 1H, 3-H), 3.87 (s, 3H, 8-OCH3), 3.84 (s, 2H, CH2), 2.86 (s, 4H, CH2), 2.71 (s, 4H, CH2).

Reference： [1]Patent: US2010/197619,2010,A1 .Location in patent: Page/Page column 8

43
[ 123-90-0 ]
[ 4533-95-3 ]
[ 1155519-84-8 ]

Yield	Reaction Conditions	Operation in experiment
55.2%	triethylamine; In dichloromethane; at 20℃; for 18h;	[0191] 2) Preparation of 4-(2-chloro-5-nitrophenylsulfonyl)thiomorpholine - To a solution of 2-chloro-5 -nitrobenzene- 1-sulfonyl chloride (0.200 g, 0.78 mmol) in 8 mL CH2Cl2 was added thiomorpholine (0.111 mL, 1.17 mmol) and triethylamine (0.162 mL, 1.17 mmol). The thus obtained reaction mixture was stirred at room temperature for 18 hours, and was purified via column chromatography (8% -->; 15% -->; 20% EtOAc in Hexanes). Fractions containing the desired product were combined and condensed in vacuo, then triturated with EtOAc and Hexanes. The solids were filtered to obtain the product as a light yellow powder. (0.139 g, 99.6% purity by HPLC, 55.2% yield). 1H-NMR: (500 MHz, DMSO-J6) 8.62 (d, J = 3 Hz, IH), 8.47 (dd, Ji = 9 Hz, J2 = 3 Hz, IH), 8.01 (d, J = 9 Hz, IH), 3.54 (m, 4H), 2.65 (m, 4H).

Reference： [1]Patent: WO2010/123959,2010,A2 .Location in patent: Page/Page column 57

44
[ 123-90-0 ]
[ 7693-46-1 ]
[ 1256841-19-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In dichloromethane; at 0 - 20℃;	Example 31A 4-Nitrophenyl thiomorpholine-4-carboxylate 7.7 g (74.4 mmol) of thiomorpholine were initially charged in 100 ml of dichloromethane and, while cooling with an ice bath, admixed with 20.7 ml (15.1 g, 148.8 mmol) of triethylamine. 10.0 g (49.6 mmol) of 4-nitrophenyl chloroformate were added in portions. The reaction mixture was stirred at RT for one hour, and admixed with water and ethyl acetate. The organic phase was removed, washed with 1 N hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 13.2 g (99% of theory) LC-MS (Method 5B): Rt=0.98 min; MS (ESIpos): m/z=269 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta=8.28 (d, 2H), 7.46 (d, 2H), 3.86 (br. s., 2H), 3.72 (br. s., 2H), 2.71 (br. d., 4H).
99%	With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with an ice bath;	Example 27A4-Nitrophenyl thiomorpholine-4-carboxylate 7.7 g (74.4 mmol) of thiomorpholine were initially charged in 100 ml of dichloromethane and, while cooling with an ice bath, admixed with 20.7 ml (15.1 g, 148.8 mmol) of triethylamine. 10.0 g (49.6 mmol) of 4-nitrophenyl chloroformate were added in portions. The reaction mixture was stirred at RT for one hour, and admixed with water and ethyl acetate. The organic phase was removed, washed with 1 N hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 13.2 g (99% of theory)LC-MS (Method 6B): Rt=0.98 min; MS (ESIpos): m/z=269 [M+H]+.
1.46 g		Step a To a stirred solution of thiomorpholine (CAS No. 123-90-0; available from Combi Blocks) (0.8 g, 7.76 mmol) in dichloromethane (16 ml) was added diisopropylethylamine (4 ml, 23.28 mmol) and allowed to stir at 0C for 15 min, followed by addition of 4-nitrophenyl chloroformate (CAS No. 7693-46-1 ; available from Spectrochem) (1.72 g, 8.54 mmol) and allowed to stir at 0C for 1 h. After completion of reaction, reaction mixture was poured into water (50 ml). The resulting reaction mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (6% ethyl acetate in hexane) yielding 4- nitrophenyl thiomorpholine-4-carboxylate (1.46 g, 5.44 mmol). 1H-NMR (400 MHz, CDCI3) delta ppm: 8.304-8.265 (m, 2H), 7.337-7.298 (m, 2H), 3.982-3.863 (m, 4H), 2.751 -2.726 (m, 4H).

Reference： [1]Patent: US2010/305111,2010,A1 .Location in patent: Page/Page column 21
[2]Patent: US2011/21489,2011,A1 .Location in patent: Page/Page column 24
[3]ChemMedChem,2013,vol. 8,p. 1104 - 1116
[4]Patent: WO2018/167269,2018,A1 .Location in patent: Paragraph 00144

45
[ 123-90-0 ]
[ 328-67-6 ]
[ 1198181-29-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 16h;	Reference Example 61 4-[3-bromo-5-(trifluoromethyl)phenyl]carbonyl}thiomorpholine; A solution of <strong>[328-67-6]3-bromo-5-(trifluoromethyl)benzoic acid</strong> (10 g), thiomorpholine (5.0 g), HOBt (7.4 g) and EDCI (9.26 g) in acetonitrile (113 mL) was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (12.3 g, yield 94%) a yellow oil. 1H-NMR (300 MHz, CDCl3)delta:2.61 (br. s, 2 H), 2.73 (br. s, 2 H), 3.66 (br. s, 2 H), 4.11 (br. s, 2 H), 7.55 - 7.59 (m, 1 H), 7.69 - 7.72 (m, 1 H), 7.81 - 7.84 (m, 1 H).
94%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 16h;	A solution of <strong>[328-67-6]3-bromo-5-(trifluoromethyl)benzoic acid</strong> (10 g), thiomorpholine (5.0 g), HOBt (7.4 g) and EDCI (9.26 g) in acetonitrile (113 ml) was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (12.3 g, yield 94%) a yellow oil.1H-NMR (300 MHz, CDCl3) delta: 2.61 (br. s, 2H), 2.73 (br. s, 2H), 3.66 (br. s, 2H), 4.11 (br. s, 2H), 7.55-7.59 (m, 1H), 7.69-7.72 (m, 1H), 7.81-7.84 (m, 1H).

Reference： [1]Patent: EP2295406,2011,A1 .Location in patent: Page/Page column 68-69
[2]Patent: US2011/251187,2011,A1 .Location in patent: Page/Page column 49

46
[ 123-90-0 ]
[ 75-15-0 ]
[ 39186-58-8 ]
[ 1309367-28-9 ]

Reference： [1]Archiv der Pharmazie,2011,vol. 344,p. 320 - 332

47
[ 123-90-0 ]
[ 1254319-51-1 ]
[ 1338478-36-6 ]

Reference： [1]E-Journal of Chemistry,2011,vol. 8,p. 1108 - 1113

48
[ 123-90-0 ]
[ 501-65-5 ]
[ 1378029-94-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With silver tetrakis(pentafluorophenyl)borate;AuCl*C31H43NO; In toluene; at 110℃;	Example 2: Hydroamination of diphenylacetylene with primary and secondary alkylamines.1. 2.5 mol% [(L6)AuCI] (1)2.5 mol% AgB(C6F5)4 - h R¾ I, R25 toluene, 110 C R2 R25 + NH2. NaB(OAc)3H, AcOH, CH2CI2, Ph'or LiAIH4, Et20 PhE2A E2B E2C[0232] The enamine yield and a description of the primary and secondary alkyl amines are provided in Tables 1 and 2.Table 1: Hydroamination yields.entry amine yield" entry amine yield"1 E2Ca 86 11 E2Ck 72e 2C E2Cb 80 12 E2C1 753 E2Cc 92 13 E2Cm 844 E2Cd 90 14c/ E2Cn 905C E2Ce 80 15c E2Co 856 E2Cf 91 16 E2Cp 91 ld E2Cg 90e 17 E2Cq 868 E2Ch 80 18c/ E2Cr 93 entry amine yield" entry amine yield"9 E2Ci 83 19 E2Cs 7610 E2Cj 84e 20c'g E2Ct 80'[0233] Conditions. alkyne:amine:l:AgB(C6F5)4 = 1:1.1:0.025:0.025 (0.8 mmol of alkyne) in 0.8 mL of toluene at 110 C for 16 h. " Isolated yield of reduction product. c 5 mol % 1 and 5 mol % AgB(C6F5)4 used. d In THF/l,4-dioxane (3:2) at 90 C for 16 h. e GC yield of E- enamine relative to dodecane as an internal standard/ Reaction time = 24 h. s In 1,4-dioxane ([alkyne] = 0.5 mM). h lR NMR yield relative to 1,3,5-trimethoxybenzene as an internal standard. ' Isolated as the enamine hydrolysis product.9 Table 2: Description of amine used in hydroamination

Reference： [1]Patent: WO2012/68335,2012,A2 .Location in patent: Page/Page column 53-54

49
[ 123-90-0 ]
[ 938443-20-0 ]
C₁₁H₁₀Cl₂N₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1212 - 1216

50
[ 123-90-0 ]
[ 5424-47-5 ]
3-(thiomorpholin-4-yl)-1-(thiophen-2-yl)-1-propanone hydrochloride [ No CAS ]

Reference： [1]Acta Chimica Slovenica,2013,vol. 60,p. 70 - 80

51
[ 123-90-0 ]
[ 94-36-0 ]
[ 1446513-60-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With dipotassium hydrogenphosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;	General procedure: A 100-mL, one-necked, round-bottomed flask equipped with a magnetic stir bar was charged with benzoyl peroxide (3.03 g, 12.5 mmol, 1.00 equiv), dipotassium hydrogenphosphate (3.27 g, 18.8 mmol, 1.50 equiv), and N,N-dimethylformamide (30mL). The suspension was stirred and amine (15.0 mmol, 1.20 equiv) was added via syringe in one portion. The flask was capped with a septum and the reaction mixture was stirred at room temperature for 1-24 h, during which time a gradual change in coloration of the reaction mixture occurred. Deionized water (50 mL) was added and the contents were stirred vigorously for 30 min. The reaction mixture was transferred to a separatory funnel and extracted with EtOAc (1 × 40 mL). The organic phase was collected and washed with saturated aqueous NaHCO3 solution (2 × 25mL). All of the aqueous fractions were combined and extracted with EtOAc (2 × 25 mL). All of the organic fractions were combined and washed with 30 mL of deionized water, 25 mLof brine, dried over Na2SO4, filtered, and concentratedby rotary evaporation. The resulting solid was purified by flash column chromatography to afford desired O-benzoyl hydroxylamine 2 (Table S-1).

Reference： [1]Tetrahedron,2013,vol. 69,p. 6627 - 6633
[2]Angewandte Chemie - International Edition,2017,vol. 56,p. 14948 - 14952
Angew. Chem.,2017,vol. 129,p. 15144 - 15148,5
[3]Chemistry - A European Journal,2018,vol. 24,p. 5775 - 5778
[4]Journal of the American Chemical Society,2018,vol. 140,p. 8551 - 8562
[5]Journal of Organic Chemistry,2019,vol. 84,p. 3725 - 3734
[6]Organic Letters,2019,vol. 21,p. 4250 - 4254
[7]Journal of the American Chemical Society,2019,vol. 141,p. 9731 - 9738
[8]Chemical Communications,2020,vol. 56,p. 5933 - 5936
[9]Journal of Organic Chemistry,2020,vol. 85,p. 7817 - 7839

52
[ 123-90-0 ]
[ 93-55-0 ]
1-phenyl-2-thiomorpholinopropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With 2,6-bis[(4,4-dimethyl)-2-oxazolin-2-yl]pyridine copper bromide; In dimethyl sulfoxide; at 20℃; for 15h;	In the air atmosphere, a polytetrafluoroethylene magnet granule was placed in the reactor, then added 2-6-bis [4- (1,1-dimethyl) -2-oxazolin-2-yl] pyridine and Cupric bromide reagent (0.06mmol (5mol%) prepared by the method of Example 1 , 1.2 mmol of propiophenone, 3.6 mmol of <strong>[123-90-0]Thiomorpholin</strong>e and 1.2 ml of dimethyl sulfoxide solvent and at room temperate carried out open stirring for 15h. The reaction mixture was subjected to silica gel column chromatography using ethyl acetate / n-hexane eluent to give alpha-<strong>[123-90-0]Thiomorpholin</strong>e propiophenone compound (0.25g, yield 90%)

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5509 - 5516
[2]Patent: CN103848854,2016,B .Location in patent: Paragraph 0039; 0040
[3]Journal of the American Chemical Society,2013,vol. 135,p. 16074 - 16077
[4]Journal of Organic Chemistry,2014,vol. 79,p. 8750 - 8756

53
[ 123-90-0 ]
[ 630125-49-4 ]
[ 1529769-87-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	Add l-bromo-3-nitro-5-(trifluoromethy 0l)benzene (500 mg, 2.9 mmol), thiomorpholine (455 mg, 4.4 mmol), Cs2C03 (2.86 g, 8.8 mmol), BINAP (55 mg, 0.09 mmol) and Pd2(dba)3 (54 mg, 0.06 mmol) under N2 tol,4-dioxane (10 mL), stir the reaction under N2 at 100C for 16 hrs. TLC (100% PE) shows the reaction is complete. Cool the reaction to room temperature, filter and concentrate the filtrate under reduced pressure to get crude product. Purification by chromatography (silica gel, 100% PE) affords the target compound (475 mg, 55%). MS: (M+l): 293.1.
55%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	Add <strong>[630125-49-4]1-bromo-3-nitro-5-(trifluoromethyl)benzene</strong> (500 mg, 2.9 mmol), thiomorpholine (455 mg, 4.4 mmol), Cs2CO3 (2.86 g, 8.8 mmol), BINAP (55 mg, 0.09 mmol) and Pd2(dba)3 (54 mg, 0.06 mmol) under N2 to 1,4-dioxane (10 mL), stir the reaction under N2 at 100 C. for 16 hrs. TLC (100% PE) shows the reaction is complete. Cool the reaction to room temperature, filter and concentrate the filtrate under reduced pressure to get crude product. Purification by chromatography (silica gel, 100% PE) affords the target compound (475 mg, 55%). MS: (M+1): 293.1.
1.05 g	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 45℃; for 4h;	General procedure: To a solution of di-tert-butyl (3-bromo-5-(trifluoromethyl)phenyl)imidodicarbonate (step 1 intermediate) (2.2 g, 4.89 mmol) in 1,4-dioxane (20 mL) were added N,N,N?25 trimethylethylenediamine (636 jiL, 4.89 mmol), sodium tert-butoxide (1.40 g, 14.7 mmol),tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (447 mg, 0.49 mmol) and (2- biphenyl)di-tert-butylphosphinetriethylamine (JohnPhos) (37 mg, 1 .47mmol) at RT and the reaction mixture was stirred at 45 C for 4 h. The mixture was cooled to RT and filteredthrough celite. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic solution was washed with 0.1 N HC1 followed by water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 2.01 g of the desired compound. The compound was as suchcarried forward to the next step without characterization.

Reference： [1]Patent: WO2014/418,2014,A1 .Location in patent: Page/Page column 78; 79
[2]Patent: US2015/197511,2015,A1 .Location in patent: Paragraph 0366; 0367
[3]Patent: WO2018/215668,2018,A1 .Location in patent: Page/Page column 78; 79; 83

54
[ 123-90-0 ]
[ 39551-54-7 ]
[ 39551-50-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 613 - 631

55
[ 123-90-0 ]
[ 10320-42-0 ]
[ 1562399-15-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1583 - 1598

56
[ 123-90-0 ]
[ 1477-49-2 ]
[ 1584164-16-8 ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: To the THF (5mL) and DMF (0.5mL) solution of 2-(Benzo[d]thiazol-2-ylthio)acetic acid (100 mg; mM) was added EDC.HCl (1.5molar equivalents) and HOBt (10mg). The reaction mixture was stirred for five minutes under nitrogen atmosphere at room temperature. Then 1.2 molar equivalents of amine (1/2) were added to the reaction mixture and the reaction mixture was continued to stir for further 12-16h. After the completion of the reaction monitored by TLC, the reaction mixture was quenched with excess of water (100mL) and extracted with ethylacetate (2×20mL). Combined organic layers were dried over anhydrous sodium sulfate and evaporated to obtain the target compound.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 76,p. 274 - 283

57
[ 123-90-0 ]
[ 10354-53-7 ]
[ 1575753-93-3 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1764 - 1767
[2]Journal of the American Chemical Society,2018,vol. 140,p. 11487 - 11494
[3]Organic and biomolecular chemistry,2020,vol. 18,p. 4802 - 4814

58
[ 123-90-0 ]
[ 176433-57-1 ]
5-phenyl-2-thiomorpholinonicotinaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 5h;	General procedure: Morpholine 17a (1.2mmol) was added to a stirred solution of 2-chloro-5-methylnicotinaldehyde 8a (1mmol) in N,N-dimethylformamide and K2CO3 (1.5mmol) at room temperature. The reaction mixture was heated at 110C for 5h. After completion of the reaction (TLC), the mixture was quenched with ice water and solid was filtered off. The solid was recrystallized (EtOAc/hexane) gave 5-methyl-2-morpholinonicotinaldehyde 18a as yellow color solid. Similarly 18b-f was prepared from corresponding substituted 2-chloronicotinaldehydes 8a-c.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 90,p. 603 - 619
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 882 - 887

59
[ 123-90-0 ]
2-chloro-5-(p-tolyl)pyridine-3-carbaldehyde [ No CAS ]
2-thiomorpholino-5-p-tolylnicotinaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 5h;	General procedure: Morpholine 17a (1.2mmol) was added to a stirred solution of 2-chloro-5-methylnicotinaldehyde 8a (1mmol) in N,N-dimethylformamide and K2CO3 (1.5mmol) at room temperature. The reaction mixture was heated at 110C for 5h. After completion of the reaction (TLC), the mixture was quenched with ice water and solid was filtered off. The solid was recrystallized (EtOAc/hexane) gave 5-methyl-2-morpholinonicotinaldehyde 18a as yellow color solid. Similarly 18b-f was prepared from corresponding substituted 2-chloronicotinaldehydes 8a-c.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 90,p. 603 - 619
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 882 - 887

60
[ 123-90-0 ]
[ 106-37-6 ]
[ 90254-20-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 86℃;Inert atmosphere;	To the solution of thiomorpholine (7 g, 67.8 mmol) in toluene (170 mL) in a 500 mL round bottom flask under 2 were added 1 ,4-dibromobenzene (20.8 g, 88 mmol), Pd2(dba)3 (1.55 g, 1.7 mmol), BINAP (2.112 g, 3.39 mmol), and tert- uOK (16.3 g, 170 mmol). The reaction mixture was heated at 86 C for 1.5-2 h. The reaction mixture was quenched with water (600 mL). The resulting mixture was extracted with EtOAc (3 x 600 mL). The combined organic fractions were washed with brine (600 mL), dried (MgS04), filtered, and solvent was removed under reduced pressure. The residue was purified by flash chromatography on ISCO silica gel column (Hexane/EtOAc (0-10%) giving 14.1 g (81% ) of the 4-(4-bromophenyl)thiomorpholine as light yellow solid.
81%	With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 86℃;Inert atmosphere;	To the solution of thiomorpholine (7 g, 67.8 mmol) in toluene (170 mL) in a 500 mL round bottom flask under N2 were added 1,4-dibromobenzene (20.8 g, 88 mmol), Pd2(dba)3(1.55 g, 1.7 mmol), BINAP (2.112 g, 3.39 mmol), and tert-BuOK (16.3 g, 170 mmol). The reaction mixture was heated at 86 C for 1.5-2 h. The reaction mixture was quenched with water(600 mL). The resulting mixture was extracted with EtOAc (3 x 600 mL). The combined organic fractions were washed with brine (600 mL), dried (Mg504), filtered, and solvent was removedunder reduced pressure. The residue was purified by flash chromatography on ISCO silica gel column (Hexane/EtOAc (0-10%) giving 14.1 g (81% ) of the 4-(4-bromophenyl)thiomorpholine as light yellow solid.
0.82 g	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 80℃; for 16h;	A) 4-(4-bromophenyl)thiomorpholine [0921] A mixture of 1,4-dibromobenzene (1.0 g), thiomorpholine (0.44 g), tris(dibenzylideneacetone)dipalladium(0) (0.097 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.20 g) and sodium tert-butoxide (0.49 g) in toluene (10 mL) was stirred at 80C for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.82 g). MS(ESI+): [M+H]+ 258.0. MS(ESI+), found: 258.1. 1.

With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 86℃;Inert atmosphere;

To the solution of thiomorpholine (7 g, 67.8 mmol) in toluene (170 mL) in 500 mL round bottom flask under N2 were added 1 ,4-dibromobenzene (20.8 g, 88 mmol), Pd2(dba)3 (1.55 g, 1.7 mmol), BINAP (2.112 g, 3.39 mmol), and tert-BuOK (16.3 g, 170 mmol). The reaction mixture was heated at 86 C for 1.5-2 h. The reaction mixture was quenched with water (600 mL). The resulting mixture was extracted with EtOAc (3 x 600 mL). The combined organic fractions were washed with brine (600 mL), dried (MgSC^), filtered, and solvent was removed under reduced pressure. The residue was purified by flash chromatography on ISCO silica gel column (Hexane/EtOAc (0-10%) giving 4-(4-bromophenyl)thiomorpholine as light yellow solid.

Reference： [1]Patent: WO2015/51479,2015,A1 .Location in patent: Page/Page column 54
[2]Patent: WO2015/54038,2015,A1 .Location in patent: Page/Page column 48
[3]Patent: EP2857400,2015,A1 .Location in patent: Paragraph 0921
[4]Patent: WO2015/123089,2015,A1 .Location in patent: Page/Page column 45

61
[ 123-90-0 ]
[ 1003845-06-4 ]
(2-thiomorpholinopyrimidin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; In ethanol; at 80℃; for 4h;	<strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (52.3 mmol, 8.53 g), thiomorpholine (52.3 mmol, 5.3 ml) and TEA (52.3 mmol, 7.3 ml) were dissolved in EtOH (100 ml) and heated at 80C for 4h. The solvent was removed in vacuo and the resulting solid triturated with Et20 yielding the title compound (8.64 g, 74%). deltaEta(300MHz, DMSO-d6) 8.63 (s, 2H); 8.06 (s, 2H); 4.08 (m, 4H); 2.59 (m, 4H). LCMS (ES+) RT 0.21 min 226.8 (M+H)+. -

Reference： [1]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 128
[2]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 128

62
[ 123-90-0 ]
[ 171663-13-1 ]
tert-butyl N-[(3-thiomorpholinophenyl)methyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With palladium diacetate; johnphos; sodium t-butanolate; In toluene; at 80℃; for 5h;Inert atmosphere;	Example 105 Production of tert-Butyl N-[(3-thiomorpholinophenyl)methyl]carbamate. Thiomorpholine (9.9 mL, 105 mmol), palladium acetate (0.8 g, 3.5 mmol), 2-(di-tert-butylphosphino)biphenyl (2.1 g, 7.0 mmol), and sodium tert-butoxide (3.7 g, 38 mmol) were added to a toluene (70 mL) solution of the compound obtained in Example 104 (10.0 g, 35 mmol), in an argon atmosphere at room temperature, and the mixture was stirred at 80C for 5 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered away. The residue obtained by distilling off the solvent of the filtrate under a reduced pressure was purified with silica gel column chromatography (n-hexane : ethyl acetate = 5:1), to give the captioned compound (3.1 g, 28%) as a solid. Mp 62-63C. 1H-NMR (DMSO-d6) delta: 1.39 (s, 9H), 2.64-2.66 (m, 4H), 3.48-3.50 (m, 4H), 4.06 (d, J=6.1 Hz, 2H), 6.64 (d, J=7.4 Hz, 1H), 6.77-6.79 (m, 2H), 7.12-7.16 (m, 1H), 7.30 (t, J=5.9 Hz, 1H).

Reference： [1]Patent: EP2940003,2015,A1 .Location in patent: Paragraph 0133

63
[ 123-90-0 ]
3-(2-ethoxy-2-oxoethyl) 5-ethyl 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [ No CAS ]
3-ethyl 5-(2-oxo-2-thiomorpholinoethyl) 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine; In N,N-dimethyl-formamide; at 30℃; for 3h;	General procedure: To the mixture of 1,4-DHP 3a-d (1 equiv.) and the appropriate amine (3 equiv.) in DMF (1 mLwas used per 3 mmol of the corresponding 1,4-DHP 3a-d) TBD (20 mol %) was added at rt. Afterbeing stirred at 30 C for 2, 3, or 4 h, the reaction mixture was concentrated under reduced pressure.The residue was triturated with water, filtered off and crystallised from ethanol giving amides 4a-m.

Reference： [1]Molecules,2015,vol. 20,p. 20341 - 20354

64
[ 123-90-0 ]
[ 31737-09-4 ]
4-hydroxy-1-methyl-6-thiomorpholinopyrimidin-2(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 2674 - 2687

65
[ 123-90-0 ]
[ 32137-76-1 ]
benzo[d]thiazol-2-yl(thiomorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With ammonium chloride; In neat (no solvent); at 100℃;	General procedure: The 5-substituted benzo[d]thiazole-2-carboxylate 2a/2b/2c (1 mmol) was taken in a round bottom flask (10 mL). To it theamine (1 equiv) was added along with catalytic amount (20 mol%)of NH4Cl and reaction mixturewas heated at 100 C for 1e2 h undermagnetic stirring. After completion of reaction (TLC), ice-coldwater(2 mL) was added to the reaction mixture and the mixture wasallowed to stir for 10 min. The solid precipitate was filtered and airdried to furnish the final product that did not require any furtherpurification.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 116,p. 187 - 199

66
[ 123-90-0 ]
[ 618-91-7 ]
methyl3-thiomorpholinobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 60℃; for 8h;	General procedure: A mixture ofmethyl 3-iodobenzoate (1 mmol), corresponding amine (3 mmol), K2CO3(4 mmol), CuI (0.2 mmol) and L-proline (0.4 mmol) in 15 mL of DMSO was heatedat 60 °C for 8 h. The cooled mixture was pour into 150 ml water, and extractedwith ethyl acetate (3 × 15 mL), the organic fractions were combined, washedwith saturated brine (2 × 15 ml) prior to drying over anhydrous sodium sulfate.After filtration and concentrate using a rotary evaporator, the residue was purified by silica gel column chromatographyusing a mixture of petroleum ether/ethyl acetate (20 : 1, v/v) as eluent toafford the desired product.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 1981 - 1987

67
[ 123-90-0 ]
[ 15307-86-5 ]
2-(2-((2,6-dichlorophenyl)amino)phenyl)-1-thiomorpholinoethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;	General procedure: To the corresponding acid (1 mmol) dissolved in CH2Cl2, thiomorpholine(1.2 mmol) was added followed by the addition of N,N?-dicyclohexylcarbodiimide(DCC, 1.3 mmol) in the same solvent. The mixture was stirred for 4 hours at room temperature. After the removal of N,N?-dicyclohexylurea (DCU) byfiltration, the final compounds were isolated with flash chromatography using asuitable mixture of petroleum ether and ethyl acetate as eluent.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 910 - 913

68
[ 123-90-0 ]
[ 13710-19-5 ]
(2-((3-chloro-2-methylphenyl)amino)phenyl)(thiomorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;	General procedure: To the corresponding acid (1 mmol) dissolved in CH2Cl2, thiomorpholine(1.2 mmol) was added followed by the addition of N,N?-dicyclohexylcarbodiimide(DCC, 1.3 mmol) in the same solvent. The mixture was stirred for 4 hours at room temperature. After the removal of N,N?-dicyclohexylurea (DCU) byfiltration, the final compounds were isolated with flash chromatography using asuitable mixture of petroleum ether and ethyl acetate as eluent.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 910 - 913

69
[ 123-90-0 ]
[ 530-78-9 ]
thiomorpholino(2-((3-(trifluoromethyl)phenyl)amino)phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;	General procedure: To the corresponding acid (1 mmol) dissolved in CH2Cl2, thiomorpholine(1.2 mmol) was added followed by the addition of N,N?-dicyclohexylcarbodiimide(DCC, 1.3 mmol) in the same solvent. The mixture was stirred for 4 hours at room temperature. After the removal of N,N?-dicyclohexylurea (DCU) byfiltration, the final compounds were isolated with flash chromatography using asuitable mixture of petroleum ether and ethyl acetate as eluent.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 910 - 913

70
[ 123-90-0 ]
[ 61-68-7 ]
(2-((2,3-dimethylphenyl)amino)phenyl)(thiomorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;	General procedure: To the corresponding acid (1 mmol) dissolved in CH2Cl2, thiomorpholine(1.2 mmol) was added followed by the addition of N,N?-dicyclohexylcarbodiimide(DCC, 1.3 mmol) in the same solvent. The mixture was stirred for 4 hours at room temperature. After the removal of N,N?-dicyclohexylurea (DCU) byfiltration, the final compounds were isolated with flash chromatography using asuitable mixture of petroleum ether and ethyl acetate as eluent.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 910 - 913

71
[ 123-90-0 ]
[ 118591-58-5 ]
2-(2-thiomorpholin-4-yl-ethoxy)-ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.8%	With potassium carbonate; In 1,4-dioxane; at 70℃;	Compound 1-3 (3.12 g, 12 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 23-1 (1 g, 10 mmol), and under stirring potassium carbonate (1.65 g, 12 mmol) was added, followed by stirring the reaction overnight at 70 C., TLC monitoring showed the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 23-2 (1.2 g, 62.8%) as a pale yellow oil, LC-MS: m/z=192[M+H]+.

Reference： [1]Patent: US2017/2028,2017,A1 .Location in patent: Paragraph 0159; 0160

72
[ 123-90-0 ]
[ 273-53-0 ]
[ 1439378-21-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With tert.-butylhydroperoxide; 1-(n-butyl)pyridinium iodide; acetic acid; In water; acetonitrile; at 20℃; for 3.5h;Green chemistry;	General procedure: A reaction vessel was charged with acetic acid (2.016 mmol) and TBHP (70% inwater, 1.008 mmol) in acetonitrile (2 mL). After the addition of [Bpy]I (0.1008 mmol),benzoxazole (0.672 mmol) and secondary amines (1.344 mmol) were added. Then thereaction mixture was stirred at room temperature for 3.5 hours. After the reactionfinished, the mixture was extracted with dichloromethane (5 × 10 mL), and thecombined organic phases were dried over anhydrous Na2SO4. The solvent wasevaporated under vacuo, and the crude residue was purified by columnchromatography on silica gel. Aqueous phase was dried in a vacuum evaporator torecover the ionic liquid and directly reused in subsequent runs.
80%	With tetra-(n-butyl)ammonium iodide; acetic acid; In acetonitrile; at 20℃;Electrochemical reaction; Green chemistry;	General procedure: A 30 mL screw capped vial with a septum was inserted carbon anode and aluminum cathode (CAUTION: Electrodes should not come in contact with each other). The electrodes were connected to a cell phone charger (5V) by use of alligator clips. To the reaction vial were added benzoxazole 1 (119 mg, 1 mmol), N-Boc piperazine 2a (372 mg, 2 mmol), acetic acid (300 mg, 5 mmol, 5 equiv.) and TBAI (37 mg, 10 mol%) and the mixture was dissolved in 20mL of acetonitrile and stirred gently at room temperature. Electric current was passed through the reaction vial at room temperature for 3 h. The progress of the reaction was monitored by TLC and LC-MS. After the completion of the reaction, the solvent was removed in vacuo and the crude material was re-dissolved in ethyl acetate (25 mL) and then washed with saturated aqueous sodium carbonate solution (3×10mL). The organic layer was separated, washed with water and then dried over sodium sulfate. The product was purified by column chromatography using hexane and ethyl acetate as eluent to afford 282 mg of compound 3a (93 % yield).

Reference： [1]Molecules,2017,vol. 22
[2]Tetrahedron Letters,2019,vol. 60,p. 358 - 361
[3]Catalysis science and technology,2020,vol. 10,p. 940 - 943

73
[ 123-90-0 ]
[ 1079179-12-6 ]
4-(3-fluoro-5-nitropyridin-2-yl)thiomorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 16h;	To a solution of <strong>[1079179-12-6]2-chloro-3-fluoro-5-nitropyridine</strong> (3.0 g, 15.3 mmol) in DMF (30 mL) was added thiomorpholine (1.6 g, 15.3 mmol) and DIEA (5.3 mL, 30.6 mmol). The mixture was stirred at 60C for 16 hours. The reaction was cooled to roomtemperature, and then then was diluted with water (50 mL). The precipitated solid was collected by filtration, and dried to give 4-(3-fluoro-5-nitropyridin-2-yl)thiomorpholine asa solid. ?HNMRoe 8.87 (s, 1H), 7.98 (dd, J= 2.0, 13.6Hz, 1H), 4.15-4.12 (m, 4H), 2.76-2.74 (m, 4H).

Reference： [1]Patent: WO2017/66964,2017,A1 .Location in patent: Page/Page column 53; 54

74
[ 123-90-0 ]
[ 10242-12-3 ]
(5-nitrobenzofuran-2-yl)(thiomorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		Exam ple 32 : - Synthesis of (5-nitrobenzofuran-2-yl)(thiom orpholino)- m ethano (0679) To a solution of <strong>[10242-12-3]5-nitrobenzofuran-2-carboxylic acid</strong> (1.03 g, 1 equiv.) in DMF (10 mL) were sequentially added HATU (1.3 equiv.) and DIPEA (3 equiv.). The reaction mixture was left under magnetic stirrer for 15 minutes and the thiomorpholine (1.5 equiv.) was added. The reaction was left overnight under magnetic stirrer at room temperature. TLC and LC-MS analysis showed formation of the product. The reaction was quenched by addition of water (10 mL) that was then extracted with ethyl acetate (3 X 10 mL). The organic phase was then sequentially washed with NaHC03 saturated aqueous solution (20 mL) and brine (20 mL). The collected organic phase was dried over MgS04 and subsequently evaporated using a rotary evaporator. The crude of reaction was purified by column chromatography (mobile phase: from DCM /EA, 90/10, v/v) affording pure final compound 22 (1.2 g, 80%) as a yellow solid. NMR (400 MHz, DMSO-d6) delta: 8.66 (d, J = 2.27 Hz, lH), 8.27 (dd, J = 2.52, 9.06 Hz, lH), 7.88 (d, J = 9.57 Hz, lH), 7.55 (d, J = 0.76 Hz, lH), 3.88 (br. s., 4H), 2.66 - 2.72 (m, 4H). FontWeight="Bold" FontSize="10" C NMR (101 MHz, DMSO-d6) delta: 158.4, 156.6, 150.9, 144.1, 127.3, 121.8, 119.0, 112.9, m-i- m/z (+EI) calc. for C13H12N204S (M)+ 292.0 found 293.0 ([M]+H)+

Reference： [1]Patent: WO2017/98257,2017,A1 .Location in patent: Page/Page column 76

75
[ 123-90-0 ]
[ 89763-93-9 ]
2-thiomorpholino-4-(trifluoromethyl)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium carbonate; In dimethyl sulfoxide; at 80℃;Inert atmosphere;	Example 92: 1,1,1,3,3,3-Hexafluoropropan-2-yl 1-(2-(1,1-dioxidothiomorpholino)-4- (trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate Step 1: Preparation of 2-thiomorpholino-4-(trifluoromethyl)benzaldehyde A flask was charged with <strong>[89763-93-9]2-fluoro-4-(trifluoromethyl)benzaldehyde</strong> (300 mg, 1.56 mmol, 1.00 equiv) in DMSO (10 mL), thiomorpholine (241 mg, 2.34 mmol, 1.49 equiv), and potassium carbonate (647 mg, 4.69 mmol, 3.01 equiv) under nitrogen. The resulting solution was stirred overnight at 80 ^C and then quenched with H2O (10 mL). The resulting solution was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column (1:4 EtOAc/petroleum ether) to provide 210 mg (49% yield) of 2-thiomorpholino-4- (trifluoromethyl)benzaldehyde as a light-yellow solid. LCMS (ESI, m/z): 276 [M+H]+.

Reference： [1]Patent: WO2017/197192,2017,A1 .Location in patent: Paragraph 00295

76
[ 123-90-0 ]
[ 215184-78-4 ]
tert-butyl 5-thiomorpholino-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9703 - 9723

77
[ 123-90-0 ]
[ 51417-51-7 ]
4-(1H-indol-7-yl)thiomorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.79%	With [2-(2-aminoethyl)phenyl]-chloro-palladium di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane; sodium t-butanolate; In tetrahydrofuran; at 85℃; for 12h;Inert atmosphere;	To a mixture of <strong>[51417-51-7]7-bromo-1H-indole</strong> (2.00 g, 10.20 mmol, 1.00 eq) and thiomorpholine (1.05 g, 10.20 mmol, 965.82 uL, 1.00 eq) in THF (50.00 mL) was added NaOt-bu (1.96 g, 20.40 mmol, 2.00 eq) and [2-(2-aminoethyl) phenyl]-chloro-palladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (700.56 mg, 1.02 mmol, 0.10 eq) in one portion at 15 C under N2. The mixture was stirred at 85 C for 12 h. The mixture (combined with another batch) was poured into water (100 mL) and extracted with EtOAc (30 mLx2). The combined organic phase was washed with brine (50 mLx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EtOAc=20/1,5/1) to afford the title compound (2.20 g, 10.08 mmol, 98.79% yield) as kelly solid

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 295

78
[ 123-90-0 ]
[ 40851-91-0 ]
4-(6-methoxy-5-nitropyridin-2-yl)thiomorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.5%	With potassium carbonate; In tetrahydrofuran; at 50℃; for 3h;	General procedure: To a solution of C-1?C-3 (5.3mmol) or 2-chloro-5-nitropyridine (5.3mmol) in THF (5mL) was added K2CO3 (10.6mmol) and different alicyclic amines (0.011mol). The reaction mixture was heated and stirred for 3.0hat 50C. The solvent was evaporated under reduced pressure whereafter water was poured into the mixture and stirring for 1h. Production D-1?D-16 was gained after filtration.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 158,p. 322 - 333

79
[ 123-90-0 ]
[ 3939-12-6 ]
[ 1042784-91-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 8h;	General procedure: To a stirred solution of 3 (4, 5) (0.10 mmol) in DMSO (10 ml) were added ZH (0.12 mmol) and K2CO3 (27.6 mg 0.20 mmol). After stirring at 80 °C for 8 hours, the mixture was cooled to room temperature and poured into water, the precipitation was filtered and dried directly for next step. To a solution of above solid (0.10 mmol) in dry THF (10 ml) was added LiAlH4 (11.4 mg, 0.30 mmol) at 0 °C. After stirring at room temperature for 4 h, the mixture was quenched with water and extracted by CH2Cl2 (10 ml). The extraction was dried over anhydrous MgSO4 and filtered. The filtration was concentrated for next step. To a solution of above crude solid (0.12 mmol) in dry CH2Cl2 (10 ml) were added compound 6 (7-11) (0.10 mmol), TEA (22.2mg, 0.22 mmol) and BopCl (30.4 mg, 0.12 mmol). After stirring at room temperature for 12 h, the mixture was washed with brine and dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel column (CH2Cl2 : MeOH = 100 : 1) to yield compounds 1, 2, A, B, C.

Reference： [1]Chinese Chemical Letters,2019,vol. 30,p. 413 - 416

80
[ 123-90-0 ]
[ 51991-94-7 ]
6-(thiomorpholine-4-carbonyl)-5H-thiazolo[3,2-a]pyrimidin-5-one [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 14915 - 14925

81
[ 123-90-0 ]
[ 83012-13-9 ]
C₁₅H₁₂F₆N₂S [ No CAS ]

Reference： [1]Journal of Agricultural and Food Chemistry,2019,vol. 67,p. 11340 - 11353

82
[ 123-90-0 ]
[ 1421372-94-2 ]
N-(2-methoxy-5-nitro-4-thiomorpholinophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 4h;	To a solution of 1 (393 mg, 1 mmol) and thiomorpholine(154 mg, 1.5 mmol) in DMF (20 mL), DIPEA (194 mg, 1.5 mmol) wasadded. After stirring at 60 C for 4 h, the mixture was poured intoice water. The resulting precipitate was filtered off, washed withwater, and dried under vacuum to give the product as a yellowsolid. 66% yield. 1H NMR (400 MHz, Chloroform-d) d 9.62 (s, 1H),8.39 (t, J 5.1 Hz, 1H), 8.25 (s, 1H), 8.17 (dd, J 6.4, 2.5 Hz, 1H), 7.59(s, 1H), 7.45e7.39 (m, 1H), 7.31 (td, J 4.2, 3.6, 1.9 Hz, 1H), 7.20 (dd,J 8.2, 5.3 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.39e3.25(m, 4H), 2.90e2.77 (m, 4H).

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 183

83
[ 123-90-0 ]
[ 117324-58-0 ]
methyl 2-(thiomorpholine-4-sulfonamido)-5-(trifluoromethyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of <strong>[117324-58-0]methyl 2-amino-5-(trifluoromethyl)benzoate</strong> (512 mg, 2.3 mmol) in dichloromethane (11 mL) of was added chlorosulfonic acid (170 muL, 2.6 mmol) followed by phosphorus pentoxide (535 mg, 2.6 mmol). The mixture was heated at 75 C. block overnight. After cooling, the reaction mixture was added to a solution of triethylamine (0.81 mL, 5.8 mmol) in dichloromethane (5 mL) that was cooled in an ice-water bath. A mixture of N,N-diisopropylethylamine (0.81 mL, 4.7 mmol) and thiomorpholine (244 muL, 2.6 mmol) in dichloromethane (5 mL) was added to the mixture, which was then stirred at 0 C. for 45 minutes. The cooling bath was removed, and the mixture was allowed to warm to room temperature. Ethyl acetate and saturated aqueous sodium chloride solution were added, and the layers were separated. The organic phase was washed once each with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to a residue, which was then purified by flash chromatography (silica gel) to provide the desired intermediate. LCMS-ESI- (m/z): [M-H]- calcd 383.04; found 383.18

Reference： [1]Patent: US2019/359565,2019,A1 .Location in patent: Paragraph 0619

84
[ 123-90-0 ]
[ 3476-89-9 ]
4,4'-(quinoxaline-2,6-diyl)bis(thiomorpholine) [ No CAS ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 15858 - 15862

85
[ 123-90-0 ]
[ 3939-13-7 ]
2-thiomorpholinopyridine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2020/14243,2020,A1 .Location in patent: Page/Page column 58-59

86
[ 123-90-0 ]
[ 587-03-1 ]
4-(3-methylbenzyl)thiomorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With bis(triphenylphosphine)carbonylmonohydrate ruthenium dichloride; In toluene; at 140℃; for 6h;	Dissolve <strong>[587-03-1]3-methylbenzyl alcohol</strong> (0.360g, 3mmol) and thiomorpholine (0.103g, 1mmol) in 1mL of toluene, and combine with 0.01mmol (7.4mg) of bis(triphenylphosphine) carbonyl monohydrate. Ruthenium chloride was added to the pressure tube together, and reacted at 140C for 6 hours. The obtained reaction solution was cooled to room temperature, desolvated, and purified by rapid preparative liquid chromatography (the volume ratio of ethyl acetate: petroleum ether was 5:100),The eluent containing the target compound is collected, and rotary steamed under reduced pressure to obtain 0.193 g of the compound represented by Formula 3, with a yield of 93% and a liquid phase purity of 99%.
93%	With bis(triphenylphosphine)carbonylmonohydrate ruthenium dichloride; In toluene; at 140℃; for 6h;	Dissolve <strong>[587-03-1]3-methylbenzyl alcohol</strong> (0.360g, 3mmol) and thiomorpholine (0.103g, 1mmol) in 1mL of toluene, and combine with 0.01mmol (7.4mg) of bis(triphenylphosphine) carbonyl monohydrate. Ruthenium chloride was added to the pressure tube together, and reacted at 140C for 6 hours. The obtained reaction solution was cooled to room temperature, desolventized, and purified by rapid preparative liquid chromatography (the volume ratio of ethyl acetate: petroleum ether was 5:100), the eluent containing the target compound was collected, and the mixture was evaporated under reduced pressure to obtain 0.193g formula The compound shown in 3 has a yield of 93% and a liquid phase purity of 99%.

Reference： [1]Organic and Biomolecular Chemistry,2021,vol. 19,p. 4478 - 4482
[2]Patent: CN113087684,2021,A .Location in patent: Paragraph 0097-0099
[3]Patent: CN113201020,2021,A .Location in patent: Paragraph 0100-0102

87
[ 123-90-0 ]
[ 341-41-3 ]
C₁₄H₁₄FNS [ No CAS ]

Reference： [1]Catalysis science and technology,2021,vol. 11,p. 5223 - 5231

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P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
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

[ CAS No. 123-90-0 ] {[proInfo.proName]}

Quality Control of [ 123-90-0 ]

Related Doc. of [ 123-90-0 ]

Product Details of [ 123-90-0 ]

Calculated chemistry of [ 123-90-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

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Application In Synthesis of [ 123-90-0 ]

[ 123-90-0 ] Synthesis Path-Upstream 1~11

[ 123-90-0 ] Synthesis Path-Downstream 1~87

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Thiomorpholines

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Prevention

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[ 123-90-0 ]