[ CAS No. 39093-93-1 ] {[proInfo.proName]}

Name: 39093-93-1|Thiomorpholine 1,1-dioxide|95%
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Quality Control of [ 39093-93-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 39093-93-1 ]

Product Details of [ 39093-93-1 ]

CAS No. :	39093-93-1	MDL No. :	MFCD05861623
Formula :	C₄H₉NO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NDOVLWQBFFJETK-UHFFFAOYSA-N
M.W :	135.18	Pubchem ID :	6484228
Synonyms :

Calculated chemistry of [ 39093-93-1 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	34.91
TPSA :	54.55 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) :	-7.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.79
Log Po/w (XLOGP3) :	-1.05
Log Po/w (WLOGP) :	-0.3
Log Po/w (MLOGP) :	-0.89
Log Po/w (SILICOS-IT) :	0.41
Consensus Log Po/w :	-0.21

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.02
Solubility :	130.0 mg/ml ; 0.962 mol/l
Class :	Very soluble
Log S (Ali) :	0.39
Solubility :	334.0 mg/ml ; 2.47 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.93
Solubility :	15.7 mg/ml ; 0.116 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.94

Safety of [ 39093-93-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 39093-93-1 ]

* 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 [ 39093-93-1 ]
Downstream synthetic route of [ 39093-93-1 ]

[ 39093-93-1 ] Synthesis Path-Upstream 1~11

1
[ 215791-95-0 ]
[ 39093-93-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With trifluoroacetic acid In dichloromethane at 25℃; for 5 h;	To the solution of 11 (5.8g, 0.024mol) in 22 DCM (50mL) was added 21 trifluoroacetic acid (70mL). The resulted mixture stirred for 5hat 25°C until completion of the reaction by TLC. Then the resulted mixture was concentrated under reduced pressure. 13 Water (30mL) was added and the mixture basified to PH 8.0 with ammonia solution, then the misture was extracted three times with DCM(50mL×3). The organic extracts were combined, washed with water and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to yield 6h as a white solid in 82percent yield. MS (ESI) m/z(percent): 136.0 [M+H]⁺.

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258
[2] Patent: US2006/100426, 2006, A1, . Location in patent: Page/Page column 17
[3] Patent: US2006/135764, 2006, A1, . Location in patent: Page/Page column 21
[4] Patent: US2006/100236, 2006, A1, . Location in patent: Page/Page column 19
[5] Patent: US2006/199839, 2006, A1, . Location in patent: Page/Page column 21
[6] Patent: WO2005/80389, 2005, A1, . Location in patent: Page/Page column 35

2
[ 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

3
[ 220655-09-4 ]
[ 39093-93-1 ]

Reference： [1] Patent: EP1522540, 2005, A1, . Location in patent: Page/Page column 70

4
[ 107-61-9 ]
[ 39093-93-1 ]

Reference： [1] Monatshefte fuer Chemie, 1981, vol. 112, p. 643 - 657

5
[ 5967-90-8 ]
[ 39093-93-1 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 913 - 923

6
[ 123-90-0 ]
[ 39213-13-3 ]
[ 39093-93-1 ]

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

7
[ 17688-68-5 ]
[ 39093-93-1 ]

Reference： [1] Journal of the Chemical Society, 1949, p. 3433,3439

8
[ 39093-93-1 ]
[ 540-51-2 ]
[ 26475-62-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: With potassium carbonate In acetonitrile at 20℃; for 0.5 h; Stage #2: Reflux	To a stirred solution of 2-bromoethan-l-ol (11.78 mL, 165.92 mmol, 7.0 eq) in acetonitrile (68 ml) was added potassium carbonate (9.8 g, 71.10 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added thiomorpholine 1,1- dioxide (3.2 g, 23.70 mmol, 1.0 eq). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to get crude residue which was purified by column chromatography by using 3percent MeOH in DCM as an eluent to afford the desired compound (2.5 g, yield: 60.0percent) as a brown colour liquid. 1H NMR (DMSO-d₆, 300 MHz): δ 4.50 (t, 1H), 3.51 (q, 2H), 3.07 (m, 4H), 2.95 (m, 4H) and 2.58 (t, 2H); Mass: [M+H]⁺180.19 (10percent).

Reference： [1] Patent: WO2017/149518, 2017, A1, . Location in patent: Page/Page column 24; 25

9
[ 39093-93-1 ]
[ 37595-74-7 ]
[ 456-64-4 ]

Reference： [1] Russian Journal of Organic Chemistry, 2003, vol. 39, # 8, p. 1180 - 1182

10
[ 39093-93-1 ]
[ 1159600-32-4 ]
[ 1159600-41-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1 h; Stage #2: With dmap; triethylamine In tetrahydrofuranReflux	Example 4 Preparation of Form A 700.0 g of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (Ex. 1 step f), 10 L of THF and 469.0 g of 1,1-carbodiimidazol were stirred at ambient temperature for one hour. 407.0 g of thiomorpholine-S,S-dioxide, 12.0 g of 4-dimethylaminopyridine and 340 mL of triethylamine p.a. were added successively and refluxed under stirring over two nights. Additional 82.0 g of thiomorpholine-S,S-dioxide and 68.0 mL of triethylamine p.a. were added and further refluxed under stirring overnight (o.n.). The experiment was cooled down to approx. 30° C. 10 L of desalinated water and 16 L of ethanol were added successively. The emerging solution was cooled down to 20° C., seeded with 12 g of Form A and stirred at ambient temperature for 30 min. The suspension was reduced to 16 L at max. 35° C. In order to replace THF, 20 L of ethanol were added. The suspension was stirred at ambient temperature o.n. and then filtrated. The filter cake was rinsed with 7.4 L of a 1:1 desalinated water/ethanol mixture and dried at 50° C. o.n. yielding 820 g of Form A (86percent).
55%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h;	To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 μ.) were added 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), Ν,Ν-diisopropyl ethyl amine (171 μ, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 μ, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (73 mg, 55percent) as a white solid. MS: m/e = 446.1 [M+H]⁺.
55%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h;	Step g: crystalline (U-dioxo-1 6-thiomorpholin-4-yl)-{6-r3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxyl-pyridin-3-yl\|-methanone in anhydrous polymorphic form A (Form A ({drug4a})) To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 µ) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 µl, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 µl, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (73 mg, 55percent) as a white solid. MS: m/e = 446.1 [M+H]+.

Reference： [1] Patent: US2013/172329, 2013, A1, . Location in patent: Paragraph 0251
[2] Patent: WO2013/57124, 2013, A1, . Location in patent: Page/Page column 34
[3] Patent: EP2792360, 2014, A1, . Location in patent: Paragraph 0168

11
[ 39093-93-1 ]
[ 1206163-59-8 ]
[ 1206161-97-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With diisopropylamine In methanol; dichloromethane at 20℃; for 16 h; Inert atmosphere	The starting material [5-(4-bromomethyl-phenyl)- l ,2,4]triazolo[l ,5-a]pyridine-2- yl] amide (1 g; 2.7 mmol leq) and diisopropylamine (0.92 raL; 5.4 mmol 2eq) were dissolved in a methanol/ dichloromethane mixture (1 :5; 1.7 mL/8.5 mL) and stirred under N₂ at room temperature for 10 minutes. Thiomorpholine dioxide (0.4 g; 3 mmol 1.1 eq) was added. The yellow solution was stirred at room temperature for 16 hours. The solvent was evaporated. The compound was dissolved in dichloromethane (80 mL), washed with water (30 mL) and dried over MgS0₄ (~5min). MgS0₄ was filtrated off and the product solution was evaporated, yielding a white solid raw product (1.09 g, 95percent oftheory).
92%	With N-ethyl-N,N-diisopropylamine In methanol; dichloromethane at 23℃;	[5-(4-bromomethyl-phenyl)-l,2,4]triazolo[l,5-a]pyridine-2-yl] amide (9 g; 24 mmol) was dissolved in a mixture of methanol (15 ml) and dichloromethane (75 ml). Diisopropylethylamine (8.25 ml; 48.5 mmol) was added. Thiomorpholine dioxide (3.61 g; 26.7 mmol) was added in one portion. The mixture was stirred over night at 23°C. After completion of the reaction the solvent was evaporated. The grey compound was suspended in a mixture of ethyl acetate (100 ml) and methanol (10 ml) and stirred for 2 hours at 23°C. The product was filtered dried under vacuum at 17 mbar and 50°C for 3 hours. Yield: 9.53 g (92percent of theory) purity (HPLC/UV, method A, 98.6percent t_r= 2.2 min, λ=230 nm): 1H-NMR (400 MHz, DMSO-rf₆) 0.74 - 0.86 (m, 4 H) 2.01 (br. s„ 1 H) 2.91 (s, 4 H) [δ ppm] 3.10 - 3.15 (m, 4 H) 3.75 (s, 2 H) 7.27 (dd, J=6.26, 1.56 Hz, 1 H)7.50 (d, J=8.21 Hz, 2 H) 7.65 - 7.71 (ni, 2 H) 7.97 (d, J=8.21 Hz, 2 H) 11.02 (br. s., 1 H) FT-IR (ATR) [cm^{" 1}] 3288, 3230, 3188, 3088, 3057, 3003 , 2935, 2843, 2820, 1699, 1635 , 1576, 1552, 1525 , 1495, 1398, 1369, 1333, 1321 , 1298, 1269, 1215, 1186, 1 157 , 1 126, 1 1 13, 1084, 1053, 1038, 1020, 978, 962, 941 , 891 , 862, 854, 822, 779, 729, 677, 656, 631 , 625, 615 XRPD 1 ^st priority reflections 7. 1 , 8.1 , 10.8, 18.4, 27.3°2Θ 2^nd priority reflections 14.2, 16.2, 17.2, 19.8 , 25.2°2Θ DSC endotherms (onset T) :214°C; 319°C (br.) residual solvent content 0.5.-2percent (dichloromethane)

Reference： [1] Patent: WO2017/12773, 2017, A1, . Location in patent: Page/Page column 25; 26; 27; 28; 29
[2] Patent: WO2017/12771, 2017, A1, . Location in patent: Page/Page column 33-34
[3] Patent: US2010/331319, 2010, A1, . Location in patent: Page/Page column 13-14
[4] Patent: US2010/331319, 2010, A1, . Location in patent: Page/Page column 14-15
[5] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[6] Patent: US2015/224199, 2015, A1, . Location in patent: Paragraph 0287-0288
[7] Patent: US2015/225398, 2015, A1, . Location in patent: Paragraph 0278; 0279
[8] Patent: WO2016/165952, 2016, A1, . Location in patent: Paragraph 0172

[ 39093-93-1 ] Synthesis Path-Downstream 1~88

1
[ 19975-56-5 ]
[ 39093-93-1 ]
[ 59801-81-9 ]

Reference： [1]Indian Journal of Chemistry,1975,vol. 13,p. 1262 - 1266

2
[ 107-61-9 ]
[ 39093-93-1 ]

Reference： [1]Monatshefte fur Chemie,1981,vol. 112,p. 643 - 657

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
[ 39093-93-1 ]
[ 37595-74-7 ]
[ 456-64-4 ]
4-(trifluoromethanesulfonyl)-1λ⁶,4-thiazinane-1,1-dione [ No CAS ]
1,1-dioxo-1λ⁶,4-thiazinan-4-ium trifluoromethanesulfonate [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2003,vol. 39,p. 1180 - 1182

5
benzyl 4-thiomorpholine-carboxylate 1,1-dioxide [ No CAS ]
[ 39093-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In 1,4-dioxane; methanol; at 20℃; under 2584.17 Torr; for 4h;	To a solution of benzyl 4-thiomorpholinecarboxylate 1,1-dioxide (3.8 g) in methanol (32mL) and 1,4-dioxane (8mL) was added Palladium, 10 wt. percent on activated carbon (380 mg) at ambient temperature. The mixture was stirred at ambient temperature for 4 hours underH2 (3.4 atom). The mixture was filtered and evaporated in vacuo to give thiomorpholine 1,1-dioxide as a colorless solid (2.22 g). thiomorpholine 1,1-dioxide 'H NMR (300 MHz,CDCl3) delta 3.03 (4H, t,J = 5 Hz), 3.33 (4H, t, J = 5 Hz). MS (m/z) 136 (M+H).

Reference： [1]Patent: WO2004/63197,2004,A1 .Location in patent: Page 251-252

6
[ 39093-93-1 ]
[ 666853-92-5 ]
[ 666853-77-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;	A mixture of 143 (0.558 g; 2.54 mmol), thiomorpholine-l, l-dioxide (0.516 g; 3.82 mmol), EDCI (0.585 g; 3.05 mmol) and HOBT (0.344 g; 2.54 mmol) in methylene chloride (10 ml) was stirred at room temperature under argon atmosphere for 24 hours. The crude mixture was dissolved in ethyl acetate and washed with a 2 N [NAOH] solution. The organic layer was dried on magnesium sulphate, evaporated and purified by flash chromatography eluting with a gradient [5-10percent] of 3.5 N NH3 in MeOH/methylene chloride to give 144 as an oil. Yield: 82percent [1H] NMR [(CDC13)] : 1.43 (m, 1H); 2.13 (m, 1H) ; 2.27 (m, 1H); 2.48 (m, [3H)] ; 2.66 (m, 3H); 2.99 (m, 4H); 3.54 (d, J = 13 Hz, 1H) ; 3.62 (d, J = 13 Hz, 1H); 3.92 (m, 2H); 4.07 (m, [2H)] ; 7.26 (m, 2H); 7.30 (m, 3H).

Reference： [1]Patent: WO2004/18480,2004,A1 .Location in patent: Page 185

7
[ 39093-93-1 ]
[ 24424-99-5 ]
[ 215791-95-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In tetrahydrofuran; at 20℃;	<strong>[39093-93-1]Thiomorpholine 1,1-dioxide</strong> (2.00 g, 14.8 mmol) was dissolved in THF (20 mL) at 0 °C. Di-tert-butyl dicarbonate (3.55 g, 16.3 mmol) was added, followed by triethylamine (4.12 mL, 29.6 mmol). The resulting mixture was stirred at room temperature overnight. It was diluted with EtOAc and washed with brine. The organic layer was dried over MgS04 and concentrated. The crude residue obtained was subjected to purification on the ISCO using an 80 g column and eluting with 0-70percent EtOAc/hexanes (5percent KMnCn aq. was used in staining the TLC plates). The appropriate fractions were combined and concentrated to obtain (3.46 g, 99percent) of the title compound. NMR (400MHz, CDCh) delta 4.00 - 3.89 (m, 4H), 3.06 - 2.97 (m, 4H), 1.51 (s, 10H)
91.6%	With triethylamine; In dichloromethane; at 0 - 20℃; for 10h;	tert-Butyl thiomorpholine-4-carboxylate (1.91 g, 9.42 mmol) was dissolved in dichloromethane (50 ml); m-chloroperbenzoic acid (5.0 g, 19 mmol) was gradually added while cooled with ice bath, stirred, and under nitrogen atmosphere; and the reaction mixture was stirred at room temperature for 12 hours. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was kept stirred for a while; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylamine (8.1 ml, 58 mmol) were added to the obtained crystals; 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 obtained crystals were suspended with a solvent mixture of diethyl ether: ethanol = 10: 1, filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (2.03 g, 8.63 mmol, 91.6percent). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 1.40 (9H, s), 3.09 (4H, t, J=5.2 Hz), 3.72 (4H, t, J=5.2 Hz).

Reference： [1]Patent: WO2016/183118,2016,A1 .Location in patent: Page/Page column 319; 320
[2]Patent: EP1522540,2005,A1 .Location in patent: Page/Page column 70

8
[ 215791-95-0 ]
[ 39093-93-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With trifluoroacetic acid; In dichloromethane; at 25℃; for 5h;	To the solution of 11 (5.8g, 0.024mol) in 22 DCM (50mL) was added 21 trifluoroacetic acid (70mL). The resulted mixture stirred for 5hat 25C until completion of the reaction by TLC. Then the resulted mixture was concentrated under reduced pressure. 13 Water (30mL) was added and the mixture basified to PH 8.0 with ammonia solution, then the misture was extracted three times with DCM(50mL×3). The organic extracts were combined, washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to yield 6h as a white solid in 82% yield. MS (ESI) m/z(%): 136.0 [M+H]+.
	With trifluoroacetic acid; In dichloromethane;	Thiomorpholine-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.
	With trifluoroacetic acid; In dichloromethane;	Thiomorpholine-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.

	With trifluoroacetic acid; In dichloromethane;	Thiomorpholine-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.
	With trifluoroacetic acid; In dichloromethane;	Thiomorpholine-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.
	With trifluoroacetic acid; In dichloromethane;	Preparation of secondary amines; Thiomorpholine-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.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 158,p. 247 - 258
[2]Patent: US2006/100426,2006,A1 .Location in patent: Page/Page column 17
[3]Patent: US2006/135764,2006,A1 .Location in patent: Page/Page column 21
[4]Patent: US2006/100236,2006,A1 .Location in patent: Page/Page column 19
[5]Patent: US2006/199839,2006,A1 .Location in patent: Page/Page column 21
[6]Patent: WO2005/80389,2005,A1 .Location in patent: Page/Page column 35
[7]European Journal of Medicinal Chemistry,2020,vol. 185

9
[ 39093-93-1 ]
5-tert-butyl-2-(3-(4-(pyridin-4-yloxy)phenyl)ureido)thiophene-3-carboxylic acid [ No CAS ]
1-(5-tert-butyl-3-(thiomorpholine-1,1-dioxide-4-carbonyl)thiophen-2-yl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 16h;	Example 5; l-(5-tert-Butyl-3-(thiomorpholine-l,l-dioxide-4-carbonyl)thiophen-2-yl)-3-(4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea [0228] To a solution of 6-tert-butyl-l/f-thieno[2,3-cTj[l,3]oxazine-2,4-dione (3.7 g, 15 mmol) in dioxane (30 mL) was added 4-(4-aminophenoxy)-N-methylpicolinamide (3.4 g, 14 mmol), and the reaction mixture was heated at 90 0C for 4 h. The volatiles were evaporated under reduced pressure to give the crude product which was used in the next step without further purification. EPO <DP n="55"/>[0229] To a solution of 5-tert-butyl-2-(3-(4-(rhoyridin-4-yloxy)rhohenyl)ureido)thiorhohene-3- carboxylic acid (ca 14 mmol) in THF (70 mL) were added thiomorpholine 1,1 -dioxide (2.27 g, 16.8 mmol, 1.2 eq), HOBt (2.08 g, 15,4 mmol, 1.1 eq), EDCI (3.22 g, 16.8 mmol, 1.2 eq), and the mixture was stirred at room temperature for 16 h. The volatiles were evaporated under reduced pressure to give the crude product which was extracted with saturated sodium bicarbonate (3 x 40 mL) and ethyl acetate (150 mL). The organic layer was dried and diluted with ethanol (40 mL). Upon concentration of the solution using rotary evaporator, precipitation of solid occurred. The solid was digested with ethanol (70 mL), filtered, washed with ethanol to give the product which was dried under vacuum at 70 0C for 24 h. (yield = 7.2 g, 82percent). 1H NMR (400 MHz, DMSOd6) delta 9.89 (s, IH), 9.63 (s, IH), 8.73 (m, IH), 8.47 (d, J = 6.8 Hz, IH), 7.54 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 2.8 Hz, IH), 7.13 (d, J = 8.8 Hz, 2H), 7.11 (m, IHO, 6.65 (s, IH), 3.93 (m, 4H), 3.27 (m, 4H), 2.75 (d, J = 5.2 Hz3 3H), 1.30 (s, 9H).

Reference： [1]Patent: WO2006/62984,2006,A2 .Location in patent: Page/Page column 52-53

10
[ 39093-93-1 ]
[ 628-11-5 ]
1,1-dioxo-1λ<SP>6</SP>-thiomorpholine-4-carboxylic acid 3-chloropropyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 0.166667h;	c. Preparation of 1,1-dioxo-1lambda6-thiomorpholine-4-carboxylic acid 3-chloropropyl ester In a 500 mL flask, thiomorpholine dioxide (13.5 g, 100 mmol) was dissolved in dichloromethane (150 mL) at room temperature and N,N-diisopropylethylamine (19.2 mL, 110 mmol) was added. After stirring at room temperature for 10 min, the reaction mixture was cooled in an ice bath to approximately 5° C. To the reaction mixture, was added 1-chloro-3-chloromethoxypropane (11.8 mL, 100 mmol) via addition funnel at a rate which maintained the reaction temperature below 10° C. When the addition was complete, the reaction mixture was allowed to warm to room temperature. The reaction mixture was washed with water (2*100 mL), and the organic phase dried over anhydrous sodium sulfate (25 g). After filtration, the solvent was removed by distillation to yield the title compound as an oily solid that solidified upon standing (24.0 g, 94percent yield).

Reference： [1]Patent: US2007/117796,2007,A1 .Location in patent: Page/Page column 19-20

11
[ 39093-93-1 ]
[ 938081-53-9 ]
(1,1-dioxo-1λ6-thiomorpholin-4-yl)-(5-hydroxy-1-isopropyl-1H-indol-2-yl)-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;	Example 1 Step 3: (1,1-Dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone A mixture of 5-(1-isopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid, hydrochloric salt with one equivalent of lithium chloride (650 mg, 1.0 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurunium tetrafluoroborate (563 mg, 1.2 eq.), thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201) and diisopropylethylamine (1.22 mL, 5 eq.) in dimethylformamide was stirred at room temperature for 24 h and then partitioned between an aqueous solution of sodium hydrogenocarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, evaporated in vacuo and purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 468 mg (66percent) of the desired product as off-white solid. MS (m/e): 502.5 (MH+, 100percent). ; Example20 Step 4: (1,1-Dioxo-1lambda6-thiomorpholin-4-yl)-(5-hydroxy-1-isopropyl-1H-indol-2-yl)-methanone In analogy to the procedure described for the synthesis of example 1, step 3, the title compound was synthesised from 5-Hydroxy-1-isopropyl-1H-indole-2-carboxylic acid (Example 20, step 3) and thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201). The desired product was obtained in a yield of 75percent as white solid. MS (m/e): 335.5 (M-H, 100percent).

Reference： [1]Patent: US2007/123526,2007,A1 .Location in patent: Page/Page column 14; 17

12
[ 39093-93-1 ]
[ 51693-17-5 ]
(5S)-5-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 150℃; for 6.25h;Microwave irradiation;	Diisopropylethylamine (1.19 g, 9.19 mmol, 1.5 eq) and [(2S)-5-oxopyrrolidin-2- yljmethyl 4-methylbenzenesulfonate al3 (2.48 g, 9.19 mmol, 1.5 eq) are added to a solution of thiomorpholine 1,1-dioxide (1.24 g at 66 % of purity, 6.07 mmol, 1 eq) in acetonitrile (14 ml). The mixture is heated under microwave irradiation at 150 0C for 6.25 hours. The residue is then taken up in water and extracted with dichloromethane (3 x 50 ml). The organic layers are washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 0.45 g of yellow solid. The aqueous phase is then brought to pH ~ 12 with sodium hydroxide (pellets) and extracted with dichloromethane (3 x 40 ml). The organics layers are washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford another batch of 0.85 g of an orange oil. The two residues are combined and purified by chromatography over silicagel (dichloromethane/methanol/ammonia 96/4/0.4) to afford 0.24 g of (5S)-5-[(l,l- dioxidothiomophiholin-4-yl)methyl]pyrrolidin-2-one a96. Yield: 17 %. LC-MS (MH+): 233.

Reference： [1]Patent: WO2007/48595,2007,A1 .Location in patent: Page/Page column 74

13
[ 39093-93-1 ]
[ 402-13-1 ]
[ 943976-18-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	[0266] To a solution of <strong>[402-13-1]2-amino-4-(trifluoromethyl)benzoic acid</strong> (410 mg, 2 mmol) inDCM (5 mL) were added thiomorpholine 1,1 -dioxide (405 mg, 3 mmol), HOBt (340 mg, 2.5 mmol), EDCI (479 mg, 2.5 mmol), and the mixture was stirred at room temperature for 16 h. The volatiles were evaporated under reduced pressure to give the crude product which was extracted twice with ethyl acetate/aq NaHCO3. The organic layer was dried, concentrated, and the residue was used as such in the next step (yield = 580 mg).

Reference： [1]Patent: WO2007/81690,2007,A2 .Location in patent: Page/Page column 54

14
[ 39093-93-1 ]
[ 874959-68-9 ]
[ 1089669-61-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 2h;	5-Bromo-2-pyridinesulfonyl chloride (1 g, 3.899mmol), thiomorpholine 1 ,1-dioxide (0.633g, 4.678 mmol) and DIPEA (0.756g, 5.849mmol) were dissolved in DCM (30ml) and the reaction occurred at room temperature for 2 h. The mixture was taken into a separating funnel and submitted to an extraction using a saturated solution of sodium carbonate (50ml) and a mixture of DCM/EtOAc (1 :1 , 150ml). The organic phase was recovered, passed through a phase separator and the solvent evaporated. The aqueous phase was extracted with DCM:EtOAc (250ml) to extract more product. Both the extractions were combined to obtain the title compound (1.278g). MH+ = 356/354, rt = 2.35 min

Reference： [1]Patent: WO2008/145688,2008,A2 .Location in patent: Page/Page column 113

15
[ 39093-93-1 ]
[ 79055-52-0 ]
[ 952443-67-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine; at 135℃; for 27.0h;	(1) A mixture of <strong>[79055-52-0]2,4-dibromo-6-methylpyridine</strong> (0.50 g), thiomorpholine 1,1-dioxide (0.32 g), N,N-diisopropylethylamine (0.70 mL), and N-methylpyrrolidone (2.0 mL) was stirred at 135C for 27 h. The reaction mixture was cooled to room temperature, followed by addition of water, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate = 1:1 - ethyl acetate) to obtain 4-(2-bromo-6-methylpyridin-4-yl)thiomorpholine 1,1-oxide (0.11 g).

Reference： [1]Patent: EP2003131,2008,A1 .Location in patent: Page/Page column 42

16
[ 39093-93-1 ]
[ 32315-10-9 ]
[ 39093-77-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	In acetonitrile; at 20℃;Cooling with ice; Inert atmosphere;	To the acetonitrile (7.4 mL) solution of <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (0.500 g, 3.70 mmol) in ice-cold condition, triphosgene (1.10 g, 3.70 mmol) was added under an argon gas atmosphere , and the mixture was stirred overnight at room temperature. Hexane was added to the reaction solution and a solid obtained by concentration is sonicated. The solid was collected by filtration, washed with hexane, and dried under reduced pressure,The title compound was obtained (white solid, 0.731 g, 3.70 mmol, quantitative).
96%	With triethylamine; In tetrahydrofuran; at 20℃;Inert atmosphere;	Step 1: preparation of compound 15-2: To a solution of compound 15-1 (541 mg, 4.0 mmol) and Et3N (1.21 g, 12.0 mmol) in THF (20.0 mL), a solution of triphosgene (1.42 g, 4.8 mmol) in THF (5.0 mL) was added dropwise. After the mixture was stirred at rt o.n., water was added and it was extracted with EtOAc. The organic layer was combined and washed with brine, dried over Na2S04, filtered. Solvent was removed and the residue was purified by column chromatography to give a white solid (760 mg, yield: 96percent). HNMR (400 MHz, DMSO- 6) ^ 4.23 (m, 2H), 4.08-4.14 (m, 2H), 3.39-3.48 (m, 1H), 3.13-3.15 (m, 4H), 1.18-1.27 (m, 2H).
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;	A) 1,1-Dioxo-thiomorpholine-4-carbonyl Chloride To a solution of <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (0.181 g, 0.00105 mol) in dry THF (5 mL) was added DIPEA (0.3 mL, 0.00191 mol) at 0° C. To the resulting mixture was added triphosgene (0.11 g, 0.00037 mol) and the mixture was stirred for 2 h at ambient temperature.

Reference： [1]Patent: JP5829520,2015,B2 .Location in patent: Paragraph 0110
[2]Patent: WO2013/113669,2013,A1 .Location in patent: Page/Page column 92-93
[3]Patent: US2009/118259,2009,A1 .Location in patent: Page/Page column 46

17
[ 39093-93-1 ]
[ 1159600-25-5 ]
[ 1159600-29-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	Example 24 {6-[3-(3-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-methanone To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) in DMF (300 muL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 muL, 1.0 mmol) and thiomorpholine-S,S-dioxide (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (80 mg, 87percent) which was obtained as a white solid. MS: m/e=462.1 [M+H]+.
87%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	Example 24 {6-[3-(3-?1iota1thetaGammatheta-rho1?6etagamma1)-5^6?1iotagamma1-?8thetaChi3zetaomicron1-4-gamma^6?1iotaomicronchigamma]-rhogammapi??eta-3-gamma1}-(1,1-??omicronchiomicron-1lambda6- thiomorpholin-4-yl)-methanone To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) in DMF (300 L) were added 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), Nu,Nu-diisopropyl ethyl amine (171 muL, 1.0 mmol) and thiomorpholine-S,S-dioxide (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (80 mg, 87percent) which was obtained as a white solid. MS: m/e = 462.1 [M+H]+.

Reference： [1]Patent: US2013/102778,2013,A1 .Location in patent: Paragraph 0276; 0277
[2]Patent: WO2013/57123,2013,A1 .Location in patent: Page/Page column 49; 50

18
[ 39093-93-1 ]
[ 1159600-32-4 ]
[ 1159600-41-5 ]

Yield	Reaction Conditions	Operation in experiment
86%		Example 4 Preparation of Form A 700.0 g of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (Ex. 1 step f), 10 L of THF and 469.0 g of 1,1-carbodiimidazol were stirred at ambient temperature for one hour. 407.0 g of thiomorpholine-S,S-dioxide, 12.0 g of 4-dimethylaminopyridine and 340 mL of triethylamine p.a. were added successively and refluxed under stirring over two nights. Additional 82.0 g of thiomorpholine-S,S-dioxide and 68.0 mL of triethylamine p.a. were added and further refluxed under stirring overnight (o.n.). The experiment was cooled down to approx. 30 C. 10 L of desalinated water and 16 L of ethanol were added successively. The emerging solution was cooled down to 20 C., seeded with 12 g of Form A and stirred at ambient temperature for 30 min. The suspension was reduced to 16 L at max. 35 C. In order to replace THF, 20 L of ethanol were added. The suspension was stirred at ambient temperature o.n. and then filtrated. The filter cake was rinsed with 7.4 L of a 1:1 desalinated water/ethanol mixture and dried at 50 C. o.n. yielding 820 g of Form A (86%).
55%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 mu.) were added 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), Nu,Nu-diisopropyl ethyl amine (171 mu, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 mu, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (73 mg, 55%) as a white solid. MS: m/e = 446.1 [M+H]+.
55%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	Step g: crystalline (U-dioxo-1 6-thiomorpholin-4-yl)-{6-r3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxyl-pyridin-3-yl\|-methanone in anhydrous polymorphic form A (Form A ({drug4a})) To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 mu) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 mul, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 mul, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (73 mg, 55%) as a white solid. MS: m/e = 446.1 [M+H]+.

Reference： [1]Patent: US2013/172329,2013,A1 .Location in patent: Paragraph 0251
[2]Patent: WO2013/57124,2013,A1 .Location in patent: Page/Page column 34
[3]Patent: EP2792360,2014,A1 .Location in patent: Paragraph 0168
[4]Patent: WO2019/46300,2019,A1 .Location in patent: Paragraph 0065

19
[ 39093-93-1 ]
[ 589-15-1 ]
4-[(4-bromophenyl)methyl]-1,4-thiazinane 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran; at 20℃; for 18h;	To a solution of 4-bromobenzylbromide (625 mg, 2.5 mmol) in THF (12 mL) was added thiomorpholine-1,1-dioxide in one portion (400 mg, 3.0 mmol). The resulting mixture was stirred at rt for 18 h whereupon a white ppt formed. The solvent was removed underreduced pressure to give a residue that was dissolved in DCM and sequentially washedwith NaHCO3 (aq. Sat.) (40 mL), water (40 mL) and brine (40 mL), before finally passing through a phase separator cartridge (Biotage). Removal of the organic extracts in vacuo afforded the title compound as a white solid (755 mg, 2.5 mmol, 99percent).
74%	With triethylamine; In tetrahydrofuran; at 20℃; for 16h;	A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL,6.0 mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (1.09 g, 8.0 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.90 g, 74percent). 1H NMR (CDCl3, 300MHz): 7.50-7.44 (m, 2H), 7.22-7.16 (m, 2H), 3.60 (s, 2H), 3.09-3.02 (m, 4H), 3.00-2.94 (m, 4H).
50.9%	With triethylamine; In tetrahydrofuran; at 20℃; for 15h;	To a mixture of 1-bromo-4- (bromomethyl) benzene (500 mg, 2.00 mmol) and thiomorpholine 1, 1-dioxide (513 mg, 2.99 mmol) was added THF (10 mL) and triethylamine (0.84 mL) in turn. After the mixture was stirred at rt for 15 h, the raw materail was consumed monitored by TLC. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaCl (50 mL) three times. The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 3/1 to give a white solid product (310 mg, 50.9) .[0893]MS (ESI, pos. ion) m/z: 304.1 [M+1]+ and[0894]1H NMR (400 MHz, CDCl3) : delta (ppm) 7.46 (d, J 8.4 Hz, 2H) , 7.19 (d, J 8.4 Hz, 2H) , 3.59 (s, 2H) , 3.07-3.05 (m, 4H) , 2.98-2.95 (m, 4H)

47%		A mixture of <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (270 mg, 2.0 mmol) in DMF (10 ml) was prepared at room temperature and sodium hydride (60 wtpercent in oil, 96 mg, 2.40 mmol) added in one portion and the mixture stirred at room temperature for 1h. 1-Bromo-4-(bromomethyl)benzene was then added in one portion and the mixture stirred overnight for 17.5 h under argon. The mixture was then quenched with saturated aqueous ammonium chloride solution (10 ml) and diluted with ethyl acetate (30 ml). The mixture was partitioned and the aqueous layer removed. The organic layers were then washed with 5percent aqueous lithium chloride solution (2x 10 ml), brine (10 ml), dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was then purified by column (0-5percent methanol/dichloromethane) to afford 4-(4- bromobenzyl)<strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> as a colourless solid (283 mg, 0.93 mmol,47percent). 1H NMR (500 MHz; CDCl3) delta 2.98 (brs, 4H), 3.06 (brs, 4H), 3.60 (5, 2H), 7.20 (d, 2H, J 8.1 Hz), 7.47 (d, 2H, J= 8.3 Hz) ppm.Purity by LCMS (UV Chromatogram, 190-450nm) 95percent, rt = 5.0 min m/z 306 (M+H)+
47%		Preparation 14 4-(4-bromobenzyl)<strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> A mixture of <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (270 mg, 2.0 mmol) in DMF (10 ml) was prepared at room temperature and sodium hydride (60 wt percent in oil, 96 mg, 2.40 mmol) added in one portion and the mixture stirred at room temperature for 1 h. 1-Bromo-4-(bromomethyl)benzene was then added in one portion and the mixture stirred overnight for 17.5 h under argon. The mixture was then quenched with saturated aqueous ammonium chloride solution (10 ml) and diluted with ethyl acetate (30 ml). The mixture was partitioned and the aqueous layer removed. The organic layers were then washed with 5percent aqueous lithium chloride solution (2*10 ml), brine (10 ml), dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was then purified by column (0-5percent methanol/dichloromethane) to afford 4-(4-bromobenzyl)<strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> as a colourless solid (283 mg, 0.93 mmol, 47percent). 1H NMR (500 MHz; CDCl3) delta 2.98 (brs, 4H), 3.06 (brs, 4H), 3.60 (s, 2H), 7.20 (d, 2H, J=8.1 Hz), 7.47 (d, 2H, J=8.3 Hz) ppm. Purity by LCMS (UV Chromatogram, 190-450 nm) 95percent, rt=5.0 min, m/z 306 (M+H)+

Reference： [1]Patent: WO2017/93544,2017,A1 .Location in patent: Page/Page column 85
[2]Patent: CN110627775,2019,A .Location in patent: Paragraph 0354-0357
[3]Patent: WO2009/151598,2009,A1 .Location in patent: Page/Page column 150
[4]Patent: WO2016/615,2016,A1 .Location in patent: Paragraph 00510
[5]Patent: WO2013/153357,2013,A1 .Location in patent: Page/Page column 46; 47
[6]Patent: US2015/45354,2015,A1 .Location in patent: Paragraph 0286-0289

20
[ 39093-93-1 ]
[ 1028854-31-0 ]
[ 1028854-00-3 ]

Yield	Reaction Conditions	Operation in experiment
54%	With N-ethyl-N,N-diisopropylamine;dmap; In N,N-dimethyl-formamide; at 60℃;	The above acteyl chloride (1.122 g; 3.27 mmol) was dissolved in 10 mL DMF. <strong>[39093-93-1]Thiomorpholine 1,1-dioxide</strong> (0.442 g; 3.27 mmol) was added followed by DIPEA (0.63 mL; 3.6 mol) and DMAP (16 mg; 0.131 mmol). The reaction mixture was heated in a 60° C. oil bath overnight. Water was added to the reaction mixture, and it was extracted with EtOAc three times. The organics were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The yellow residue obtained was purified by flash column chromatography on silica gel using 2.5percent methanol in DCM mixture as eluent then switched to 5percent methanol in DCM. The title compound was obtained in >95percent purity (HPLC) as a white foam (781 mg; 54percent yield).

Reference： [1]Patent: US2010/9964,2010,A1 .Location in patent: Page/Page column 19

21
[ 39093-93-1 ]
[ 1082068-88-9 ]
[ 1082068-92-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With dmap; In acetonitrile; for 12h;	B. Synthesis of 5?-O-DMT-3?-O-[methyl-(N,N-diisopropyl)]-phosphoramidite-2?-O-thiomorpholino-1, 1-dioxidethionocarbamateuridine. 3?-5?-tetraisopropyldisiloxane Uridine (ChemeGenes), 10 mmol, 4.8 grams was dissolved in 100mls of anhydrous acetonitril in a 500 ml roundbottom flask fitted with a serum stopper. To the reaction 1.9 grams of1, 1?-thiocarbonyldiimidazole (Aldrich) was added with 0.2 grams of 4-(dimethyl)aminopyridine. The reaction washeated using a heat gun and stirred until the reagents had dissolved and the solution was clear. The reaction wasallowed to stir overnight (12 hours). After 12 hours, the reaction mixture was a slurry of crystals. The crystals wereisolated by filtration through a medium sintered glass funnel. The product was washed with cold acetonitrile anddried under vacuum. TLC analysis confirmed that the product was a single species giving 5.97 grams of product(100percent) ESI-Q-TOF mass spectroscopy analysis confirmed the product as the 5?,3?-O-(tetraisopropyldisiloxane-1,3-diyl)-2?-thionoimidazole with a mass of M+1, 598.12 m/e. The product was redissolved in 100 ml of anhydrousacetonitrile by heating using a heat gun. To the reaction was added 11 mmol of thiomorpholine-1, 1-dioxide (TCIAmerica) and 1.1 mmol of 4-(dimethyl)aminopyridine. The reaction was stoppered and stirred for 12 hours. After 12hours, the reaction mixture was a slurry of crystals. The crystals were isolated by filtration through a medium sinteredglass funnel. The product was washed with cold acetonitrile and dried under vacuum. TLC analysis confirmed thatthe product was a single species giving 6.61 grams of product (99percent). ESI-Q-TOF mass spectroscopy analysisconfirmed the product as the 5?,3?-O-(tetraisopropyldisiloxane-1, 3-diyl)-2?-O-thiomorpholino-1, 1-dioxidethionocarbamatewith a mass of M+1, 664.21 m/e. Hydrogen fluoride-pyridine complex (HF:Py 7:3, 7 mL) was carefully toice-cold solution of pyridine (8 mL) in acetonitrile (46.5 mL). The pyridine-HF reagent so formed (32 mL) was thentransferred to the flask with 5?, 3?-O-(tetraisopropyldisiloxane-1,3-diyl)- 2?-O-thiomorpholino-1, 1-dioxidethionocarbamateprotected uridine (10 mmole), and the mixture was stirred at room temperature for 2 hours. The reactionwas quenched with 5percent solution of calcium chloride in water (300 mL). Crude product was extracted with EtOAc(3-5 times), and dried with anhydrous Na2SO4. After filtration organic layer was concentrated to a viscous oil giving3.4 grams (80percent yield) of product shown as a single spot by TLC with a confirmed identity of the 2?-O-thiomorpholino-1, 1-dioxidethionocarbamate protected uridine by ESI-Q-TOF mass spectroscopy with a mass of M+ 1, 422.10 m/e.2?-O-thiomorpholino-1, 1-dioxidethionocarbamate protected uridine (8.0 mmole) was redissolved in anhydrous THF(80 mL), 2,4,6-collidine (60 mmole) and dimethoxytrityl chloride (10.0 mmole) were added, and the mixture wasstirred at room temperature until TLC (CHCl3/MeOH 9:1) showed full disappearance of nucleoside substrate (16-24hours). 2,4,6-Collidine (8.0 mmole) and 1-methylimidazole (4.0 mmole) were added in one portion and N,N-diisopropylmethylphosphonamidicchloride (20 mmol) was added slowly to the reaction mixture over 10-15 minutes. Thereaction mixture was then stirred for another 2 hours. The solvent was removed in vacuo, and the crude productwas purified by column chromatography using hexanes with a gradient of EtOAc (0-50percent).
	In 2-methyltetrahydrofuran; at 20℃; for 2h;	3',5'-O-(Tetraisopropyldisiloxane-1,3-diyl)-2'-O-(1,1-dioxo-1lambda6-thiomorpholine-4-carbothioate)-uridine (8.9 g, 15 mmol) was dissolved in Me-THF (75 mL, 0.2 M) and thiomorpholine-1,1-dioxide (2.23 g, 16.5 mmol) was added. Reaction mixture was stirred for 2 h at ambient temperature. Hydrogen fluoride pyridine (HFxPy) (2.33 mL, 90 mmol) and pyridine (5.05 mL, 63 mmol) were added drop-wise. Reaction mixture might be cooled if warmed up. The mixture was stirred for 2.5 h at ambient temperature. The reaction mixture was extracted with water (75 mL). The aqueous phase was extracted with Me-THF (2.x.150 mL), organics were combined and dried (100 g Na2SO4), filtered and evaporated. Yield 6.3 g (100percent). Rf (TLC 10percent MeOH/DCM): 0.25.

Reference： [1]Patent: EP2476689,2015,B1 .Location in patent: Paragraph 0176
[2]Patent: US2010/76183,2010,A1 .Location in patent: Page/Page column 48-49
[3]Journal of the American Chemical Society,2011,vol. 133,p. 11540 - 11556

22
[ 39093-93-1 ]
[ 1246924-68-4 ]
[ 1246924-04-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;	g) (1,1-Dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone; To a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (250 mg, 0.73 mmol) in THF (6.6 mL) was added 1-hydroxybenzotriazole hydrate (113 mg, 0.73 mmol), N-ethyldiisopropylamine (317 ul, 1.82 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (142 mg, 0.73 mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (98.1 mg, 0.73 mmol). The reaction mixture was stirred overnight at room temperature. Evaporation of the mixture followed by chromatography (silica, dichloromethane:methanol=1:0 to 9:1) afforded the title compound (0.27 g, 80percent) as a white solid. MS: m/e=462.3 [M+H]+.

Reference： [1]Patent: US2010/256127,2010,A1 .Location in patent: Page/Page column 16

23
[ 39093-93-1 ]
[ 1246924-99-1 ]
(1,1-dioxo-thiomorpholin-4-yl)-{6-[3-(5-fluoro-pyridin-2-yl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	i) (1,1-Dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(5-fluoro-pyridin-2-yl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone; To a solution of 6-((3-(5-fluoropyridin-2-yl)-5-(hydroxymethyl)isoxazol-4-yl)methoxy)nicotinic acid (384 mg, 1.11 mmol) in DMF (10 mL) was added <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (165 mg, 1.22 mmol), N,N,N',N'-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (393 mg, 1.22 mmol) and N,N-diisopropyl ethylamine (0.95 mL, 5.56 mmol). The reaction mixture was stirred for 30 min at room temperature. After evaporation of the solvent the residue purified by chromatography (silica, ethylacetate:heptane=1:1 to 1:0) to afford the title compound (422 mg, 82percent) as a white solid. MS: m/e=463.2 [M+H]+.

Reference： [1]Patent: US2010/256127,2010,A1 .Location in patent: Page/Page column 34

24
[ 39093-93-1 ]
[ 1120334-24-8 ]
[ 1174672-67-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine; In dichloromethane; at 20℃; for 12h;	(Step 3)1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole (1.0 g, 2 mmol) obtained in Step 2 was dissolved in DCM (10 mL), and thereto Et3N (560 uL, 4 mmol) and 1,1-dioxo-thio-morpholine (300 mg, 3 mmol) were added. The mixture was stirred for 12 hours at room temperature. At the end of the reaction, added saturated aqueous NH4Cl solution, extracted with DCM. After drying the extract, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give 1-BOC-3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indole (825 mg, 78percent).

Reference： [1]Patent: US2010/291533,2010,A1 .Location in patent: Page/Page column 56

25
[ 39093-93-1 ]
[ 68162-47-0 ]
[ 747413-23-6 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of (4-bromomethylphenyl)boronic acid (2.00 g, 9.31 mmol), thiomorpholine 1,1-dioxide (1.50 g, 11.1 mmol) and potassium carbonate (2.60 g, 18.8 mmol) in acetone (25 mL, 340 mmol) was heated at 400C for 18 hours then cooled to room temperature. The volatiles were evaporated and the residue was suspended in saturated aqueous ammonium chloride (100 mL). The aqueous was decanted from the waxy solid and the solid was dissolved in methanol (50 mL), filtered to remove insoluble salts and evaporated. 4- [(4-boronophenyl)methyl] -thiomorpholine 1,1-dioxide was isolated as a tan foam. The crude material was used without further purification.

Reference： [1]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 179; 180

26
[ 39093-93-1 ]
[ 589-17-3 ]
4-[(4-bromophenyl)methyl]-1,4-thiazinane 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In acetone; at 20℃; for 48h;	To a well stirred suspension of thiomorpholine 1,1 -dioxide (0.36 g, 2.7 mmol) and potassium carbonate (0.37 g, 2.7 mmol) in acetone (5 mL) was added l-bromo-4- chloromethyl-benzene (0.50 g, 2.4 mmol). The mixture was stirred for 48 hours at room temperature. The mixture was filtered and the volatiles were evaporated. The residue was suspended in ether (100 mL), filtered and evaporated to a solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10percent - >;100percent ethyl acetate in hexane). 4-(4-Bromo-benzyl)-thiomorpholine 1,1- dioxide was isolated as a white solid (0.72 g, 97percent). 1H NMR (400 MHz, CDCl3, delta, ppm): 7.47 (d, J=7.6 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 3.60 (s, 2H), 3.08-2.94 (m, 8H). MS = 304, 306 (MH)+.

Reference： [1]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 209; 210

27
[ 39093-93-1 ]
[ 138500-85-3 ]
[ 1092563-25-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of 2-(4-(bromomethyl)phenyl)-4,4,5 ,5 -tetramethyl- 1,3,2-dioxaborolane (0.50 g, 1.68 mmol) in DMF (8 mL) were added K2C03 (0.58 g, 4.21mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (0.27 g, 2.02 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and washed with brine, dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as a white solid (0.53 g, 89%). ?H NMR(DMSO-d6) oe 7.65 (d, J= 8.1 Hz, 2 H), 7.35 (d, J= 7.9 Hz, 2 H), 3.68 (s, 2 H), 3.16 -3.01 (m, 4 H), 2.85 (dd, J 6.2, 4.0 Hz, 4 H), 1.29 (s, 12 H); MS(ESIj mlz 352.1 (M + H).
79.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	4-bromomethylphenylboronic acid pinacol ester (50.00 g, 16.84 mmol), 1,1-dioxide thiomorpholine(27.36 g, 20.24 mmol), potassium carbonate (27.92 g, 20.20 mmol) was added to a reaction flask, 250 mL of N,N-dimethylformamide was added, and the reaction was stirred at 80 C. for 4 hours. After cooling to room temperature, the reaction solution was poured into 1250 mL of ice water, stirred for 30 minutes, and the title product was collected by suction filtration. The white solid was 47.2 g, and the yield was 79.7%.
79.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	4-bromomethylboronic acid pinacol ester 50.00 g (16.84 mmol), 1,1-dioxide thiomorpholine 27.36 g (20.24 mmol), potassium carbonate 27.92 g (20.20 mmol) were added to the reaction flask,250ml of N,N-dimethylformamide was added and the reaction was stirred at 80C for 4h.After cooling to room temperature, the reaction solution was poured into 1250 ml of ice water, stirred for 30 minutes, and the title product was collected by suction filtration. The white solid was 47.2 g. The yield was 79.7%.

79.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	4-Bromomethylbenzeneboronic acid pinacol ester (5.0 g,1.68 mmol), 1,1-dioxide thiomorpholine 2.74 g (2.02 mmol), and potassium carbonate (2.79 g, 2.02 mmol) were added to a flask and added with DMF (25mL). The mixture was stirred at 80oC for 4 hours. The reaction mixture was cooled to rt., and poured into ice water (125 mL), and stirred for 30 min. The mixture was filtered to give 4.72 g of the title compound as white solid (yield of 79.7%).
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	Synthesis of the Compound of the Invention and Comparative ExamplesCompound 1 (the Compound of the Invention); Step 1: 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (2 eq) was added portionwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO4. Organic layers were filtered and evaporated. The final compound was isolated without further purification.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (2 eq) wasadded portion wise. The resulting solution was stirred at room temperature for 16h. After this time,the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAcand water, washed with brine and dried over anhydrous MgS04. Organic layers were filtered andevaporated. The final compound was isolated without further purification.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	Example 1. Preparation of Compound 1 1.1. Route 1 1.1.1. 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N2 and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (2 eq) is added portionwise. The resulting solution is stirred at room temperature for 16 h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO4. Organic layers are filtered and evaporated. The final compound is isolated without further purification.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	1.1.1. 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N2 and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (2 eq) is added portionwise. The resulting solution is stirred at room temperature for 16 h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO4. Organic layers are filtered and evaporated. The final compound is isolated without further purification.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	[0162] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5: 1 v:v) under N2 and thiomorpho line 1,1 -dioxide (2 eq) is added portionwise. The resulting solution is stirred at room temperature for 16 h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated without further purification.

Reference： [1]Patent: WO2015/77193,2015,A1 .Location in patent: Page/Page column 58
[2]Patent: CN107759587,2018,A .Location in patent: Paragraph 0220-0221
[3]Patent: CN107880038,2018,A .Location in patent: Paragraph 0164-0167
[4]Patent: EP3556761,2019,A1 .Location in patent: Paragraph 0221; 0222
[5]Patent: US2010/331319,2010,A1 .Location in patent: Page/Page column 13
[6]Patent: WO2013/189771,2013,A1 .Location in patent: Paragraph 00160
[7]Drugs of the Future,2014,vol. 39,p. 547 - 551
[8]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342
[9]Patent: US2015/224199,2015,A1 .Location in patent: Paragraph 0273-0274
[10]Patent: US2015/225398,2015,A1 .Location in patent: Paragraph 0264; 0265
[11]Patent: WO2016/165952,2016,A1 .Location in patent: Paragraph 0162

28
[ 39093-93-1 ]
[ 1206163-59-8 ]
[ 1206161-97-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	The starting material [5-(4-bromomethyl-phenyl)- l ,2,4]triazolo[l ,5-a]pyridine-2- yl] amide (1 g; 2.7 mmol leq) and diisopropylamine (0.92 raL; 5.4 mmol 2eq) were dissolved in a methanol/ dichloromethane mixture (1 :5; 1.7 mL/8.5 mL) and stirred under N2 at room temperature for 10 minutes. Thiomorpholine dioxide (0.4 g; 3 mmol 1.1 eq) was added. The yellow solution was stirred at room temperature for 16 hours. The solvent was evaporated. The compound was dissolved in dichloromethane (80 mL), washed with water (30 mL) and dried over MgS04 (~5min). MgS04 was filtrated off and the product solution was evaporated, yielding a white solid raw product (1.09 g, 95% oftheory).
92%	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 23℃;	[5-(4-bromomethyl-phenyl)-l,2,4]triazolo[l,5-a]pyridine-2-yl] amide (9 g; 24 mmol) was dissolved in a mixture of methanol (15 ml) and dichloromethane (75 ml). Diisopropylethylamine (8.25 ml; 48.5 mmol) was added. Thiomorpholine dioxide (3.61 g; 26.7 mmol) was added in one portion. The mixture was stirred over night at 23C. After completion of the reaction the solvent was evaporated. The grey compound was suspended in a mixture of ethyl acetate (100 ml) and methanol (10 ml) and stirred for 2 hours at 23C. The product was filtered dried under vacuum at 17 mbar and 50C for 3 hours. Yield: 9.53 g (92% of theory) purity (HPLC/UV, method A, 98.6% tr= 2.2 min, lambda=230 nm): 1H-NMR (400 MHz, DMSO-rf6) 0.74 - 0.86 (m, 4 H) 2.01 (br. s? 1 H) 2.91 (s, 4 H) [delta ppm] 3.10 - 3.15 (m, 4 H) 3.75 (s, 2 H) 7.27 (dd, J=6.26, 1.56 Hz, 1 H)7.50 (d, J=8.21 Hz, 2 H) 7.65 - 7.71 (ni, 2 H) 7.97 (d, J=8.21 Hz, 2 H) 11.02 (br. s., 1 H) FT-IR (ATR) [cm" 1] 3288, 3230, 3188, 3088, 3057, 3003 , 2935, 2843, 2820, 1699, 1635 , 1576, 1552, 1525 , 1495, 1398, 1369, 1333, 1321 , 1298, 1269, 1215, 1186, 1 157 , 1 126, 1 1 13, 1084, 1053, 1038, 1020, 978, 962, 941 , 891 , 862, 854, 822, 779, 729, 677, 656, 631 , 625, 615 XRPD 1 st priority reflections 7. 1 , 8.1 , 10.8, 18.4, 27.32Theta 2nd priority reflections 14.2, 16.2, 17.2, 19.8 , 25.22Theta DSC endotherms (onset T) :214C; 319C (br.) residual solvent content 0.5.-2% (dichloromethane)
82.5%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	Compound 5 (60 g, 0.16 mol), thiomorpholine-1,1-dioxide (24 g, 0.18 mol),Potassium carbonate (44.6 g, 0.32 mol) and N,N-dimethylformamide (500 ml) were added to a reaction flask, heated to 80 C for 5 h, and the reaction was monitored by TLC.After cooling to room temperature, the reaction solution was slowly poured into 1500 ml of ice water, stirred for 20 minutes, filtered, and the filter cake was washed with methyl t-butyl ether and dried. Obtaining N-(5-(4-((1,1-dioxothiomorpholine)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine- 2-yl)cyclopropanecarboxamide in 56.7 g, yield 82.5%.

	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;Product distribution / selectivity;	STEP 2: Suzuki coupling 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90 C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	Step 3:; Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO4. Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	Step 3: Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16 h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO4. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	Step 310279] Cyclopropanecarboxylic acid [5-(4-bromomethyl- phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) are dissolved in DCMJMeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (1.1 eq) is added drop- wise. The resulting solution is stirred at room temperature for 16 h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous Mg504. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.
	With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;	[0172] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl]- amide (l eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5: 1 v:v) under N2 and thiomorpholine 1,1- dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.

Reference： [1]Patent: WO2017/12773,2017,A1 .Location in patent: Page/Page column 25; 26; 27; 28; 29
[2]Patent: WO2017/12771,2017,A1 .Location in patent: Page/Page column 33-34
[3]Patent: CN110204542,2019,A .Location in patent: Paragraph 0062-0064; 0073-0077
[4]Patent: US2010/331319,2010,A1 .Location in patent: Page/Page column 13-14
[5]Patent: US2010/331319,2010,A1 .Location in patent: Page/Page column 14-15
[6]Drugs of the Future,2014,vol. 39,p. 547 - 551
[7]Patent: US2015/224199,2015,A1 .Location in patent: Paragraph 0287-0288
[8]Patent: US2015/225398,2015,A1 .Location in patent: Paragraph 0278; 0279
[9]Patent: WO2016/165952,2016,A1 .Location in patent: Paragraph 0172

29
[ 39093-93-1 ]
[ 106-37-6 ]
[ 1093878-42-2 ]

Yield	Reaction Conditions	Operation in experiment
50%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃;Inert atmosphere;	Dissolved a mixture of 1 ,4-dibromobenzene (10.014 g, 42.4 mmol) and thiomorpholine 1,1- dioxide (5.16 g, 38.2 mmol) in dioxane (150 mL), then added Pd(OAc)2 (959 mg, 4.24 mmol), BINAP (racemic) (2.64 g, 4.24 mmol), and Cs2C03 (41.48 g, 127 mmol). The reaction mixture was degassed several times then connected to a reflux condensor under nitrogen and heated to 100 °C for overnight. The reaction was cooled to RT then filtered through celite, and washed with EtOAc. The resulting solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (0-50percent EtOAc in hexanes) to yield 6.45 g (50percent) of the desired 4-(4-Bromophenyl)thiomorpholine 1 , 1 -dioxideas a light yellow solid. MS(ES,m/z):292.1 (M + 1).
50%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃;Inert atmosphere;	Dissolved a mixture of 1,4-dibromobenzene (10.0 14 g, 42.4 mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (5.16 g, 38.2 mmol) in dioxane (150 mL), then added Pd(OAc)2 (959 mg, 4.24 mmol), BNAP (racemic) (2.64 g, 4.24 mmol), and Cs2CO3 (41.48 g, 127 mmol). The reaction mixture was degassed several times then connected to a reflux condensor under nitrogen andheated to 100 °C for overnight. The reaction was cooled to RT then filtered through celite, and washed with EtOAc. The resulting solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (0-50percent EtOAc in hexanes) to yield 6.45 g (50percent) of the desired 4-(4-Bromophenyl)<strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> as a light yellow solid. MS (ES, m/z): 292.1 (M + 1).
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃;	A mixture of 1 ,4-dibromobenzene (118 mg, 0.5 mmol), thiomorpholine- 1,1 -dioxide (68 mg, 0.5 mmol), Pd2dba3 (12 mg, 2.5molpercent), BINAP (24 mg, 7.5 molpercent), sodium 2-methylpropan-2-olate (72 mg,0.75 mmol) and toluene (2 mL) was stirred at 800C for overnight. The reaction mixture was cooled down to room temperature and worked-up. The residue was purified on slilica gel flash column chromatography(eluent: 0-50percent EtOAc in hexane) to afford 4-(4-bromophenyl)thiomorpholine- 1,1 -dioxide as a white solid.

With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃;Inert atmosphere;

Dissolved a mixture of 1 ,4-dibromobenzene (10.014 g, 42.4 mmol) and thiomorpholine 1 ,1 - dioxide (5.16 g, 38.2 mmol) in dioxane (150 mL), then added Pd(OAc)2 (959 mg, 4.24 mmol), BINAP (racemic) (2.64 g, 4.24 mmol), and CS2CO3 (41.48 g, 127 mmol). The reaction mixture was degassed several times then connected to a reflux condensor under nitrogen and heated to 100 °C for overnight. The reaction was cooled to RT then filtered through celite, and washed with EtOAc. The resulting solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (0-50percent EtOAc in hexanes) to yield the desired 4-(4-Bromophenyl)thiomorpholine 1 ,1 -dioxide as a light yellow solid. MS (ES, m/z): 292.1 (M + 1).

Reference： [1]Patent: WO2015/51479,2015,A1 .Location in patent: Page/Page column 53
[2]Patent: WO2015/54038,2015,A1 .Location in patent: Page/Page column 47
[3]Patent: WO2011/14795,2011,A2 .Location in patent: Page/Page column 91
[4]Patent: WO2015/123089,2015,A1 .Location in patent: Page/Page column 48-49

30
[ 39093-93-1 ]
isopropyl 4-((1r,4r)-4-(5-bromopyrazin-2-yloxy)cyclohexyloxy)piperidine-1-carboxylate [ No CAS ]
isopropyl 4-((1r,4r)-4-(5-(1,1-dioxo-thiomorpholin-4-yl)pyrazin-2-yloxy)cyclohexyloxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.1%	With sodium t-butanolate;1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; at 100℃; for 1h;microwave irradiation;	A mixture isopropyl 4-((lr,4r)-4-(5-chloropyrazin-2-yloxy)cyclohexyloxy)piperidine-l- carboxylate (50 mg, 0.126 mmol), diacetoxypalladium (2.8 mg, 0.013 mmol), thiomorpholine- 1 ,1-dioxide (17 mg, 0.126 mmol), sodium 2-methylpropan-2-olate (29 mg, 0.302 mmol), and l ,l'-3/4w(di-t-butylphosphino)ferrocene (12 mg, 0.025 mmol) in 1 ,4-dioxane (0.8 mL) was heated at 100 °C for 1 h under microwave irradiation. LCMS showed product had formed and no starting material remained. Water was added to the reaction mixture and it was extracted with DCM (3 x 15 mL). The organic layer was rinsed with brine, dried with Na2S04 and concentrated to give a brown oil. The brown oil was purified using Biotage.(TM). flash chromatography and a 25 g SNAP.(TM). column, 20-100percent EtOAc-hexanes, 15 column volumes. Fractions containing product were combined and concentrated to give the title compound (25 mg, 0.050 mmol, 40.1 percent yield) as a light brown solid. 'H NMR (CDCI3 , 400 MHz) delta 1.23 (d, J = 4 Hz, 6H), 1.46-1.55 (m, 6H), 1.77-1.82 (m, 2H), 1.96-2.01 (m, 2H), 2.09-2.14 (m, 2H), 3.06 (t, J = 4Hz , 4H), 3.09-3.16 (m, 2H), 3.48-3.52 (m, 1H), 3.54-3.59 (m, 1H), 3.78-3.84 (m, 2H), 4.06 (t, J = 4Hz , 4H), 4.85-4.94 (m, 2H), 7.73 (s, 1H), 7.82 (s, 1H), LCMS m/z: 497.6 [M+H]+.

Reference： [1]Patent: WO2011/127051,2011,A1 .Location in patent: Page/Page column 176

31
[ 39093-93-1 ]
[ 885267-36-7 ]
[ 1228660-62-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7350 - 7362

32
[ 39093-93-1 ]
[ 590-17-0 ]
[ 79207-43-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In acetonitrile; at 60℃; for 16h;	Step 1: (1,1-Dioxidothiomorpholin-4-yl)acetonitrile; 2.66 g (19.3 mmol) of potassium carbonate were added to a solution of 1.74 g (12.8 mmol) of <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> [E. S. Lazer et al., J. Med. Chem. 2007, 37 (7), 913-923] and 1.69 g (14.1 mmol) of bromoacetonitrile in 30 ml of acetonitrile, and the mixture was stirred for 16 h at 60° C. After cooling, precipitated salts were filtered off and the filtrate was evaporated to dryness on a rotary evaporator. The residue obtained was purified by MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 1:1). 2.03 g (91percent of theory) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 3.61 (s, 2H), 3.13 (s, 8H).MS (DCI, NH3): m/z=192 [M+NH4]+.GC/MS (method I, EIpos): Rt=6.66 min, m/z=174 [M]+.

Reference： [1]Patent: US2011/312930,2011,A1 .Location in patent: Page/Page column 65

33
[ 39093-93-1 ]
[ 1351666-99-3 ]
1-(5-tert-butyl-3-(1,1-dioxothiomorpholine-4-carbonyl)thiophen-2-yl)-3-(naphthalen-1-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 27h;	General procedure: To a vial containing a solution of urea acid, 8a, (369.7 mg, 1 mmol), EDCI (230.8 mg, 1.2 mmol) and HOBt (147.6 mg, 1.1 mmol) in 1:1 DCM:N,N-dimethylformamide (DMF; 10 mL) was added 1,1-dioxothiomorpholine (133.1 mg, 1 mmol). The vial was capped, and the solution was stirred at room temperature for 27 h. The reaction mixture was diluted with EtOAc and washed with water (x3) and brine (x1). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica flash column using 97:3 DCM:MeOH gave 401.0 mg (82percent) of 13a as a white solid. 1H NMR (400 MHz, acetone-d6): delta 10.03 (s, 1H), 9.23 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.49-7.41 (m, 2H), 7.40-7.34 (m, 1H), 6.70 (s, 1H), 4.14-4.05 (m, 4H), 3.20 (t, J = 4.8 Hz, 4H), 1.30 (s, 9H). MS m/z (APCI+) Found (M+H): 486.2

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7155 - 7165

34
[ 39093-93-1 ]
5-tert-butyl-2-(3-naphthalen-2-ylureido)thiophene-3-carboxylic acid triethylamine [ No CAS ]
1-(5-tert-butyl-3-(1,1-dioxothiomorpholine-4-carbonyl)thiophen-2-yl)-3-(naphthalen-2-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 27h;	General procedure: To a vial containing a solution of urea acid, 8a, (369.7 mg, 1 mmol), EDCI (230.8 mg, 1.2 mmol) and HOBt (147.6 mg, 1.1 mmol) in 1:1 DCM:N,N-dimethylformamide (DMF; 10 mL) was added 1,1-dioxothiomorpholine (133.1 mg, 1 mmol). The vial was capped, and the solution was stirred at room temperature for 27 h. The reaction mixture was diluted with EtOAc and washed with water (x3) and brine (x1). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica flash column using 97:3 DCM:MeOH gave 401.0 mg (82percent) of 13a as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7155 - 7165

35
[ 39093-93-1 ]
[ 56256-14-5 ]
[ 1352620-97-3 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate Example Int09.074-bromo-3-methoxyphenyl)(1 , 1 -dioxidothiomorpholin-4-yl)methanoneTo a stirred suspension of <strong>[56256-14-5]4-bromo-3-methoxybenzoic acid</strong> (1.32 g) indichloromethane (14 mL) and DMF (0.5 mL) was added oxalyl chloride (0.87 g) at 0C. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. The residue was dissolved in THF (30 mL) and Hiinig Base (3.0 mL) and thiomorpholine 1 ,1 -dioxide (1.2 g) were added. The mixture was stirred at room temperature for 18 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate and methanol (10: 1 ). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum.Trituration of the residue with warm ethanol gave 1.8 g of the title compound.
		Intermediate Example Int09.074-bromo-3-methoxyphenyl)(1 , 1 -dioxidothiomorpholin-4-yl)methanoneTo a stirred suspension of <strong>[56256-14-5]4-bromo-3-methoxybenzoic acid</strong> (1.32 g) in DCM (14 mL) and DMF (0.5 mL) was added oxalyl chloride (0.87 g) at 0C. The mixture was stirred at r.t. for 1 h. The solvent was removed in vacuum. The residue was dissolved in THF (30 mL) and Hiinig Base (3.0 mL) and thiomorpholine 1 ,1 - dioxide (1.2 g) were added. The mixture was stirred at r.t. for 18 h. A half- saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate and methanol (10:1 ). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Trituration of the residue with warm ethanol gave 1.8 g of the title compound.

Reference： [1]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 114
[2]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 90

36
[ 39093-93-1 ]
[ 1256577-57-7 ]
[ 1256577-69-1 ]

Yield	Reaction Conditions	Operation in experiment
7%	With potassium phosphate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃;	Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 30 mg, 0.069 mmol) was dissolved in 1,4-dioxane (1 mL), added with <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (19 mg, 2 eq.), Pd2 (dba)3 (6.3 mg, 0.1 eq.), BINAP (8.6 mg, 0.2 eq.) and K3PO4 (29 mg, 2 eq.), and stirred at 100° C. overnight. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 2.1 mg, 7percent). 1H-NMR (270 MHz, DMSO-d6) delta: 8. 29 (1H, d, J=8.6 Hz), 8. 07 (1H, d, J=8. 9 Hz), 8.00 (1H, s), 7. 55 (1H, dd, J=8. 5, 1. 7 Hz), 7. 34 (1H, d, J=2. 0 Hz), 7. 15 (1H, dd, J=9.1, 2.7 Hz), 4. 01 (4H, s), 3. 16 (4H, s), 1. 77 (6H, s).LCMS: m/z 420 [M+H]+
	With potassium phosphate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃;	Production Example 4 Compound J7-4 9-(4-Isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile [0519] trifluoro-methane sulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 30 mg, 0.069 mmol) was dissolved in 1,4-dioxane (1 mL), added with <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (19 mg, 2 eq.), Pd2dba3 (6.3 mg, 0.1 eq.), BINAP (8.6 mg, 0.2 eq.) and K3PO4 (29 mg, 2 eq.), and stirred at 100° C. all night and all day. The reaction solution was poured into water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the Compound B2-10 (8-(1,1-dioxothiomorpholino)-6,6-dimethyl-11-oxo-6,11 dih dro-5H-benzo b carbazole-3-carbonitrile) (white powder, 2.1 mg, 7percent)), the title compound was synthesized from the Compound J6 and 1-isopropyl-piperazine. [0521] 1H-NMR (270 MHz, DMSO-d6) delta: 12.80 (1H, s), 8.33 (1H, d, J=7.6 Hz), 8.02 (1H, s), 7.66 (3H, m), 7.33 (1H, d, J=8.2 Hz), 3.21 (4H, br), 2.66 (5H, m), 1.72 (6H, s), 1.02 (6H, d, J=6.3 Hz). [0522] LCMS: m/z 413 [M+H]+ [0523] HPLC retention time: 1.38 minutes (analysis condition S)

Reference： [1]Patent: US2012/83488,2012,A1 .Location in patent: Page/Page column 63
[2]Patent: US2013/143877,2013,A1 .Location in patent: Paragraph 0519; 0520; 0521; 0522; 0523

37
[ 39093-93-1 ]
[ 1254319-51-1 ]
[ 1338478-37-7 ]

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

38
[ 39093-93-1 ]
[ 1380329-77-0 ]
[ 1380329-97-4 ]

Yield	Reaction Conditions	Operation in experiment
84.7%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 25 - 70℃; for 64h;Inert atmosphere;	Example 224-(1,1-Dioxo-thiomorpholine-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amideA mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 mumol), thiomorpholine-1,1-dioxide (44.8 mg, 331 mumol), diisopropylethylamine (145 mul, 828 mumol) and propylphosphonic anhydride (50percent in ethyl acetate, 407 mul, 690 mumol) in tetrahydrofurane (7.00 ml) is stirred for 4 hours at 70° C. and then for 60 hours at 25° C. under nitrogen atmosphere.The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution.The mixture is stirred for 20 minutes while a white solid precipitates.The solid is collected by filtration, washed with diethylether and dried affording 4-(1,1-dioxo-thiomorpholine-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (112 mg, 84.7percent) as a white solid. mp.: >250° C. MS: m/z=480.2 (M+H+).
84.7%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 25℃; for 60h;Inert atmosphere;	A mixture of l-methyl-5-(2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-ylcarbamoyl)-lH-pyrazole-4- carboxylic acid (100 mg, 276 muiotaetaomicron), thiomorpholine- 1,1 -dioxide (44.8 mg, 331 muiotaetaomicron) , diisopropylethylamine (145 mu, 828 mumol) and propylphosphonic anhydride (50percent in ethyl acetate, 407 mu, 690 muiotaetaomicron) in tetrahydrofurane (7.00 ml) is stirred for 4 hours at 70 °C and then for 60 hours at 25 °C under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-( 1 , 1 -dioxo-thiomorpholine-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-7-yl)-amide (112 mg, 84.7percent) as a white solid, mp.: > 250°C. MS: m/z= 480.2 (M+H+).

Reference： [1]Patent: US2012/142665,2012,A1 .Location in patent: Page/Page column 25
[2]Patent: WO2012/76430,2012,A1 .Location in patent: Page/Page column 69-70

39
[ 39093-93-1 ]
[ 23145-65-5 ]
[ 1400287-14-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In tetrahydrofuran; at 20℃;	Preparation 75: 4-(3-Methoxy-4-nitrobenzyl)thiomorpholine-1 ,1 -dioxide; [00245] Thiomorpholine 1 ,1 -dioxide (0.242g, 1 .788mmol) and triethylamine (0.19ml_, 1 .341 mmol) were added to a solution of 4-(bromomethyl)-2-methoxy-1 -nitrobenzene (Preparation 74, 0.22g, 0.894mmol) in THF (2.2ml_). The reaction mixture was stirred overnight at room temperature before being concentrated under reduced pressure and purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 90/10) to afford the title product as a white solid (242mg, 90percent). 1 H NMR (500 MHz, CDCI3): delta 3.00-3.04 (m, 4H), 3.09-3.12 (m, 4H), 3.71 (s, 2H), 3.98 (s, 3H), 7.01 (m, 1 H), 7.09 (m, 1 H), 7.84 (d, J = 8.2Hz, 1 H). LC (Method C)-MS (ESI, m/z) fR 2.03 min, 301 [(M+H+), 100percent].
90%	With triethylamine; In tetrahydrofuran; at 20℃;	Preparation 75 4-(3-Methoxy-4-nitrobenzyl)thiomorpholine-1,1-dioxide <strong>[39093-93-1]Thiomorpholine 1,1-dioxide</strong> (0.242 g, 1.788 mmol) and triethylamine (0.19 mL, 1.341 mmol) were added to a solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 74, 0.22 g, 0.894 mmol) in THF (2.2 mL). The reaction mixture was stirred overnight at room temperature before being concentrated under reduced pressure and purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 90/10) to afford the title product as a white solid (242 mg, 90percent). 1H NMR (500 MHz, CDCl3): delta 3.00-3.04 (m, 4H), 3.09-3.12 (m, 4H), 3.71 (s, 2H), 3.98 (s, 3H), 7.01 (m, 1H), 7.09 (m, 1H), 7.84 (d, J=8.2 Hz, 1H). LC (Method C)-MS (ESI, m/z) tR 2.03 min, 301 [(M+H+), 100percent].

Reference： [1]Patent: WO2012/123745,2012,A1 .Location in patent: Page/Page column 88
[2]Patent: US2013/345181,2013,A1 .Location in patent: Paragraph 0680

40
[ 39093-93-1 ]
[ 1041181-58-1 ]
[ 1413066-59-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium t-butanolate;bis(tri-t-butylphosphine)palladium(0); In toluene; at 80℃; for 1h;	Step 1. In a 25 mL round-bottomed flask, 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (420 mg, 1.19 mmol, Eq: 1.00) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (482 mg, 3.57 mmol) were combined with toluene (3 ml) to give a yellow solution. Bis(tri-tert-butylphosphine)palladium(0) (60.7 mg, 119 mumol) and sodium tert-butoxide (400 mg, 4.16 mmol, Eq: 3.5) were added. The reaction mixture was heated to 80° C. and stirred for 1 h. The reaction mixture was poured into 20 mL sat NaCl and extracted with EtOAc (3.x.20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20percent to 40percent EtOAc in hexanes) to give 6-(1,1-Dioxo-1lambda6-thiomorpholin-4-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (327 mg, 68percent) as a yellow oil that solidified as off white solid upon standing.

Reference： [1]Patent: US2012/295885,2012,A1 .Location in patent: Page/Page column 68

41
[ 39093-93-1 ]
[ 108-36-1 ]
[ 1380487-26-2 ]

Yield	Reaction Conditions	Operation in experiment
48.4%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 11h;Inert atmosphere;	Example 39Synthesis of 3-{3-[4-(1-Aminocyclobutyl)phenyl]-5-[3-(1,1-dioxidothiomorpholin-4-yl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine trihydrochloride Step 14-(3-Bromophenyl)<strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong>A mixture of 1,3-dibromobenzene (242 muL, 2.00 mmol), <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (270 mg, 2.00 mmol), Pd2(dba)3 (45.8 mg, 0.0500 mmol), rac-BINAP (96.3 mg, 0.150 mmol) and NaOtBu (231 mg, 2.40 mmol) in toluene was heated at 80° C. for 11 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=90:10-->80:20-->75:25) to afford desired product (281 mg, 48.4percent) as pale yellow solid.400 MHz 1H-NMR (CDCl3) delta: 7.16 (t, J=8.4 Hz, 1H), 7.07-7.02 (m, 2H), 6.85-6.80 (m, 1H), 3.95-3.76 (m, 4H), 3.20-3.02 (m, 4H).
90 mg	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 18h;Inert atmosphere;	1,3-dibromobenzene (1.6g, 6.81mmol),thiomorpholine dioxide (300mg, 2.22mmol) BINAP (300mg, 0.48mmol), cesium carbonate (2.5g, 23.67mmol) and palladiumacetate (150mg) were dissolved in 10mL dry toluene in a 50mL single-neck flask. The reaction solution washeated to 90°C under argon atmosphere and stirred for 18 hours. After completion of the reaction, the reaction solutionwas filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by columnchromatography to give 90mg product, which was directly used in the next step.

Reference： [1]Patent: US2012/329791,2012,A1 .Location in patent: Page/Page column 81
[2]Patent: EP3424928,2019,A1 .Location in patent: Paragraph 0497

42
[ 39093-93-1 ]
[ 1417190-42-1 ]
[ 534-17-8 ]
[ 564483-18-7 ]
[ 1417183-87-9 ]

Yield	Reaction Conditions	Operation in experiment
	tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide;	Example 234 7-(1,1-Dioxothiomorpholin-4-yl)-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one A mixture of 7-bromo-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one from Example 20.1 (100 mg, 0.281 mmol), thiomorpholine 1,1-dioxide (76 mg, 0.561 mmol), CS2CO3 (183 mg, 0.561 mmol), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine (13.38 mg, 0.028 mmol) and Pd2(dba)3 (25.7 mg, 0.028 mmol) in DMF (2 mL) was heated to 100 C. for one hour in a microwave. The solvent was removed under reduced pressure, and the residue was purified by pre-HPLC to give the title compound (40 mg, 0.097 mmol, 34.7% yield) as white solid. LC-MS: m/z=411 (M+H+) Rt=1.66 min. 1H NMR (400 MHz, CDCl3): delta=8.06 (d, J=6.4 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.46-7.40 (m, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.79 (t, J=6.8 Hz, 1H), 4.32 (s, 2H), 4.03 (t, J=7.2 Hz, 2H), 3.76 (s, 4H), 3.36 (s, 4H), 3.19 (t, J=7.2 Hz, 2H).

Reference： [1]Patent: US2013/5705,2013,A1

43
[ 39093-93-1 ]
[ 6693-08-9 ]
[ 1431864-27-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3105 - 3110

44
[ 39093-93-1 ]
[ 598-21-0 ]
[ 887571-06-4 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium phosphate; In dichloromethane; at 0 - 20℃;Inert atmosphere;	A solution of MuomicronetaiotaomicronphiIotaiotaomicronGammaetaepsilon 1,1-dioxide (1.0 g, 7.40 mmol) in DCM (30 mL) was added dropwise over 20 min to a cooled (0 °C) and argon flushed mixture of 2-bromoacetyl bromide (970 \L, 11.10 mmol) and K3PO4 (3.93 g, 18.5 mmol) in DCM (20 mL) and the mixture was stirred at RT overnight. The reaction mixture was diluted with DCM (50 mL) and quenched with aq. 0.5 M HC1 (10 mL). Water (50 mL) and brine (50 mL) were added and the layers were separated. The aqueous layer was extracted with DCM (50 mL) and the combined organic layers were washed with aq. 10percent KHCO3 (100 mL) and brine (50 mL), dried over Na2S04(s) and concentrated to dryness. The residue was triturated with Et20 (50 mL) for 30 min. The solid material was filtered off, washed with some Et20 and dried under reduced pressure to afford 2-bromo-l-(l,l- dioxidothiomo holino)ethanone (1.20 g, 4.69 mmol, 63percent). LCMS: calculated for [M+H]+= 256.1/258.1, found 256.0/258.0.

Reference： [1]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1407 - 1413
[2]Patent: WO2019/12037,2019,A1 .Location in patent: Paragraph 0199; 0200; 0201

45
[ 39093-93-1 ]
[ 1449662-09-2 ]
[ 1449662-18-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With boron trifluoride diethyl etherate; In toluene; at 20℃; for 120h;Inert atmosphere;	Step 2 Preparation of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one (4.0 g, 8.85 mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (4.79 g, 35.4 mmol) in toluene (30 mL) was added boron trifluoride diethyl etherate (1 mL in 100 mL of toluene, 10 mL) forming a yellow suspension. The mixture was sonicated for 2 min, then stirred at RT for 5 days. The reaction mixture was diluted with EtOAc (200 mL), washed with NaHCO3 (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by a silica gel column (160 gm) eluted with 20-50percent of EtOAc/Hexane to give desired ketone (2.95 g, 57percent) as a solid. MS: m/e 587.5 (M+H)+, 2.39 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) delta 4.74-4.70 (m, 1H), 4.62-4.59 (m, 1H), 3.11-2.99 (m, 7H), 2.72-2.36 (m, H), 1.98-0.82 (m. 23H), 1.69 (s, 3H), 1.08 (s, 6H), 1.04 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).
57%	With boron trifluoride diethyl etherate; In toluene; at 20℃; for 120h;Sonication; Inert atmosphere;	To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one (4.0 g, 8.85 mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (4.79 g, 35.4 mmol) in toluene (30 mL) was added boron trifluoride diethyl etherate (1 mL in 100 mL of toluene, mL) forming a yellow suspension. The mixture was sonicated for 2 min, then stirred at RT for 5 days. The reaction mixture was diluted with EtOAc (200 mL), washed with NaHCO3 (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by a silica gel column (160 gm) eluted with 20-50percent of EtOAc/Hexane to give desired ketone (2.95 g, 57percent) as a solid. MS: m/e 587.5 (M+H)+, 2.39 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) delta 4.74-4.70 (m, 1H), 4.62-4.59 (m, 1H), 3.11-2.99 (m, 7H), 2.72-2.36 (m, H), 1.98-0.82 (m. 23H), 1.69 (s, 3H), 1.08 (s, 6H), 1.04 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).

Reference： [1]Patent: US2013/210787,2013,A1 .Location in patent: Paragraph 0315; 0317
[2]Patent: US2014/243298,2014,A1 .Location in patent: Paragraph 0234

46
[ 39093-93-1 ]
[ 51035-17-7 ]
(9H-carbazol-3-yl)(1,1-dioxothiomorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
119 mg	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;Cooling with ice; Inert atmosphere;	General procedure: Potassium hydroxide (3g, 53.47mmol) was added to a stirred solution of methyl ester 37 (818mg, 3.63mmol) in a mixture of ethanol (40mL) and water (10mL). The reaction mixture was stirred at reflux for 16h and then cooled to room temperature. The solvents were evaporated under reduced pressure, and the residue was diluted with DI water. Using external cooling (ice-bath), the solution was acidified to pH ca. 2 by dropwise addition of 1M aqueous HCl. The precipitated product was extracted with EtOAc (150mL). The organic layer was washed with brine under acidic pH, dried over MgSO4, and filtered. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by silica chromatography using 70% EtOAc in heptane to yield the title compound as a beige solid. Yield: 737mg (96%); mp 271C. The obtained <strong>[51035-17-7]9H-<strong>[51035-17-7]carbazole-3-carboxylic acid</strong></strong> (742mg, 3.51mmol), piperidine (416muL, 4.21mmol), DIPEA (966muL, 5.68mmol), and DMAP (43mg, 0.35mmol) were added to DCM (30mL) under nitrogen. The obtained solution was cooled down on an ice-water bath. EDAC (808mg, 4.21mmol) was added to the solution, and the reaction mixture was stirred for 16h while warming at room temperature. The solvent was removed in vacuo, and the obtained residue was extracted with EtOAc (150mL). The organic layer was washed consecutively with 5% citric acid solution (50mL×3), concentrated sodium bicarbonate (50mL×3), and brine (50mL). The organic phase was then dried (MgSO4), filtered, and concentrated in vacuo. The obtained residue was purified by column chromatography on silica gel eluting with EtOAc/heptanes in different proportions to give the title compound as a beige solid. Yield: 839mg (86%).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 69,p. 881 - 907

47
[ 39093-93-1 ]
2-bromo-1-(9-pentyl-9H-carbazol-3-yl)ethanone [ No CAS ]
1-(9-pentyl-9H-carbazol-3-yl)-2-(1,1-dioxo-thiomorpholino)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 0.0833333h;Inert atmosphere; Microwave irradiation;	General procedure: Under nitrogen atmosphere, a mixture of bromide 19 (208mg, 0.58mmol), piperidine (165muL, 1.67mmol), and triethylamine (234muL, 1.68mmol) in DMF (3mL) was subjected to microwave irradiation at 90°C for 5min. The mixture was allowed to cool to room temperature, and the organic solvents were evaporated in vacuo. The residue was purified on a Biotage® KP-NH cartridge (amino-modified silica gel) using cyclohexane/EtOAc in different proportions to afford to give the title compound as a clear yellowish oil (202mg, 100percent), which darkened on standing.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 69,p. 881 - 907

48
[ 39093-93-1 ]
[ 2486-71-7 ]
[ 1400287-09-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 10045 - 10065

49
[ 39093-93-1 ]
[ 39551-54-7 ]
[ 39551-64-9 ]

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

50
[ 39093-93-1 ]
[ 10397-13-4 ]
4-(6-chloro-2-morpholinopyrimidin-4-yl)thiomorpholine 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	In tetrahydrofuran; ethanol; at 100℃; for 42h;	Step 1. To a solution of <strong>[10397-13-4]4-(4,6-dichloropyrimidin-2-yl)morpholine</strong> (1.0 equiv.) in EtOH:THF (1:1, 0.25 M) was added thiomorpholine 1,1-dioxide (1.0 equiv.) in one portion. The resulting mixture was heated to 100 C. for 42 h. The resulting mixture was then cooled to RT and concentrated in vacuo to yield an off white solid in The reaction mixture was then concentrated in vacuo and dried under high vacuum over 20 h to yield 4-(6-chloropyrimidin-4-yl)morpholine as a white solid in 97% yield. LCMS (m/z) (M+H)=333.0/334.9, Rt=0.68 min.

Reference： [1]Patent: US2014/275003,2014,A1 .Location in patent: Paragraph 0264; 0265

51
[ 73290-22-9 ]
[ 39093-93-1 ]
4-(6-bromopyridin-3-yl)-1-thiomorpholine-1,1-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 20℃; for 96h;Inert atmosphere;	Step 1: 2-bromo-5-iodopyridine (1.24 g, 4.35 mmol), thiomorpholine-1,1-dioxide (882 mg, 6.53 mmol) and NaOtBu (1 .04 g, 10.87 mmol) were charged to a screw cap tube, dry toluene (25 mL) was added and the mixture was degassed by nitrogen bubbling for 5 mm. Then XantPhos (250 mg, 0.44 mmol) and Pd2(dba)3 (200 mg, 0.22 mmol) were incorporated and the tube was closed under nitrogen atmosphere. The reaction mixture was stirred at rt for 4 days. EtOAc and water were added. The phases were separated. The organic layer was dried over Mg504, filtered and the solution was concentrated to dryness. The crude material was absorbed on silica gel and purified by column chromatography eluting with CH2CI2 and a gradient of CH2CI2/MeOH from [100:0] to [95:5]. The product fractions were combined and concentrated to dryness to afford 4-(6-bromopyridin-3-yl)-1-thiomorpholine-1 ,1-dione Ex.36a (730 mg, 57percent) as yellow solid.
420 mg	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 20℃; for 96h;Inert atmosphere;	A mixture of 2-bromo-5-iodopyridine (1.0 g), <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (0.51 g), tris(dibenzylideneacetone)dipalladium(0) (0.11 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.20 g), sodium tert-butoxide (0.85 g) and toluene (30 mL) was stirred under argon atmosphere at room temperature for 4 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (420 mg). MS(ESI+): [M+H]+ 290.9.

Reference： [1]Patent: WO2018/138359,2018,A1 .Location in patent: Page/Page column 56
[2]Patent: US2016/159773,2016,A1 .Location in patent: Paragraph 1118-1120

52
[ 39093-93-1 ]
(1R,2R)-2-(4-(4-bromophenyl)-2-(4-fluorophenyl)oxazol-5-yl)-N-(1-cyanocyclopropyl)cyclohexanecarboxamide [ No CAS ]
(1R,2R)-N-(1-cyanocyclopropyl)-2-{4-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)phenyl]-2-(4-fluorophenyl)-1,3-oxazol-5-yl}cyclohexanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium phosphate monohydrate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In tetrahydrofuran; at 100℃; for 2h;Inert atmosphere;	Step-E: (1R,2R)?N-(1-Cyanocyclopropyl)-2-{4-[4-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)phenyl]-2-(4-fluorophenyl)-1,3-oxazol-5-yl}cyclohexanecarboxamide (Compound 7) [0274] To a mixture of (1R,2R)-2-(4-(4-bromophenyl)-2-(4-fluorophenyl)oxazol-5-yl)-N-(1-cyanocyclopropyl)cyclohexanecarboxamide (116 mg, 0.228 mmol), <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (93 mg, 0.685 mmol), Chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (8.43 mg, 0.011 mmol) and K3PO4.H2O (63.1 mg, 0.274 mmol) in a vial under an inert atmosphere was added THF (1.5 mL). The vial was sealed and heated at 100° C. for 2 h., cooled to rt and concentrated. The residue was taken in DMSO, filtered and the filtrate was subjected to reverse phase HPLC purification (Sunfire C18 30×150 mm column; 10 to 95percent MeCN in water. 0.1percent TFA modifier for MeCN and water). Desired fractions were partitioned between saturated aqueous sodium bicarbonate and dichloromethane. Layers were separated. Aqueous layer was extrated with dichloromethane (3×). Combined organic solutions were dried over Na2SO4 and concentrated to give desired product as a white solid (120 mg, 93percent). MS [M+H]+ 563.1. 1H NMR (400 MHz, CDCl3) delta 8.05-8.02 (m, 2H), 7.68-7.63 (m, 2H), 7.21-7.14 (m, 2H), 7.20-6.97 (m, 2H), 5.66 (s, 1H), 3.94-3.91 (m, 1H), 3.30-3.22 (m, 1H), 3.14-3.12 (m, 4H), 2.51-2.44 (m, 1H), 2.1-1.3 (m, 10H), 0.78-0.58 (m, 2H).

Reference： [1]Patent: US2015/99719,2015,A1 .Location in patent: Paragraph 0274

53
[ 39093-93-1 ]
[ 27996-87-8 ]
2-(1,1-dioxidothiomorpholino)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of 2?fluoro?5?nitrobenzaldehyde (2 g, 11.83mmol), thiomorpholine 1,1?dioxide (1.599 g, 11.83 mmol)and potassium carbonate (2.452 g, 17.74 mmol) inanhydrous DMF (10 mL) was heated to 50 °C under anitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (70 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washed with water, slurried in 1M HC1 solution (50 mL), isolatedby filtration, sucked dry and freeze?dried overnight to give the title compound as a yellow solid (2.68 g, 80percent) ?H NMR (300 MHz, DMSO?d6) : 5 10.11 (s, 1H), 8.54 (d, 1H), 8.34 (dd, 1H), 7.43 (d, 1H), 3.69?3.80 (m, 4H), 3.36?3.45 (m, 4H) . LCMS (Method C) : = 0.95 mi m/z = 285 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 286; 287

54
[ 39093-93-1 ]
2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-((S)-4-((benzyloxy)carbonyl)-4-(fluoromethyl)cyclohex-1-en-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)acetic acid trifluoroacetate [ No CAS ]
[ 76-05-1 ]
(S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)-2-oxoethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(fluoromethyl)cyclohex-3-enecarboxylate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		Step 1. Preparation of (S)-benzyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- ((2-( 1 , 1 -dioxidothiomorpholino)-2-oxoethyl)amino)-5 a,5b,8, 8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)-l-(fluoromethyl)cyclohex-3-enecarboxylate. In a 1 dram vial with PTFE lined screw cap were combined 2- (((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9-((S)-4-((benzyloxy)carbonyl)-4- (fluoromethyl)cyclohex- 1 -en- 1 -yl)-5a,5b, 8, 8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-3a-yl)amino)acetic acid, TFA (0.025 g, 0.030 mmol) with <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (10.20 mg, 0.075 mmol) and HATU (0.029 g, 0.075 mmol) in THF (1 mL). To the mixture was added DIPEA (0.026 mL, 0.151 mmol), and the resulting solution was agitated overnight at rt. The crude mixture was purified by reverse phase preparative HPLC (Prep HPLC Method 16) to give the product (0.0269 g, 94percent yield) as a white powder TFA salt. LCMS: m/z 831.5 (M+H)+, 2.50 min (method 1).

Reference： [1]Patent: WO2015/157483,2015,A1 .Location in patent: Page/Page column 159; 160

55
[ 39093-93-1 ]
[ 618-91-7 ]
[ 900015-34-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	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

56
[ 39093-93-1 ]
[ 4487-56-3 ]
4-(2-chloro-5-nitropyridin-4-yl)thiomorpholine 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;	Step A: 4-(2-Chloro-5-nitropyridin-4-vl)thiomorpholine 1,1-dioxide To a stirred solution of <strong>[4487-56-3]2,4-dichloro-5-nitropyridine</strong> (500 mg, 2.59 mmol) and thiomorpholine 1,1-dioxide (368 mg, 2.72 mmol) in DMF (5 mL) at 0 °C was added DIEA (1.35 mL, 7.77 mmol) and the resulting mixture was warmed to ambient temperature and stirred for 3 h. Water (10 mL) was added and the resulting precipitate was isolated by filtration, washing with water, and the solid was dried to give the title compound, which was used without further purification. MS: m/z = 292.0 (M + 1).

Reference： [1]Patent: WO2016/22644,2016,A1 .Location in patent: Page/Page column 100

57
[ 39093-93-1 ]
(E)-3-((1R,3aR,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)acrylic acid [ No CAS ]
tert-butyl 4-((1R,3aR,5aR,5bR,7aR,11aS,11bR,13aR,113bR)-3a-((E)-3-(1,1-dioxidothiomorpholino)-3-oxoprop-1-en-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1Hcyclopenta[a]chrysen-9-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	To a solution of (E)-3-((lR,3aR,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9-(4-(tert- butoxycarbonyl)phenyl)-5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-3a-yl)acrylic acid (100 mg, 0.16 mmol) and thiomorpholine 1,1- dioxide (25 mg, 0.19 mmol) in CH2CI2 (5 mL) was added DIPEA (0.14 mL, 0.78 mmol) followed by HATU (89 mg, 0.23 mmol). The solution was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified on silica gel to give the title compound (115 mg, 97percent) as a solid. MS: m/e 758.6 (M+H)+, 2.80 min (method 1). XH NMR (400MHz, CHLOROFORM-d) delta 7.89 (d, J=8.3 Hz, 2H), 7.29 (d, J=14.3 Hz, IH), 7.17 (d, J=8.3 Hz, 2H), 6.31 (d, J=15.6 Hz, IH), 5.28 (d, J=4.5 Hz, IH), 4.74 (s, IH), 4.64 (s, IH), 4.20 - 4.04 (m, 4H), 3.17 - 3.01 (m, 4H), 2.57 (dt, J=l l. l, 5.9 Hz, IH), 2.10 (dd, J=l 7.2, 6.4 Hz, IH), 1.96 - 0.85 (m, 21H), 1.72 (s, 3H), 1.60 (s, 9H), 1.03 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.92 (s, 6H).

Reference： [1]Patent: WO2016/77572,2016,A1 .Location in patent: Page/Page column 51-52

58
[ 39093-93-1 ]
tert-butyl 4-((1R,3aR,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-oxoethyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate [ No CAS ]
tert-butyl 4-((1R,3 aR,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(1,1-dioxidothiomorpholino)ethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		To a solution of tert-butyl 4-((lR,3aR,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-3a-(2-oxoethyl)-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.082 mmol) in DCE (2 mL) was added acetic acid (0.014 mL, 0.245 mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (25.4 mg, 0.188 mmol). The mixture became cloudy at first but turned into clear solution 10 min later. The mixture was stirred at RT for 2 hours. Sodium triacetoxyborohydride (86 mg, 0.408 mmol) was added, and the stirring was continued for 72 hours. The resulting mixture was diluted with saturated NaHCC (7 mL) and extracted with dichloromethane (3 x 7 mL). The combined organic layers were dried over anhydrous a2S04. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel column, eluted with mixtures of hexane/acetone first, followed by MeOH/CLkCh to afford the title compound as a white solid (50 mg, 83percent). MS: m/e 732.73 (M+H)+, 3.01 min (method 6). NMR (400MHz, CHLOROFORM-d) delta 7.93 - 7.83 (m, 2H), 7.23 - 7.09 (m, 2H), 5.30 - 5.25 (m, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.62 - 4.58 (m, 1H), 3.36 - 3.29 (m, 4H), 3.13 - 3.06 (m, 4H), 3.06 - 3.00 (m, 2H), 2.54 - 2.37 (m, 2H), 2.11 (dd, J=17.2, 6.4 Hz, 1H), 2.00 - 1.78 (m, 3H), 1.74 (m, 4H), 1.70 (s, 3H), 1.67 - 1.62 (m, 2H), 1.60 (s, 9H), 1.56 - 1.17 (m, 11H), 1.11 - 1.08 (m, 3H), 1.07 - 1.03 (m, 2H), 1.01 (s, 3H), 0.99 (s, 3H), 0.93 (s, 6H).

Reference： [1]Patent: WO2016/77572,2016,A1 .Location in patent: Page/Page column 70; 72-73

59
[ 39093-93-1 ]
[ 954-81-4 ]
N-(5-(1,1-dioxothiomorpholin-4-yl)pentyl)phthalimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 105℃; for 16h;	N-(5-bromopentyl)phthalimide (1.2g, 4mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (1.08g, 80mmol) and DIPEA (2ml, 11mmol) was added 10mL i-PrOH, the temperature was raised to 105 deg. C stirred for 16 hours. LCMS traced the reaction. After completion of the reaction it was concentrated, 50ml of water was added, sonicated, and filtered to give a white solid N-(5-(1,1-dioxothiomorpholin-4-yl)pentyl)phthalimide (1.0g, 97percent yield).

Reference： [1]Patent: CN105481778,2016,A .Location in patent: Paragraph 0156; 0157; 0158

60
[ 39093-93-1 ]
[ 463-71-8 ]
4-bromodeacetyl colchicine [ No CAS ]
4-bromo-N-(1,1-dioxothiomorpholine 4-yl-thiocarbonyl)deacetyl colchicine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.8%		4-bromodeacetyl colchicine (59 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Thiophosgene (0.011 mL, 0.14x1.05 mmol) and triethylamine (0.047 mL, 0.14x2.4 mmol) were added, and stirred at room temperature for 2 hours. Thiomorpholine-1,1-dioxide (38 mg, 0.14x2 mmol) was added, and stirred at room temperature overnight. The solvent was distilled off after the reaction. The residue was purified by Silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform/methanol) to obtain title compound (a yellow solid, 78 mg, 90.8percent) .

Reference： [1]Patent: JP5829520,2015,B2 .Location in patent: Paragraph 0309

61
[ 39093-93-1 ]
(S)-4-(1-(4-fluorophenyl)-2-methoxyethylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid [ No CAS ]
(S)-(1,1-dioxothiomorpholine){4-[1-(4-fluorophenyl)-2-methoxyethylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.4%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	A mixture of (S) - 4 - (1 - (4-fluoro-phenyl) - 2-methoxy-ethylamine) - 5-methyl-pyrrolo [2,1-f] [1, 2, 4] triazine-6-carboxylic acid (100 mg, 0 . 29mmol) and thiomorpholine -1,1-dioxide (58 mg, 0 . 44mmol) dissolved in N, N-dimethyl formamide (5 ml) in, then add 1-hydroxy benzotriazole (51 mg, 0 . 38mmol), 1-ethyl-3 - (3-dimethylamino-propyl) carbodiimide hydrochloride (74 mg, 0 . 38mmol) and triethylamine (88 mg, 0 . 87mmol), stirring the mixture at room temperature until the TLC reaction monitoring raw material the reaction is complete, to be added in to the reaction solution (100 ml), ethyl acetate (50 ml × 3) extraction, then by saturated sodium chloride solution (100 ml × 2) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, the resulting residue is purified with silica gel column chromatography, to obtain (S) - (1,1-dioxy thiophosphoro morphline) - {4 - [1 - (4-fluorophenyl) - 2-methoxy-ethylamine] - 5-methyl-pyrrolo [2,1-f] [1, 2, 4] triazin-6-yl}}-methyl ketone (105 mg, white solid), yield: 78.4percent.

Reference： [1]Patent: CN103848833,2016,B .Location in patent: Paragraph 0278; 0279; 0280

62
[ 39093-93-1 ]
(2S)-4-[(tert-butyldiphenylsilyl)oxy]-2-[[4-(4-fluorophenyl)phenyl]formamido]butanoic acid [ No CAS ]
N-[(2S)-4-[(tert-butyldiphenylsilyl)oxy]-1-oxo-1-(thiomorpholine-1,1-dioxide-4-yl)butan-2-yl]-4-(4-fluorophenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		Into a 250-mL round-bottom flask, was placed a solution of (2S)-4-[(tert-butyldiphenylsilyl)oxy]-2-[[4-(4-fluorophenyl)phenyl]formamido]butanoic acid (2 g, 3.60 mmol, 1.00 equiv) in tetrahydrofuran (50 mL), DEPBT (1.62 g, 5.41 mmol, 1.50 equiv). This was followed by the addition of imidazole (370 mg, 5.44 mmol, 1.50 equiv). stirred for 40 min at 0° C. To this was added a solution of thiomorpholine-1,1-dioxide (890 mg, 6.58 mmol, 1.50 equiv) in tetrahydrofuran (20 mL) dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred for 16 h at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2 g (82percent) of (1) as a off-white solid.

Reference： [1]Patent: US2016/237043,2016,A1 .Location in patent: Paragraph 0588; 0589

63
[ 39093-93-1 ]
[ 287714-35-6 ]
methyl 2-(1,1-dioxidothiomorpholin-4-yl)pyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With 4-methyl-morpholine; sodium carbonate; In water; at 100℃; for 20h;	55 mg of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.32 mmol) and 43 mg of thiomorpholine 1,1-dioxide (0.32 mmol) were initially charged in 1 ml of N-methylmorpholinone, and 40 mg of sodium carbonate (0.38 mmol) were added. The mixture was then stirred at 100 C. for 20 h. The mixture was stirred with water and the precipitated product was filtered off with suction and washed with water. This gave 62 mg (72% of theory) of the target compound. LC-MS [Method 1]: Rt=0.64 min; MS (ESIpos): m/z=272 (M+H)+

Reference： [1]Patent: US2016/318901,2016,A1 .Location in patent: Paragraph 0387; 0388; 0389

64
[ 39093-93-1 ]
[ 936342-91-5 ]
[ 1206641-02-2 ]

Yield	Reaction Conditions	Operation in experiment
81.8%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	5-bromo-2-chloromethyl-pyridine (486mg, 2mmol) and thiomorpholine 1,1-dioxide (406mg, 3mmol) was dissolved in N, N- dimethylformamide (10ml) and then potassium carbonate (986mg, 7mmol), the reaction was stirred for 12 hours at room temperature, 100ml of water was added to the reaction mixture was cooled, (100ml * 3) and extracted with ethyl acetate, then with saturated sodium chloride solution (100ml * 2), dried the organic phase was dried over anhydrous magnesium sulfate filtered, and concentrated under reduced pressure to give 1- (5-bromo - pyridin-2-ylmethyl) - (1,1-dioxo - thiomorpholine) - piperazine (499 mg of the , white solid), yield: 81.8percent.

Reference： [1]Patent: CN103360407,2016,B .Location in patent: Paragraph 0216-0219

65
[ 39093-93-1 ]
(S)-3-bromo-7-chloro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b’] dipyridine [ No CAS ]
(S)-4-(3-bromo-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b‘]dipyridin-7-yl)thiomorpholine-1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In dimethyl sulfoxide; at 175℃; for 2h;Microwave irradiation;	(S)-3-Bromo-7-chloro-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H- pyrrolo[2,3-b:4,5-b']dipyridine (150 mg, 0.328 mmol), <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (311 mg, 2.30 mmol) and the triethylamine (0.365 mL, 2.63 mmol) were dissolved in 1.2 mL of DMSO and microwaved at 175 °C for 2 h. It was diluted with 1percent MeOH/EtOAc and washed twice with brine. The organic layer was dried over MgS04 and concentrated to obtain 181 mg of crude. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge CI 8, 19 x 200 mm, 5-muiotatauiota particles; Mobile Phase A: 5:95 ACN: water with 10-mM NH4OAc; Mobile Phase B: 95:5 ACN: water with 10- mM NH4OAc; Gradient: 40-80percent B over 15 min, then a 5-min hold at 100percent B; Flow: 20 mL/min. Fractions containing the title compound were combined and dried via centrifugal evaporation. The yield of the product was 76percent. NMR (500MHz, DMSO- d6) delta 8.62 (br. s., 1H), 8.43 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.24 (t, J=7.3 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 5.61 (br. s., 1H), 4.28 (br. s., 4H), 3.90 - 3.82 (m, 1H), 3.76 (d, J=10.3 Hz, 1H), 3.53 (br. s., 1H), 3.30 - 3.16 (m, 6H), 1.50 - 1.38 (m, 2H), 1.24 (d, J=7.3 Hz, 1H), 1.13 (d, J=l 1.0 Hz, 1H); LC/MS (M+H) = 555.0 [Column: Waters Aquity BEH C18 2.1 X 50 mm 1.7u; Mobile Phase A: water with 0.05percent TFA; Mobile Phase B: ACN with 0.05percent TFA; Temperature: 40 °C; Gradient: 2-98percent B over 1.5 min; Flow: 0.8 mL/min].

Reference： [1]Patent: WO2016/183118,2016,A1 .Location in patent: Page/Page column 308; 309

66
[ 39093-93-1 ]
(S)-isopropyl 2-(6-(bromomethyl)-4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate [ No CAS ]
(S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-6-((1,1-dioxidothiomorpholino)methyl)-5-(2-(4-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-methylpyridin-3-yl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		To a solution of <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (37.4 mg, 0.277 mmol) in ethanol (1 mL) was added (S)i sopropyl 2-(6-(bromomethyl)-4-(4,4-dimethylpiperidin- l-yl)-5 -(2-(4-fluoro-2- methylbenzyl)- 1,2,3 ,4-tetrahydroi soquinolin-6-yl)-2-methylpyridin-3 -yl)-2-(tert-butoxy)acetate (20 mg, 0.028 mmol) and the resulting mixture was stirred at room temp for 16 h. Mixture was then treated with iON NaOH (0.028 mL, 0.277 mmol) at 80 °C for 4 h. Mixture was then cooled and purified by prep HPLC to afford (S)-2-(tert-butoxy)-2- (4-(4,4-dimethylpiperidin- 1 -yl)-6-((1, 1 -dioxidothiomorpholino)methyl)-5-(2-(4-fluoro-2- methylbenzyl)- 1,2,3 ,4-tetrahydroi soquinolin-6-yl)-2-methylpyridin-3 -yl)acetic acid (15.8mg, 0.021 mmol, 78 percent yield). ?HNMR (500MHz, DMSO-d6) oe 7.40-7.27 (m, 1H),7.25 -7.15 (m, 1H), 7.14-6.96 (m, 3H), 6.90 (br. s., 1H), 5.79 (br. s., 1H), 3.61 (br. s.,4H), 3.47 - 3.34 (m, 3H), 3.34 - 3.18 (m, 2H), 2.94 (br. s., 2H), 2.84 (d, J=9.9 Hz, 3H),2.77 - 2.68 (m, 6H), 2.47 (s, 3H), 2.36 (br. s., 3H), 2.12 (br. s., 1H), 1.89 - 1.79 (m, 1H),1.49 (br. s., 1H), 1.35 - 1.14 (m, 2H), 1.12 (s, 9H), 1.06-0.91 (m, 1H), 0.85 (br. s., 3H),0.61 (br. s., 3H). LCMS (M+H) = 735.1.

Reference： [1]Patent: WO2017/25915,2017,A1 .Location in patent: Page/Page column 179

67
[ 39093-93-1 ]
[ 3958-57-4 ]
4-(3-nitrobenzyl)thiomorpholine-1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.2%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 24h;	A solution of 1-(bromomethyl)-3-nitrobenzene (2.400 g, 11.110 mmol), <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (1.427 g, 10.554 mmol) and N,N-diisopropylethylamine (2.5 16 mL, 14.442 mmol) in acetonitrile (16 mL) was stirred at the room temperature for 24 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 percent to 50 percent) to give 4-(3-nitrobenzyl)<strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> as yellow solid (2.800 g, 93.2 percent).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1589; 1590; 1591

68
[ 39093-93-1 ]
[ 32315-10-9 ]
methyl 3-fluoro-4-(((1-methyl-1H-indazol-7-yl)amino)methyl)benzoate [ No CAS ]
methyl 3-fluoro-4-((N-(1-methyl-1H-indazol-7-yl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.7%		[3712] A solution of methyl 3-fluoi -4-(( l -mf.i yl- l H-indazol-7-yl)amino)methyl)benzoate (0.384 g, 1.226 mmol), N,N-diisopropylethylamine (1.281 mL, 7.353 mmol) and triphosgene (0.182 g, 0.613 mmol) in dichloromethane (5 mL) was stirred at the room temperature for 30 min, and mixed with thiomorpholine 1 , 1-dioxide (0.166 g, 1.226 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; methanol / dichloromethane = 0 percent to 5 percent) to give methyl 3-fluoro-4-((N-( 1 -methyl- 1 H-indazol-7-y 1)- 1 , 1 -dioxidothiomorpholine-4-carboxamido )methyl)benzoate as pale yellow oil (0.510 g, 87.7 percent).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3710-3712

69
[ 39093-93-1 ]
[ 32315-10-9 ]
methyl 3-fluoro-4-(((1-methyl-1H-indazol-4-yl)amino)methyl)benzoate [ No CAS ]
methyl 3-fluoro-4-((N-(1-methyl-1H-indazol-4-yl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.3%		[3740] A solution of methyl 3-fluoiO-4-((( l-methyl- l H-indazol-4-yl)amino)methyl)benzoate (0.384 g, 1.225 mmol), N,N-diisopropylethylamine ( 1.280 mL, 7.351 mmol) and triphosgene (0.182 g, 0.61 mmol) in dichloromethane (5 mL) was stirred at the room temperature for 30 min, and mixed with thiomorpholine 1 , 1 -dioxide (0.166 g, 1.225 mmol). The reaction mixture was stirred at the same temperature for additional 1 8 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; methanol / dichloromethane = 0 percent to 5 percent ) to give methyl 3-fluoro-4-((N-( l-methyl- l H-indazol-4-yl)- l , l-dioxidothiomorpholine-4-carboxamido )methyl)benzoate as pale yellow oil (0.531 g, 91.3 percent).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3738-3740

70
[ 39093-93-1 ]
[ 2285-12-3 ]
N-(2-(trifluoromethyl)phenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.2%	In diethyl ether; at 20℃; for 16h;	[ 1771 ] A solution of l-isocyanato-2-(trifluoromethyl)benzene ( 1.000 g, 5.344 mmol) and thiomorpholine 1 , 1 -dioxide (0.722 g, 5.344 mmol) in diethylether (20 mL) was stirred at the room temperature for 16 hr. The precipitates were collected by filtration, washed by diethylether, and dried to give the title compound N- (2-(trifluoromethyl)phenyl)thiomoipholine-4-carboxamide 1 , 1 -dioxide as white solid ( 1.674 g, 97.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 1769-1771

71
[ 39093-93-1 ]
[ 540-51-2 ]
[ 26475-62-7 ]

Yield	Reaction Conditions	Operation in experiment
60.0%		To a stirred solution of 2-bromoethan-l-ol (11.78 mL, 165.92 mmol, 7.0 eq) in acetonitrile (68 ml) was added potassium carbonate (9.8 g, 71.10 mmol, 3.0 eq). The reaction mixture was stirred for about 30 minutes at room temperature then added thiomorpholine 1,1- dioxide (3.2 g, 23.70 mmol, 1.0 eq). The reaction mixture was refluxed for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to get crude residue which was purified by column chromatography by using 3percent MeOH in DCM as an eluent to afford the desired compound (2.5 g, yield: 60.0percent) as a brown colour liquid. 1H NMR (DMSO-d6, 300 MHz): delta 4.50 (t, 1H), 3.51 (q, 2H), 3.07 (m, 4H), 2.95 (m, 4H) and 2.58 (t, 2H); Mass: [M+H]+180.19 (10percent).

Reference： [1]Patent: WO2017/149518,2017,A1 .Location in patent: Page/Page column 24; 25

72
[ 39093-93-1 ]
[ 215184-78-4 ]
tert-butyl 5-(1,1-dioxidothiomorpholino)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

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

73
[ 39093-93-1 ]
[ 633328-95-7 ]
4-(5-bromo-4-methylpyrimidin-2-yl)-1-thiomorpholine-1,1-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 48h;	Step 1: DIPEA (804 pL, 4.70 mmol) was added to 5-bromo-2-chloro-4- methylpyrimidine (650 mg, 3.13 mmol) dissolved in CH3CN (20 mL). Then, thiomorpholine-1 ,1-dioxide (508 mg, 3.76 mmol) was added to the mixture. The mixture reaction was heated at 75C for 48h. Solvent was removed under reduced pressure. H20 and AcOEt were added to the residue. The organic layer was separated, dried over Mg504, filtered and the solution was concentrated to dryness to afford 4-(5-bromo-4-methylpyrimid in-2-yl)-1 - thiomorpholine-1 ,1-dione Ex.30a (732 mg, 76%) as yellow solid. The compound was used as such in the next step.

Reference： [1]Patent: WO2018/138359,2018,A1 .Location in patent: Page/Page column 41; 53; 54

74
[ 39093-93-1 ]
[ 398489-26-4 ]
1-tert-butoxycarbonyl[3-(1,1-dioxothiomorpholine-4-yl)]cyclobutylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 8h;	1-tert-Butoxycarbonyl-3-oxocyclobutanamine (lg, 5mm0l) and 1,1-dioxythiomorpholine (0.8g, 5mmol) were dissolved in 1,2-dichloroethane (30mL) Sodium triacetoxyborohydride (lg, 20 mmOl) was added and stirred at room temperature for 8 hours. The reaction solution was concentrated to dryness.Purified by silica gel column chromatography,A white solid (0.92 g, 92percent) was obtained.

Reference： [1]Patent: CN108341814,2018,A .Location in patent: Paragraph 0129-0130; 0132-0134

75
[ 39093-93-1 ]
[ 114165-31-0 ]
1-acetyl-3-(1,1-dioxothiomorpholine-4-yl)-6-bromoindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium tris(acetoxy)borohydride; In ethylenediamine; at 20℃; for 8h;	1-acetyl-6-bromoindolin-3-one (1 g, 4 mmol)And 1,1-dioxothiomorpholine (0.7g, 4mmol) dissolved In 1,2-dichloroethane (30 mL),Sodium triacetylborohydride (1 g, 20 mmol) was added.Stir at room temperature for 8 hours.The reaction solution was concentrated to dryness.Purified by silica gel column chromatography,A white solid (0.92 g, 92percent) was obtained.

Reference： [1]Patent: CN108341814,2018,A .Location in patent: Paragraph 0174-0175; 0177-0179

76
[ 39093-93-1 ]
[ 201809-69-0 ]
3-(1,1-dioxothiomorpholine-4-yl)-6-bromodihydrobenzofuran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 8.0h;	<strong>[201809-69-0]6-bromodihydrobenzofuran-3-one</strong> (1 g, 4 mmol)And 1,1-dioxothiomorpholine (0.7 g, 4 mmol) soluble in 1,2-dichloroethane (30mL), Sodium triacetylborohydride (1 g, 20 mmol) was added.Stir at room temperature for 8 hours.The reaction solution was concentrated to dryness.Purified by silica gel column chromatography,A white solid (0.9 g, 91%) was obtained.

Reference： [1]Patent: CN108341814,2018,A .Location in patent: Paragraph 0190-0191; 0193-0195

77
[ 39093-93-1 ]
7-bromoisochroman-4-one [ No CAS ]
7-bromo-4-(1,1-dioxothiomorpholine-4-yl)isochromane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 8h;	7-Bromo-isochroman-4-one (0.45 g, 2 mmol) and 1,1-dioxothiomorpholine (0.3 g, 2 mmol) were dissolved in 1,2-dichloroethane (30 mL) and added Sodium triacetoxyborohydride (1 g, 20 mmol) was stirred at room temperature for 8 hours. The reaction solution was concentrated to dryness.Purified by silica gel column chromatography,A white solid (0.5 g, 85percent) was obtained.

Reference： [1]Patent: CN108341814,2018,A .Location in patent: Paragraph 0274-0275; 0277-0279

78
[ 39093-93-1 ]
6-bromo-2,2-dimethylbenzofuran-3-one [ No CAS ]
6-bromo-3-(1,1-dioxothiomorpholine-yl)-2,2-dimethylbenzofuran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 8h;	6-bromo-2,2-dimethylbenzofuran-3-one (0.45 g, 2 mmol)And 1,1-dioxothiomorpholine (0.3g,2mmol) was dissolved in 1,2-dichloroethane (30mL),Sodium triacetylborohydride (1 g, 20 mmol) was added.Stir at room temperature for 8 hours. The reaction solution was concentrated to dryness.Purified by silica gel column chromatography,A white solid (0.5 g, 85percent) was obtained.

Reference： [1]Patent: CN108341814,2018,A .Location in patent: Paragraph 0287; 0289; 0291-0293

79
[ 39093-93-1 ]
tert-butyl (R)-5-bromo-3-((methyl((S)-5,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]
C₂₉H₄₀N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 140℃; for 3h;Inert atmosphere;	A 5 mL jiW tube equipped with a stir bar was charged with 250 mg of tert-butyl (R)-5-bromo-3-((methyl((S)-5 ,6,7,8-tetrahydroquinolin-8-yl)amino)methyl)-3 ,4-dihydroisoquinoline-2( 1H)-carboxylate(0.514 mmol, 1 equiv), 90.0 mg of <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> (0.668 mmol, 1.3 equiv), 48.0mg of BNAP(0.077 mmol, 0.15 equiv), 0.25 1 g of Cs2CO3 (0.771 mmol, 1.5 equiv), and 24.0mg of Pd2(dba)3 (0.026mmol, 0.05 equiv) and the system was set under Ar atmosphere by flashing through Ar for 1 h. Then 2.57mL of dioxane (degassed by bubbling through Ar for 1 h) was added. After stirring at 140°C for 3 h in thejiW reactor (normal power), EA was added and the suspension was filtered through celite plug. The cmde product was purified on silica gel column using 0-100percent EA in hexanes as eluent affording 252 mg (91percent) of the product 15. 1H NMR (400 MHz, CDCl3) 8.28 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.07-6.99 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.80- 6.72 (m, 1H), 4.70 (br s, 0.5H), 4.58 (d, J = 17.1Hz, 1H), 4.50 (br s, 0.5H), 3.89-3.77 (m, 1H), 3.65 (s, 1H), 3.50-3.34 (m, 4H), 3.31 -3.15 (m, 5H), 2.872.61 (m, 4H), 2.47 - 2.20 (m, 1H), 2.23 (s, 3H), 2.02 - 1.80 (m, 3H), 1.66 - 1.56 (m, 1H), 1.50 (s, 9H); LC-MS (ESI-API, 254 nm) 75-95percent MeOH in H20 (0.1percent HCO2H), 3 mm, 1.00 mL/min, C18 (Agilent Zorbax XDB-18, 50mm x 4.6 mm, 3.5 .im), m/z = 541.2 (M + H), t = 0.514 mm.

Reference： [1]Patent: WO2018/156595,2018,A1 .Location in patent: Page/Page column 164

80
[ 39093-93-1 ]
[ 149849-94-5 ]
methyl 2-(1,1-dioxidothiomorpholino)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere;	Methyl 2-chloropyrimidine-4-carboxylate (300 mg) and thiomorpholine 1,1 -dioxide (306 mg) were dissolved in dioxane (10 mL) under argon atmosphere. Triethylamine (0.97 mL) was added and the reaction mixture was degassed with argon for 15 minutes. The reaction mixture was stirred at 80 C for 12 hours. Dioxane was evaporated and the residue diluted with dichloromethane. The organic phase was washed with brine and aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (2 times). The combined organic layers were dried over magnesium sulfate, filtrated, and concentrated. Purification was performed on a silica gel column (12 g, 0-2% methanol in dichloromethane). The desired fractions were combined and the solvents were removed under reduced pressure to provide the title compound. MS (ESI) m/z 272.1 (M+H)+.

Reference： [1]Patent: WO2019/35927,2019,A1 .Location in patent: Paragraph 00580

81
[ 39093-93-1 ]
[ 138274-14-3 ]
4-(5-benzyloxypyrimidin-2-yl)-1,4-thiomorpholine-1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With 1-methyl-pyrrolidin-2-one; potassium fluoride; at 140℃; for 23h;	To <strong>[138274-14-3]5-benzyloxy-2-chloro-pyrimidine</strong> 34b (0.20 g, 0.91 mmol) of N-methylpyrrolidone (5 mL)Potassium fluoride (0.17 g, 2.9 mmol) was added to the solution.Thiomorpholine dioxide (0.13 g, 0.91 mmol). After the addition, the reaction solution was heated to 140 C for 23 hours.The heating was stopped, and after the reaction solution was cooled to room temperature, dichloromethane (30 mL) and water (10 mL) were added and stirred for 10 minutes.The lower organic phase was separated, the aqueous phase was extracted with dichloromethane (10 mL×3), and the combined organic phases were washed with saturated sodium chloride solution (10 mL).Dry over anhydrous sodium sulfate, concentrate by suction filtration, and the residue obtained was purified by silica gel column chromatography[Petroleum ether / ethyl acetate (v / v) = 5 / 1] purified to give the title compound50a (60 mg, 21% yield) as a pale yellow solid.

Reference： [1]Patent: CN109251166,2019,A .Location in patent: Paragraph 0763; 0765; 0766; 0767

82
[ 39093-93-1 ]
[ 459-57-4 ]
[ 27913-96-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; at 100℃; for 16h;Inert atmosphere;	[1357] 4-(1,1-dioxidothiomorpholino)benzaldehyde : To a solution of 4-fluorobenzaldehyde (0.4 g, 3.22 mmol, 1.0 eq.) and thiomorpholine 1,1-dioxide (0.65 g, 4.83 mmol, 1.5 eq.) in water (20.0 mL) was added K2CO3 (0.67 g, 4.83 mmol, 1.5 eq.). The mixture was stirred at 100C. for 16 h under N2 atmosphere. TLC (30% EtOAc in hexane) showed the reaction was completed. The reaction was cooled to room temperature and was extracted with EtOAc (2100 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to get the crude. The crude product was purified by flash column chromatography using 25-30% EtOAc in hexane as an eluent to give 4-(1,1-dioxidothiomorpholino)benzaldehyde. LC-MS (m/z)=240.1[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.12 (s, 4H), 3.95 (s, 4H), 7.14 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 9.74 (s, 1H).

Reference： [1]Patent: US2019/263802,2019,A1 .Location in patent: Paragraph 1357

83
[ 39093-93-1 ]
2-(((2S,3R,4S,5R,6R)-5-hydroxy-2-(((3R,4R,5S)-4-hydroxy-5-(4-(2-methoxypyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid [ No CAS ]
1-(2,6-dioxidothiomorpholino)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-2-(((3R,4R,5S)-4-hydroxy-5-(4-(2-methoxypyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 14h;	To a solution of 2-(((2S,3R,4S,5R,6R)-5-hydroxy-2-(((3R,4R,5S)-4-hydroxy-5- (4-(2-methoxypyrimidin-5-yl)- 1 /'/· 1 ,2,3 -triazol- 1 -yi)tetrahydro-2i7-pyran-3 -yl)thi o)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-l//-l,2,3-triazol-l-yl)tetrahydro-2//-pyran- 3-y])oxy)acetic acid (23 mg, 0 032 rnmol) and ihiomorphoiine 1 ,1 -dioxide (8 75 mg, 0 065 mmol) in DMF (0.8 mL) was added AW-diisopropylethylamine (0.028 mL, 0.162 mmol) followed by HATU (24.61 mg, 0.065 mmol). The reaction mixture was stirred at rt for 14 h. The mixture was diluted with acetonitrile and a small amount of water and was filtered and purified by reverse phase preparative HPLC (Method 2). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford l-(l, l -dioxidothiomorpholino)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-2-(((3R,4R,5S)- 4-hydroxy-5-(4-(2-methoxypyrimidin-5-yl)-li/-l,2,3-triazol-l-yl)tetrahydro-2//-pyran- 3-yl)?.hio)-6-(hydroxymethyl)~4-(4-(3, 4, 5~tri fluorophenyl)- 17/-T, 2, 3-?.riazol-l - yl)tetrahydro-2//-pyran-3-yl)oxy)ethan-l-one (25.5 rng, 0.030 mmol, 92% yield) as a white amorphous solid. NMR (500 MHz, DMSO-de) d 9.03 (s, 2H), 8.91 (s, IH, major), 8.89 (s, 1 H, minor), 8.75 (s, 1H, major), 8.74 (s, 1 H, minor), 7.85 - 7.76 (m, 2H), 5.29 - 5.24 (m, 1H, minor), 5.08 (dd, ,7=10.5, 2.7 Hz, 1H), 5.04 (d, J= 9.5 Hz, 1H, minor), 4.87 (d, .7=9.2 Hz, 1H), 4 67 - 4.58 (m, 21 1 ), 4.57 - 4.52 (m, i l l minor), 4.29 - 4.05 (m, 6H), 3.97 (s, 3H), 3.96 (hr d, 7=3. 1 Hz, 1H), 3.94 - 3.90 (m, 1H), 3.86 - 3.79 (m, 2H), 3.73 - 3 59 (m, 31 1 ), 3.56 - 3.45 (m, 5H), 3 28 (id, 7=10 8, 5.0 Hz, 1 1 1), 3.12 - 2.86 (m, 4H); LC/MS (ESI) m/e 828.2 [(M+H)+, caicd for C32H37F3N9O10S2 828.2], & = 1.57 min (Method 1); HPLC (Method 1): ts. = 5.94 min; HPLC (Method 2): fa = 5.71 min. hGal-3 ICso = 0 012 mM.

Reference： [1]Patent: WO2019/241461,2019,A1 .Location in patent: Page/Page column 124-125

84
[ 39093-93-1 ]
[ 162744-60-7 ]
4-(4-bromo-2,6-difluorobenzyl)thiomorpholine 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	5-Bromo-2-(bromomethyl)-1,3-difluorobenzene (5 g, 17.49 mmol), thiomorpholine 1,1-dioxide (2.60g, 19.24 mmol) and triethylamine (7.56 mL, 54.2 mmol) was added DMF (58 mL) and the reactionmixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (20 mL)and extracted with DCM (3 x 20 mL). The organic layers were combined, passed through a hydrophobicfrit and the solvent was removed in vacuo. The residue was purified by normal phase columnchromatography (0 - 100 % EtOAc in cyclohexane, 120 g SiO2) to afford 4-(4-bromo-2,6-difluorobenzyl)thiomorpholine 1,1-dioxide (3.42 g, 10.05 mmol, 58 % yield) as a white solid. M.pt.:154 - 156 C; numax (neat): 2943, 2822, 1328, 1117 cm1; 1H NMR (400 MHz, CDCl3) delta = 7.10 - 7.17 (2H,m), 3.80 (2H, t, J = 1.3 Hz), 3.02 - 3.08 (8H, m); 13C NMR (101 MHz, CDCl3) delta = 161.7 (2C, dd, J = 252.4,8.8 Hz), 122.0 (t, J = 12.8 Hz), 115.52 (2C, dd, J = 27.9, 2.2 Hz), 111.5 (t, J = 19.8 Hz), 51.4 (2C), 50.1(2C), 47.8; 19F NMR (376 MHz, CDCl3) delta = -111.86 (s); LCMS (Method A): tR = 0.99 min, [M+H]+ 340 &342, (100 % purity); HRMS: (C11H12BrF2NO2S) [M+H]+ requires 339.9818, found [M+H]+ 339.9821.

Reference： [1]Bioorganic and medicinal chemistry,2020

85
[ 39093-93-1 ]
C₂₁H₁₈N₄O₃ [ No CAS ]
C₂₅H₂₇N₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.6%		A three-necked flask was charged with compound formula 4 (37.44 g, 100 mmol) and <strong>[39093-93-1]thiomorpholine 1,1-dioxide</strong> 5a (16.70 g, 110 mmol),Add tetrahydrofuran (187mL),After stirring for 1-2 hours, add acetic acid (6.01g, 100mmol). After stirring for 30 minutes, cool to 0-5 C and add in batches.Sodium borohydride acetate(25.43g, 120mmol),After stirring at room temperature for 1 hour, the temperature was slowly raised to room temperature and the reaction was carried out for 12 to 18 hours.Unscrew part of the solvent,Slowly add water (374 mL) and stir,Ethyl acetate (187 mL) was added and extracted twice.The combined organic phases were washed once with water (93 mL),Concentrated to dryness and added petroleum ether (187mL),Slow cooling crystallizationfilter,Collect solids to dry,Intermediate 6 was obtained (42.25 g, 85.6%).

Reference： [1]Patent: CN110878097,2020,A .Location in patent: Paragraph 0069-0073

86
[ 39093-93-1 ]
[ 203661-69-2 ]
tert-butyl 2-(1,1-dioxo-1,4-thiazinan-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	[0268] No. Tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (3A) (129 mg, 0.54mmol), No.35 acetic acid (65 mg, 1.08mmol), No.35 1,4-thiazinan 1,1-dioxide(72 mg, 0.54 mmol), No.35 sodium triacetoxyborohydride (229m g, 1.08mmol) and No.2 dichloromethane(20 mL) were added sequentially in a 50 mL reaction flask. After the addition, the reaction was allowed to proceed at room temperature for 16 h. The reaction solution was suction filtered, and the filtrate was washed with a saturated sodium bicarbonate solution (50 mL). After separation, the organic layer was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure, to obtain No.35 tert-butyl (1,1-dioxo-1,4-thiazinan-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate (21A) as white powder (147 mg, yield 76%).

Reference： [1]Patent: EP3656782,2020,A1 .Location in patent: Paragraph 0268

87
[ 39093-93-1 ]
[ 7304-32-7 ]
2-(1,1-dioxidothiomorpholino)-5-nitrobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.3%	In 1,4-dioxane; at 20℃; for 2h;	General procedure: To a solution of 2-fluorobenzoic acid (10) (5.0 g, 35.7 mmol) in10 mL concentrated H2SO4, 10 mL concentrated HNO3 was addeddropwise at 0 C. After stirring for 2 h at room temperature, themixture was slowly poured into ice water. The resulting precipitatewere collected by filtration, which werewashed bywater, and driedto give 4.7 g <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (11) as yellow solid, yield 71.2%; To the solution of 11 (500 mg, 2.7 mmol) in 10 mL dioxane,morpholine (1.2 mL, 13.5 mmol) was added in one potion. Afterstirring for 2 h at room temperature, the solvent and remainingmorpholine were removed in vacuo. Then, the residues were dissolvedinto water and neutralized by 10% HCl aqueous. Theresulting precipitate were collected, washed by water, and dried togive 520 mg 2- morpholine-5-nitrobenzoic acid (12) as yellowsolid, yield 76.4%.

Reference： [1]European Journal of Medicinal Chemistry,2021,vol. 216

88
[ 39093-93-1 ]
[ 232275-53-5 ]
methyl 2,6-dichloro-4-(1,1-dioxo-1,4-thiazinan-4-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.56%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Inert atmosphere; Sealed tube;	Methyl 4-bromo-2,6-dichloro-benzoate (70 mg, 246.54 umol), 1,4-thiazinanel,1-dioxide hydrochloride (50.78 mg, 295.84 umol), diacetoxypalladium (2.77 mg, 12.33 umol), binap (9.21 mg, 14.79 umol), Cesium carbonate (240.98 mg, 739.61 umol) in toluene (5 mL) was added to a nitrogen-filled sealed tube, and the subsequent reaction mixture was stirred at 100 C. overnight, TLC showed that the starting material was consumed, then the reaction mixture was diluted with DCM, and filtered to collect the filtrate. The crude material was purified by silica gel column (PE:EA=4:1) to afford methyl 2,6-dichloro-4-(1,1-dioxo-1,4-thiazinan-4-yl)benzoate (63 mg, 186.28 umol, 75.56% yield) LC-MS (Agilent LCMS 1260-6120, Column: Waters X-Bridge C18 (50 mm4.6 mm3.5 μm); Column Temperature: 40 C.; Flow Rate: 1.5 mL/min; Mobile Phase: from 95% [water+10 MmNH4HCO3] and 5% [CH3CN] to 5% [water+10 MmNH4HCO3] and 95% [CH3CN] in 2 min, then under this condition for 2 min. Purity is 100%. Rt=2.362 min; MS Calcd.: 337.0; MS Found: 337.8 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 6.80 (s, 2H), 3.95 (s, 3H), 3.92-3.85 (m, 4H), 3.13-3.05 (m, 4H).

Reference： [1]Patent: US2021/171455,2021,A1 .Location in patent: Paragraph 0759; 0927; 0930-0932

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P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
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. 39093-93-1 ] {[proInfo.proName]}

Quality Control of [ 39093-93-1 ]

Related Doc. of [ 39093-93-1 ]

Product Details of [ 39093-93-1 ]

Calculated chemistry of [ 39093-93-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 39093-93-1 ]

Application In Synthesis of [ 39093-93-1 ]

[ 39093-93-1 ] Synthesis Path-Upstream 1~11

[ 39093-93-1 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 39093-93-1 ]

Sulfones

Related Parent Nucleus of [ 39093-93-1 ]

Aliphatic Heterocycles

Thiomorpholines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 39093-93-1 ]

Related Parent Nucleus of
[ 39093-93-1 ]