Name: 608523-94-0|N-tert-Butyl 3-Aminophenylsulfonamide|98%
Brand: Ambeed
SKU: A107312
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1
[ 608523-94-0 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-amino-N-(dimethylethyl)benzenesulfonamide With hydrogenchloride; sodium nitrite at 0℃; Stage #2: With tin(ll) chloride

Reference： [1]Lam, Patrick Y. S.; Clark, Charles G.; Li, Renhua; Pinto, Donald J. P.; Orwat, Michael J.; Galemmo, Robert A.; Fevig, John M.; Teleha, Christopher A.; Alexander, Richard S.; Smallwood, Angela M.; Rossi, Karen A.; Wright, Matthew R.; Bai, Stephen A.; He, Kan; Luettgen, Joseph M.; Wong, Pancras C.; Knabb, Robert M.; Wexler, Ruth R. [Journal of Medicinal Chemistry, 2003, vol. 46, # 21, p. 4405 - 4418]

2
[ 608523-94-0 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: NaNO₂; HCl / 0 °C 1.2: SnCl₂ 2.1: ethanol / 5 h / Heating

Reference： [1]Lam, Patrick Y. S.; Clark, Charles G.; Li, Renhua; Pinto, Donald J. P.; Orwat, Michael J.; Galemmo, Robert A.; Fevig, John M.; Teleha, Christopher A.; Alexander, Richard S.; Smallwood, Angela M.; Rossi, Karen A.; Wright, Matthew R.; Bai, Stephen A.; He, Kan; Luettgen, Joseph M.; Wong, Pancras C.; Knabb, Robert M.; Wexler, Ruth R. [Journal of Medicinal Chemistry, 2003, vol. 46, # 21, p. 4405 - 4418]

3
[ 608523-94-0 ]
[ 629610-28-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: NaNO₂; HCl / 0 °C 1.2: SnCl₂ 2.1: ethanol / 5 h / Heating 3.1: Me₃Al / CH₂Cl₂; hexane / 0.25 h / 20 °C 3.2: CH₂Cl₂; hexane / 18 h / 40 °C 4.1: TFA / 1 h / Heating

Reference： [1]Lam, Patrick Y. S.; Clark, Charles G.; Li, Renhua; Pinto, Donald J. P.; Orwat, Michael J.; Galemmo, Robert A.; Fevig, John M.; Teleha, Christopher A.; Alexander, Richard S.; Smallwood, Angela M.; Rossi, Karen A.; Wright, Matthew R.; Bai, Stephen A.; He, Kan; Luettgen, Joseph M.; Wong, Pancras C.; Knabb, Robert M.; Wexler, Ruth R. [Journal of Medicinal Chemistry, 2003, vol. 46, # 21, p. 4405 - 4418]

4
[ 608523-94-0 ]
[ 1026322-19-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: NaNO₂; HCl / 0 °C 1.2: SnCl₂ 2.1: ethanol / 5 h / Heating 3.1: Me₃Al / CH₂Cl₂; hexane / 0.25 h / 20 °C 3.2: CH₂Cl₂; hexane / 18 h / 40 °C

Reference： [1]Lam, Patrick Y. S.; Clark, Charles G.; Li, Renhua; Pinto, Donald J. P.; Orwat, Michael J.; Galemmo, Robert A.; Fevig, John M.; Teleha, Christopher A.; Alexander, Richard S.; Smallwood, Angela M.; Rossi, Karen A.; Wright, Matthew R.; Bai, Stephen A.; He, Kan; Luettgen, Joseph M.; Wong, Pancras C.; Knabb, Robert M.; Wexler, Ruth R. [Journal of Medicinal Chemistry, 2003, vol. 46, # 21, p. 4405 - 4418]

5
[ 54-47-7 ]
3-amino-N-(dimethylethyl)benzenesulfonamide [ No CAS ]
[ 608523-49-5 ]

Yield	Reaction Conditions	Operation in experiment
75%		9.B Step B. Step B. Preparation of 6-[3-(tert-Butylsulfamoyl)phenylazo]-pyridoxal-5-phosphate The title material was prepared from 3-amino-N-tert-butyl-benzenesulfonamide (step A) and pyridoxal-5-phosphate as described in general procedure D, method A. The final productproduct was obtained in 75% yield. 1H NMR (D2O): δ 1.00 (5, 9H), 2.33 (s, 3H), 5.63 (s, 2H), 7.45 (t, J=8.0, 1H), 7.72 (d, J=7.0, 1H), 7.99 (t, J=8.1, 1H), 8.11 (s, 1H), 10.32 (s, 1H). 31P NMR (D2O): δ 7.02 (s).

Reference： [1]Current Patent Assignee: TAIMED BIOLOGICS, INC. - US6638921, 2003, B1

6
[ 815-17-8 ]
[ 608523-94-0 ]
[ 1028253-11-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: trimethylpyruvic acid; 3-amino-N-(dimethylethyl)benzenesulfonamide With titanium(IV) isopropylate at 20 - 75℃; for 0.25h; Stage #2: With sodium cyanoborohydride In ethanol at 20℃; Stage #3: With water In ethanol	206.1 Compound 206 Isomers; N-(3-(tert-butylsulfamoyl)phenyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide andN-(3-(tert-butylsulfamoyl)phenyl)-3-methyl-D-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide; Example 206; Preparation of Compounds 206A and 206B; Step 1:; To a mixture of 3-amino-N-tert-butylbenzenesulfonamide (180 mg, 0.788 mmol) and 3,3-dimethyl-2-oxobutanoic acid (308 mg, 2.365 mmol) in a 100 mL RBF at RT was added tetraisopropoxytitanium (2 ml,) via a pipet. The color of the mixture soon changed into a characteristic canary color. The solution was warmed to 75° C. for about 15 minutes and the color remained the same. The solution was diluted with absolute ethanol (8 ml) at RT, followed by the addition of 1.5× of sodium cyanotrihydroborate (245 mg, 3.90 mmol), and the remaining half after the bubbling and sizzling was over. The color of the solution became lighter. The solution was mixed with 4 mL of water, forming a suspension, the white PPT was removed by centrifuge. The organic was extracted into ethyl acetate, and the organic phase was dried over Na2SO4, filtered, and evaporated to dryness. A yellow oil was obtained and used in the next step without further purification. LC-MS, MS m/z 343 (M++H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/119461, 2008, A1 Location in patent: Page/Page column 92-93

7
[ 1042918-04-6 ]
[ 608523-94-0 ]
[ 1042918-05-7 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate In <i>tert</i>-butyl alcohol at 20 - 100℃;	12.b b) 2-[3-(/V-rerr-Butyl)aminosufonylphenyl]amino-6-{4-[3- (hydroxymethyl)piperidin-1-yl]phenyl}-9-(tetrahydropyran-2-yl)-9H-purineTo a solution of the compound obtained in the previous section (150 mg, 0.351 mmol) in te/t-butanol (4 ml_) under Ar-atmosphere, potassium carbonate (106 mg, 0,768 mmol), X-Phos (17 mg, 0,036 mmol), Pd2(dba)3 (16 mg, 0,017 mmol) and 3- amino-λ/-fe/t-butylbenzenesulfonamide (160 mg, 0,701 mmol) were added at room temperature. The mixture was purgued under Ar-atmosphere and heated at 100 °C overnight. The reaction crude was filtered through a plug of Celite, washed with methanol and evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 99 mg of the desired compound (46% yield). LC-MS (method 5): tR = 2.53 min; m/z = 620 (MH+)

Reference： [1]Current Patent Assignee: PALAU PHARMA SA - WO2008/90181, 2008, A1 Location in patent: Page/Page column 105

8
[ 1138472-86-2 ]
[ 608523-94-0 ]
[ 1138473-28-5 ]

Yield	Reaction Conditions	Operation in experiment
14%	With caesium carbonate In 1,4-dioxane at 150℃; for 2h;	40 [0213] A suspension of [4-(5-Chloro-thiophen-2-yl)-5-methyl-pyrimidin-2-yl]-[4-(2- pyrrolidin-l-yl-ethoxy)-phenyl] -amine (0.10 g, 0.24 mmol), 3-amino-/V-te/t-butyl- benzenesulfonamide (75 mg, 0.33 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.16 g, 0.49 mmol) in dioxane (6 mL) was heated at 150 0C under argon atmosphere for 2 h. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a brown solid (20 mg, 14%).[0214] 1H NMR (500 MHz, DMSO-d6): δ 1.11 (s, 9H), 1.65-1.72 (m, 4H), 2.37 (s, 3H), 2.48- 2.58 (m, 4H), 2.78-2.83 (m, 2H), 4.03 (t, J = 5.9 Hz, 2H), 6.71 (d, J = 4.2 Hz, IH), 6.88 (d, J = 9.1 Hz, 2H), 7.33 (d, J = 7.1 Hz, IH), 7.35 (dd, J = 7.7, 2.5 Hz, IH), 7.48 (t, J = 7.9 Hz, IH), 7.55 (s, IH), 7.57 (d, J = 4.3 Hz, IH), 7.65 (t, J = 2.0 Hz, IH), 7.68 (d, J = 9.0 Hz, 2H), 8.22 (s, IH), 9.17 (s, IH), 9.68 (s, IH)[0215] MS (ES+): m/z 607 (M+H)+

Reference： [1]Current Patent Assignee: SANOFI - WO2009/46416, 2009, A1 Location in patent: Page/Page column 66-67

9
[ 1780-31-0 ]
3-amino-N-(tert-butyl)benzenesulfonamide [ No CAS ]
[ 936092-53-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	In methanol; lithium hydroxide monohydrate at 45℃; for 20h;	1.3 (3) Intermediate 4a: Preparation of N-(tert-butyl)-3-((2-chloro-5-methylpyrimidin-4-yl)amino)benzenesulfonamide Compound 3 (2.3 g, 10.00 mmol) and 2,4-dichloro-5-methylpyrimidine (1.9 g, 11.50 mmol) were added to methanol and water (v:v=1:1.5, 50 mL) at 25°C During the reaction at 45°C for 20 hours, a solid was gradually precipitated during the reaction. After the reaction was monitored by TLC, the reaction solution was allowed to stand at room temperature, filtered, and the solid was washed with methanol and water (v:v=1:1.5). 2 times, dried in vacuo to give 2.96 g of white solid in 83% yield.
79%	In methanol; lithium hydroxide monohydrate at 45℃; for 20h; Industry scale; Inert atmosphere;	4.1.b Example 4.1(b) SM1 SM2 Intermediate[0136] The Intermediate was synthesized from 2,4-dichloro-5-methylpyrimidine (SMI) and N-t-butyl-3-aminobenzenesulfonamide (SM2) in the following steps: (1) Mix MeOH (6.7UOa) and SMI (Combi Blocks) (UOa); (2) Add SM2 (1.15UOa, 082eq) and H20 (8.5UOa); (3) Heat 45°C, 20h, N2, IPC CPL SM2<2%; (4) Cool 20°C; (5) Centrifuge, N2; (6) Wash H20 (2.1UOa) + MeOH (1.7UOa); (7) Mix solid in H20 (4.3UOa) + MeOH (3.4UOa); (8) Centrifuge, N2; (9) Wash H20 (2.1UOa) + MeOH (1.7UOa); and (10) Dry 45°C, vacuum, 15h. Obtained Intermediate, mass 49.6kg (UOb); Yield 79%; OP: 99.6%.
60.17%	In methanol; lithium hydroxide monohydrate at 45℃; Inert atmosphere;	1.3 Step 3 Synthesis of Compound 6. Magnetic stirring at room temperatureCompound 5 (1.0 g, 6.13 mmol) was added to a 50 mL single-mouth bottle.And methanol/water mixture (15mL, 1/1),Stir and dissolve,Compound 4 (1.26 g, 5.52 mmol) was added.The reaction mixture was warmed to 45 ° C under nitrogen and stirred to react overnight.Cool to room temperature,A large amount of white solid precipitated,filter,The filter cake was washed with methanol/water (3.4 mL / 4.0 mL).Drain,Drying at 50 ° C under vacuum gave 1.31 g of a white solid.The yield was 60.17%.

41%

With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 120℃; for 72h;

(S)-2-((3-(4-((4-((3-(N-(tert-Butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2- yl)amino)phenoxy)propyl)amino)-N-(2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4- yl)acetamide (Compound 66) [0554] To a solution of 3-amino-N-(tert-butyl)benzenesulfonamide (3.4 g, 14.9 mmol) and 2,4-dichloro-5-methyl-pyrimidine (608.0 mg, 3.7 mmol) in dioxane (20 mL) was added DIEA (955.0 mg, 7.4 mmol). The reaction mixture was stirred at 120°C for 72 hrs, cooled to rt, concentrated, and the residue was purified on silica gel with 20%-50% EA/petroleum ether) to afford N-(tert-butyl)-3-((2-chloro-5-methylpyrimidin-4- yl)amino)benzenesulfonamide (544.0 mg, 41% yield) as yellow solid. MS (ESI) m/z 355.0 [M+H]+.

Reference： [1]Current Patent Assignee: SHANDONG UNIVERSITY - CN113754591, 2021, A Location in patent: Paragraph 0050; 0055-0056
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2012/60847, 2012, A1 Location in patent: Page/Page column 42-43
[3]Current Patent Assignee: SHENZHEN TARGETRX INC - CN109232440, 2019, A Location in patent: Paragraph 0131; 0132; 0133; 0134; 0140; 0141
[4]Current Patent Assignee: BIOTHERYX INC - WO2017/201069, 2017, A1 Location in patent: Paragraph 0542; 0554

10
[ 22282-70-8 ]
[ 179899-07-1 ]
[ 608523-94-0 ]
[ 1395493-44-3 ]

Yield	Reaction Conditions	Operation in experiment
5%	Stage #1: 2-fluoro-4-iodopyridine; 3-amino-N-(dimethylethyl)benzenesulfonamide With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 1.5h; microwave irradiation; Stage #2: 4-fluoro-2-methoxyphenylboronic acid In N,N-dimethyl-formamide at 140℃; for 1.5h; Inert atmosphere; microwave irradiation;	5 A mixture of 2-fluoro-4-iodopyridine (100 mg, 0.45 mmol), 3-amino-N-(tert- butyl)benzenesulfonamide (153 mg, 0.67 mmol), and CS2CO3 (291 mg, 0.89 mmol) in dry DMF (3 ml_) was heated at 150°C for 1 .5 h in a microwave oven. After addition of (4- fluoro-2-methoxyphenyl)boronic acid (152 mg, 0.89 mmol) the mixture was degassed with a stream of nitrogen for 5 minutes. Pd(dppf)Cl2 (73 mg, 0.09 mmol) was added and the reaction mixture was heated to 140°C for 90 minutes in a microwave oven. The mixture was diluted with EtOAc and washed twice with sat. aq. NaHC03-solution and once with brine. The organic layer was dried over MgS04 and concentrated under reduced pressure, and the residue was purified by preparative HPLC (water/ACN 95:5 to 0: 100) to yield the desired product D2 as a yellow solid (9 mg, 5%). 1 H NMR (400MHz, de-DMSO, 300K) 5 1 .12 (s, 9H), 3.82 (s, 3H), 6.89 (m, 2H), 6.97 (s, 1 H), 7.06 (dd, J = 1 1 .5 Hz, J = 2.4 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.39 (m, 2H), 7.44 (s, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 8.24 (m, 1 H), 9.39 (s, 1 H). MS (ES) C22H24FN3O3S requires: 429, found: 430 (M+H)+.

Reference： [1]Current Patent Assignee: BAYER AG - WO2012/117059, 2012, A1 Location in patent: Page/Page column 45

11
[ 1445880-62-5 ]
[ 608523-94-0 ]
[ 1445879-52-6 ]

Yield	Reaction Conditions	Operation in experiment
58.7%	With acetic acid In 1,4-dioxane at 80℃; for 2h;	70 Example 70 4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide Example 70 4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-N-cvclopropyl-7-(2,4-dimethoxypyrimidin-5- yl)quinoline-3-sulfonamide To a solution of 4-chloro-N-cyclopropyl-7-(2, 4-dimethoxypyrimidin-5-yl)quinoline- 3-sulfonamide (147 mg, 0.35 mmol) in 1 ,4-dioxane (5 mL) and acetic acid (1 mL) was added 3-amino-N-ferf-butylbenzenesulfonamide (80 mg, 0.35 mmol). The mixture was stirred at 80 °C for 2 h. TLC showed no starting materials left. Water (20 mL) was added with stirring. The reaction mixture was extracted with ethyl acetate (50 mL x 2). The extracts were dried over Na2S04, filtered and concentrated in vacuo to afford the crude product. Further purification by column chromatography (2% methanol/dichloromethane) afforded the title compound (124 mg, 57.7%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (d, J=5.1 Hz, 4 H), 0.99 (s, 9 H), 2.18-2.22 (m, 1 H), 3.97 (s, 3 H), 3.98 (s, 3 H), 7.24-7.64 (m, 7 H), 8.26 (s, 1 H), 8.49-8.55 (m, 3 H), 9.10 (s, 1 H). LCMS (ES+) m/e 613 [M+H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/96153, 2013, A1 Location in patent: Page/Page column 145

12
[ 1393900-79-2 ]
[ 76-05-1 ]
[ 608523-94-0 ]
[ 1877285-79-4 ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate; 3-amino-N-(dimethylethyl)benzenesulfonamide With hydrogenchloride In ethanol; water at 85℃; for 2h; Stage #2: trifluoroacetic acid In water; acetonitrile	2 5-Trifluoromethyl-7V⁴-(3-[iV-(l,l-dimethylethyl)sulfamoyl]phenyl)-iV²-[4-(piperazin- l-yl)phenyl]pyrimidine-2,4-diamine (SG2-033-01-1) (3 TFA salt) 5-Trifluoromethyl-7V4-(3-[iV-(l,l-dimethylethyl)sulfamoyl]phenyl)-iV2-[4-(piperazin- l-yl)phenyl]pyrimidine-2,4-diamine (SG2-033-01-1) (3 TFA salt): To a solution of SG2-022 (100 mg, 0.218 mmol) and SG1-137 (50 mg, 0.218 mmol) in EtOH (1 mL) was added 3 drops of 4 M HC1 (aq). The mixture was stirred at 85 °C for 2 hours. The solution was diluted with EtOAc (40 mL) and washed with saturated NaHCC (40 mL). The aqueous layer was then re- extracted with EtOAc (40 mL). The combined organic layers were washed with water and brine (40 mL each), dried over Na2S04, and concentrated under reduced pressure to provide a crude oil. The crude oil was purified via HPLC eluting with 30% MeCN and 70% water (with 0.1% TFA) to provide the title compound SG2-033-01-1 as a yellow solid (35 mg, 29%). Mp: 183 °C (dec). HPLC: 99% [tn = 6.8 min, 50% MeOH, 50% water (with 0.1% TFA), 20 min]. XH NMR at 80 °C (400 MHz, DMSO-): δ 9.22 (s, IH, disappeared on D2O shake), 8.62 (s, IH, disappeared on D2O shake), 8.60 (br s, IH, disappeared on D2O shake), 8.33 (s, IH), 7.89 (s, IH), 7.77 (d, J = 8.0 Hz, IH), 7.65 (d, J= 8.0 Hz, IH), 7.50 (t, J= 8.0 Hz, IH), 7.37 (d, J= 8.7 Hz, 2H), 7.18 (s, IH, disappeared on D2O shake), 6.79 (d, J= 8.7 Hz, 2H), 1.13 (s, 9H). 19F NMR (376 MHz, DMSO-): δ -59.20 (3F), -74.25 (9F). HPLC-MS (ESI+): m/z 550.3 [100%, (M+H)+], 275.7 [50%, (M+2H)2+]. LC-MS (ESI+): 572.2 [15%, (M+Na)+], 550.2 [100%, (M+H)+]. HRMS (ESI+): m/z calcd for C25H30F3N7O2S (M+H)+ 550.2207, found 550.2194.

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1 Location in patent: Page/Page column 167

13
[ 424818-25-7 ]
[ 608523-94-0 ]

Yield	Reaction Conditions	Operation in experiment
95.79%	With iron; ammonium chloride In ethanol; water at 85℃; Inert atmosphere;	1.2 Step 2 Synthesis of Compound 4. Add to a 100 mL single-mouth flask equipped with a magnetic stirrer and condenserEthanol/water mixture (60mL, 2/1)And compound 3 (3.0 g, 11.66 mmol),Reduced iron powder (6.51g, 116.6mmol) with stirringAnd ammonium chloride (3.12g, 58.3mmol),Raise to 85 ° C under nitrogen,The mixture was stirred and reacted for 1 hour.After cooling to room temperature, the insoluble solid was filtered off, and the organic solvent was evaporated under reduced pressure.Add saturated aqueous NaHCO3 (5 mL), EtOAc (EtOAc)Concentrated to a white solid 2.55 g, yield 95.79%.
90%	With 10% Pd/C; hydrogen In methanol at 20℃;	21 Preparation of N-tert-butyl-3-nitrobenzenesulfonamide To a solution of 2.58 g N-tert-butyl-3-nitrobenzenesulfonamide (10.0 mmol, 1.00 equiv) in methanol was added palladium on activated carbon (550 mg wet catalyst, 10 wt. % palladium dry basis). The mixture was placed under hydrogen gas via balloon and stirred at room temperature for overnight. The mixture was filtered and the filtrate concentrated to afford 2.05 g 3-amino-N-tert-butylbenzenesulfonamide as a light yellow solid (90 % yield). MS (ESI+) m/z 229 [M+H]+.
89%	With ammonium chloride; zinc In 1,4-dioxane; water at 0 - 20℃; for 4h;

79%	With 10% Pd/C; hydrazine hydrate In ethanol for 3h; Inert atmosphere; Reflux;	3 Method b General procedure: Method b: To a solution of nitroarene (1.0 equiv.) in EtOH or MeOH (deoxygenated with bubbled Argon) was added Pd/C (10%) and hydrazine monohydrate 65% (3.0 equiv.) under Argon. The solution was stirred and heated at reflux for the indicated time. The reaction mixture was filtered over Celite, and the filtrate concentrated under reduced pressure.
76%	With 10% Pd/C; hydrazine hydrate In ethanol at 25℃; for 3h; Inert atmosphere; Reflux;	1.2 (2) Intermediate 3: Preparation of 3-amino-N-(tert-butyl)benzenesulfonamide Compound 2 (5.00 g, 19.36 mmol) was dissolved in 80 mL of ethanol at 25°C, and 10% palladium on carbon (0.50 g) and 80% hydrazine hydrate (3.63 g, 58.08 mmol) were added. Under the protection of argon, the reaction was refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained solid was dissolved in dichloromethane and washed twice with water. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to give 3.35 g of a white solid with a yield of 76%.
80 %	With Pd/C In ethyl acetate at 30℃; Autoclave;
90 %	With 10% Pd/C; hydrazine hydrate In methanol at 70 - 80℃; Inert atmosphere;	4.2.2. Preparation of intermediated 3: 3-amino-N-(tert-butyl)benzenesulfonamide A 1 l three-necked round-bottomed flask equipped with a magneticstir bar was charged with compound 2 (24.5 g, 95 mmol), methylalcohol (250 mL), and Pd/C (10 % w/w, 50 % wet, 2 g), and then waspurged with nitrogen before hydrazine hydrate (30 mL) being added.The resulting mixture was refluxed at 70 C for 8 h before being filteredwhile hot through Celite and then washed with methyl alcohol. Theorganic phase was concentrated in vacuo, to give a yellow gummy solid.The organic phase was concentrated in vacuo and purification of thisresidue by flash chromatography on silica gel (330 g column, gradient:0-30 % EA in petroleum ether) gave 3 (19.5 g, 90 %) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.03(t, J = 2.1 Hz, 1H), 6.93 (ddd, J = 7.7, 1.8, 1.0 Hz, 1H), 6.71 (ddd, J =8.1, 2.3, 1.0 Hz, 1H), 5.50 (s, 2H), 1.10 (s, 9H).
90 %	With 10% Pd/C; hydrazine hydrate In methanol at 70 - 80℃; Inert atmosphere;	4.2.2. Preparation of intermediated 3: 3-amino-N-(tert-butyl)benzenesulfonamide A 1 l three-necked round-bottomed flask equipped with a magneticstir bar was charged with compound 2 (24.5 g, 95 mmol), methylalcohol (250 mL), and Pd/C (10 % w/w, 50 % wet, 2 g), and then waspurged with nitrogen before hydrazine hydrate (30 mL) being added.The resulting mixture was refluxed at 70 C for 8 h before being filteredwhile hot through Celite and then washed with methyl alcohol. Theorganic phase was concentrated in vacuo, to give a yellow gummy solid.The organic phase was concentrated in vacuo and purification of thisresidue by flash chromatography on silica gel (330 g column, gradient:0-30 % EA in petroleum ether) gave 3 (19.5 g, 90 %) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.03(t, J = 2.1 Hz, 1H), 6.93 (ddd, J = 7.7, 1.8, 1.0 Hz, 1H), 6.71 (ddd, J =8.1, 2.3, 1.0 Hz, 1H), 5.50 (s, 2H), 1.10 (s, 9H).

Reference： [1]Current Patent Assignee: SHENZHEN TARGETRX INC - CN109232440, 2019, A Location in patent: Paragraph 0131; 0132; 0133; 0134; 0137; 0138; 0139
[2]Current Patent Assignee: VINCERE BIOSCIENCES - WO2021/50992, 2021, A1 Location in patent: Paragraph 00549; 00551-00552
[3]Patwari, Shivaji B.; Murali, Medari S.; Jadhav, Vivekanand B. [Journal of Heterocyclic Chemistry, 2018, vol. 55, # 12, p. 2911 - 2918]
[4]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1 Location in patent: Page/Page column 122; 124
[5]Current Patent Assignee: SHANDONG UNIVERSITY - CN113754591, 2021, A Location in patent: Paragraph 0050; 0053-0054
[6]Current Patent Assignee: AMI ORGANICS - WO2022/269384, 2022, A1 Location in patent: Page/Page column 10-12
[7]Guo, Yong; Zou, Yurong; Chen, Yong; Deng, Dexin; Zhang, Zihao; Liu, Kongjun; Tang, Minghai; Yang, Tao; Fu, Suhong; Zhang, Chufeng; Si, Wenting; Ma, Ziyan; Zhang, Shunjie; Peng, Bin; Xu, Dingguo; Chen, Lijuan [Bioorganic Chemistry, 2023, vol. 132]
[8]Guo, Yong; Zou, Yurong; Chen, Yong; Deng, Dexin; Zhang, Zihao; Liu, Kongjun; Tang, Minghai; Yang, Tao; Fu, Suhong; Zhang, Chufeng; Si, Wenting; Ma, Ziyan; Zhang, Shunjie; Peng, Bin; Xu, Dingguo; Chen, Lijuan [Bioorganic Chemistry, 2023, vol. 132]

14
[ 121-51-7 ]
[ 608523-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrahydrofuran / 0.5 h / 20 °C 2: 10% Pd/C; hydrazine hydrate / ethanol / 3 h / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C 2: ammonium chloride; zinc / 1,4-dioxane; water / 4 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: tetrahydrofuran / 1 h / 0 - 20 °C / Cooling with ice; Inert atmosphere 2: ammonium chloride; iron / ethanol; water / 85 °C / Inert atmosphere

	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C 2: hydrogen; 10% Pd/C / methanol / 20 °C
	Multi-step reaction with 2 steps 1: tetrahydrofuran / 0.5 h / 25 °C 2: 10% Pd/C; hydrazine hydrate / ethanol / 3 h / 25 °C / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1: tetrahydrofuran / 20 °C 2: 10% Pd/C; hydrazine hydrate / methanol / 8 h / 70 - 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1
[2]Patwari, Shivaji B.; Murali, Medari S.; Jadhav, Vivekanand B. [Journal of Heterocyclic Chemistry, 2018, vol. 55, # 12, p. 2911 - 2918]
[3]Current Patent Assignee: SHENZHEN TARGETRX INC - CN109232440, 2019, A
[4]Current Patent Assignee: VINCERE BIOSCIENCES - WO2021/50992, 2021, A1
[5]Current Patent Assignee: SHANDONG UNIVERSITY - CN113754591, 2021, A
[6]Guo, Yong; Zou, Yurong; Chen, Yong; Deng, Dexin; Zhang, Zihao; Liu, Kongjun; Tang, Minghai; Yang, Tao; Fu, Suhong; Zhang, Chufeng; Si, Wenting; Ma, Ziyan; Zhang, Shunjie; Peng, Bin; Xu, Dingguo; Chen, Lijuan [Bioorganic Chemistry, 2023, vol. 132]

15
[ 1393900-79-2 ]
[ 608523-94-0 ]
[ 1877285-78-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In ethanol; water at 85℃; for 2h;	2 The 4-chloropyrimidine SG2-022 (50 mg, 0.109 mmol) and SG1-137 (25 mg, 0.109 mmol) and HC1 (aq. 37%, 0.067 mL, 0.818 mmol) were mixed in EtOH (1 mL) and stirred at 85 °C for 2 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCCb (20 mL). The aqueous layer was then re-extracted with EtOAc (20 mL). The combined organic layers were washed with water and brine (20 mL each), dried over a2S04, and concentrated under reduced pressure. The residue was triturated with hexanes/EtOAc and provided SG2-024 (0.046 g) as an off-white solid which was used in the next step without purification.
	With hydrogenchloride In ethanol; water at 85℃; for 2h;	5-Trifluoromethyl-^V⁴-(3-[^V-(l,l-dimethylethyl)sulfamoyl]phenyl)-^V²-[4-(4- methylpiperazin-l-yl)phenyl]pyrimidine-2,4-diamine (SG2-029-01) (2 TFA salt): The 4- chloropyrimidine SG2-022 was prepared using the previously reported method.1 A solution of 2,4-dichloro-5-trifluoromethylpyrimidine (120 mg, 0.550 mmol) in i-BuOH/DCM (1:1, 4 mL) was cooled to 0 °C. Zinc chloride (1 M in diethyl ether, 0.633 mL, 0.633 mmol) was added dropwise over 10 minutes at 0 °C and the solution stirred at the same temperature for 30 minutes. A solution of i3N (0.089 mL, 0.633 mmol) in i-BuOH/DCM (1:1, 2 mL). The mixture was warmed to room temperature and stirred for 24 hours. The solvent was removed under reduced pressure and water (20 mL) was added. The suspension was sonicated for 30 minutes and the precipitate was filtered, dried to provide SG2-022 (0.210 g) which was used in the next step without purification. The 4-chloropyrimidine SG2-022 (50 mg, 0.109 mmol) and SG1-137 (25 mg, 0.109 mmol) and HC1 (aq. 37%, 0.067 mL, 0.818 mmol) were mixed in EtOH (1 mL) and stirred at 85 °C for 2 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCCb (20 mL). The aqueous layer was then re-extracted with EtOAc (20 mL). The combined organic layers were washed with water and brine (20 mL each), dried over Na2S04, and concentrated under reduced pressure. The residue was triturated with hexanes/EtOAc and provided SG2-024 (0.046 g) as an off-white solid which was used in the next step without purification. To a solution of SG2-024 (40 mg, 0.073 mmol) in dry MeOH (1 mL) was added formaldehyde (37% aq. solution, 0.024 ml, 0.328 mmol) and sodium triacetoxyborohydride (0.077 mg, 0.364 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with EtOAc (10 mL) and washed with saturated NaHCCb (15 mL). The aqueous layer was then re-extracted with EtOAc (10 mL). The combined organic layers were washed with water and brine (10 mL each), dried over Na2S04, and concentrated under reduced pressure. The resulting crude oil was purified via HPLC eluting with 35% MeCN and 65% water (with 0.1% TFA) to provide the title compound SG2-029-01 as light brown thin film (8 mg, 20%). HPLC: 99% [tR = 6.6 min, 50% MeOH, 50% water (with 0.1% TFA), 20 min]. NMR at 80 °C (400 MHz, DMSO-ifc): δ 9.22 (s, IH, disappeared on D2O shake), 8.62 (s, IH, disappeared on D2O shake), 8.32 (s, IH), 7.89 (s, IH), 7.77 (d, J = 8.1 Hz, IH), 7.64 (d, / = 8.1 Hz, IH), 7.51 (t, / = 8.1 Hz, IH), 7.37 (d, / = 9.0 Hz, 2H), 7.18 (s, IH, disappeared on D20 shake), 6.80 (d, / = 9.0 Hz, 2H), 2.85 (s, 3H), 1.13 (s, 9H). 19F NMR (376 MHz, DMSO-ifc): δ -58.61 (s, 3F), -73.54 (s, 6F). HPLC-MS (ESI+): m/z 564.3 [100%, (M+H)+], 282.7 [40%, (M+2H)2+]. LC-MS (ESI+): 564.2 [100%, (M+H)+]. HRMS (ESI+): m/z calcd for C26H32F3N7O2S (M+H)+ 564.2363, found 564.2370.

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1 Location in patent: Page/Page column 166
[2]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2017/66428, 2017, A1 Location in patent: Page/Page column 108-109

16
[ 514843-12-0 ]
[ 608523-94-0 ]
[ 1877285-91-0 ]

Yield	Reaction Conditions	Operation in experiment
17%	In methanol at 150℃; for 0.25h; Microwave irradiation;	2 5-Isopropyl-iV⁴,iV²-bis-[3-(sulfamoyl)phenyl]pyrimidine-2,4-diamine (MA1-036B) 5-Isopropyl-iV4,iV2-bis-[3-(sulfamoyl)phenyl]pyrimidine-2,4-diamine (MA1-036B): A mixture of SG1-137 (57 mg) and MA1-034-2 (47 mg) in dry MeOH (2 mL) in a 5 mL microwave vial were heated in microwave at 150 °C for 15 minutes. Upon cooling to room temperature, and evaporation of the methanol the crude material was directly purified using column chromatography (ethyl acetate-hexane) to provide the title compound as a solid (20 mg, 17%). Mp: 291 °C (dec). HPLC: 99% [tR = 7.5 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min]. δ 10.27 (brs, 1H, disappeared on D2O shake), 9.80 (brs, 1H, disappeared on D2O shake), 7.95 (s, 1H), 7.91-7.86 (m, 2H), 7.79 (d, J= 8.0 Hz, 1H), 7.74 (brs, 1H), 7.66 (d, J= 7.6 Hz, 1H), 7.58 (t, J= 7.9 Hz, 1H), 7.50 (d, J= 7.3 Hz, 1H), 7.45-7.35 (m, 5H, 4H disappeared on D2O shake), 3.21 (septet, J= 6.7 Hz, 1H, partially overlapped by residual DMSO signal), 1.25 (d, J= 6.7 Hz, 6H). HPLC-MS (ESI+): m/z 463.2 [100%, (M+H)+]. LC-MS (ESI+): 463.1 [100%, (M+H)+], 485.1 [30%, (M+Na)+]. HRMS (ESI+): m/z calcd for C19H22N6O4S2 (M+H) 463.1217, found 463.1214.
17%	In methanol at 150℃; for 0.25h; Microwave irradiation;	5-Isopropyl-^V⁴^V -bis-[3-(sulfamoyl)phenyl]pyrimidine-2,4-diamine (MA1-036B): A mixture of SGl-137 (57 mg) and MAl-034-2 (47 mg) in dry MeOH (2 mL) in a 5 mL microwave vial were heated in microwave at 150 °C for 15 minutes. Upon cooling to room temperature, and evaporation of the methanol the crude material was directly purified using column chromatography (ethyl acetate-hexane) to provide the title compound as a solid (20 mg, 17%). Mp: 291 °C (dec). HPLC: 99% [tR = 7.5 min, 35% MeOH, 65% water (with 0.1% TFA), 20 min]. δ 10.27 (brs, IH, disappeared on D2O shake), 9.80 (brs, IH, disappeared on D2O shake), 7.95 (s, IH), 7.91-7.86 (m, 2H), 7.79 (d, J = 8.0 Hz, IH), 7.74 (brs, IH), 7.66 (d, / = 7.6 Hz, IH), 7.58 (t, / = 7.9 Hz, IH), 7.50 (d, / = 7.3 Hz, IH), 7.45-7.35 (m, 5H, 4H disappeared on D2O shake), 3.21 (septet, / = 6.7 Hz, IH, partially overlapped by residual DMSO signal), 1.25 (d, / = 6.7 Hz, 6H). HPLC-MS (ESI+): m/z 463.2 [100%, (M+H)+]. LC-MS (ESI+): 463.1 [100%, (M+H)+], 485.1 [30%, (M+Na)+]. HRMS (ESI+): m/z calcd for C19H22N6O4S2 (M+H)+ 463.1217, found 463.1214.

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1 Location in patent: Page/Page column 173-174
[2]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2017/66428, 2017, A1 Location in patent: Page/Page column 115-116

17
[ 1240390-28-6 ]
3-amino-N-(dimethylethyl)benzenesulfonamide [ No CAS ]
2-chloro-N⁴-(3-[N-(1,1-dimethylethyl)sulfamoyl]phenyl)-5-carbamoylpyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	In methanol; water; at 45℃; for 13.5h;	General procedure: Procedure A: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.) and substituted aniline (1.15 equiv.) in MeOH/water (1 : 1.5, 0.2 M) was stirred at 45 C. The reaction time is indicated below. Upon cooling to ambient temperature, the desired product precipitated and was filtered, washed with MeOH/water (1 : 1.5, 20 mL), and dried.
27%	In methanol; water; at 45℃; for 13.5h;	A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.) and substituted aniline (1.15 equiv.) in MeOH/water (1 : 1.5, 0.2 M) was stirred at 45 C. The reaction time is indicated below. Upon cooling to ambient temperature, the desired product precipitated and was filtered, washed with MeOH/water (1 : 1.5, 20 mL), and dried. 2-Chloro-/V4-(3-[/V-(l,l-dimethylethyl)sulfamoyl]phenyl)-5-carbamoylpyrimidin-4- amine (SG2-139-01): This was prepared from SG2-138 (0.192 g) and SG1-137 (0.228 g) using procedure A (reaction time, 13.5 h). The resulting residue was purified via column chromatography (SiC ) eluting with hexanes/EtOAc (2:8 to 6:4 v/v) to give the title compound as a white solid (0.105 g, 27%). Mp: 243 C (dec). NMR (400 MHz, DMSO-ifc): delta 11.65 (s, 1H, disappeared on D2O shake), 8.80 (s, 1H), 8.47 (s, 1H, disappeared on D2O shake), 8.10 (s, 1H), 8.01 (s, 1H, disappeared on D20 shake), 7.83-7.75 (m, 1H), 7.59-7.53 (m, 3H; 1H disappeared on D20 shake), 1.11 (s, 9H). HPLC-MS (ESI+): m/z 769.1 [40%, (2M37C1+H)+], 767.1 [100%, (2M35C1+H)+], 386.1 [40%, (M37C1+H)+], 384.1 [100%, (M35C1+H)+].

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 77; 86
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 186; 195

18
[ 5750-76-5 ]
[ 608523-94-0 ]
[ 1220451-56-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	In methanol; water at 45℃; for 21h;	2 Procedure A General procedure: Procedure A: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.) and substituted aniline (1.15 equiv.) in MeOH/water (1 : 1.5, 0.2 M) was stirred at 45 °C. The reaction time is indicated below. Upon cooling to ambient temperature, the desired product precipitated and was filtered, washed with MeOH/water (1 : 1.5, 20 mL), and dried.
93%	In methanol; water at 45℃; for 21h;	Procedure A: Procedure A: A mixture of substituted 2,4-dichloropyrimidine (1.0 equiv.) and substituted aniline (1.15 equiv.) in MeOH/water (1 : 1.5, 0.2 M) was stirred at 45 °C. The reaction time is indicated below. Upon cooling to ambient temperature, the desired product precipitated and was filtered, washed with MeOH/water (1 : 1.5, 20 mL), and dried. 2,5-Dichloro-/V4-(3-[/V-(l,l-dimethylethyl)sulfamoyl]phenyl)pyrimidin-4-amine (SG1-149): This was prepared from 2,4,5-trichloropyrimidine (0.100 g) and SG1-137 (0.031 g) using procedure A (reaction time, 21 h) to give the title compound as a white solid (0.190 g, 93%). Mp: 172-173 °C. NMR (400 MHz, DMSO-ifc): δ 9.79 (s, 1H, disappeared on D20 shake), 8.42 (s, 1H), 8.07 (s, 1H), 7.77 (d, / = 8.2 Hz, 1H), 7.64-7.52 (m, 3H; 1H disappeared on D20 shake), 1.11 (s, 9H). HPLC-MS (ESI+): m/z 773.1 [30%, (M35Cl35Cl+M35Cl37Cl+Na)+], 377.1 [70%, (M35C137C1+H)+], 375.1 [100%, (M35C135C1+H)+].

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1 Location in patent: Page/Page column 77-78
[2]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2017/66428, 2017, A1 Location in patent: Page/Page column 186

19
[ 608523-94-0 ]
[ 1877285-69-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: methanol; water / 26 h / 40 - 80 °C 2: hydrogenchloride / ethanol / 0.25 h / 160 °C / Microwave irradiation
	Multi-step reaction with 2 steps 1: water; methanol / 0.44 h / 80 °C / Reflux 2: hydrogenchloride / ethanol; water / 0.25 h / 160 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1
[2]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2017/66428, 2017, A1

20
[ 608523-94-0 ]
[ 1877285-71-6 ]
[ 1877285-72-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: methanol; water / 26 h / 40 - 80 °C 2: hydrogenchloride / ethanol / 0.25 h / 160 °C / Microwave irradiation
	Multi-step reaction with 2 steps 1: water; methanol / 0.44 h / 80 °C / Reflux 2: hydrogenchloride / ethanol; water / 0.25 h / 160 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2016/22460, 2016, A1
[2]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2017/66428, 2017, A1

21
[ 1780-32-1 ]
3-amino-N-(dimethylethyl)benzenesulfonamide [ No CAS ]
N-tert-butyl-3-(2-chloro-5,6-dimethylpyrimidin-4-ylamino)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	In methanol; water; at 40 - 80℃; for 26h;	iV-teri-Butyl-3-(2-chloro-5,6-dimethylpyrimidin-4-ylamino)benzenesulfonamide (RJl-010): A mixture of RJ1-008 (0.500 g, 2.82 mmol), 3-amino-N-tert- butylbenzenesulfonamide (SG1-137) (0.74 g, 3.24 mmol), MeOH (5 mL), and water (7.5 mL) was heated to reflux at 40 C. The reflux temperature was raised to 80 C and the reaction was further heated for 26 hours. Upon cooling to ambient temperature, the precipitate which formed was then filtered and washed with water (50 mL) to yield RJl-010 as an off-white solid (0.649 g, 62%). m.p. = 232 C (decomposed). NMR (400 MHz, DMSO-) delta 8.99 (s, 1H), 8.05 (s, 1H), 7.82-7.78 (m, 1H), 7.53-7.50 (m, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.11 (s, 9H). LRMS (ESI+) m/z 369.2 (M35C1+H)+, 371.2 (M37C1+H)+; (ESI-) m/z 1612 (M35C1-H)", 369.2 (M37C1- H)-; HRMS (ESI+) m/z calculated for + 369.11465, found 369.11431.
62%	In methanol; water; at 80℃; for 0.4445h;Reflux;	A mixture of RJ1-008 (0.500 g, 2.82 mmol), 3-amino-N-ri- butylbenzenesulfonamide (SG1-137) (0.74 g, 3.24 mmol), MeOH (5 mL), and water (7.5 mL) was heated to reflux at 40 C. The reflux temperature was raised to 80 C and the reaction was further heated for 26 hours. Upon cooling to ambient temperature, the precipitate which formed was then filtered and washed with water (50 mL) to yield RJl-010 as an off-white solid (0.649 g, 62%). m.p. = 232 C (decomposed). lH NMR (400 MHz, DMSO-ifc) delta 8.99 (s, 1H), 8.05 (s, 1H), 7.82-7.78 (m, 1H), 7.53-7.50 (m, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.11 (s, 9H). LRMS (ESI+) m/z 369.2 (M35C1+H)+, 371.2 (M37C1+H)+; (ESI-) m/z 367.2 (M35C1-H)-, 369.2 (M37C1- H)-; HRMS (ESI+) m/z calculated for C16H21CIN4O2S (M+H)+ 369.11465, found 369.11431.

Reference： [1]Patent: WO2016/22460,2016,A1 .Location in patent: Page/Page column 95
[2]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 204

22
[ 3177-24-0 ]
3-amino-N-(dimethylethyl)benzenesulfonamide [ No CAS ]
N-tert-butyl-3-[2-chloro-5-cyano-pyrimidin-4-yl]benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%		General procedure: DIPEA (0.86mmol) was added to the solution of 2,4-dichloropyrimidine-5-carnonitrile (0.57mmol) in DMF (0.5ml) and stirred at room temperature for 10min. A solution of aminobenzene reagent corresponding to desired product (0.57mmol) in DMF (0.5ml) was added dropwise to the reaction mixture and stirred for 1h. The resultant was evaporated under vacuum and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, filtered, and dried under reduced pressure. 4c was obtained from the reaction of 4b, whereby substitution at the 2-position occurred.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 124,p. 896 - 905

23
[ 51940-64-8 ]
3-amino-N-(dimethylethyl)benzenesulfonamide [ No CAS ]
ethyl 4-(3-(N-tert-butylsulfamoyl)phenylamino)-2-chloropyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-ethyl-N,N-diisopropylamine; In methanol; water; at 45℃; for 17h;Sealed tube;	A mixture of ethyl 2,4-dichloropyrimdine-5-carboxylate (0.221 g, 1.0 mmol), 3- amino-N-ri-butylbenzenesulfonamide SG1-137 (0.265 g, 1.15 mmol), MeOH (2 mL), and water (3 mL) was reacted and worked up following the same procedure used to make RJ1-050, with the exception that the reaction was run for 17 hours, to yield a tan solid. The solid was then purified via flash chromatography eluting with hexanes/EtOAc to provide RJl-063-01 as a white flaky solid (0.211 g, 51%). m.p. = 161 C (decomposed). lH NMR (400 MHz, DMSO-ifc) delta 10.35 (s, 1H), 8.82 (s, 1H), 8.11 (t, / = 1.9 Hz, 1H), 7.80-7.72 (m, 1H), 7.63 (dt, / = 7.8, 1.5 Hz, 1H), 7.61-7.55 (m, 2H), 4.38 (q, / = 7.1 Hz, 2H), 1.34 (t, / = 7.1 Hz, 3H), 1.11 (s, 9H). LRMS (ESI+) m/z 413.1 (M35C1+H)+, 415.1 (M37C1+H)+; (ESI-) m/z 411.1 (M35C1-H)-; HRMS (ESI+) m/z calculated for C17H21CIN4O4S (M+H)+ 413.10448, found 413.10573.

Reference： [1]Patent: WO2017/66428,2017,A1 .Location in patent: Page/Page column 207; 209-210

24
[ 1393900-79-2 ]
[ 76-05-1 ]
[ 608523-94-0 ]
[ 1877285-79-4 ]

Yield	Reaction Conditions	Operation in experiment
35 mg	Stage #1: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate; 3-amino-N-(dimethylethyl)benzenesulfonamide With hydrogenchloride In ethanol; water at 85℃; for 2h; Stage #2: trifluoroacetic acid In water; acetonitrile	5-Trifluoromethyl-^V⁴-(3-[^V-(l,l-dimethylethyl)sulfamoyl]phenyl)-^V²-[4-(piperazin- l-yl)phenyl]pyrimidine-2,4-diamine (SG2-033-01-1) (3 TFA salt): To a solution of SG2-022 (100 mg, 0.218 mmol) and SGl-137 (50 mg, 0.218 mmol) in EtOH (1 mL) was added 3 drops of 4 M HCl (aq). The mixture was stirred at 85 °C for 2 hours. The solution was diluted with EtOAc (40 mL) and washed with saturated NaHCCb (40 mL). The aqueous layer was then re- extracted with EtOAc (40 mL). The combined organic layers were washed with water and brine (40 mL each), dried over Na2S04, and concentrated under reduced pressure to provide a crude oil. The crude oil was purified via HPLC eluting with 30% MeCN and 70% water (with 0.1% TFA) to provide the title compound SG2-033-01-1 as a yellow solid (35 mg, 29%). Mp: 183 °C (dec). HPLC: 99% [tR = 6.8 min, 50% MeOH, 50% water (with 0.1% TFA), 20 min]. NMR at 80 °C (400 MHz, DMSO-ifc): δ 9.22 (s, IH, disappeared on D20 shake), 8.62 (s, IH, disappeared on D20 shake), 8.60 (br s, IH, disappeared on D20 shake), 8.33 (s, IH), 7.89 (s, IH), 7.77 (d, / = 8.0 Hz, IH), 7.65 (d, / = 8.0 Hz, IH), 7.50 (t, / = 8.0 Hz, IH), 7.37 (d, / = 8.7 Hz, 2H), 7.18 (s, IH, disappeared on D20 shake), 6.79 (d, / = 8.7 Hz, 2H), 1.13 (s, 9H). 19F NMR (376 MHz, DMSO-ifc): δ -59.20 (3F), -74.25 (9F). HPLC-MS (ESI+): m/z 550.3 [100%, (M+H)+], 275.7 [50%, (M+2H)2+]. LC-MS (ESI+): 572.2 [15%, (M+Na)+], 550.2 [100%, (M+H)+]. HRMS (ESI+): m/z calcd for C25H30F3N7O2S (M+H)+ 550.2207, found 550.2194.

Reference： [1]Current Patent Assignee: H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE - WO2017/66428, 2017, A1 Location in patent: Page/Page column 109

25
[ 3934-20-1 ]
[ 608523-94-0 ]
[ 2153486-80-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	In methanol at 50℃; for 12h;
26%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 72h;	(S)-2-((3-(4-((4-((3-(N-(tert-Butyl)sulfamoyl)phenyl)amino)pyrimidin-2- yl)amino)phenoxy)propyl)amino)-N-(2-(2,7-dioxoazepan-3-yl)-1,3-dioxoisoindolin-4- yl)acetamide (Compound 58) [0522] To a solution of 3-amino-N-(tert-butyl)benzenesulfonamide (6.1 g, 26.8 mmol) and 2,4-dichloro-pyrimidine (2.0 g, 13.4 mmol) in dioxane (120 mL) and DIEA (3.5 g, 26.8 mmol) was added. The reaction mixture was stirred at 100°C for 72 hrs, cooled to rt, concentrated under vacuum, and the residue was purified on silica gel using 20%-50% EA in petroleum ether to afford N-(tert-butyl)-3-((2-chloropyrimidin-4- yl)amino)benzenesulfonamide (2.4 g, 7.04 mmol, 26% yield) as yellow solid. MS (ESI) m/z 340.9 [M+H]+.

Reference： [1]Patwari, Shivaji B.; Murali, Medari S.; Jadhav, Vivekanand B. [Journal of Heterocyclic Chemistry, 2018, vol. 55, # 12, p. 2911 - 2918]
[2]Current Patent Assignee: BIOTHERYX INC - WO2017/201069, 2017, A1 Location in patent: Paragraph 0522

26
[ 2304858-76-0 ]
[ 608523-94-0 ]
[ 2349449-87-0 ]

Yield	Reaction Conditions	Operation in experiment
46.7%	In deuteromethanol; water-d2 at 45℃; Inert atmosphere;	2.3 Step 3 Synthesis of Compound 15. Add compound 14 (400 mg, 2.39 mmol) to a 50 mL single-mouth bottle with magnetic stirring at room temperature.And MeOD/heavy water mixture (10mL, 1/1),Stir and dissolve,Compound 4 (382 mg, 1.68 mmol) was added.The reaction mixture was warmed to 45 ° C under nitrogen and stirred to react overnight.Cool to room temperature,A large amount of white solid precipitated,filter,The filter cake was washed with MeOD/heavy water (2 mL/2 mL).Drain,Drying at 50 ° C under vacuum gave a white solid (400 mg, yield 46.7%).

Reference： [1]Current Patent Assignee: SHENZHEN TARGETRX INC - CN109232440, 2019, A Location in patent: Paragraph 0150; 0151; 0152; 0153; 0158; 0159

27
[ 61727-34-2 ]
3-amino-N-(dimethylethyl)benzenesulfonamide [ No CAS ]
C₁₉H₂₆N₄O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	In dimethyl sulfoxide; at 150℃; for 2.0h;	Compound 1 (246 mg, 1.0 mmol), 2 (228 mg, 1.0 mmol) was added to DMSO (8 mL), and the mixture was stirred at 150 C for 2 h.The reaction mixture was concentrated to dryness under reduced pressure.The residue was purified by silica gel column chromatography (mobile phase dichloromethane)Yellow solid intermediate 3 (186 mg, yield 42%).

Reference： [1]Patent: CN110305140,2019,A .Location in patent: Paragraph 0062-0066

28
[ 2446464-76-0 ]
[ 608523-94-0 ]
[ 2600448-06-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	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 24h;	105-1; 105-2 (R)-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-3-(6-azaspiro[2.5]octan-6- yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxamide and (S)-N-(3-(N-(tert- butyl)sulfamoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine- 2-carboxamide To a stirred mixture of 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2- yl)pyrazine-2-carboxylic acid (150mg, 0.434 mmol, Intermediate 9), 3-amino-N-(tert- butyl)benzenesulfonamide (119 mg, 0.52 mmol), and DIPEA (0.19 mL, 1.09 mmol) in DMF (2 mL) was added HATU (0.21 g, 0.56 mmol). The reaction mixture was stirred at rt for 18 h and diluted with water. The precipitated solid was collected by filtration, washed with water and dried. The crude material was purified by silica gel chromatography (0-30% EtOAc:EtOH (3:1) in heptane) to give N-(3-(N-(tert- butyl)sulfamoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine- 2-carboxamide (192 mg, 0.346 mmol, 80 % yield) as a white solid.1H NMR (DMSO-d6) d: 10.98 (s, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.87 (dt, J=6.9, 2.1 Hz, 1H), 7.51-7.61 (m, 3H), 6.94 (s, 1H), 3.50-3.59 (m, 4H), 1.69 (s, 3H), 1.34-1.41 (m, 4H), 1.11 (s, 9H), 0.32 (s, 4H). ). m/z (ESI): 556.1 (M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26099, 2021, A1 Location in patent: Paragraph 0189; 0322-0323

29
[ 2490660-21-2 ]
[ 608523-94-0 ]
[ 2601475-59-4 ]

Yield	Reaction Conditions	Operation in experiment
3.02 g	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;	A 250-mL round-bottomed flask was charged with 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (2.0 g, 8.00 mmol, Intermediate 9) and DCM (30 mL). To the reaction mixture at RT was added oxalyl dichloride (6.00 mL, 11.99 mmol), followed by a couple of drops of DMF. The mixture was stirred at rt for 30 min and the solvent was removed under vacuum. The residue was redissolved in DCM (30 mL) and treated with 3-amino-N-(tert-butyl)benzenesulfonamide (1.80 g, 7.90 mmol) followed by DIPEA (6.98 mL, 40.0 mmol). The reaction mixture was stirred at RT for 1 h before it was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 5 % to 50 % EtOAc in heptane to afford N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-fluoro-2-(spiro[2.5]octan-6-yl)nicotinamide (3.02 g, 82 % yield) as an off-white solid. 1H NMR (400MHz, CHLOROFORM-d) d = 11.33 (s, 1H), 8.54 (t, J=8.3 Hz, 1H), 8.27 (t, J=1.9 Hz, 1H), 7.93 (dd, J=1.1, 8.1 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.55 - 7.47 (m, 1H), 6.78 (dd, J=3.3, 8.4 Hz, 1H), 4.62 (s, 1H), 3.32 - 3.25 (m, 4H), 1.61 - 1.56 (m, 4H), 1.29 (s, 9H), 0.41 (s, 4H). m/z (ESI): 461.1(M+H)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1 Location in patent: Paragraph 0338-0339

30
[ CAS Unavailable ]
[ 608523-94-0 ]
[ 2601475-86-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	105.1 Step 1 A 100-mL round-bottomed flask was charged with 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)- 2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (549 mg, 1.59 mmol, Intermediate 11) and DCM (8 mL). To the reaction mixture at RT was added oxalyl dichloride (1.43 mL, 2.86 mmol, 2M in DCM) was added followed by a couple of drops of DMF. The mixture was stirred at rt for 1 h and the solvent was removed under vacuum. The residue was redissolved in DCM (10 mL) and treated with 3-amino-N-(tert- butyl)benzenesulfonamide (0.38 mL, 1.67 mmol), and DIPEA (1.39 mL, 7.95 mmol). The reaction mixture was stirred at RT for 18 h before it was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by flash column chromatography eluting with 0 % to 60 % EtOAc in heptane to N-(3-(N-(tert- butyl)sulfamoyl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide (703 mg, 1.26 mmol, 80 % yield) as light-yellow solid. MS (ESI, Positive ion) m/z: 556.1 [M+1].

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1 Location in patent: Paragraph 0360-0361

31
[ CAS Unavailable ]
[ 608523-94-0 ]
[ 2601475-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	107-1; 107-2 A 100-mL round-bottomed flask was charged with 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro- 2-hydroxypropan-2-yl)nicotinic acid (0.87 g, 2.52 mmol, Intermediate 12) and DCM (8 mL). To the reaction mixture at RT was added oxalyl dichloride (2.52 mL, 5.05 mmol, 2 M in DCM) was added followed by a couple of drops of DMF. The mixture was stirred at rt for 1 h and the solvent was removed under vacuum. The residue was redissolved in DCM (10 mL) and treated with 3-amino-N-(tert-butyl)benzenesulfonamide (0.576 g, 2.52 mmol), and DIPEA (2.20 mL, 12.62 mmol). The reaction mixture was stirred at RT for 18 h before it was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by flash column chromatography eluting with 10 % to 60 % EtOAc in heptane to give racemic N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6- azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide. 1H NMR (400 MHz, CHLOROFORM-d) d 11.19 (s, 1H), 8.52 (d, J=8.02 Hz, 1H), 8.26 (s, 1H), 7.94 (dd, J=1.17, 8.22 Hz, 1H), 7.68 (d, J=7.82 Hz, 1H), 7.47-7.54 (m, 1H), 7.37 (d, J=8.02 Hz, 1H), 5.85 (s, 1H), 4.79 (br s, 1H), 3.29- 3.38 (m, 4H), 1.76 (s, 3H), 1.57-1.65 (m, 4H), 1.28 (s, 9H), 0.42 (s, 4H). MS (ESI, Positive ion) m/z: 555.2 [M+1].

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1 Location in patent: Paragraph 0366-0367

32
[ 2446465-06-9 ]
[ 608523-94-0 ]
[ 2601475-30-1 ]

Yield	Reaction Conditions	Operation in experiment
28%	Stage #1: 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: 3-amino-N-(dimethylethyl)benzenesulfonamide In N,N-dimethyl-formamide at 20℃; for 24h;	113 To a solution of 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (0.1 g, 0.308 mmol, Intermediate 10) in DMF (2 mL) were added HATU (0.176 g, 0.462 mmol), and diisopropylethylamine (0.135 mL, 0.771 mmol) at 0 °C and stirred for 10 min. 3-Amino-N-(tert- butyl)benzenesulfonamide (0.070 g, 0.308 mmol) was added to the reaction mixture and stirred at room temperature for 24 h. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 x 15 mL). The organic layer was washed with brine solution (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified through silica gel chromatography using a gradient of 50 % EtOAc in hexanes to give the title compound (68 mg, 28 % yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): d 10.76 (s, 1H), 8.32 (s, 1H), 7.93 - 7.81 (m, 2H), 7.62 - 7.51 (m, 3H), 7.02 (d, J = 7.7 Hz, 1H), 4.57 (s, 2H), 3.36 (t, J = 7.6 Hz, 4H), 3.13 (s, 3H), 1.36 (t, J = 7.6 Hz, 4H), 1.11 (s, 9H), 0.28 (s, 4H). MS (ESI, Positive ion) m/z: 535.2 [M+1].

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26100, 2021, A1 Location in patent: Paragraph 0389-0390

33
[ 312736-49-5 ]
[ 608523-94-0 ]
[ 2600448-36-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In N,N-dimethyl-formamide at 20℃; for 24h;	Intermediate 10: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-3,5-dichloropyrazine-2-carboxamide. To a stirred mixture of 3,5-dichloropyrazine-2-carboxylic acid (2.19 g, 11.35 mmol), 3-amino-N-(tert- butyl)benzenesulfonamide (2.85 g, 12.48 mmol) in DMF (20 mL) at rt was added 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (4.71 g, 17.02 mmol). The reaction mixture was stirred at RT for 24 h and water was added to the mixture. The precipitate obtained was filtered off, washed with water, and dried. N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2,6-dichloronicotinamide (4.10 g, 90 % yield) was obtained as a white solid. m/z (ESI): 425.0 (M+Na)+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26099, 2021, A1 Location in patent: Paragraph 0189; 0297

34
[ 124700-40-9 ]
[ 608523-94-0 ]
[ 2600559-98-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: 2-fluoro-4-iodo-benzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Stage #2: 3-amino-N-(tert-butyl)benzenesulfonamide With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h;
78%	With 4-methyl-morpholine; 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h;	1 [0376] Intermediate 19: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-iodo-2-(6-azaspiro[2.5]octan-6- yl)benzamide. [0377] Step-1: To a solution of 2-fluoro-4-iodobenzoic acid (2.0 g, 7.52 mmol) in DMF (20 mL) were added 3-amino-N-(tert-butyl)benzenesulfonamide (1.72 g, 7.52 mmol), (1-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (3.86 g, 9.02 mmol) and N-methylmorpholine (2.48 mL, 22.56 mmol) slowly at RT and stirred for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column, eluting with a gradient of 0-50% EtOAc in hexanes, to give N-(3-(N-(tert- butyl)sulfamoyl)phenyl)-2-fluoro-4-iodobenzamide (2.8 g, 78% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): d 10.72 (s, 1H), 8.29 (s, 1H), 7.86 - 7.71 (m, 3H), 7.61 - 7.51 (m, 3H), 7.48 (t, J=7.83 Hz, 1H), 1.12 (s, 9H). m/z (ESI): 475.0 [M-1].

Reference： [1]Tamayo, Nuria A.; Bourbeau, Matthew P.; Allen, Jennifer R.; Ashton, Kate S.; Chen, Jian Jeffrey; Kaller, Matthew R.; Nguyen, Thomas T.; Nishimura, Nobuko; Pettus, Liping H.; Walton, Mary; Belmontes, Brian; Moriguchi, Jodi; Chen, Kui; McCarter, John D.; Hanestad, Kelly; Chung, Grace; Ninniri, Maria Stefania S.; Sun, Jan; Poppe, Leszek; Spahr, Chris; Hui, John; Jia, Lei; Wu, Tian; Dahal, Upendra P.; Edson, Katheryne Z.; Payton, Marc [Journal of Medicinal Chemistry, 2022, vol. 65, # 6, p. 4972 - 4990]
[2]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1 Location in patent: Paragraph 0376; 0377

35
[ 608523-94-0 ]
[ 2600559-99-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate; 4-methyl-morpholine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 16 h / 100 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 1.2: 0.5 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 8 h / Heating

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1
[2]Tamayo, Nuria A.; Bourbeau, Matthew P.; Allen, Jennifer R.; Ashton, Kate S.; Chen, Jian Jeffrey; Kaller, Matthew R.; Nguyen, Thomas T.; Nishimura, Nobuko; Pettus, Liping H.; Walton, Mary; Belmontes, Brian; Moriguchi, Jodi; Chen, Kui; McCarter, John D.; Hanestad, Kelly; Chung, Grace; Ninniri, Maria Stefania S.; Sun, Jan; Poppe, Leszek; Spahr, Chris; Hui, John; Jia, Lei; Wu, Tian; Dahal, Upendra P.; Edson, Katheryne Z.; Payton, Marc [Journal of Medicinal Chemistry, 2022, vol. 65, # 6, p. 4972 - 4990]

36
[ 608523-94-0 ]
[ 2600577-49-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate; 4-methyl-morpholine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 16 h / 100 °C / Inert atmosphere 3: (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; copper (I) iodide; tripotassium phosphate tribasic / N,N-dimethyl-formamide / 16 h / 100 °C / Inert atmosphere; Sealed tube
	Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 1.2: 0.5 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 8 h / Heating 3.1: copper (I) iodide; sarcosine; tripotassium phosphate tribasic / N,N-dimethyl-formamide / 18 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1
[2]Tamayo, Nuria A.; Bourbeau, Matthew P.; Allen, Jennifer R.; Ashton, Kate S.; Chen, Jian Jeffrey; Kaller, Matthew R.; Nguyen, Thomas T.; Nishimura, Nobuko; Pettus, Liping H.; Walton, Mary; Belmontes, Brian; Moriguchi, Jodi; Chen, Kui; McCarter, John D.; Hanestad, Kelly; Chung, Grace; Ninniri, Maria Stefania S.; Sun, Jan; Poppe, Leszek; Spahr, Chris; Hui, John; Jia, Lei; Wu, Tian; Dahal, Upendra P.; Edson, Katheryne Z.; Payton, Marc [Journal of Medicinal Chemistry, 2022, vol. 65, # 6, p. 4972 - 4990]

37
[ 2600559-89-3 ]
[ 608523-94-0 ]
[ 2600558-99-2 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: 4-((3-methyloxeten-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yI)benzoic acid 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 0.166667h; Stage #2: 3-amino-N-(dimethylethyl)benzenesulfonamide In N,N-dimethyl-formamide at 20℃; for 12h;	100 [0394] Example 100: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl)-2-(6- azaspiro[2.5]octan-6-yl)benzamide [0395] To a solution of 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (120 mg, 0.33 mmol, Intermediate 15) in DMF (2 mL) were added HATU (187 mg, 0.49 mmol) and DIPEA (143 L, 0.821 mmol) at RT and stirred for 10 min. To this reaction mixture, 3-amino-N-(tert- butyl)benzenesulfonamide (82 mg, 0.36 mmol) was added and stirred for 12 h at RT. The reaction mixture was quenched with water (20 mL) and extracted by EtOAc (3 x 25 mL). The combined organic extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 30% EtOAc in hexanes to give the title compound (110 mg, 58% yield) as an off-white solid.1H NMR (400 MHz, Chloroform-d): d 12.33 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 2.1Hz, 1H), 8.06 - 7.95 (m, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 5.19 (d, J = 7.0 Hz, 2H), 4.52 (s, 1H), 4.47 (d, J = 7.0 Hz, 2H), 3.16 (t, J = 5.5 Hz, 4H), 1.73 (s, 3H), 1.70 - 1.60 (b s, 3H), 1.30 (s, 9H), 0.48 (s, 4H). m/z (ESI): 576.2 [M+1].
58%	Stage #1: 4-((3-methyloxeten-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yI)benzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3-amino-N-(dimethylethyl)benzenesulfonamide In N,N-dimethyl-formamide at 20℃; for 12h;	C8 Example C8: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl)- 2-(6-azaspiro[2.5]octan-6-yl)benzamide To a solution of 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6- yl)benzoic acid (120 mg, 0.33 mmol, Intermediate 15) in DMF (2 mL) were added HATU (187 mg, 0.49 mmol) and DIPEA (143 μL, 0.821 mmol) at RT and stirred for 10 min. To this reaction mixture, 3-amino-N-(tert-butyl)benzenesulfonamide (82 mg, 0.36 mmol) was added and stirred for 12 h at RT. The reaction mixture was quenched with water (20 mL) and extracted by EtOAc (3 x 25 mL). The combined organic extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 30% EtOAc in hexanes to give the title compound (110 mg, 58% yield) as an off-white solid.1H NMR (400 MHz, Chloroform-d): 12.33 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.06 - 7.95 (m, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 5.19 (d, J = 7.0 Hz, 2H), 4.52 (s, 1H), 4.47 (d, J = 7.0 Hz, 2H), 3.16 (t, J = 5.5 Hz, 4H), 1.73 (s, 3H), 1.70 - 1.60 (b s, 3H), 1.30 (s, 9H), 0.48 (s, 4H). m/z (ESI): 576.2 [M+1].
58%	Stage #1: 4-((3-methyloxeten-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yI)benzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3-amino-N-(dimethylethyl)benzenesulfonamide In N,N-dimethyl-formamide at 20℃; for 12h;	C8 Example C8: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl)- 2-(6-azaspiro[2.5]octan-6-yl)benzamide To a solution of 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6- yl)benzoic acid (120 mg, 0.33 mmol, Intermediate 15) in DMF (2 mL) were added HATU (187 mg, 0.49 mmol) and DIPEA (143 μL, 0.821 mmol) at RT and stirred for 10 min. To this reaction mixture, 3-amino-N-(tert-butyl)benzenesulfonamide (82 mg, 0.36 mmol) was added and stirred for 12 h at RT. The reaction mixture was quenched with water (20 mL) and extracted by EtOAc (3 x 25 mL). The combined organic extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 30% EtOAc in hexanes to give the title compound (110 mg, 58% yield) as an off-white solid.1H NMR (400 MHz, Chloroform-d): 12.33 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.06 - 7.95 (m, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 5.19 (d, J = 7.0 Hz, 2H), 4.52 (s, 1H), 4.47 (d, J = 7.0 Hz, 2H), 3.16 (t, J = 5.5 Hz, 4H), 1.73 (s, 3H), 1.70 - 1.60 (b s, 3H), 1.30 (s, 9H), 0.48 (s, 4H). m/z (ESI): 576.2 [M+1].

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1 Location in patent: Paragraph 0394; 0395
[2]Current Patent Assignee: AMGEN INC - WO2021/211549, 2021, A1 Location in patent: Paragraph 00360-00361
[3]Current Patent Assignee: AMGEN INC - WO2021/211549, 2021, A1 Location in patent: Paragraph 00360-00361

38
[ 2446464-96-4 ]
[ 608523-94-0 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
2.0 g	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 3h;	108-1.5; 108-2.5 [0431] Step 5: To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4- yl)nicotinic acid (2.0 g, 5.77 mmol) in DMF (20 mL) were added 3-amino-N-(tert- butyl)benzenesulfonamide (1.32 g, 5.77 mmol), HATU (2.195 g, 5.77 mmol) and DIPEA (1.01 mL, 5.77 mmol) at rt and stirred for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether (50 mL), filtered, and dried under vacuum to give N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6- azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinamide (2.0 g, 62% yield) as an off- white solid. 1H NMR (400 MHz, Chloroform-d): d 12.94 (s, 1H), 8.31 (s, 1H), 8.27 (bs, 1H), 8.01 (d, J = 8.22 Hz, 1H), 7.64 (d, J = 7.82 Hz, 1H), 7.46 - 7.55 (m, 2H), 7.23 (d, J = 8.22 Hz, 1H), 4.54 (d, J = 8.61Hz, 1H), 4.08 - 4.17 (m, 1H), 3.04 - 3.18 (m, 4H), 1.66 (s, 3H), 1.67 - 1.59 (m, 4H), 1.57 (s, 3H), 1.43 (s, 3H), 1.29 (s, 9H), 0.45 (s, 4H). m/z (ESI): 556.2 [M+1].

Reference： [1]Current Patent Assignee: AMGEN INC - WO2021/26098, 2021, A1 Location in patent: Paragraph 0426; 0431

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CAS No. :	608523-94-0	MDL No. :	MFCD06660528
Formula :	C₁₀H₁₆N₂O₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KLQVFEHOLLUULE-UHFFFAOYSA-N
M.W :	228.31	Pubchem ID :	3162838
Synonyms :

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.4
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	61.2
TPSA :	80.57 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.98 cm/s

Log Po/w (iLOGP) :	1.64
Log Po/w (XLOGP3) :	1.01
Log Po/w (WLOGP) :	2.43
Log Po/w (MLOGP) :	1.0
Log Po/w (SILICOS-IT) :	0.35
Consensus Log Po/w :	1.29

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[ 608523-94-0 ]

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

Log S (ESOL) :	-1.99
Solubility :	2.34 mg/ml ; 0.0102 mol/l
Class :	Very soluble
Log S (Ali) :	-2.29
Solubility :	1.17 mg/ml ; 0.00511 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.23
Solubility :	0.134 mg/ml ; 0.000585 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.22

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

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P370	In case of fire:
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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.
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P411
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P413
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P422
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P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
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P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 608523-94-0 ] {[proInfo.proName]}

Quality Control of [ 608523-94-0 ]

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Application In Synthesis of [ 608523-94-0 ]

[ 608523-94-0 ] Synthesis Path-Downstream 1~38

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Aryls

Amines

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Related Functional Groups of
[ 608523-94-0 ]