Name: 1633-82-5|3-Chloropropane-1-sulfonyl chloride|98%
Brand: Ambeed
SKU: A606018
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1
[ 1633-82-5 ]
[ 35578-28-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium hydroxide In dichloromethane for 1h; Ambient temperature;
95%	With ammonium hydroxide In dichloromethane; water for 3h;
93%	With ammonia In tetrahydrofuran

93%	With ammonia In tetrahydrofuran; water at 0 - 20℃; for 1.5h;	A.II.3.3a.1 3. Preparation of Cl-Substituted Cyclopropanesulfonamides The use of an N-Boc protecting Group 3a. Preparation of cyclopropylsulfonylamine tert-butyl carbamate, a key intermediate in the preparation of Cl-substituted cyclopropylsulfonamides Step 1: Preparation of 3-chloropropylsulfonamide A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4×500 mL). The combined dichloromethane layer was washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 1.5h;	A.II.7.C.2 C.2) Preparation of 3-chloropropylsulfonamide A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with CH2Cl2 (4*500-mL). The combined CH2Cl2 layer was washed with 1 N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of CH2Cl2 in hexanes to provide 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia In tetrahydrofuran; water at 0 - 20℃; for 1.5h;	A.II.3.3a.1 Preparation of 3-chloropropylsulfonamide A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer extracted with dichloromethane (4*500 mL). The combined extracts were washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to provide the desired product as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia In tetrahydrofuran; water at 0℃; for 1.5h;	13.1 A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4×500 mL). The combined dichloromethane layer was washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonium hydroxide In tetrahydrofuran	1.2.a.1 Step 1: Step 1: Preparation of 3-chloropropylsulfonamide A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer extracted with dichloromethane (4*500 mL). The combined extracts were washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to provide the desired product as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia In tetrahydrofuran; water at 0 - 20℃; for 1.5h;	A.II.a A solution of 3-Chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 min to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to rt, stirred 1 h, and the aqueous layer partioned multiple time with CH2Cl2 (4×500-mL). The combined CH2Cl2 layer was washed with 1 N HCl (150 mL), water (150 mL), dried over MgSO4 and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of CH2Cl2 in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia In tetrahydrofuran; water at 0 - 20℃; for 1h;	15.1 Step 1: Preparation of 3-chloropropylsulfonamide; A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0 0C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4 x 500 mL). The combined dichloromethane layer was washed with IN HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia In tetrahydrofuran; water at 0 - 20℃; for 1.5h;	15.1 A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4*500 mL). The combined dichloromethane layer was washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia In tetrahydrofuran; water at 0 - 20℃; for 1.5h;	13.1 Step 1: Preparation of 3-chloropropylsulfonamide A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4*500 mL). The combined dichloromethane layer was washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 1.5h;	13.1 A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4×500 mL). The combined dichloromethane layer was washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonium hydroxide In tetrahydrofuran at 0℃; for 0.5h;	13.1 A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4×500 mL). The combined dichloromethane layer was washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia In tetrahydrofuran; water at 0 - 20℃; for 1.5h;	I.3.3a.1 Step 1: Preparation of 3-chloropropylsulfonamide A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer extracted with dichloromethane (4*500 mL). The combined extracts were washed with 1N HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to provide the desired product as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
93%	With ammonia; water In tetrahydrofuran at 0 - 20℃; for 1.5h;	15.1 A solution of 3-chloropropanesulfonyl chloride (55 g, 310.7 mmol) was dissolved in THF (200 mL) and added dropwise over 30 minutes to a solution of NH4OH (200 mL) cooled to 0 0C. The reaction mixture was warmed to room temperature, stirred 1 hour, and the aqueous layer partioned multiple time with dichloromethane (4 x 500 mL). The combined dichloromethane layer was washed with IN HCl (150 mL), water (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was recrystallized from the minimum amount of dichloromethane in hexanes to afford 3-chloropropylsulfonamide as a white solid (45.3 g, 93%). 1H NMR (CDCl3) δ 2.34 (m, 2H), 3.32 (t, J=7.3 Hz, 2H), 3.70 (t, J=6.2 Hz, 2H), 4.83 (s, 2H); 13C NMR (CDCl3) δ 27.10, 42.63, 52.57.
91%	With ammonia In dichloromethane
88.7%	With ammonia In dichloromethane at 0 - 20℃; for 1.5h;	77.a Ammonia gas was bubbled through a stirred solution of 3-chloropropane-1-sulfonyl chloride (CAN 1633-82-5, 10 g, 56 mmol) in methylene chloride (100 mL) for 30 min at 0° C. The reaction mixture was stirred for 1 h at room temperature. The ammonium chloride precipitate was removed by filtration. The solvent was removed under reduced pressure, the solid was purified by re-crystallization from methylene chloride to give the title compound (7.9 g, 0.05 mol, 88.7%) as white solid. 1H NMR (300 MHz, d6-DMSO): δ 6.88 (s, 2H), 3.75 (t, J=6.5 Hz, 2H), 3.11-3.06 (m, 2H), 2.16-2.07 (m, 2H).
88.7%	With ammonia In dichloromethane at 0 - 20℃; for 1.5h;	77.a Ammonia gas was bubbled through a stirred solution of 3-chloropropane-l-sulfonyl chloride (CAN 1633-82-5, 10 g, 56 mmol) in methylene chloride (100 mL) for 30 min at 0°C. The reaction mixture was stirred for 1 h at room temperature. The ammonium chloride precipitate was removed by filtration. The solvent was removed under reduced pressure, the solid was purified by re-crystallization from methylene chloride to give the title compound (7.9 g, 0.05 mol, 88.7%) as white solid. 1H NMR (300 MHz , cf-DMSO): δ 6.88 (s, 2H), 3.75 (t, J = 6.5 Hz, 2H), 3.1 1 - 3.06 (m, 2H), 2.16 - 2.07 (m, 2H).
75%	With ammonia In dichloromethane for 1h;
69%	With ammonia In dichloromethane; water at 0 - 20℃; for 16h;	21a Description 21a; 3-CHLORO-1-PROPANESULFONAMIDE (D21A) To an ice-cooled solution of 3-CHLORO-1-PROPANESULFONYL chloride (Chem. Pharm. Bull, 40 (1), 75-84,1999) (30 ML, 250 MMOL, 1 equiv) in CH2CI2 (150 ml) was slowly added aqueous ammonia solution (32%, 30 ml). The resulting mixture was stirred at room temperature for 16 h and H20 (20 mi) was added. The layers were separated and the organic layer was dried over MGS04 and concentrated in vacuo to give crude 3-CHLORO-1-PROPANESULFONAMIDE (D21A) (27 g, 69%) as a white solid Chem. Pharm. Bull, 40 (1), 75-84,1999].
57%	With ammonium hydroxide In dichloromethane; water at 0 - 20℃; for 1h; Inert atmosphere;
	With ammonium nitrate; ammonia
	With ammonia In water	2 Production of 6-(3-sulfamoylpropylthio)imidazo [1,2-b]pyridazine EXAMPLE 2 Production of 6-(3-sulfamoylpropylthio)imidazo [1,2-b]pyridazine Into a solution of 3-chloropropanesulfonyl chloride (25 g) in ether (20 ml) was bubbled ammonia gas for 30 minutes under ice-cooling. Then, 50 ml of water was added to the reaction mixture. The ether layer was separated and the aqueous layer was extracted with 100 ml of ethyl acetate. The ether layer and ethyl acetate layer were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from n-hexane to obtain 21 g of 3-chloropropanesulfonamide (mp: 64°-65° C.).
	With ammonia In dichloromethane	219 3-Chloropropane-1-sulfonyl chloride (0. 38 ml) is dissolved in methylene chloride (15 ml), and ammonia gas is blown into the mixture for 15 minutes. The reaction solution is stirred overnight, and the resulting ammonium chloride is removed by filtration. The filtrate is concentrated, and the resulting 3-chloropropane-1-sulfonamide and (2R, 4S)-4-[3, 5- bis (trifluoromethyl) benzyl]- (5-hydro. xypyrimidin-2-yl)} amino-2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (500 mg), potassium iodide (1.3 g), and potassium hydroxide (352 mg) are dissolved in dimethylsulfoxide (4 ml), and the mixture is stirred at 60°C for 24 hours. The mixture is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-1 : 1) to give (2R, 4S)-4- { [3, 5-bis (trifluoromethyl) benzyl]- [5- (3-sulfamoylpropoxT)- pyrimidin-2-yl] amino-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline- 1-carboxylic acid ethyl ester (22 mg). MS (m/z): 758 [M+H] +
	With ammonium hydroxide In dichloromethane; water at 0 - 20℃; for 60h;	134 3-Chloropropanesulfonyl chloride (15.0 mL, 120 mmol) was added to 125 mL of DCM and cooled to 0 °C. Concentrated ammonium hydroxide solution (-29% w/w) was added dropwise and the reaction was allowed to warm to rt and stirred for 2.5 days. Water (40 mL) was added and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated to give the crude intermediate 3-chloropropane-l -sulfonamide (contained -50% of desired final product). This material was directly submitted to the subsequent cyclization reaction. The crude 3-chloropropane-l -sulfonamide (6.89 g, 43.7 mmol) was slurried in EtOH (25 mL) and sodium ethoxide (2.1 g, 30.9 mmol) was added and the mixture was refluxed for 24 h. The reaction mixture was concentrated and then the residue was partitioned between DCM and water (~20 mL). The layers were separated and the aq. layer was extracted (3 x 50 mL) with DCM. The organic layers were combined and dried over magnesium sulfate to produce crude isothiazolidine 1,1-dioxide. 1H NMR (400 MHz, CDC13) δ ppm 4.19 (1 H, br. s.), 3.44 (2 H, q, J=6.7 Hz), 3.10 (2 H, t, J=7.4 Hz), 2.40 - 2.55 (2 H, m). Mass Spectrum (ESI) m/e = 122.1 (M + 1).
	In tetrahydrofuran	27.A A) A) 3-Chloropropane-1-sulfonamide To a solution of 3-chloropropane-1-sulfonyl chloride (Aldrich, 1.4 g, 8 mmol) in THF (10 mL) at 0° C. was added dropwise aq. ammonia (15 mL). The solution was allowed to warm to room temperature and stirred at room temperature for 1 h. The resulting suspension was extracted with DCM (2*). The combined organic extracts were washed with water and then aq. HCl, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.63 (br. s., 2H), 3.55 (t, J=6.5 Hz, 2H), 3.39-3.19 (m, 2H), 2.32-2.11 (m, 2H).
	With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere;	27.A 3-Chloropropane-l-sulfonamide To a solution of 3-chloropropane-1-sulfonyl chloride (Aldrich, 1.4 g, 8 mmol) in THF (10 niL) at 0 °C was added dropwise aq. ammonia (15 mL). The solution was allowed to warm to room temperature and stirred at room temperature for 1 h. The resulting suspension was extracted with DCM (2x). The combined organic extracts were washed with water and then aq. HCl, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.63 (br. s., 2H), 3.55 (t, J= 6.5 Hz, 2H), 3.39 - 3.19 (m, 2H), 2.32 - 2.1 1 (m, 2H)

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2
[ 110-91-8 ]
[ 1633-82-5 ]
[ 21297-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine
	In ethyl acetate at 0℃; for 0.5h;
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	1 [00648] N6-cyclohexyl-N2-r2-methoxy-4-ri-(3-morpholinosulfonylpropyl)-4- piperidyl1phenyl1-9H-purine-2,6-diamine (C239) : To the amine 116 (40 mg, 0.088 mmol, 1.0 equiv.) in DMF (0.5 mL) at 0 0C was added DIEA (230 μL, 1.32 mmol, 15 equiv.). 4- (3-chloropropyl-sulfonyl)morpholine (2 μL, 0.025 mmol, 1.1 equiv., prepared by treating 3-chloropropane- l-sulfonyl chloride (103 μL, 0.284 mmol), DIEA (222 μL, 0.426 mmol), morpholine (26 μL, 0.3 mmol) in DMF (1 mL)) was added after 5 minutes, followed with a catalytic amount of KI and the reaction was stirred at room temperature for 18 hours. The residue obtained afater evaporation of the solvent was purified by reverse phase HPLC to get C239.

	With triethylamine In dichloromethane at 0 - 20℃; for 2h;	I-20 A solution of 3-chloropropane-l-sulfonyl chloride (170 μ, 1.4 mmol) in CH2CI2 (2 mL) at 0 °C was treated with a solution of morpholine (140 μ, 1.6 mmol) and Et3N (210 μ, 1.5 mmol) in CH2CI2 (4 mL) and immediately allowed to warm to rt. After 2 h the reaction was concentrated. Ethyl acetate was added and a resulting precipitate was filtered. The filtrate was concentrated to provide the title compound. 1H NMR (CDC13) δ 3.81-3.76 (m, 4H), 3.73-3.68 (m, 2H), 3.33-3.26 (m, 4H), 3.14-3.06 (m, 2H), 2.38-2.26 (m, 2H).
	With triethylamine In dichloromethane at 0 - 20℃;	64.a To a stirred solution of piperidine (0.395 ml, 4.0 mmol) in 8 ml of dry CH2Cl2, NEt3 (0.584 ml, 4.2 mmol) was added, at 0 0C, followed by the slow addition of 3- chloropropane sulfonylchloride (0.51 ml, 4.2 mmol) in 8 ml of dry CH2Cl2. The reaction mixture was stirred at 0 0C for 15 min, ice bath was removed, and then mixture was stirred at r.t., overnight. The mixture was diluted with 100 ml Of CH2Cl2, washed with IN HCl (2x25 ml), H2O (2x25 ml) and sat. NaHCO3 solution (2x25 ml). The organic layer was separated, dried over anhyd.MgSO4, solvents removed in vacuo and the residue was dried under high vacuo to obtain 0.8 g of the product which was used for next step without purification. 1H NMR 500 MHz CDCl3: 3.75, t, J = 4.7, 4H, 3.68, t, J = 6.2, 2H, 3.27, t, J = 4.7, 4H, 3.07, t, J = 7.3, 2H, 2.31-2.26, m, 2H.

Reference： [1]Truce,W.E.; Goralski,C.T. [Journal of Organic Chemistry, 1969, vol. 34, p. 3324 - 3328]
[2]Kuwahara; Kato; Sugawara; Miyake [Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 9, p. 1511 - 1515]
[3]Clark, Robin D.; Jahangir, Alam; Alam, Muzaffar; Rocha, Cynthia; Lin, Lin; Bjorner, Bodil; Nguyen, Khanh; Grady, Carole; Williams, Timothy J.; Stepan, George; Tang, Hai Ming; Ford, Anthony P.D.W. [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 6, p. 1697 - 1700]
[4]Current Patent Assignee: MYREXIS, INC. - WO2010/111406, 2010, A2 Location in patent: Page/Page column 152
[5]Current Patent Assignee: MYREXIS, INC.; ALZHEIMER'S INSTITUTE OF AMERICA, INC. - WO2011/46970, 2011, A1 Location in patent: Page/Page column 103
[6]Current Patent Assignee: ITHERX PHARMACEUTICALS, INC. - WO2009/103022, 2009, A1 Location in patent: Page/Page column 73

3
[ 1633-82-5 ]
[ 62-53-3 ]
[ 90415-85-3 ]

Yield	Reaction Conditions	Operation in experiment
79.7%	With triethylamine In dichloromethane at 20℃; for 5h;	161.1 [Step 1] 3-chloro-N-phenylpropane- 1- sulfonamide A solution of aniline (0.980 mL, 10.738 mmol), triethylamine (1.796 mL, 12.885mmol) and 3-chloropropane-1-sulfonyl chloride (2.091 g, 11.811 mmol) in dichloromethane (30 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 24 g cartridge; ethyl acetate / hexane = 0 % to 5 %) to give 3-chloro-N-phenylpropane-1-sulfonamide as yellow oil (2.000 g, 79.7 %).
	(i) aq. HCl, (ii) /BRN= 1754119/, aq. Na₂CO₃; Multistep reaction;
	In benzene for 1h; Heating;

With TEA In dichloromethane for 1h; Heating;

Reference： [1]Current Patent Assignee: CHONGKUNDANG HOLDINGS CORP. - WO2017/18803, 2017, A1 Location in patent: Paragraph 2237; 2238; 2239; 2442; 2443; 2444
[2]Helferich,B.; Hoffmann,R. [Justus Liebigs Annalen der Chemie, 1962, vol. 657, p. 86 - 94]
[3]Kuwahara; Kawano; Kawai; Ashida; Miyake [Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 9, p. 1505 - 1510]
[4]Valente, Claudia; Guedes, Rita C.; Moreira, Rui; Iley, Jim; Gut, Jiri; Rosenthal, Philip J. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4115 - 4119]

4
[ 1633-82-5 ]
[ 100-46-9 ]
[ 90945-14-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In dichloromethane at 0 - 20℃;	1.6 3-chloro-propylsulfonyl chloride was added dropwise to a stirred solution of benzylamine (1 eq) and triethylamine (1.1 eq) in DCM (0.6 M) at 0° C. The solution was stirred at RT overnight. The solvent was then removed in vacuo, Et2O was added to get a precipitate that was eliminated by filtration, while the filtrate was concentrated in vacuo. Subsequent addition of PE resulted in the formation of a white precipitate that was collected by filtration to afford the title compound (86%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 2.02-2.09 (m, 2H), 3.03-3.07 (m, 2H), 3.67 (t, J 6.6, 2H), 4.14 (d, J 6.1, 2H), 7.25-7.30 (m, 1H), 7.32-7.36 (m, 4H), 7.73 (t, J 6.1, 1H).
	In benzene
	In dichloromethane at -10℃; for 1h;

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2008/153895, 2008, A1 Location in patent: Page/Page column 7
[2]Helferich,B.; Hoffmann,R. [Justus Liebigs Annalen der Chemie, 1962, vol. 657, p. 86 - 94]
[3]Valente, Claudia; Guedes, Rita C.; Moreira, Rui; Iley, Jim; Gut, Jiri; Rosenthal, Philip J. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4115 - 4119]

5
[ 1120-71-4 ]
[ 1633-82-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With thionyl chloride; N,N-dimethyl-formamide Heating;
82%	With thionyl chloride In N,N-dimethyl-formamide for 12h; Reflux;	3.3.1. Synthesis of 3-Chloropropane-1-Sulfonyl Chloride (2) To a round-bottom flask containing 1,3-propanesultone 1 (3 g, 24.7 mmol) was addedthionyl chloride (3.6 mL, 49.5 mmol) and DMF (0.2 mL). The mixture was refluxed for 12h. The excess thionyl chloride was removed by vacuum to obtain sulfonyl chloride productas a pale yellow liquid 2 (3.58 g, 82% yield).

Reference： [1]King,J.F.; Loosmore,S.M.; Aslam,M. [Journal of the American Chemical Society, 1982, vol. 104, p. 7108]
[2]Chen, Chien-Yuan; Chen, Jin-Syuan; Chu, Yen-Ho [Molecules, 2022, vol. 27, # 1]

6
[ 1633-82-5 ]
[ 124-40-3 ]
[ 78472-00-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In dichloromethane
	In methanol; ethyl acetate for 0.5h;
5.19 g	In tetrahydrofuran at 0 - 10℃; for 0.5h;	30.a 3-Chloro-propane-1-sulfonic acid dimethylamide A stirred solution of 3-chloropropylsulfonylchloride (6.00 g, 33.90 mmol) in THF (35 mL) was cooled in an ice bath to 0-5° C. Dimethylamine (2 M in THF; 36 mL, 72 mmol) was added drop-wise, maintaining the temperature below 10° C., and the resultant suspension stirred at 5° C. for 30 minutes then allowed to warm to RT. After 1 hour, the mixture was diluted with water and extracted into EtOAc and the extract washed with water, brine and then dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (5.19 g). 1H NMR (400 MHz, CDCl3): δ 3.70 (2H, t, J 6.2 Hz), 3.06-3.12 (2H, m), 2.90 (6H, s), 2.25 (2H, m).

5.19 g	In tetrahydrofuran at 0 - 20℃; for 1.5h; Cooling with ice;	a) 3-Chloro-propane-1-sulfonic acid dimethylamide A stirred solution of 3-chloropropylsulfonylchloride (6.00 g, 33.90 mmol) in THF (35 mL) was cooled in an ice bath to 0-5 °C. Dimethylamine (2 M in THF; 36 mL, 72 mmol) was added drop-wise, maintaining the temperature below 10°C, and the resultant suspension stirred at 5°C for 30 min then allowed to warm to RT. After 1 h, the mixture was diluted with water and extracted into EtOAc and the extract washed with water, brine and then dried (Na2S04), filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (5.19 g). NMR (400 MHz, CDC13): δ 3.70 (2H, t, J 6.2 Hz), 3.06-3.12 (2H, m), 2.90 (6H, s), 2.25 (2H, m).
1.86 g	With triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 1.5h; Cooling with ice;	89 Reference Example 88 ompound 2 (200 mg) and triethylamine (410 μL)In dichloromethane (2 mL)Compound 1 (120 μL) was added under ice cooling,And the mixture was stirred at room temperature for 1.5 hours.Hydrochloric acid water (1 mol / L) was added to the reaction mixture, and after stirring,The organic layer was separated,Drying,And concentrated under reduced pressure.To a solution of the obtained compound in N, N-dimethylformamide (2 mL)To the solution,Under ice-cooling, sodium hydride (60%in oil, 45.2 mg)Is added,And the mixture was stirred at 80 ° C. for 16.5 hours.The reaction mixture was allowed to cool to room temperature,After adding chloroform and water and stirring,The organic layer was separated, dried and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70: 30 to 50: 50) to obtain Compound 3(78.4 mg) as a colorless liquid.

Reference： [1]King, James F.; Lam, Joe Y. L.; Ferrazzi, Gabriele [Journal of Organic Chemistry, 1993, vol. 58, # 5, p. 1128 - 1135]
[2]Kuwahara; Kawano; Kawai; Ashida; Miyake [Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 9, p. 1505 - 1510]
[3]Current Patent Assignee: Valline SRL - US2014/171414, 2014, A1 Location in patent: Paragraph 0664; 0665; 0666
[4]Current Patent Assignee: Valline SRL - WO2014/95700, 2014, A1 Location in patent: Page/Page column 130-131
[5]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - JP2018/199673, 2018, A Location in patent: Paragraph 0200; 0201

7
[ 1633-82-5 ]
[ 71-36-3 ]
1-butyl 3-chloro-1-propanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In dichloromethane at 0℃; for 16h;	12.A Triethylamine (28 ml, 200 mmol) in CH2Cl2 (50 ml) was slowly added to an ice- cooled solution of 3 -chloro- 1-propanesulfonyl chloride (36.6g, 200 mmol) and 1-butanol (18.4 g, 240 m mol) in CH2Cl2 (250 ml) and stirring was continued for 16h. The mixture was diluted with CH2Cl2 (200 ml), washed (aqueous HCl) and dried (MgSO4) and the solvent was evaporated to obtain the titled product 1 (40.85 g, 95%) in crude form as slightly yellow oil which was used for the next reaction without further purification. 1H NMR (CDCl3)) δ 0.94 (t, J = 7.5 Hz, 3H), 1.44 (sextet, 2H), 1.72 (quintet, 2H), 2.31 (quintet, 2H), 3.27(t, J = 6.9 Hz, 2H), 3.68 (t, J = 6.3 Hz), 4.23 (t, J = 6.6 Hz, 2H).
76%	With triethylamine In dichloromethane for 0.333333h;

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/14011, 2007, A2 Location in patent: Page/Page column 48
[2]King, James F.; Lam, Joe Y. L.; Ferrazzi, Gabriele [Journal of Organic Chemistry, 1993, vol. 58, # 5, p. 1128 - 1135]

8
[ 109-01-3 ]
[ 1633-82-5 ]
[ 261767-18-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydroxide In toluene	6 1-(3-Chloropropane-1-sulfonyl)-4-methylpiperazine PREPARATION 6 1-(3-Chloropropane-1-sulfonyl)-4-methylpiperazine The following is the preparation of a compound of formula 6b wherein R3and R4 are each hydrogen, L is chloro, m is 3, Y is -SO2, and Z is 4-methylpiperazine. To a cooled solution of N-methylpiperazine (8.49 g), toluene (43 mL), and sodium hydroxide (25%, 43 mL) was added a solution of 3-chloro-propanesulfonyl chloride (15 g) in toluene (30 mL) over a period 30 minutes. The mixture was stirred for 1 hour in a cold bath and then for another hour at room temperature. The top organic layer was separated, washed with aqueous sodium chloride, dried (MgSO4), filtered, and concentrated to give the title compound (17.9 g, 88%); m.p. 43.0-44.5° C.
	In ethyl acetate at 0℃; for 0.5h;
	With triethylamine In dichloromethane at 0 - 20℃; for 2h;	I-17 A solution of 3-chloropropane-l-sulfonyl chloride (170 μ, 1.4 mmol) in CH2CI2 (2 mL) at 0 °C was treated with a solution of 1-methylpiperazine (170 μ, 1.5 mmol) and Et3N (210 μ, 1.5 mmol) in CH2CI2 (4 mL) and immediately allowed to warm to rt. After 2 h the reaction was concentrated. Ethyl acetate was added and the resulting suspension filtered. The filtrate was concentrated to provide the title compound. 1H NMR (CDC13) δ 3.72-3.68 (m, 2H), 3.39-3.32 (m, 4H), 3.12-3.06 (m, 2H), 2.58-2.50 (m, 4H), 2.36 (s, 3H), 2.34-2.26 (m, 2H).

Reference： [1]Current Patent Assignee: Syntex (USA) LLC - US6172062, 2001, B2
[2]Kuwahara; Kato; Sugawara; Miyake [Chemical and Pharmaceutical Bulletin, 1995, vol. 43, # 9, p. 1511 - 1515]
[3]Clark, Robin D.; Jahangir, Alam; Alam, Muzaffar; Rocha, Cynthia; Lin, Lin; Bjorner, Bodil; Nguyen, Khanh; Grady, Carole; Williams, Timothy J.; Stepan, George; Tang, Hai Ming; Ford, Anthony P.D.W. [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 6, p. 1697 - 1700]
[4]Current Patent Assignee: MYREXIS, INC.; ALZHEIMER'S INSTITUTE OF AMERICA, INC. - WO2011/46970, 2011, A1 Location in patent: Page/Page column 102

9
[ 1633-82-5 ]
[ 19961-27-4 ]
[ 200114-16-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 2635 - 2638

10
[ 1633-82-5 ]
[ 254881-77-1 ]
[ 1055034-49-5 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4948 - 4963

11
[ 5308-28-1 ]
[ 1633-82-5 ]
1-(3-chloro-propane-1-sulfonyl)-4-isobutyl-piperazine [ No CAS ]

Reference： [1]Clark, Robin D.; Jahangir, Alam; Alam, Muzaffar; Rocha, Cynthia; Lin, Lin; Bjorner, Bodil; Nguyen, Khanh; Grady, Carole; Williams, Timothy J.; Stepan, George; Tang, Hai Ming; Ford, Anthony P.D.W. [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 6, p. 1697 - 1700]

12
[ 21867-64-1 ]
[ 1633-82-5 ]
1-(3-chloro-propane-1-sulfonyl)-4-propyl-piperazine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1697 - 1700

13
[ 1633-82-5 ]
[ 21043-40-3 ]
1-(3-chloro-propane-1-sulfonyl)-4-cyclopentyl-piperazine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1697 - 1700

14
[ 1633-82-5 ]
[ 57260-71-6 ]
[ 222987-83-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In chloroform at 0℃; for 2h;	2 Example 2: 2-(lH-IndoI-4-yl)-4-morpholm-4-vI-6-f4-(3-inorpholin-4-vI- propane-l-sulfonyl)'-piperazin-l-ylmethvn-thienof3.2-d1pyrimidine; 4-C3-Chloro-propane-l-sulfonylVpiperazine-l-carboxylic acid tert-bntyl ester; To a solution of 1-BOC-piperazine (3.26 g) and triethylamine (2.68 mL) in dry chloroform (25 mL) was added 3-chloropropanesulfonyl chloride (2.62 g) at 0 ° C. After 2 h wash with water, dry (Na2SO4), filter and concentrate to give crude material. Product was isolated by flash chromatography (95%)
91%	With triethylamine In dichloromethane	5 4-(3-Chloropropane-1-sulfonyl)piperazine-1-carboxylic acid tert-butyl ester PREPARATION 5 4-(3-Chloropropane-1-sulfonyl)piperazine-1-carboxylic acid tert-butyl ester The following is the preparation of a compound of formula 6a wherein R3and R4 are each hydrogen, L is chloro, m is 3, Y is -SO2, and P is BOC. To a 0° C. solution of piperazine-1-carboxylic acid tert-butyl ester (4.7 g, 25 mmol) and triethylamine (7 mL, 50 mmol) in dichloromethane (50 mL) was added 3-chloropropanesulfonyl chloride (4.4 g, 25 mmol). The mixture was stirred for 2 hours with warming to room temperature and was then washed sequentially with dilute aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried (Na2SO4) and evaporated in vacuo to give the title compound as a white solid (7.4 g, 91%); m.p. 112-114° C.
83%	With triethylamine In dichloromethane	R.160 4-tert-Butoxycarbonyl-1-[(3-chloro-1-propyl)sulfonyl]piperazine Referential Example 160 4-tert-Butoxycarbonyl-1-[(3-chloro-1-propyl)sulfonyl]piperazine Under an argon gas atmosphere, 1-tert-butoxycarbonylpiperazine (3.00 g) and triethylamine (2.24 ml) were dissolved in dichloromethane (40 ml) under ice cooling, followed by the addition of 3-chloro-1-propanesulfonic acid chloride (1.96 g). The resulting mixture was stirred for 20 minutes under ice cooling and then, at room temperature for 10 minutes. The reaction mixture was diluted with dichloromethane, washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane, whereby the title compound (4.36 g, 83%) was obtained. 1H-NMR (CDCl3) δ: 1.41(9H,s), 2.27-2.33(2H,m), 3.08(2H,t,J=7.3 Hz), 3.26(4H,t,J=4.9 Hz), 3.53(4H,t,J=4.9 Hz), 3.69(2H,t,J=6.1 Hz). MS (FAB) m/z: 327 (M+H)+

	In dichloromethane at 20℃; for 2h;	2A 2-(lH-Indazol-4-vϖ-4-morpholin-4-yl-6-[4-(3-morpholin-4-yl-propane-l-sulfonyl)- piperazin-l-ylmethyl]-thieno[3,2-d1pyrimidine (80).Prepared via 2-Chloro-4-morpholin-4-yl-6-[4-(3-morpholin-4-yl-propane-l- sulfonyl)-piperazin-l-ylmethyl]-thieno[3,2-d]pyrimidine, prepared from 4-[3- (piperazine- 1 -sulfonyl)-propyl] -morpholine.Amine preparation: A mixture of 1-BOC-piperazine (3.26g), 3- chloropropanesulfonyl chloride (2.63g) and triethylamine (2.68mL) was stirred at room temperature in DCM (25mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-l-sulfonyl)-piperazine-l-carboxylic acid tert-butyl ester (4.65g). A mixture of 4-(3-chloro-propane-l-sulfonyl)-piperazine-l-carboxylic acid tert-butyl ester (4.65g), potassium iodide( l.lg) ,potassium carbonate and morpholine (1.6mL) was heated to reflux in MeCN (100ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-l-sulfonyl)-piperazine-l-carboxylic acid EPO tert-butyl ester (4.8g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt. 1H NMR (400MHz, CDCl3): 1.98-2.02 (m, 2H), 2.44-2.47 (m, 6H), 2.67-2.69 (m, 4H)5 2.99-3.03 (m, 2H), 3.36-3.38 (m, 4H), 3.69-3.71 (m, 4H), 3.90 (s, 2H), 3.91- 3.93 (m, 4H), 4.08-4.10 (m, 4H), 7.39 (s, H, ArH), 7.50 (t, H, ArH, J=7.7Hz), 7.58 (d, H, ArH, J=8.32Hz), 8.27 (d, H, ArH, J=7.44Hz), 9.00 (s, H, ArH), 10.10 (br s, H, NH); MS (ESf) 627.29 (MH+).
	With triethylamine In dichloromethane at 0℃; for 2h;	3 Example 3: (3-{4-r2-(lH-IndoI-4-ylV4-morphoIm-4-vI-thienor3.2-d1pyrimidin- 6-vImethvI1-piperazine-l-sulfonvU-propyI)-dimethyl-amine; Preparation of dimethyl-[3-('piperazine-l-sulfonyl)-proρyl]-amine dihvdrochloride.; To 1-BOC-piperazine (6.00 g) in dry dichloromethane (60 ml) and triethylamine (5.85 ml) at 0 0C was added 3-chloropropanesulfonyl chloride (4.5 ml).The reaction mixture was stirred for 2 hours, diluted with dichloromethane, washed with brine, dried (MgSO4), filtered and volatiles removed in vacuo. Purification on silica gave 4-(3-chloro-propane-l-sulfonyl)-piperazine-l-carboxylic acid tert-bυXy ester (9.85 g). This was reacted with dimethylamine hydrochloride in acetonitrile and potassium carbonate to give 4-(3 -dimethylamino-propane- 1 -sulfonyl)-piperazine- 1 - carboxylic acid tert-butyl ester. BOC-group was removed using HCl in ether under standard procedures to give the title compound.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2007/122410, 2007, A1 Location in patent: Page/Page column 90
[2]Current Patent Assignee: Syntex (USA) LLC - US6172062, 2001, B2
[3]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US6525042, 2003, B1
[4]Clark, Robin D.; Jahangir, Alam; Alam, Muzaffar; Rocha, Cynthia; Lin, Lin; Bjorner, Bodil; Nguyen, Khanh; Grady, Carole; Williams, Timothy J.; Stepan, George; Tang, Hai Ming; Ford, Anthony P.D.W. [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 6, p. 1697 - 1700]
[5]Current Patent Assignee: ROCHE HOLDING AG - WO2006/46031, 2006, A1 Location in patent: Page/Page column 41-42
[6]Current Patent Assignee: ROCHE HOLDING AG - WO2007/122410, 2007, A1 Location in patent: Page/Page column 91

15
[ 860626-16-0 ]
[ 1633-82-5 ]
[ 881380-90-1 ]

Yield	Reaction Conditions	Operation in experiment
64%	With triethylamine In dichloromethane at 0℃; for 0.5h;	11 To a solution of 5-phenyl-3-(4-piperidinyl)-1 /-/-indole-7-carboxamide (404 mg, 1.26 mmol) in CH2CI2 at O0C, triethylamine (0.7 ml_, 5.04 mmol) and 3-chloropropanesulfonyl chloride (0.23 ml_, 1.89 mmol) were added. The reaction mixture was stirred at O0C for 30 min. The reaction mixture was partitioned between CH2CI2 (100 ml_) and water (50 ml_). The organic layer was separated and the aqueous layer was extracted with CH2CI2 (2x100 ml_). The combined organic phase was washed with brine (50 ml_), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified via filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the title compound (370 mg, 64%). LCMS m/z 460.0 (M+H).
64%	With triethylamine at 0℃; for 0.5h; Inert atmosphere;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/34317, 2006, A2 Location in patent: Page/Page column 77-78
[2]Kerns, Jeffrey K.; Busch-Petersen, Jakob; Fu, Wei; Boehm, Jeffrey C.; Nie, Hong; Muratore, Michael; Bullion, Ann; Lin, Guoliang; Li, Huijie; Davis, Roderick; Lin, Xichen; Lakdawala, Ami S.; Cousins, Rick; Field, Rita; Payne, Jeremy; Miller, David D.; Bamborough, Paul; Christopher, John A.; Baldwin, Ian; Osborn, Ruth R.; Yonchuk, John; Webb, Edward; Rumsey, William L. [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 12, p. 1164 - 1169]

16
[ 1633-82-5 ]
[ 75-64-9 ]
[ 63132-85-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran at 20℃; for 24h;
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	A.II.1.2.1 Method 2 (of 2): Step 1: Preparation of N-tert-butyl-(3-chloro)propylsulfonamide tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (2.0 L). The resulting solution was washed with 1N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (br, 1H).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	A.II.7.B.2 B.2) Preparation of N-tert-Butyl-(3-chloro)propylsulfonamide tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. The mixture was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to provide the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).

99%	In tetrahydrofuran; dichloromethane	O.12.1 Step 1 Step 1 Preparation of N-tert-Butyl-(3-chloro)propylsulfonamide tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	A.II.2.1 Preparation of N-tert-butyl-(3-chloro)propylsulfonamide tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -20° C. and treated slowly with 3-chloropropanesulfonyl chloride (1.5 mol, 182.4 mL). The reaction mixture was warmed to room temperature and stirred for 24 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The concentrate was dissolved in dichloromethane (2.0 L), washed with 1N HCl (1.0 L), water (1.0 L), brine (1.0 L), dried over Na2SO4, filtered, and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to provide the desired product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (br, 1H).
99%	In tetrahydrofuran at -200 - 20℃; for 24h;	4.B.1 tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -200 C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).
99%	In tetrahydrofuran at 20℃; for 24h;	A.II.1.1 1. Preparation of cyclopropylsulfonamide; Step 1: Preparationof N-tert-Butyl- (3-chloro) propylsulfonamide tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooledto-20 C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved inCH2CI2 (2.0 L). The resulting solution was washed with1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). *'H NMR(CDC13)8 1.38 (s, 9H), 2.30-2. 27 (m, 2H), 3.22 (t, J = 7.35 Hz,2H), 3.68 (t,J = 6.2 Hz, 2H), 4.35 (b,1H).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	A.I.a Method I (Steps a-d). Preparation of 1-Substituted Cyclopropanesulfonamides Required for N-acylsulfonamide Coupling Steps 3e-8e (Examples 3-8 used to Prepare Compounds 1-6 Respectively). Step Ia: N-tert-Butyl-(3-chloro)propylsulfonamide. Step Ia) A neat solution of tert-Butylamine (315.3 mL, 3.0 mol) was dissolved in THF (2.5 L), cooled to -20° C., and 3-Chloropropanesulfonyl chloride (182.4 mL, 1.5 mol) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%): 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (bs, 1 H).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	A.III.1.1 tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to-20°C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2C12 (2.0 L). The resulting solution was washed with 1 N HC1 (1.0 L), water (1. 0 L), brine (1.0 L) and dried over Na2S04. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 'H NMR (CDC13) 8 1. 38 (s, 9H), 2.30-2. 27 (m, 2H), 3.22 (t, J= 7.35 Hz, 2H), 3.68 (t, J= 6. 2 Hz, 2H), 4.35 (b, 1H).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	6.B.1 METHOD B:; Step 1: Preparation ofN-tert-Butyl-(3-chloro)propylsulfonamide; tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to - 200C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J= 7.35 Hz, 2H), 3.68 (t, J= 6.2 Hz, 2H), 4.35 (b, IH).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	6.B.1; 7.1a tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	4.B.1 Step 1: Preparation of N-tert-Butyl-(3-chloro)propylsulfonamide tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).
99%	In tetrahydrofuran at -200 - 20℃; for 24h;	4.B.1 tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -200 C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).
99%	In tetrahydrofuran at -200 - 20℃; for 24h;	4.B.1 tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to -200C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	I.1.1.1; I.2.2a.1 I. Preparation of P1' Intermediates; 1. Preparation of Cyclopropylsulfonamide; Method 1:; Step 1:; tert-Butylamine (3.0 mol, 315 mL) was dissolved in THF (2.5 L). The solution was cooled to -20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 (2.0 L). The resulting solution was washed with 1.0M HCl (1.0 L), water (1.0 L), and brine (1.0 L), dried over Na2SO4, filtered, and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to provide the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J=7.35 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 4.35 (b, 1H).; 2. Preparation of C1-Substituted Cyclopropylsulfonamides; 2a. Preparation of N-tert-butyl-(1-methyl)cyclopropyl-sulfonamide; Step 1: Preparation of N-tert-butyl-(3-chloro)propylsulfonamide; Prepared as described above.
99%	In tetrahydrofuran at -20 - 20℃; for 24h;	6.B.1; 7.1.a tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to - 200C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 24 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in CH2CI2 (2.0 L). The resulting solution was washed with 1 N HCl (1.0 L), water (1.0 L), brine (1.0 L) and dried over Na2SO4. It was filtered and concentrated in vacuo to give a slightly yellow solid, which was crystallized from hexane to afford the product as a white solid (316.0 g, 99%). 1H NMR (CDCl3) δ 1.38 (s, 9H), 2.30-2.27 (m, 2H), 3.22 (t, J= 7.35 Hz, 2H), 3.68 (t, J= 6.2 Hz, 2H), 4.35 (b, IH).
97%	In dichloromethane at 20℃; Cooling with ice-water bath;	41 3-Chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide 3-Chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide To a solution of 3-chloropropanesulfonyl chloride (commercially available, for example, from Aldrich) (1 g, 6 mmol) in DCM (10 ml) in an ice-water bath was added t-butylamine (commercially available, for example, from Aldrich) (1.3 ml, 12 mmol). The solution was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was applied to a SCX-2 cartridge (50 g) (preconditioned with methanol) and the cartridge eluted with methanol (2 column volumes). The methanol fraction was concentrated in vacuo to give the title compound as a white waxy solid (1.17 g, 97%). LCMS RT=2.61 min, ES+ve m/z 214 (M+H)+.
88%	With triethylamine In dichloromethane at 0℃; for 1.75h;	2D.1 Step 1 :; A dry 3 L 3-neck flask equipped with a magnetic stir bar, addition funnel andargon inlet was flushed with argon, then charged with 3-chloropropanesulfonylchloride 2d1 (100.48 g, 0.57 mol, 1 .0 eq). Anhydrous dichloromethane (900 ml_) wastransferred into the flask via cannula, the mixture was cooled in an ice/water bath andtert-butylamine (72 ml_, 0.68 mol, 1.2 eq) was added. The mixture was stirred 15minutes then a solution of triethylamine (158 ml, 1.13 mol, 2.0 eq) in anhydrousdichloromethane (100 ml) was added dropwise over 45 minutes and stirring was 'continued for 1 h. The mixture was diluted with dichloromethane (500 ml_) andwashed with 1N HCI (3 x 400 ml_) and brine. The organic layer was dried over sodiumsulfate, filtered and evaporated to dryness to give compound 2d2 as an orange-beigesolid (107.04 g, 88% yield). 1H NMR (CDCI3, 400 MHz): 84.46 (s, 1H), 3.71 (tr, 2H),3.25 (tr, 2H), 2.31 (m, 2H), 1.41 (s, 9H).
88%	Stage #1: 3-chloro-n-propanesulfonyl chloride; <i>tert</i>-butylamine In dichloromethane at 0℃; for 0.25h; Stage #2: With triethylamine In dichloromethane for 1.75h;	2D.1 A dry 3 L 3-neck flask equipped with a magnetic stir bar, addition funnel and argon inlet was flushed with argon, then charged with 3-chloropropanesulfonyl chloride 2d1 (100.48 g, 0.57 mol, 1.0 eq). Anhydrous dichloromethane (900 mL) was transferred into the flask via cannula, the mixture was cooled in an ice/water bath and tert-butylamine (72 mL, 0.68 mol, 1.2 eq) was added. The mixture was stirred 15 minutes then a solution of triethylamine (158 mL, 1.13 mol, 2.0 eq) in anhydrous dichloromethane (100 mL) was added dropwise over 45 minutes and stirring was continued for 1 h. The mixture was diluted with dichloromethane (500 mL) and washed with 1 NHCl (3×400 mL) and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give compound 2d2 as an orange-beige solid (107.04 g, 88% yield). 1H NMR (CDCl3, 400 MHz): δ4.46 (s,1H), 3.71 (tr, 2H), 3.25 (tr, 2H), 2.31 (m, 2H), 1.41 (s, 9H).
88%	With triethylamine In dichloromethane at 0℃; for 2h;	4A.A EXAMPLE 4A; Preparation of PV fragments Cyclopropylsulfonamide (4A4) and 1- methylcyclopropylsulfonamide (4A7); Cyclopropanesulfonamide can be prepared by amination of cyclopropanesulfonyl chloride, according to the literature reference of J. King et al., J. Org. Chem., 1993, 58, 1128-1135, or as set out below.; Step A; A dry 3 L 3-neck flask equipped with a magnetic stir bar, addition funnel and argon inlet was flushed with argon, then charged with 3-chloropropanesulfonyl chloride 4A1 (100.48 g, 0.57 mol, 1.0 eq). Anhydrous dichloromethane (900 mL) was transferred into the flask via cannula, the mixture was cooled in an ice/water bath and tert- butylamine (72 mL, 0.68 mol, 1.2 eq) was added. The mixture was stirred 15 minutes then a solution of triethylamine (158 mL, 1.13 mol, 2.0 eq) in anhydrous dichloromethane (100 mL) was added dropwise over 45 minutes and stirring was continued for 1 h. The mixture was diluted with dichloromethane (500 mL) and washed with 1 N HCI (3 x 400 mL) and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give compound 4A2 as an orange-beige solid (107.04 g, 88% yield). 1H NMR (CDCI3, 400 MHz): 54.46 (s, 1H), 3.71 (tr, 2H), EPO 3.25 (tr, 2H), 2.31 (m, 2H), 1.41 (s, 9H).
83%	In tetrahydrofuran at -20 - 20℃; for 24h; Inert atmosphere;
	Stage #1: 3-chloro-n-propanesulfonyl chloride; <i>tert</i>-butylamine With triethylamine In toluene at 0 - 20℃; for 0.666667 - 1.5h; Stage #2: With hydrogenchloride In water; toluene	1; 2 EXAMPLE 1 To a solution of 36.6 g (0.50 mol) tert-butylamine and 50.4 g (0.50 mol) triethylamine in 400 mL of toluene cooled to 0° C. to 5° C. was added 3-chloropropane sulfonyl chloride (73.0 g, 0.41 mol) within 30 to 60 minutes and the resulting mixture was stirred at 5° C. for 10 min. The mixture was warmed to room temperature and treated with 200 mL of 1 M hydrochloric acid. The layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with water (1100 mL). From the organic layer approx. 250 mL of toluene were distilled off. THF (700 mL) was added and distillation was continued until the residual volume in the reaction vessel was approx. 600 mL. The mixture was cooled to -30° C. and 385 g of BuLi (15% in hexane, 2.2 eq) was added. After 30 min at -30° C. the mixture was warmed to 0° C. treated with water (200 mL). The layers were allowed to separate. The aqueous layer was removed and the organic layer was washed with water (1100 mL) and concentrated. The residue was treated with formic acid (300 mL) at 80° C. for 20 h. During the entire reaction a slight stream of nitrogen was bubbled through the solution. After complete conversion the mixture was concentrated to dryness. Residual amounts of formic acid were removed by co-evaporation with toluene (2*250 mL). The remaining residue was treated with toluene (100 mL) and ethanol (35 mL), heated to 70 to 75° C. and stirred at this temperature until a clear solution was obtained. The solution was cooled to 50° C. and treated at this temperature with 300 mL of toluene. The mixture was then cooled to -10 to -15° C. and stirred at this temperature for 5 h. The crystals were filtered off, washed with 50 ml of pre-cooled toluene and dried at 50° C./<30 mbar to afford 34.5 g (69.9%) of cyclopropyl sulfonamide as colorless crystals with a purity of 99.8% (GC, % area). EXAMPLE 2To a solution of 18.3 g (0.25 mol) tert-butylamine and 25 g (0.25 mol) triethylamine in 200 mL of toluene cooled to 10° C. to 20° C. was added 3-chloropropane sulfonyl chloride (36.0 g, 0.21 mol) within 30 to 60 minutes and the resulting mixture was stirred at 15° C. for 30 min. The mixture was treated with 90 mL of 1M hydrochloric acid. The layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with water (1×50 mL). From the organic layer toluene was distilled off and replaced by THF. The resulting mixture (150 mL) was cooled to -25° C. and treated at this temperature with 210 g (0.49 mol) of BuLi (15% in hexane). After 30 min at -25° C. the mixture was warmed to 0° C. and treated with water (100 mL). The layers were allowed to separate. The organic layer was washed with water (4×100 mL). The combined aqueous layers were treated with 37% hydrochloric acid (32 mL) and then extracted with toluene (2×100 mL). The combined organic layers were concentrated to a residual volume of 200 mL and then washed with water (2×20 mL). The organic layer was concentrated to dryness. The residue was treated with formic acid (135 mL) and water (15 mL) at 80° C. for 7 h. During the entire reaction a slight stream of nitrogen was bubbled through the solution. After complete conversion the mixture was concentrated to dryness. Residual amounts of formic acid were removed by co-evaporation with toluene (2×100 mL). The resulting residue was dissolved in ethanol (60 mL) at 64° C. and treated with 1.0 g of charcoal. The charcoal was filtered off and washed with ethanol (20 mL). The mixture was heated to reflux temperature and concentrated to a residual volume of approximately 40 mL. The solution was then treated within 30 min at 70° C. with toluene (125 mL). The mixture was cooled to -10° C. within 4 h and stirred at this temperature for 5 h. The crystals were filtered off, washed with 40 mL of pre-cooled toluene and dried at 50° C./<30 mbar to afford 18.73 g (75%) of cyclopropyl sulfonamide as colorless crystals with a purity of 99.9% (GC, % area).

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[ 950785-37-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine In N,N-dimethyl-formamide for 0.666667h; Inert atmosphere; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃;	15 A solution of 4-bromobenzylamine (1.85 g, 10 mmol) and triethylamine (2 g, 20 mmol) in dimethylformamide (30 ml) was treated with 3-chloropropanesulfonyl chloride (1.78 g, 10 mmol) by dropwise addition over 10 minutes with stirring under argon. This mix was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2 g, 30 mmol of NaH) portionwise and the whole mix stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50 ml) and dichloromethane (30 ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 20 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72 g, 94%).1H-NMR (400 MHz, CDCl3) δ: 7.49 (2H, m), 7.24 (2H, m), 3.21 (2H, m), 3.13 (2H, s), 3.11 (2H, m), 2.32 (2H, m); LC/MS Retention time 2.68 mins/(ES+) 290 (M+H, C10H1279BrNO2S requires 289).
94%	Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine In N,N-dimethyl-formamide for 0.666667h; Inert atmosphere; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 72h;
94%	Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine In N,N-dimethyl-formamide for 0.666667h; Stage #2: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 72h;	28 A solution of 4-bromobenzylamine (1.85g, 10mmol) and triethylamine (2g, 20mmol) in dimethylformamide (30ml) was treated with 3-chloropropanesulfonyl chloride (1.78g,10mmol) by dropwise addition over 10 minutes with stirring under argon. This mix was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2g, 30mmol of NaH) portionwise and the whole mix stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50ml) and dichloromethane (30ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 2Og pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72g, 94%).LC/Mass Spec (ES): Found 290 (ES+), retention time 2.68mins. Ci0H1279BrNO2S requires 289. 1 H-NMR (400MHz, CDCI3): 2.32 (2H, m), 3.1 1 (2H, m), 3.21 (2H, m), 3.13 (2H, s), 7.24 (2H, m), 7.49 (2H, m).

94%

Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine for 0.666667h; Stage #2: With sodium hydride at 20℃; for 72h;

20 Description 20: 2-[(4-bromophenyl)methyl]isothiazolidine 1,1 -dioxide (D20); A solution of 4-bromobenzylamine (1.85g, lOmmol) and triethylamine (2g, 20mmol) in dimethylformamide (30ml) was treated with 3-chloropropanesulfonyl chloride (1.78g, l Ommol) by dropwise addition over 10 minutes with stirring under argon. This mixture was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2g, 30mmol of NaH) portionwise and the whole mixture stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50ml) and dichloromethane (30ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 2Og pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72g, 94%).1 H-NMR (400MHz, CDCI3) δ: 7.49 (2H, m), 7.24 (2H, m), 4.13 (2H, s) 3.21 (2H, m), 3.11 (2H, m), 2.32 (2H, m); LC/MS Retention time 2.68mins/(ES+) 290 & 292 (M+H, Ci0H12BrNO2S requires 289 & 291 ).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2010/137276, 2010, A1 Location in patent: Page/Page column 19
[2]Location in patent: experimental part Ward, Simon E.; Harries, Mark; Aldegheri, Laura; Austin, Nigel E.; Ballantine, Stuart; Ballini, Elisa; Bradley, Daniel M.; Bax, Benjamin D.; Clarke, Brian P.; Harris, Andrew J.; Harrison, Stephen A.; Melarange, Rosemary A.; Mookherjee, Claudette; Mosley, Julie; Dal Negro, Gianni; Oliosi, Beatrice; Smith, Kathrine J.; Thewlis, Kevin M.; Woollard, Patrick M.; Yusaf, Shahnaz P. [Journal of Medicinal Chemistry, 2011, vol. 54, # 1, p. 78 - 94]
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/107539, 2007, A1 Location in patent: Page/Page column 96-97
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/148832, 2008, A1 Location in patent: Page/Page column 39

18
benzyl [2-(4-aminophenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate [ No CAS ]
[ 1633-82-5 ]
benzyl [2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: benzyl [2-(4-aminophenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate; 3-chloro-n-propanesulfonyl chloride With triethylamine In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: With sodium hydroxide In tetrahydrofuran; water for 16h;	11.I To a stirred solution of benzyl [2-(4-aminophenyl)hexahydro-2,5-methano pentalene-3a(lH)-yl]carbamate (1.1 g, 3.03 mmol) obtained from preparation 4, in THF (30 rnL) at 0°C was added Et3N (0.66 mL, 4.6 mmol) and 3-chloropropanesulfonylchloride (0.42 mL, 3.3 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. An aqueous solution of NaOH (50% w/v, 6 mL) was added followed by addition of W-Bu4NI (56 mg, 0.15 mmol). After stirring the reaction mixture for 16 h, it was diluted with water and extracted in EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure and the crude product was purified by column chromatography to obtain benzyl [2-[4-(l,l- dioxidoisothiazolidin-2-yl)phenyl) hexahydro-2,5-methanopentalene-3a(lH)-yl]carbamate as an off-white solid (0.93 g) in 66% yield. M.R: 215.6-219.2 °C m/z (M+l) 467; IR cm"1 3441,2953, 1716, 1516, 1314, 1215, 770. 1H NMR (CDCl3) 300 MHz δ 7.40-7.16 (m, 9H), 5.13-5.0 (bs, 2H), 3.75 (t, J = 6.6 Hz, 2H), 3.35 (t, J = 7.5 Hz, 2H), 2.59-2.38 (m, 4H), 2.30-1.60 (m, 10H).

Reference： [1]Current Patent Assignee: VIATRIS INC - WO2007/113634, 2007, A1 Location in patent: Page/Page column 91-92

19
4-(2,2-dimethyl-propylamino)-5-(3-piperazin-1-yl-prop-1-ynyl)-pyrimidine-2-carbonitrile [ No CAS ]
[ 1633-82-5 ]
5-{3-[4-(3-chloro-propane-1-sulfonyl)-piperazin-1-yl]-prop-1-ynyl}-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With triethylamine In dichloromethane at 20℃; for 12h;
51%	With triethylamine In dichloromethane at 0 - 20℃; for 14h;	12-19.C. C. 5-{3-[4-(3-chloro-propane-1-sulfonyl)-piperazin-1-yl]-prop-1-ynyl}-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile To a solution of [4- (2, 2-DIMETHYL-PROPYLAMINO)-5- (3-PIPERAZIN-1-YL-PROP-1-YNYL)-] pyrimidine-2-carbonitrile (0. [16MMOL)] in [CH2C12] [(5ML),] 3-chloropropanesulfonyl chloride (0. [192MMOL)] and triethylamine (0. [192MMOL)] are added at [0°C.] The reaction mixture is stirred at room temperature for 14 h and then saturated aqueous solution of ammonium chloride is added to the reaction mixture. The mixture is extracted with two [50ML] portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum. The purification of the residue by silica gel column chromatography affords 37mg of title compound in 51% yield. Rf = 0.33 (AcOEt only) [1H] NMR (400 MHz, CDC13) 8 0.98 (s, [9H),] 2.25-2. 35 (m, 2H), 2.71 (t, [4H),] 3.10 (t, [3H),] 3.35-3. 42 (m, [4H),] 3.38 (d, [2H),] 3.68 (s, 2H), 3.69 (t, 3H), 5.75 (m, [1H),] 8.22 (s, 1H)

Reference： [1]Teno, Naoki; Irie, Osamu; Miyake, Takahiro; Gohda, Keigo; Horiuchi, Miyuki; Tada, Sachiyo; Nonomura, Kazuhiko; Kometani, Motohiko; Iwasaki, Genji; Betschart, Claudia [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 8, p. 2599 - 2603]
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2004/20441, 2004, A1 Location in patent: Page 56-57

20
3-(2-aminoethyl)-5-methoxy-2-methylindolyl 4-chlorophenyl ketone hydrochloride [ No CAS ]
[ 1633-82-5 ]
4-chlorophenyl 3-(2-[(3-chloropropyl)sulfonyl]amino}ethyl)-5-methoxy-2-methylindolyl ketone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine In chloroform at 20℃;
77%	With triethylamine In chloroform at 20℃;	22.22a 22a. 4-Chlorophenyl 3-(2-{ [(3-chloropropyl)sulfonyl]amino }ethyl)-5-methoxy-2- methylindolyl ketone3-Chloropropanesulfonyl chloride (0.24 mL, 2.0 mmol) and NEt3 (0.5 mL, 3.6 mmol) were added to the product of Example 19b in CHCl3 (20 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between 3N HCl (30 mL) and CH2Cl2 (50 mL x 2). The combined organic extracts were washed with 3N HCl, saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated. The product EPO was purified by silica gel column chromatography eluting with EtOAc/hexane (1:2, R/ = 0.12) to give the title compound (0.55 g, 77% yield); 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.4 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 6.98 (d, J = 2.4 Hz, IH), 6.90 (d, J= 9.0 Hz, IH), 6.65 (dd, J = 9.0 and 2.4 Hz, IH), 5.00 (t, J = 6.3 Hz, IH), 3.82 (s, 3H), 3.55 (t, J = 6.0 Hz, 2H), 3.35 (br q, 2H), 3.06 (m, 2H), 2.94 (t, J = 6.9 Hz, 2H), 2.33 (s, 3H), 2.15-2.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.2, 155.9, 139.0, 135.2, 133.7, 130.9, 130.5, 128.9, 115.4, 114.9, 111.3, 101.0, 55.6, 49.7, 42.6, 26.6, 25.5, 13.2; Mass Spectrum (API-TIS) mlz 483 (MH+). Anal, calcd for C22H24Cl2N2O4S: C, 54.66; H, 5.00; N, 5.79; Found: C, 54.64; H, 4.84; N, 5.79

Reference： [1]Wey, Shiow-Jyi; Augustyniak, Michael E.; Cochran, Edward D.; Ellis, James L.; Fang, Xinqin; Garvey, David S.; Janero, David R.; Letts, L. Gordon; Martino, Allison M.; Melim, Terry L.; Murty, Madhavi G.; Richardson, Steward K.; Schroeder, Joseph D.; Selig, William M.; Trocha, A. Mark; Wexler, Roseanne S.; Young, Delano V.; Zemtseva, Irina S.; Zifcak, Brian M. [Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6367 - 6382]
[2]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - WO2006/99416, 2006, A1 Location in patent: Page/Page column 94-95

21
[ 1633-82-5 ]
[ 217314-47-1 ]
[ 1375214-08-6 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane;	Aniline 14.4 is treated which sulfonyl chloride 2 to give the corresponding sulfonamide 15.2, which is followed by the treatment of NaH to afford the cyclic sulfonamide 15.3. Basic hydrolysis (LiOH, H20/THF/MeOH) of compound 15.3 gives acid 15.1 as the intermediateds for example 57.

Reference： [1]Patent: WO2003/106405,2003,A1 .Location in patent: Page 212-214

22
[ 706792-04-3 ]
[ 1633-82-5 ]
[ 706792-08-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With pyridine; 4-(N,N-dimethylamino)phenol; In dichloromethane; at 20℃; for 16.0h;	A suspension of 3-amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv) in CH2CI2 (100 ML) was treated with DMAP (400 mg, 3.2 MMOL,) and pyridine (1.74 g, 22 mmol, 1.1 equiv) followed by 3-chloropropanesulfonyl chloride (3.89 g, 22 mmol, 1.1 equiv) dropwise. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 mi) and the resulting solution was washed with 2N aqueous HCI solution (100 ml) followed by saturated aqueous NAHC03 solution (100 ML), then dried over MGS04 and concentrated in vacuo to give 3- (3-CHLORO-PROPANE-1-SULFONYLAMINO)-5-ETHOXY- benzoic acid methyl ester (D53) (6.7 g, 98%) as a pale orange solid.
	With pyridine; In dichloromethane;	Aniline 14.4 is treated which sulfonyl chloride 2 to give the corresponding sulfonamide 15.2, which is followed by the treatment of NaH to afford the cyclic sulfonamide 15.3. Basic hydrolysis (LiOH, H20/THF/MeOH) of compound 15.3 gives acid 15.1 as the intermediateds for example 57.
	In pyridine; dichloromethane;	This example describes the synthesis of compounds of the formula wherein RF is substituted or unsubstituted aliphatic or aromatic moiety. These compounds are prepared according to Scheme 10 and the procedure below. Aniline 9.4 (Example 35) is treated which sulfonyl chloride to yield sulfonamide 10.2, which is followed by the treatment of NaH to afford cyclic sulfonamide 10.3. Basic hydrolysis (LiOH, H2O/THF/MeOH) of compound 10.3 gives acid 10.1. Compounds 10.1, acids of the formula RCCOOH, are used to make additional compounds of the invention. Table 6 shows exemplary compounds 10.1's.

Reference： [1]Patent: WO2004/50619,2004,A1 .Location in patent: Page 31
[2]Patent: WO2003/106405,2003,A1 .Location in patent: Page 212-214
[3]Patent: US2004/147454,2004,A1 .Location in patent: Page 67-68

23
[ 1633-82-5 ]
[ 23218-93-1 ]
[ 632626-88-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine;dmap; In dichloromethane; for 40h;	To a solution of <strong>[23218-93-1]3-amino-5-nitro-benzoic acid methyl ester</strong> (45 g, 229 mmol, 1 equiv) in [CH2CI2] (450 ml) was added pyridine (18.5 [ML,] 229 mmol, [1] equiv), DMAP (100 mg, 0.8 [MMOL,] catalytic) and 3-chloropropanesulfonyl chloride (28 [ML,] 230 [MMOL).] The resulting mixture was stirred for [40] h then diluted with EtOAc. The organic phase was diluted with 2MN HCI. The resulting solid was filtered to give [3- (3-CHLORO-PROPANE-1-SULFONYLAMINO)-5-] nitro-benzoic acid methyl ester (23 g, 32%). The filtrate was separated and the organic phase was washed with saturated aqueous [NAHCO3] solution, dried over [MGS04] and concentrated in vacuo. The residue was triturated with EtOAc and iso-hexane to give a further 50 g (65%) of [3- (3-CHLORO-PROPANE-1-SULFONYLAMINO)-5-NITRO-BENZOIC] acid methyl ester, as a pale brown solid, which was used in the next step without further purification. LC/MS t = 3.11 min, [[MH]] = 335.
65%	With pyridine; 4-(N,N-dimethylamino)phenol; In dichloromethane; for 40h;	To a solution of <strong>[23218-93-1]3-amino-5-nitro-benzoic acid methyl ester</strong> (D1) (45 g, 229 mmol, 1 equiv) in CH2CI2 (450 mi) was added pyridine (18.5 ML, 229 mmol, 1 equiv), DMAP (100 mg, 0.8 mmol, catalytic) and 3-chloropropanesulfonyl chloride (28 ML, 230 MMOL, 1 equiv). The resulting mixture was stirred for 40 h then diluted with AcOEt. The organic phase was diluted with 2N aqueous HCI solution. The resulting solid was filtered to give 3- (3-chloro-propane-1- sulfonylamino)-5-nitro-benzoic acid methyl ester (23 g, 32%). The filtrate was separated and the organic phase was washed with saturated aqueous NAHC03 solution, dried over MGS04 and concentrated in vacuo. The residue was triturated with AcOEt and iso-hexane to give a further 50 g (65%) of 3- (3-CHLORO-PROPANE-L-SULFONYLAMINO)-5-NITRO-BENZOIC acid methyl ester (D14) as a pale brown solid. [M-H]-= 334.9, RT = 3.11 min

Reference： [1]Patent: WO2003/101959,2003,A1 .Location in patent: Page 143
[2]Patent: WO2004/50619,2004,A1 .Location in patent: Page 21-22

24
[ 706792-14-5 ]
[ 1633-82-5 ]
[ 706792-18-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine; 4-(N,N-dimethylamino)phenol In dichloromethane at 20℃; for 2h;	66 Description 66; 3- (3-CHLORO-PROPANE-L-SULFONYLAMINO)-5-METHYLSULFANYL-BENZOIC acid methyl ester (D66) To a solution of 3-amino-5-methylsulfanyl-benzoic acid methyl ester hydrochloride (D62) (130 mg, 0.556 mmol, 1 equiv) in CH2CI2 (2 ml) was added pyridine (142 ml, 1.75 mmol, 3 equiv), DMAP (6.8 mg, 0.056 mmol, 0.1 equiv) and then 3-chloropropane SULFONYL CHLORIDE (71 L, 0.584 mmol, 1.05 equiv) dropwise over 2 min. The resulting mixture was stirred at room temperature for 2 h, diluted with AcOEt, washed sequentially with 2N aqueous HCI solution, saturated aqueous NaHCO3 solution and brine, dried over NA2SO4 and concentrated in vacuo to give 3- (3-chloro-propane-1-sulfonylamino)-5-methylsulfanyl-benzoic acid methyl ester (D66) (196 mg, 104%) as light brown crystals. [M-H]-= 336.0 RT = 3.20 min

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/50619, 2004, A1 Location in patent: Page 34

25
[ 388071-13-4 ]
[ 1633-82-5 ]
[ 706822-76-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With pyridine; 4-(N,N-dimethylamino)phenol In dichloromethane at 20℃; for 16h;	91 Description 91; 5- (3-CHLORO-PROPANE-1-SULFONYLAMINO)-N, N-DIPROPYL-ISOPHTHALAMIC acid methyl ester (D91) A solution of 5-amino-N, N-dipropyl-isophthalamic acid methyl ester (D88) (1.4 g, 5.0 mmol, 1 equiv), DMAP (100 mg) and pyridine (392 mg, 5.0 mmol, 1.1 equiv) in CH2CI2 (20 ml) was treated dropwise with 3-CHLOROPROPANE-1-SULFONYL CHLORIDE (946 mg, 5.3 mmol, 1.1 equiv). The resulting mixture was stirred for 16 h at room temperature and then diluted with AcOEt (100 ML). The resulting solution was washed with 2N aqueous HCI solution (50 ml) followed by saturated aqueous NAHC03 solution (50 ml), dried over MGS04 and concentrated in vacuo. The residue was triturated with ET20 to give 5- (3-CHLORO-PROPANE-1-SULFONYLAMINO)-N, N- dipropyl-isophthalamic acid methyl ester (D91) (1.8 g, 86%) as a pink solid.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/50619, 2004, A1 Location in patent: Page 40

26
[ 1633-82-5 ]
[ 706791-83-5 ]
[ 706791-86-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With pyridine; 4-(N,N-dimethylamino)phenol; In dichloromethane; at 20℃; for 16h;	To a solution of 3-amino-5-bromo-benzoic acid methyl ester (D12) (2.3 g, 10 mmol, 1 equiv) in CH2CI2 (30 ml) was added pyridine (1.6 ml, 20 mmol, 2 equiv), DMAP (320 mg, 2.5 mmol, 2.5 equiv) and 3-chlorosulphonyl chloride (1.46 ml, 12 mmol, 1.2 equiv) dropwise. The resulting mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase washed sequentially with 2N aqueous HCI solution, saturated aqueous NAHC03 solution and brine, dried over MGS04 and concentrated in vacuo to give 3-BROMO-5- (3-CHLORO-PROPANE-1-SULFONYLAMINO)-BENZOIC acid methyl ester (D19) (3.36 g, 91%) as a red solid. [M-H]-= 369.9, RT = 3.25 min

Reference： [1]Patent: WO2004/50619,2004,A1 .Location in patent: Page 23

27
[ 706792-05-4 ]
[ 1633-82-5 ]
[ 706792-07-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine; 4-(N,N-dimethylamino)phenol In dichloromethane at 20℃; for 16h;	52 Description 52; 3-BENZYLOXY-5- (3-CHLORO-PROPANE-L-SULFONYLAMINO)-BENZOIC acid methyl ester (D52) A suspension of 3-AMINO-5-BENZYLOXY-BENZOIC acid methyl ester hydrochloride (D50) (5.0 g, 17 mmol, 1 equiv) in CH2CI2 (100 mi) was treated with DMAP (400 mg, 3.2 MMOL) and pyridine (3.5 g, 44 mmol, 2.6 equiv) followed by 3-chloropropanesulfonyl chloride (3.54 g, 20 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with 2N aqueous HCI solution (100 ML) followed by saturated aqueous NAHC03 solution (100 ML), dried over MGS04 and concentrated in vacuo to give 3-BENZYLOXY- 5- (3-chloro-propane-1-sulfonylamino)-benzoic acid methyl ester (D52) (6.0 g, 97%) as a pale pink solid. [M+H] + = 366.1, RT = 2.34 min

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/50619, 2004, A1 Location in patent: Page 31

28
[ 582-33-2 ]
[ 1633-82-5 ]
[ 849409-73-0 ]

Yield	Reaction Conditions	Operation in experiment
46%	With trimethylamine In dichloromethane at 0 - 20℃; for 2h;	3 [Preparation Example 3] Preparation of ethyl 3- {BIS3-CHLOROPROPYL) SULFONYL] AMINOBENZOATE 0.83 g (5 mmol) of ethyl-3-aminobenzoate and 1.52 ml (12.5 mmol) of 3- CHLOROPROPANESULFONYL chloride were dissolved in 25 ml of dichloromethane, and cooled to 0°C. 2.09 ml (15 mmol) of trimethylamine was added thereto and heated to room temperature, followed by stirring for 2 hours. The solvent was removed by distillation under reduced pressure, and eluted with ethyl acetate, then washed with saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, precipitates were settled using diethylether and filtered to obtain 1.02 g of the title compound at 46% yield. 1H NMR (500 MHz, CDC13) ; 8.17 (1H, M), 8.03 (1H, s), 7.56 (2H, d), 4.40 (2H, q), 3.76 (4H, t), 3.67 (4H, t), 2.42-2. 37 (4H, M), 1.40 (3H, t).

Reference： [1]Current Patent Assignee: LG CHEM CO.,LTD.; PROMEDITECH - WO2005/30709, 2005, A1 Location in patent: Page/Page column 38

29
[ 1633-82-5 ]
[ 3081-24-1 ]
[ 819862-66-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 4-methyl-morpholine In dichloromethane at -10 - 20℃; for 2.5h;	Preparation OF N- (3-AMINOPROPANE-L-SULFONYL)-PHENYLALANINE, ethyl ester (Compound CL) The 3-CHLOROPROPANE-1-SULFONYL chloride (10 mmol, 1.21 ML) was added dropwise to a cold (-10 °C) solution of L-phenylalanine ethyl ester (10 mmol, 2.3 g) and 4-METHYLMORPHOLINE (20 mmol, 2.2 mL) in dichloromethane (30 mL). The mixture was stirred for 30 minutes at-10 °C and for 2 hours at room temperature. The mixture was diluted with dichloromethane (40 mL) and washed twice with water, once with brine, dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave rise to almost pure 3-chloropropyl sulfonamide as a yellow-oil in quantitative yield. THE H and 13C NMR were consistent with the structure. A mixture of the 3-chloropropyl sulfonamide (10 mmol), sodium azide (20 mmol) and a catalytic amount OF BU4NI in DMF (40 ML) was heated at 60 °C for 24 hours. The mixture was diluted with ethyl acetate, washed with water three times, and once with brine, dried over sodium sulfate. Evaporation of the solvent gave rise to the azide as a brown-oil (3.0489 g, 8.96 mmol, 90%). THE 1H and 13C NMR were consistent with the structure. The azide (2.70 g, 7.94 mmol) was stirred under H2 (40 psi) with 10% Pd/C (348 mg) in ethanol (16 mL) at room temperature overnight. The solid was removed by filtration over Celite. The filtrate was treated with TMSCL/ETOH in attempt to obtain a crystalline hydrochloride salt of the product. The solvent was evaporated to give a thick residue (2.2 g, 6.27 mmol, 79%) that crystallized under none of the conditions tried. The crude hydrochloric acid salt was dissolved in dichloromethane and washed once with saturated sodium bicarbonate. The organic layer was recovered and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in methanol and treated with activated charcoal. The solid was removed by filtration over Celite and the filtrate was evaporated to dryness. The residue was dried in vacuo to afford a tan oil (1. 3969 g, 56% from the azide). THE H and 13C NMR were consistent with the structure of Compound CL.

Reference： [1]Current Patent Assignee: BELLUS HEALTH INC. - WO2004/113275, 2004, A2 Location in patent: Page 162; 163

30
[ 496-15-1 ]
[ 1633-82-5 ]
[ 1018298-75-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine In acetone at 0 - 20℃; for 0.5h;	2.1. To a solution of indoline (4.00 g, 33.6 mmol) in 100 mL of acetone at 0 DEG C. was added 3-chloropropanesulfonyl chloride (5.95 g, 33.6 mmol) with stirring. A solid precipitated from the solution. Diisopropylethylamine (4.33 g, 33.6 mmol) was added in two portions and the reaction mixture became a homogenous solution. The mixture was stirred for 30 min, warmed to ambient temperature, and evaporated to dryness. The crude mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2x100 mL). Chromatography on silica (10% to 25% ethyl acetate/hexane) gave an oil which solidified on standing (7.68 g, 77%, mp 53-5 DEG C.).

Reference： [1]Current Patent Assignee: ALCON, INC. - US2005/187214, 2005, A1 Location in patent: Page/Page column 7

31
[ 1633-82-5 ]
[ 61367-07-5 ]
[ 727736-51-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In chloroform; at 0 - 20℃; for 2.33333h;	(1) Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (4.08 g) obtained in Reference Example 2(1) is suspended in chloroform (50 ml), and thereto is added triethylamine (8.8 ml) under ice-cooling. Subsequently, a solution of 3-chloropropanesulfonyl chloride (3.35 ml) in chloroform (20 ml) is added dropwise over 20 minutes under the same temperature. After stirring for 2 hours at room temperature, 5 % hydrochloric acid is added to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diisopropylamine, and filtered to collect precipitates to give methyl trans-4-[(3-chloropropyl)sulfonyl]amino}cyclohexanecarboxylate (6.14 g). APCI-MS M/Z:315/317[M+H]+.

Reference： [1]Patent: EP1582521,2005,A1 .Location in patent: Page/Page column 128

32
[ 1633-82-5 ]
[ 18595-14-7 ]
[ 864296-60-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With pyridine; at 20℃; for 16h;	100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml of pyridine are combined with 82 mul (0.67 mmol) 3-chloropropanesulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction solution is combined with water and ethyl acetate and then the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is further reacted without any more purification. Yield: 170 mg (92%) C12H16ClNO4S (305.78) Mass spectrum: (M+H)+=306/308 (chlorine isotope) Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate=8:2)

Reference： [1]Patent: WO2005/82895,2005,A1 .Location in patent: Page/Page column 138
[2]Patent: US2005/203078,2005,A1 .Location in patent: Page/Page column 56

33
[ 1633-82-5 ]
[ 1283753-59-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: 4-nitro-3-methylaniline With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 0.5h; Stage #2: 3-chloro-n-propanesulfonyl chloride In DMF (N,N-dimethyl-formamide) at 20℃; for 4.75h; Heating / reflux;	14.1 NaH (0.40 g of a 60% dispersion, 3 equiv) was added to a solution of the 134 (0.50 g, 3.29 mmol) in DMF (18 mL) at 0° C. The solution was warmed to RT. After 30 min, a DMF (4 mL) solution of 3-chloro-propane-1-sulfonyl chloride (0.81 g, 1.4 equiv) was added. The solution was stirred at RT for 45 min, and then heated to reflux for 4 h. The reaction mixture was cooled to RT and quenched with ice water. The aqueous layer was extracted with EtOAc, and the organic layers were dried (MgSO4). Filtration and evaporation of the volatile materials afforded an oil that was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (50% to 70% EtOAc) to afford the sulfonamide as a yellow solid (0.49 g, 59%). This sulfonamide was dissolved in EtOH (20 mL). 10% Pd/C (0.05 g) was added, the solution was placed under a H2 atmosphere (50 psi), and the solution was shaken for 3 h. Filtration of the reaction mixture and evaporation of the volatile materials afforded 0.44 g of 136.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2005/239881, 2005, A1 Location in patent: Page/Page column 34-35

34
[ 1633-82-5 ]
[ 106-40-1 ]
N-(4-bromophenyl)-3-chloropropane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With pyridine In dichloromethane at 0 - 20℃;	15.C 3-Chloropropylsulfonyl chloride (1.20Og, 0.00678mol) was added dropwise to a stirred solution of p-bromoaniline ( 1.032g 0.00600mol) and pyridine ( 5ml) in dichloromethane (90ml) at O0C under EPO nitrogen. The mixture was allowed to warm to rt and stirred overnight. The resultant mixture was concentrated and extracted with Et2O / aqueous sodium dihydrogen phosphate (pH=3-4) solution. The organic solution was then washed twice with saturated sodium bicarbonate solution, twice with brine, then dried with MgSO4 and concentrated to afford crude 15-C-l (1.63Og 87%).
77%	With pyridine In dichloromethane for 4h;	31.1 4-Bromoaniline (0.86 g, 5.0 mmol) was dissolved in CH2Cl2 (15 mL), pyridine (0.5 mL) was added, and 3-chloropropanesulfonyl chloride (0.6 mL, 5.0 mmol) was added. The mixture was stirred for 4 hours, diluted with ethyl acetate, and then washed with water, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep column, silica, gradient 5-60% ethyl acetate in hexane) to afford 1.2 g (77%) N-(4-bromophenyl)-3-chloropropane-1-sulfonamide. HPLC purity 98.4% at 210-370 nm, 9.3 min.; the Xterra RP18 instrument, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 311.6.
77%	With pyridine for 4h;	57.1 Example 57; 5-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile; Step 1:; 4-Bromoaniline (0.86 g, 5.0 mmol) was dissolved in CH2Cl2 (15 mL), pyridine (0.5 mL) was added, followed by the addition of 3-chloropropanesulfonyl chloride (0.6 mL, 5.0 mmol). The mixture was stirred for 4 hours, diluted with ethyl acetate, and then washed with water, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep column, silica, gradient 5-60% ethyl acetate in hexane) to afford 1.2 g (77%) N-(4-bromophenyl)-3-chloropropane-1-sulfonamide. HPLC purity 98.4% at 210-370 nm, 9.3 min.; the Xterra RP18 instrument, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 311.6.

Reference： [1]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC; MERCK & CO INC - WO2006/44497, 2006, A2 Location in patent: Page/Page column 128-129
[2]Current Patent Assignee: PFIZER INC - US2007/27126, 2007, A1 Location in patent: Page/Page column 14
[3]Current Patent Assignee: PFIZER INC - US2007/27201, 2007, A1 Location in patent: Page/Page column 21

35
N-[5-aminomethyl-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropaneamide hydrochloride [ No CAS ]
[ 1633-82-5 ]
[ 781675-12-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In dichloromethane at 0℃; for 0.333333h;	23 Hydrochloride of Compound 216 (2.80 g, 6.78 mmol) obtained in Example 21 was suspended in dichloromethane (50 mL), to the suspension was added triethylamine (3.80 mL, 27.3 mmol) and 3-chloropropanesulfonyl chloride (1.24 mL, 10.2 mmol) under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with a mixed solvent of diisopropyl ether and ethyl acetate to give Compound 218 (3.01 g, 86%). ESI-MS m/z: 515, 517 (M-H).
70%	With triethylamine In dichloromethane at 0 - 20℃; for 22h;	27.1 Compound p: N-[5-(3-Aminopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide Step 1: The hydrochloride of Compound j {N-[5-aminomethyl-4-(2,2-dimethyl-propionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide} (1.00 g, 2.42 mmol) obtained in Reference Example 23 was suspended in dichloromethane (25 mL), and triethylamine (1.35 mL, 9.69 mmol) and 3-chloropropanesulfonyl chloride (0.442 mL, 3.63 mmol) were added under ice cooling, then the mixture was stirred at room temperature for 22 hours. To the mixture were added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with a mixed solvent of diisopropyl ether and ethyl acetate to give optically active N-[5-(3-chloropropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (0.880 g, 70%). 1H NMR (270 MHz, CDCl3) δ (ppm): 1.29 (s, 9H), 1.35 (s, 9H), 2.25 (m, 2H), 3.22 (m, 2H), 3.63 (m, 2H), 4.01 (dd, J = 5.1, 13.7 Hz, 1H), 4.60 (dd, J = 8.0, 13.7 Hz, 1H), 5.19 (dd, J = 5.1, 8.0 Hz, 1H), 7.23-7.41 (m, 5H), 7.94 (s, 1H). ESI-MS m/z: 515, 517 (M-H)-.

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP.; Kyowa Kirin (in: Kirin Holdings); KIRIN HOLDINGS CO., LTD. - EP1616866, 2006, A1 Location in patent: Page/Page column 54
[2]Current Patent Assignee: FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1870404, 2007, A1 Location in patent: Page/Page column 33

36
[ 1633-82-5 ]
[ 18600-42-5 ]
[ 258856-32-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With triethylamine; In N,N-dimethyl-formamide;	Reference Example 11 Preparation of 2-(4-Aminobenzyl)-1,1-dioxotetrahydro-2H-1-isothiazole To a solution of <strong>[18600-42-5]4-nitrobenzylamine hydrochloride</strong> (5.00 g) and triethylamine (5.37 g) in DMF (30 ml) was added 3-chloropropylsulfonyl chloride (4.69 g) under ice cooling, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and the solvent removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give N-(3-chloropropylsulfonyl)-4-nitrobenzylamine (2.00 g, 26%).

Reference： [1]Patent: US6355672,2002,B1

37
3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine [ No CAS ]
[ 1633-82-5 ]
[ 878389-74-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.166667h;	Intermediate 14.1: 3-{l-[(3-chloropropvl)sulfonvll-2,3-dihvdro-lfl-indol-5-vl}-5-vinyl-3//-imidazo [4.5-61 pyridine (Scheme 12); A solution of 3-(2,3-dihydro-l//-indol-5-yl)-5-vinyl-3//-imidazo[4,5-6]pyridine (270 mg, 1.03 mmol) (Intermediate 10.1), 3-chloropropanesulfonyl chloride (0.25 ml, 2.06 mmol), and A^V-diisopropylethylamine (1.08 ml, 6.18 mmol) in dichloromethane (15 ml) is stirred for 10 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 351 mg (85%) of the respective sulfonamide. HPLC (over lOmin 10-85% MeCN/lOOmM aq. NaOAc): 92% purity, tR 8.44 min (tR(SM) 6.59 min). MS (ESI) m/z (C19H19CIN4O2S) 403.0 (M, 100), 294.9 (65) Finnegan LCQ

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2006/24666, 2006, A1 Location in patent: Page/Page column 63

38
[ 1633-82-5 ]
[ 23190-16-1 ]
3-chloro-N-[(1S,2R)-2-hydroxy-1,2-diphenylethyl]propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h;	7.a a) 213 mg (1 mmol) of (1 R, 2S)-(-)-2-amino-1 ,2-diphenylethanol were dissolved in 2 ml of DMF, and 164 μl of triethylamine (1.19 mmol) and 137 μl (1.13 mmol) of3-chloropropanesulfonyl chloride were added. After stirring at room temperature for one hour, the reaction mixture was poured into water and filtered with suction. 310 mg (88%) of the desired intermediate 3-chloro-N-[(1S, 2R)-2-hydroxy-1 ,2- diphenylethyl]propane-1 -sulfonamide were obtained.

Reference： [1]Current Patent Assignee: SANOFI - WO2006/136305, 2006, A1 Location in patent: Page/Page column 39

39
[ 1633-82-5 ]
[ 192130-34-0 ]
[ 1235487-93-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 20℃; for 0.5h;	EXAMPLE 24 2-[4-((4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-{4-[2-(11,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carbonyl}-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-3-ethoxy-phenyl]-2-methyl-propionitrile To a stirred solution of 1-Boc-4-(2-aminoethyl)-piperazine (1.26 g, 6.8 mmol, Aldrich) and triethylamine (1 mL) in tetrahydrofuran (10 mL), 3-chloro-propylsulfonyl chloride (0.68 mL, 6.94 mmol, Aldrich) was added slowly at room temperature. The mixture was stirred for 30 min at room temperature and the reaction was quenched with water. It was extracted with ethyl acetate and the extracts were combined and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 4-[2-(3-chloro-propane-1-sulfonylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester.

Reference： [1]Patent: US2007/129416,2007,A1 .Location in patent: Page/Page column 20/1

40
[ 39546-32-2 ]
[ 1633-82-5 ]
[ 1036738-79-0 ]

Yield	Reaction Conditions	Operation in experiment
77.3%	With potassium carbonate In water; acetonitrile at 15 - 25℃; for 0.25h;	1 With reference to Scheme HB, above, wherein Path B is followed in Step 2, compound 2Ba (isonipectoamide, article of commerce, used as received) (36.5 g, 285 mmol), acetonitrile (150 ml_), and saturated aqueous potassium carbonate solution (150 ml_) were added to a 1 liter jacketed vessel. To this mixture was charged 3-chloropropane sulfonyl chloride (40.0 g, 285 mmol), keeping the temperature between 15 0C and 25 0C. The reaction was then stirred for about 15 minutes. MTBE (500 ml_) was then charged, and the resulting precipitated product A1a was filtered, and washed with MTBE (3 x 100 ml_). The solids were dried under vacuum oven at 20 to 30 0C to yield 51.2 g (77.3%) of product A1 a as a white solid .1H NMR (DMSO, 400 MHz): 57.31 (1 H, s), 6.86 (1H, s), 3.58 (2H, ddd, J = 12.0, 3.2, 3.2 Hz), 2.81 (2H, ddd, J = 12.0, 12.0, 2.4 Hz), 2.57 (1 H, m), 2.21 (1 H, dddd, J = 10.8, 10.8, 3.2, 3.2 Hz), 1.79 (2H, dddd, J = 13.2, 2.8, 2.8, 2.8 Hz)1 1.53 (2H, dddd, J = 13.6, 13.6, 13.6, 4.0 Hz), 0.99 - 0.88 (4H, m). MP: 151 0C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/79284, 2008, A1 Location in patent: Page/Page column 33

41
[ 1633-82-5 ]
[ 15862-72-3 ]
[ 935760-65-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 12h;	Reference Example 97 ethyl 1-[(3-chloropropyl)sulfonyl]-piperidine-2-carboxylate wherein Et is ethyl, which is the same as in the other formulas in the present specification. To a solution of 3-chloropropane-1-sulfonyl chloride (4.72 g, 26.7 mmol) in THF (100 mL) were added successively ethyl piperidine-2-carboxylate (4.19 g, 26.7 mmol) and triethylamine (3.72 mL, 26.7 mmol) at 0C, and the mixture was stirred at room temperature for 12 hr after addition. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water, 0.1N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a yellow oil (6.44 g, 81%). 1H-NMR (300MHz, DMSO-d6) delta: 1.13-1.27 (1H, m), 1.22 (3H, t, J = 7.0 Hz), 1.33-1.50 (1H, m), 1.59-1.72 (3H, m), 2.05-2.17 (3H, m), 3.06-3.27 (3H, m), 3.54-3.63 (1H, m), 3.70-3.77 (2H, m), 4.12-4.22 (2H, m), 4.52-4.59 (1H, m).
81%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 12h;	Ethyl piperidine-2-carboxylate (14, 4.19 g, 26.7 mmol) and triethylamine (3.72 mL, 26.7 mmol) were added to a mixture of 3-chloropropane-1-sulfonyl chloride (15, 4.72 g, 26.7 mmol) in THF (100 mL) at 0 C, and the mixture was stirred for 12 h at room temperature. After the mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, successively washed with H2O, 0.1 N hydrochloric acid and brine, and dried over Na2SO4. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (6.44 g, 21.6 mmol, 81%). 1H NMR (300 MHz, DMSO-d6) d 1.13-1.27 (1H, m), 1.22 (3H, t, J = 7.0 Hz), 1.33-1.50 (1H, m), 1.59-1.72 (3H, m), 2.05-2.17 (3H, m), 3.06-3.27 (3H, m), 3.54-3.63 (1H, m), 3.70-3.77 (2H, m), 4.12-4.22 (2H, m), 4.52-4.59 (1H, m).

Reference： [1]Patent: EP1953148,2008,A1 .Location in patent: Page/Page column 155
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 6149 - 6165

42
exo-(2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethylamine [ No CAS ]
[ 1633-82-5 ]
[ 916725-05-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine In dichloromethane at 20℃;	2.c The amine 3 (0.75 g, 2.07 mmol) were dissolved in 15 ml of DCM, triethylamine (0.57 ml, 4.14 mmol) was added at RT, and 3-chloropropanesulfonyl chloride (0.37 ml, 2.07 mmol) was subsequently added dropwise, likewise at RT. The solution was stirred further overnight, the solvent was removed, the crude substance was taken up in ethyl acetate (50 ml) and extracted 2× with water. The organic phase was dried, filtered, and the solvent was removed, giving 0.85 g (1.67 mmol, 82%) of yellowish crystals, which was characterised as comp. 4.

Reference： [1]Current Patent Assignee: MERCK KGAA - US2008/194615, 2008, A1 Location in patent: Page/Page column 84

43
[ 1633-82-5 ]
[ 112734-22-2 ]
[ 1057662-34-6 ]

Yield	Reaction Conditions	Operation in experiment
55%		solution of <strong>[112734-22-2][(4-bromo-2-fluorophenyl)methyl]amine</strong> (2.Og, 9.8mmol) and triethylamine (2.73ml, 19.6mmol) in dimethylformamide (20ml) was treated with 3- chloropropanesulfonyl chloride (1.74g, 9.8mmole) dropwise over 10 minutes with stirring under argon. This mixture was stirred for 30 minutes before being treated with sodium hydride (60percent suspension in mineral oil, 1.176g, 29.4mmol) portionwise and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. Sample was then purified by column chromatography on silica using 10 to 90percent ethyl acetate in n-pentane to afford the title compound as an oil (1.7g, 55percent).LC/MS (ES): Found 308 310 (ES+), retention time 2.73mins. Ci0H11 BrFNO2S requires 307 309.1H-NMR (400MHz, CDCI3): 2.34 (2H, m), 3.19 (4H, m), 4.20 (2H, d, J=I Hz), 7.22-7.35 (3H, m).

Reference： [1]Patent: WO2008/110566,2008,A1 .Location in patent: Page/Page column 36

44
[ 1633-82-5 ]
Δ9-tetrahydrocannabinol [ No CAS ]
Δ9-tetrahydrocannabinol 3-chloropropylsulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.4%	With dmap; triethylamine In toluene at 22 - 30℃; for 16.1667h;	4 Example 4: δ9-THC 3-chloropropvl sulfonate; To a solution of crude δ9-THC, triethylamine and 4-dimethylaminopyridine in toluene at 22°C, was added a solution of 3-chloropropyl sulfonyl chloride in toluene over a period of 10min. The temperature of the resultant suspension was kept below 300C during the addition. The reaction progress was monitored by TLC. After stirring for 16h at 250C to 300C the mixture was filtered through silica gel and the silica gel washed with toluene. The combined filtrates were concentrated under reduced pressure, methanol was added and distillation continued until the solvent was exchanged to methanol. The solution was cooled to -18°C and the solid produced was filtered and washed with methanol to give the title compound as a pale yellow solid. Yield: 83.4 % yield by wt. Purity: 99.1% PAR purity by HPLC. Appearance: Pale solid. Stability: Stable to light and air at ambient temperature.1H NMR (300MHz, CDCI3): δ = 0.88 (3H, t, J=6.7Hz), 1.10 (3H, s), 1.25-1.36 (4H1 m), 1.36-1.48 (4H, m), 1.42 (3H, s), 1.52-1.65 (2H, m), 1.67-1.75 (4H, m), 1.69 (3H, s), 1.86-1.96 (1H, m), 2.12-2.22 (2H, m), 2.44-2.57 (4H, m), 3.35-3.85 (3H, m), 3.67-3.82 (2H, m), 6.12 (1 H, s), 6.63 (1H1 s), 6.67 (1 H, s). 13C NMR (75MHz; CD3OD) : δ = 13.95, 19.21 , 22.44, 23.35, 24.78, 26.71, 27.32, 30.48, 31.02, 31.36, 34.00, 35.28, 42.43, 45.53, 48.43, 77.73, 114.21 , 116.20, 116.58, 123.23, 134.97, 143.02, 147.29, 154.98. LCMS ESI m/z [MH+] 455/457. DSC 54.43 to 58.370C.

Reference： [1]Current Patent Assignee: RESOLUTION CHEMICALS - WO2008/99183, 2008, A1 Location in patent: Page/Page column 10-11

45
[ 1633-82-5 ]
trans-4-[(4S)-amino-1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester [ No CAS ]
trans-4-[1-(tert-butoxycarbonyl)-(4S)-(3-chloropropylsulfonyl)amino-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine In dichloromethane at 0 - 20℃; for 48h;	70 Trans-4-[(4S)-amino-1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid ethyl ester (1.75 g, 4.72 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (0.79 mL, 5.67 mmol) was added. The mixture was cooled to 0°C, and 3-chloropropylsulfonyl chloride (0.57 mL, 4.72 mmol) was added to the solution at 0°C. The mixture was stirred for two days while heating to room temperature. 1 N hydrochloric acid was added to the reaction liquor to make the reaction liquor weakly acidic, and the reaction liquor was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (Flash Chromatography System from Biotage AB, column size: 40S, elution solvent: n-hexane : ethyl acetate = 3:1 to 1:1), to obtain the title compound (1.71 g, 71%) as an oily matter. NMR(CDCl3)δ:1.22-1.53(total 16H, m, including 3H,t,J=7.2Hz,at δ 1.24 and including 9H,s,at δ 1.46),1.85-2.46(total 9H,series of m),3.14(2H,t,J=7.4Hz),3.28-3.31(1H,m),3.43-3.71(5H,m),3.95-4.15(5H,m,including 2H,q,J=7.2Hz at δ 4.11),6.87-6.89 and 7.05-7.08(total 1H,each m). MS(ESI)m/z:411(M++1-Boc)533 (M++Na).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1961750, 2008, A1 Location in patent: Page/Page column 126

46
[ 1633-82-5 ]
[ 863561-70-0 ]
[ 863561-71-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In ethyl acetate at 0 - 20℃;	7 A solution of G7 (750 mg; 3.07 mmol) in EtOAc (25 ml) was cooled to 0°C and treated successively with K2CO3 (470 mg; 3. 38 mmol) and 3-chloropropanesulphonyl chloride (411 111 ; 3.38 mmol). The mixture was allowed to warm to room temperature overnight and the solvent evaporated. The residue was purified by flash chromatography eluting with ammonia in MeOH (7S/CH2Cl2 (1/20) to give H7 (1. 02 g). Yield: 86%

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2005/79805, 2005, A1 Location in patent: Page/Page column 74

47
[ 1633-82-5 ]
[ 1152436-28-6 ]
[ 1152436-29-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine In tetrahydrofuran at -78 - 20℃; for 4h;	1.5 A solution of compound A5 (100 mg, 0.225 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature and the resulting solution was placed under nitrogen atmosphere. Triethylamine (0.060 mL, 0.45 mmol) was added to the reaction flask and the resulting reaction was cooled to -78 °C. A solution of compound A6 (1.38 mL, 0.326 M, 0.450 mmol) was then added dropwise and after addition was complete, the reaction mixture was allowed to warm to room temperature then allowed to stir for an additional 4 hours. The reaction mixture was then concentrated in vacuo, the residue obtained was diluted with ethyl acetate (50 mL) and to the resulting solution was added saturated aqueous sodium carbonate solution (50 mL). After separation of layers, the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (5- 60% EtOAc/Hexanes) to provide compound A7 (1 10 mg, 82% yield). M.S. found for C25H3ICl2N5O6S: 600.3 (M+H)+.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2009/64852, 2009, A1 Location in patent: Page/Page column 78

48
[ 1633-82-5 ]
[ 214360-73-3 ]
[ 756520-72-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)aniline With triethylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: 3-chloro-n-propanesulfonyl chloride In dichloromethane at 0 - 70℃; for 3h;	I.240.1 4- (4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (5 g, 22. 8 MMOL) WAS DISSOLVED in DCM (100 mL, 0. 2M), triethylamine (15 mL, 5. 0 molar EQUIVALENT) WAS ADDED to the mixture. The reaction was stirred at 0oC for 5 min. 3-chloropoane-1-sulfonyl chloride (4. 2 G, 23. 0 MMOL) was added portion wise. The reaction was stirred at 0 C for 1 hr and brought gradually to room temperature, heated to reflux at 70oC for 2 hr. The mixture was cooled to room temperature, diluted with EtOAc and water. The organic layer was washed with brine, dried over MGS04, filtered, and concentrated. The residue was purified through a silica column to afford 2- [4- (4, 4, 5, 5-TETRAMETHYL-1, 3, 2-dioxaborolan-2- yl)phenyl]isothiazolidine 1,1-dioxide as off-white solid (5. 2 G, 70% yield). 1H NMR (400 MHz, DMSO-d6) 6 7. 62 (d, 2H), 7. 18 (d, 2H), 3. 76 (T, 2H), 3.53 (t, 2H), 2.41 (t, 2H), 1. 28 (s, 12H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2004/76412, 2004, A2 Location in patent: Page 110

49
[ 1633-82-5 ]
[ 21961-31-9 ]
C₁₁H₁₃Cl₂NO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A stirred solution of <strong>[21961-31-9]3-amino-5-chloro-benzoic acid methyl ester</strong> (CAS 21961-31-9, 1.94 g) in THF (120 ml) was cooled down to -74 C. AIM solution of sodium bis(trimethylsilyl)amide in THF (31.4 ml) was slowly (5 min) added. The mixture was stirred at -74 C for 10 min. 3-Chloropropanesulfonyl chloride (2.83 g) was slowly added. The mixture was stirred for 1 h at -74 C. AIM solution of sodium bis(trimethylsilyl)amide in THF (6.3 ml) was added. After 5 min, 3-chloropropanesuifonyl chloride (0.61 ml) was added. The mixture was stirred at -74 C for 2 h. Another 0.61 ml of 3-chloropropanesulfonyl chloride was added and the mixture was stirred for 1.5 h. The reaction mixture was poured into a mixture of ice water (100 ml), saturated aqueous NH4CI solution (100 ml) and ethyl acetate (250 ml). The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and concentrated to give 6 g of a crude product as a brown oil.The crude product (3.26 g) was dissolved in N,N-dimethylacetamide (30 ml). Potassium-fe7t-butylate (1.15 g) and potassium iodide (50 mg) were added => exothermic reaction. The mixture was stirred for 10 min at r.t. and then heated to 80 C for 4 h and to 40 C for 14 h. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and concentrated. The product was purified by column chromatography (Si02, CH2CI2 => CH2CI2 / MeOH 4:1) to give 3-chloro-5-(l,l-dioxo-isothiazolidin-2-yl)-benzoic acid methyl ester (244 mg) as an off-white oil. MS 307.0 ([M+NH4]+)

Reference： [1]Patent: WO2006/27135,2006,A1 .Location in patent: Page/Page column 184

50
[ 1633-82-5 ]
[ 182223-54-7 ]
[ 1220695-10-2 ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (3 mL) was added to a dichloromethane (200 mL) solution of 1-<strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (1.2 g) at 0 C. followed by the dropwise addition of 3-chloropropane sulfonylchloride (4.3 mL; TCI) and the resulting mixture was slowly stirred overnight with raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). 100 mg of this purified compound was dissolved in acetone (10 mL) followed by the addition of sodium iodide (KANTO; 44 mg) and the resulting mixture was stirred at room temperature for 12 hours. Sodium iodide (KANTO; 44 mg) was further added, the resulting mixture was stirred at 40 C. for 24 hours followed by the addition of sodium iodide (KANTO; 132 mg), and the resulting mixture was stirred at 60 C. for 24 hours. The reaction mixture solution was cooled to room temperature, the residue was collected by filtration using a Kiriyama funnel to give the title compound (64 mg).(LCMS: 467.2 (MH+); retention time: 1.68 min; LCMS; condition A)

Reference： [1]Patent: US2010/261701,2010,A1 .Location in patent: Page/Page column 122

51
[ 1633-82-5 ]
[ 10433-52-0 ]
[ 916985-13-2 ]

Yield	Reaction Conditions	Operation in experiment
		O-Bn-D-serine (3 g, 15.36 mmol) was suspended in DMF (60 mL). BSTFA (bis(trimethylsilyl)trifluoroacetamide) (0.75 mL, 15.36 mmol) was added to the suspension, which was stirred at room temperature for 2 hours. All the starting material was dissolved. 3-Chloropropane sulfonyl chloride (2.25 mL, 18.43 mmol) was then added and the mixture was stirred at room temperature over night. The DMF was removed by evaporation in vacuo and ethyl acetate was added. The desired 4 was extracted using aqueous NaOH (1M) (70 mL). The aqueous phase was then acidified with aqueous HCl (5M) to pH 1. The desired compound was then extracted using ethyl acetate, dried over Na2SO4 and the organic solvent was evaporated in vacuo to give m=3.8 g of 4 as a dark brown oil. 1H NMR (CDCl3): 2.27 (m, 2H); 2.90-3.23 (m, 2H); 3.58 (t, 2H); 3.77 (m, 1H); 3.90 (m, 1H); 3.31 (bs, 1H); 4.54 (s, 2H); 5.50 (bs, 1H); 7.26-7.36 (m, 5H).
		O-Bn-D-serine (3g, 15.36 mmol) was suspended in DMF (60 mL). BSTFA (bis(trimethylsilyl)trifluoroacetamide) (0.75 mL, 15.36 mmol) was added to the <n="128"/>suspension, which was stirred at room temperature for 2hours. All the starting material was dissolved.3-Chloropropane sulfonyl chloride (2.25 mL, 18.43 mmol) was then added and the mixture was stirred at room temperature over night. The DMF was removed by evaporation in vacuo and ethyl acetate was added. The desired 4 was extracted using aqueous NaOH (IM) (7OmL). The aqueous phase was then acidified with aqueous HCl (5M) to pH 1. The desired compound was then extracted using ethyl acetate, dried over Na2SO4 and the organic solvent was evaporated in vacuo to give m=3.8g of 4 as a dark brown oil. 1H NMR (CDCl3): 2.27 (m, 2H); 2.90-3.23 (m, 2H); 3.58 (t, 2H); 3.77 (m, IH); 3.90 (m, IH); 3.31 (bs, IH); 4.54 (s, 2H); 5.50 (bs, IH); 7.26-7.36 (m, 5H).

Reference： [1]Patent: US2006/293370,2006,A1 .Location in patent: Page/Page column 30-31
[2]Patent: WO2008/141189,2008,A1 .Location in patent: Page/Page column 126-127

52
[ 1633-82-5 ]
[ 57260-73-8 ]
tert‐butyl N‐[2‐(3‐chloropropanesulfonamido)ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Cooling with ice;	11.1 First step Synthesis of tert-butyl 2-((3-chloropropyl)sulfonamido)ethyl)carbamate 11b N-tert-butoxycarbonyl-1,2-ethanediamine (1.6 g, 10.0 mmol)And DIPEA (1.50 g, 11.6 mmol) was dissolved in THF (20 mL).Under ice cooling, a solution of 3-chloropropane-1-sulfonyl chloride 11a (1.77 g, 10.0 mmol) in THF (5 mL) was evaporated.The temperature was gradually raised to room temperature overnight. Spin dry, add ethyl acetate and ammonium chloride solution,The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered.The title compound 11b (3.0 g, 10.0 mmol, 100%) was obtained.
96%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 8h;	C.1 Step 1 : Tert-but \ (2-((3-chloropropyl)sulfonamido)ethyl)carbamate (1-418) A solution of 3-chloropropane-l-sulfonyl chloride (cas: 1633-82-5, 1.22 g, 6.9 mmol) in anhydrous THF (5 mL) was added to a solution of /er/-butyl (2- aminoethyl)carbamate (1 g, 6.25 mmol) and DIPEA (1.30 mL) in anhydrous THF (62 mL) at 0- 5 °C. The reaction mixture was was allowed to warm to ambient temperature and stirred for 8 hours. When LC-MS analysis indicated that the reaction was complete, H20 (20 mL) was added, and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic extracts were concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (Petroleum ether: EtOAc = 1 :2) to provide 1-418 (2.0 g, 96%) as a pale oil. MS (ESI, pos. ion) m/z: 323(M+Na).
	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 30℃;	19 Reference Example 19; 2-(1,1-dioxidoisothiazolidin-2-yl)ethanamine hydrochloride; [Show Image] To a solution of tert-butyl (2-aminoethyl)carbamate (22.9 g) and diisopropylethylamine (21.97 g) in THF (250 mL) was slowly added 3-chloropropane-1-sulfonyl chloride (26.8 g) at 0°C, and the mixture was stirred overnight at room temperature. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (300 mL), sodium hydride (6.80 g) was slowly added thereto at 0°C, and the mixture was stirred at room temperature for 3 hr. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), 4N hydrogen chloride-ethyl acetate solution (100 mL) was added thereto, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to give the title compound (20.0 g, yield 70%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 1.59 (6 H, s), 2.48-2.53 (4 H, m), 4. 66 (3 H, br).

With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃;

tert-butyl (2-(3-chloropropylsulfonamido)ethyl)carbamate (I-18B). To a solution of I-18A (1.815 mL, 12.48 mmol) and DIEA (2.398 mL, 13.73 mmol) in THF (100 mL) cooled to 0° C. was added 3-chloropropane-1-sulfonyl chloride (1.670 mL, 13.73 mmol). The reaction was allowed to warm to RT. Upon completion of the reaction, the mixture was diluted with EtOAc and H2O. The phases were separated and the organic layer was washed with H2O and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-18B was isolated as an orange solid. LCMS m/z: 245 (M-55). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.40 (m, 9H) 2.02-2.11 (m, 2H) 2.94 (t, J=5.67 Hz, 2H) 2.96-3.03 (m, 2H) 3.05-3.13 (m, 2H) 3.70-3.75 (m, 2H) 6.78-6.87 (m, 1H) 7.20 (t, J=5.28 Hz, 1H).

Reference： [1]Current Patent Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD.; SHANGHAI SYNERGY PHARMACEUTICAL SCIENCES - CN109897011, 2019, A Location in patent: Paragraph 0455-0460
[2]Current Patent Assignee: CARMOT THERAPEUTICS - WO2019/183577, 2019, A1 Location in patent: Page/Page column 282
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2261213, 2010, A1 Location in patent: Page/Page column 45
[4]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2020/79772, 2020, A1 Location in patent: Paragraph 0534-0535

53
[ 1633-82-5 ]
[ 1258972-06-3 ]
[ 1258972-09-6 ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine In dichloromethane at 20℃; for 2h;	To a stirred solution of Intermediate 21 (150 mg, 0.395 mmol) in DCM (5 mL) was added TEA (83 μL, 0.593 mmol) followed by 3-chloropropanesulfonyl chloride (48 μL, 0.395 mmol). The reaction mixture was stirred at r.t. for 2 h, then diluted with DCM (5 mL) and washed with brine (2 x 1OmL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was chromatographed (SiO2, 60-100% EtOAc/hexanes), yielding the title compound (142 mg, 69%) as a white solid. δΗ (d6-DMSO at 1100C) 9.03 (s, IH), 7.94-7.91 (m, IH), 7.41-7.38 (m, IH), 7.37-7.30 (m, 2H), 7.08 (dd, J8.6, 1.5 Hz, IH), 7.03 (s, IH), 6.68 (d, J 8.3 Hz, IH), 4.34-4.26 (m, IH), 3.94-3.87 (m, 4H), 3.84-3.74 (m, 2H), 3.73 (s, 3H), 3.72-3.68 (m, 2H), 3.61 (dd, J 11.6, 3.3 Hz, IH), 3.56-3.47 (m, 2H), 3.19-3.10 (m, 4H), 2.24-2.16 (m, 2H). LCMS (ES+) 521 (M+H)+.

Reference： [1]Current Patent Assignee: UCB - WO2010/146351, 2010, A1 Location in patent: Page/Page column 46

54
[ 1633-82-5 ]
C₃₅H₄₆N₄O₁₀ [ No CAS ]
C₃₃H₄₃ClN₄O₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: C₃₅H₄₆N₄O₁₀ With hydrogenchloride In diethyl ether for 2h; Stage #2: 3-chloro-n-propanesulfonyl chloride With triethylamine In diethyl ether; dichloromethane at 0 - 20℃;	36 Compound lOe (0.55g, 0.81mmol) was suspended in lOmL 4N HC1/ ether solvent, stirred for 2 h and concentrated. lOmL DCM and triethylamine (0.82g, 8mmol) were added and cooled to 0-5 °C . The raw material sulfonyl chloride (0.29g, 1.6mmol) was added slowly and the reaction was stirred at room temperature overnight until completed. The reaction mixture was worked out and purified by flash column, and the product 13j (0.43g, yield: 73%).Compound 13j (0.4g ) was to added to the mixture solvent of NaOH (120mg, 3 mmol) , lOmL methanol and 0.5mL of water. The reaction mixture was stirred at 60 °C for 5 hr until completed. The reaction mixture was worked out and purified by flash column to obtain the product llj (0.3 lg, yield: 80%). 1H- MR for the product llj (CDC13, 500MHz): δ 7.30 (s, 1H); 6.76 (s, 1H); 6.68 (s, 1H);5.69 (q, J = 8.0Hz, 1H); 5.48 (s, 1H); 5.15 (t, J = 8.0Hz, 1H); 4.63-4.48 (m, 5H); 4.24 (s, 4H);4.23-4.14 (m, 2H); 3.86 (m, 1H ); 3.71 (m, 1H); 3.39 (m, 1H); 3.07-2.91 (m, 2H); 2.57 (m, 1H);2.44 (m, 1H); 2.36-2.22 (br, 4H); 2.04 ( m, 1H); 1.93 (m, 1H); 1.81 (m, 1H); 1.64-1.55 (br, 3H);1.46-1.29 (br, 4H); 1.24-1.20 (br, 2H), and confirmed by ESI-MS (M+H+): m/z calculated 673.2, founded 673.3.

Reference： [1]Current Patent Assignee: TOYOTA TSUSHO CORPORATION; AB PHARMA LTD - WO2011/91757, 2011, A1 Location in patent: Page/Page column 70

55
[ 1633-82-5 ]
C₃₄H₄₄N₄O₁₀ [ No CAS ]
C₃₂H₄₁ClN₄O₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: C₃₄H₄₄N₄O₁₀ With hydrogenchloride In diethyl ether for 2h; Stage #2: 3-chloro-n-propanesulfonyl chloride With triethylamine In diethyl ether; dichloromethane at 0 - 20℃;	37 Compound lOf (0.55g, 0.81mmol) was suspended in lOmL 4N HC1/ ether solvent, stirred for2 h and concentrated. lOmL DCM and triethylamine (0.82g, 8mmol) were added and cooled to 0-5°C . The raw material sulfonyl chloride (0.29g, 1.6mmol) was added slowly and the reaction was stirred at room temperature overnight until completed. The reaction mixture was worked out and purified by flash column, and the product 13k (0.48g, yield: 91%).Compound 13k (0.4g ) was added to the mixture solvent of NaOH (120mg, 3mmol) , lOmL methanol and 0.5mL of water. The reaction mixture was stirred at 60 °C for 5 hr until completed. The reaction mixture was worked out and purified by flash column to obtain the product Ilk(0.30g, yield: 78%). 1H- MR for the product Ilk (CDC13, 500MHz): δ 7.32 (s, 1H); 6.71 (s, 1H); 6.63 (s, 1H);5.96 (s, 2H); 5.69 (q, J = 8.0Hz, 1H); 5.48 (s, 1H); 5.15 (t, J = 8.0Hz, 1H); 4.64-4.49 (m, 5H);4.23-4.15 (m, 2H); 3.89 (m, 1H ); 3.72 (m, 1H); 3.40 (m, 1H); 3.09-2.89 (m, 2H); 2.58 (m, 1H);2.48 (m, 1H); 2.39-2.26 (br, 4H); 2.08 (m, 1H); 1.96 (m, 1H); 1.82 (m, 1H); 1.69-1.54 (br, 3H);1.46-1.29 (br, 4H); 1.26-1.20 (br, 2H) and confirmed by ESI-MS (M+H+): m/z calculated 659.2, founded 659.3.

Reference： [1]Current Patent Assignee: TOYOTA TSUSHO CORPORATION; AB PHARMA LTD - WO2011/91757, 2011, A1 Location in patent: Page/Page column 70; 71

56
[ 1633-82-5 ]
[ 1227862-95-4 ]
[ 1227865-53-3 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In dichloromethane at 20℃; for 6h;	306 10 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) was dissolved in 0.5 mL of methylene chloride, to which 8 mg of 3-chloropropane sulfonyl acid chloride and 6 mg of triethylamine were added, and stirred at room temperature for 3 hours. Furthermore, 8 mg of 3-chloropropane sulfonyl acid chloride and 6 mg of triethylamine were added, and stirred at room temperature twice for every 1 hour, and stirred for 1 hour. To the reaction mixture, under ice cooling, ammonia water was added, stirred for 5 minutes, the reaction mixture was extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1). The recovered product (18 mg) was dissolved in methanol, to which 2 mol/L sodium hydroxide in water was added, and stirred for 30 minutes. 2 mol/L hydrochloric acid was added thereto to neutralize the solution, extracted with chloroform, the extract was washed with saturated saline, and then dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 12 mg (84%) of the title compound as a brown crystalline powder.1H-NMR (400 MHz, CDCl3) δ: 2.10-2.50 (2H, m), 3.23 (2H, t, J=7.4 Hz), 3.66 (2H, t, J=6.1 Hz), 4.34 (2H, br), 5.83 (1H, s), 6.95 (2H, br, J=8.9 Hz), 7.09 (2H, br, J=8.9 Hz), 7.20-7.40 (5H, m), 8.18 (1H, s).

Reference： [1]Current Patent Assignee: KOWA COMPANY, LTD. - US2011/237590, 2011, A1 Location in patent: Page/Page column 102; 103

57
[ 1633-82-5 ]
[ 1346626-77-4 ]
[ 1346623-71-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 3-chloro-n-propanesulfonyl chloride; 2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole With triethylamine In dichloromethane at 0 - 20℃; for 2.25h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 20℃;	8 To a solution of 2-(l-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6- (l,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (0.15 g, 0.344 mmol) in CH2C12 (6.75 mL) at 0 °C was added Et3N (0.19 mL, 1.377 mmol), followed by a slow addition of 3-chloropropane-l-sulfonyl chloride (0.091 g, 0.517 mmol). Upon completion of addition, the reaction mixture was stirred at 0 °C for 15 min. At the conclusion of this period, the reaction mixture was allowed to warm to rt, where it stirred for an additional 2 h. After this time, the reaction mixture was quenched with aHC03 (aqueous, 1 mL) and then extracted with CH2C12 (3 x 2 mL). The combined organic layers were dried ( a2S04), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 90% EtOAc) to afford Example 8 as a light yellow solid (180 mg, 90% yield). ¾ NMR (500 MHz, chloroform-d) δ ppm 8.17 (s, 2H), 7.56 - 7.69 (m, 2H), 7.39 (d, J=8.5 Hz, 1H), 6.07 (br. s., 1H), 5.45 (ddd, J=7.6, 4.1, 3.9 Hz, 1H), 4.15 - 4.29 (m, 2H), 4.03 (d, J=1.9 Hz, 2H), 3.63 - 3.76 (m, 5H), 3.59 (t, J=5.6 Hz, 2H), 3.16 (t, J=7.3 Hz, 2H), 2.68 (br. s., 2H), 2.41 (t, J=7.4 Hz, 2H), 2.26 - 2.37 (m, 2H), 2.18 (ddd, J=12.5, 3.4, 3.3 Hz, 2H), 1.83 - 2.00 (m, J=12.5, 8.3, 8.3, 3.9 Hz, 2H), 1.58 (sxt, J=7.4 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); 13C NMR (126 MHz, chloroform-d) δ ppm 172.30, 160.60, 157.52, 149.02, 135.68, 135.32, 132.26, 123.18, 122.94, 120.46, 119.20, 117.63, 78.33, 47.12, 44.89, 42.96, 42.61, 41.12, 31.48, 30.36, 27.91, 26.49, 24.33, 13.45.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2011/140160, 2011, A1 Location in patent: Page/Page column 83-84

58
[ 1633-82-5 ]
[ 1271777-12-8 ]
[ 1357068-08-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: 3-chloro-n-propanesulfonyl chloride; C₁₄H₂₀F₂N₂O₂ With triethylamine In dichloromethane at 20℃; Stage #2: With hydrogenchloride In dichloromethane; water	1 104 (Scheme 14): A solution of 102 (282 mg, 0.986 mmol), 103 (144 μl, 1.18 mmol) and triethylamine (206 μl, 1.50 mmol) in dichloromethane (5 ml) was stirred at ambient temperature over night. 1 M hydrochloric acid (10 ml) was added and the mixture was extracted with dichloromethane. The combined organic phases were dried (MgSO4) and the solvent was evaporated under reduced pressure. 104 (300 mg, 71%) was obtained by flash chromatography on silica (eluent: pentane/diethylether).

Reference： [1]Current Patent Assignee: IMTM - US2012/28995, 2012, A1 Location in patent: Page/Page column 81

59
[ 22348-32-9 ]
[ 1633-82-5 ]
[ 1370293-22-3 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2960 - 2969

60
[ 1633-82-5 ]
[ 1198223-03-8 ]
[ 1380335-90-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In dichloromethane at 0 - 20℃; for 5h;	93.1 Step-i: Procedure for preparation of (R)-3-chloro-N-(i-(3- (cyclopentyloxy)phenyl)ethyl)propane- i-sulfonamide (59): To a stirred solution of 57 (3 g, 12.3 mmol) in DCM (50 mL) was added triethylamine (7.1 mL, 49.2 mmol) followed by 3-chloropropane-1-sulfonyl chloride 58 (2.3 mL, 18.5 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 5h. Progress of the reaction was monitored by LC-MS. Reaction mixture was quenched by adding water (100 mL), aqueous phase was extracted with DCM (100 mL x 2). Combined organic layer was washed with water (100 mL x 2) and brine (100 mL), dried over sodium sulphate and evaporated under reduced pressure to get the crude residue which was purified by combiflash column chromatography eluting with 30 % ethyl acetate in hexane to get (R)-3-chloro-N-(1-(3- (cyclopentyloxy)phenyl)ethyl)propane-1-sulfonamide 59 (2.9 g, 85 %) as a colourless liquid. ‘HNMR (400 MFIz, DMSO-d6) 1.38 (d, J=6.85 Hz, 3H), 1.54- 1.62 (m, 2 H), 1.67-1.72 (m, 5 H), 1.90 - 2.00 (m, 3H), 2.67-2.74 (m, 1 H), 2.85 - 2.95 (m, 1 H), 3.55 (t, J6.60 Hz, 2 H), 4.36 - 4.45 (m, 1 H), 4.79 (t, J=5.62 Hz, 1 H), 6.78 (dd, J8.07, 2.20 Hz, 1 H), 6.89 (d, J7.34 Hz, 1 H), 6.93 (d, J1.47 Hz, 1 H), 7.22 (t, J=8.07 Hz, 1 H), 7.82 (d, J=8.80 Hz, 1 H).
85%	With triethylamine In dichloromethane at 0 - 20℃; for 5h;	84.1 Step-1 : Synthesis of (R)-3-chloro-N-(l-(3- (cyclopentyloxy)phenyl)ethyl)propane-l-sulfonamide (10): To a stirred solution of 9 (3 g, 12.3 mmol) in DCM (50 mL) was added triethylamine (7.1 mL, 49.2 mmol) followed by 3-chloropropane-l-sulfonyl chloride (2.3 mL, 18.5 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 5h. Progress of the reaction was monitored by LC-MS. Reaction mixture was quenched by adding water (100 mL), and aqueous phase was extracted with DCM (100 mL x 2). Combined organic layer was washed with water (100 mL x 2) and brine (100 mL), dried over sodium sulphate and evaporated under reduced pressure to get the crude residue which was purified by combiflash column chromatography eluting with 30 % ethyl acetate in hexane to get (R)-3-chloro-N-(l-(3- (cyclopentyloxy)phenyl)ethyl)propane-l -sulfonamide 10 (2.9 g, 85 %) as a colourless liquid. 1H NMR (400 MHz, DMSO-d6) δ 1.38 (d, J=6.85 Hz, 3H), 1.54 - 1.62 (m, 2 H), 1.67-1.72 (m, 5 H), 1.90 - 2.00 (m, 3H), 2.67-2.74 (m, 1 H), 2.85 - 2.95 (m, 1 H), 3.55 (t, J=6.60 Hz, 2 H), 4.36 - 4.45 (m, 1 H), 4.79 (t, J=5.62 Hz, 1 H), 6.78 (dd, J=8.07, 2.20 Hz, 1 H), 6.89 (d, J=7.34 Hz, 1 H), 6.93 (d, J=1.47 Hz, 1 H), 7.22 (t, J=8.07 Hz, 1 H), 7.82 (d, J=8.80 Hz, 1 H).
73%	With triethylamine In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere;

Reference： [1]Current Patent Assignee: CV6 THERAPEUTICS - WO2018/98204, 2018, A1 Location in patent: Paragraph 0830
[2]Current Patent Assignee: CV6 THERAPEUTICS - WO2018/98206, 2018, A1 Location in patent: Paragraph 0799
[3]Miyahara, Seiji; Miyakoshi, Hitoshi; Yokogawa, Tatsushi; Chong, Khoon Tee; Taguchi, Junko; Muto, Toshiharu; Endoh, Kanji; Yano, Wakako; Wakasa, Takeshi; Ueno, Hiroyuki; Takao, Yayoi; Fujioka, Akio; Hashimoto, Akihiro; Itou, Kenjirou; Yamamura, Keisuke; Nomura, Makoto; Nagasawa, Hideko; Shuto, Satoshi; Fukuoka, Masayoshi [Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5483 - 5496]

61
[ 1633-82-5 ]
[ 135484-83-2 ]
[ 1223433-10-0 ]

Yield	Reaction Conditions	Operation in experiment
5.05 g		[0177] Preparation Example 13: Preparation of methyl 4-bromo-2-(1,1-dioxo-1lambda6-isothiazolidin-2-yl)benzoate[0178]EP 2 565 182 A124510152025303540455055[0179] Methyl 2-amino-4-bromobenzoate (5 g) and triethylamine (5.73 mL) were dissolved in methylene chloride (39mL), 3-chloropropane-1-sulfonyl chloride (3.44 mL) was added under ice-cooling, and the mixture was stirred at roomtemperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extractedwith chloroform. The organic layer was washed with dilute hydrochloric acid and saturated brine, and the solvent wasevaporated. To the obtained residue were added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)(3.9 mL) and N,N-dimethylformamide(29 mL), and the mixture was stirred at room temperature. After completion of the reaction, water wasadded to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed withdilute hydrochloric acid and saturated brine, and the solvent was evaporated. To the obtained residue was addeddiisopropyl ether, and the precipitate was collected by filtration to give the title compound (5.05 g)

Reference： [1]Patent: EP2565182,2013,A1 .Location in patent: Paragraph 0177; 0178; 0179

62
[ 1633-82-5 ]
[ 1427033-88-2 ]
[ 1427035-41-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 0 - 12℃; for 16h;	64.1 Step 1-Synthesis of 6-(3-chloropropylsulfonamido)-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide Step 1-Synthesis of 6-(3-chloropropylsulfonamido)-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (70 mg, 0.13 mmol) and Et3N (0.1 mL) in CH2Cl2 (2 mL) was added 3-chloropropane-1-sulfonyl chloride (140 mg, 0.92 mmol) dropwise at 0° C. The reaction mixture was stirred at 12° C. for 16 hours. The reaction mixture was concentrated to provide 6-(3-chloropropylsulfonamido)-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (90 mg, yield: 100%), which was used directly in the next step without further purification.
90 mg	With triethylamine In dichloromethane at 0 - 12℃; for 16h;	64.1 Step 1 - Synthesis of 6-(3-chloropropylsulfonamido)-5-(l l-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide To a solution of 6-amino-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (70 mg, 0.13 mmol) and Et3N (0.1 mL) in CH2C12 (2 mL) was added 3-chloropropane-l-sulfonyl chloride (140 mg, 0.92 mmol) dropwise at 0 °C. The reaction mixture was stirred at 12 °C for 16 hours. The reaction mixture was concentrated to provide 6-(3-chloropropylsulfonamido)-5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 Joxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide (90 mg, yield: 100%), which was used directly in the next step without further purification.

Reference： [1]Current Patent Assignee: WUXI APPTEC CO., LTD. - US2014/213571, 2014, A1 Location in patent: Paragraph 0709
[2]Current Patent Assignee: WUXI APPTEC CO., LTD. - WO2013/33971, 2013, A1 Location in patent: Page/Page column 181; 182

63
[ 1633-82-5 ]
3-chloropropane-1-sulfonyl fluoride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium fluoride In tert-butyl methyl ether; water at 20℃; for 12h;	1.1 1. Activation 1. Activation [0194] [0195] To a mixture of potassium fluoride (3.28 g, 56.5 mmol) in methyl-tert-butyl ether (MTBE) (25.00 ml) and water (15.00 ml) was added 3-chloropropanesulfonyl chloride (5.0 g, 28.2 mmol). The mixture was stirred at ambient temperature for 12 hours. The MTBE layer was separated and washed with water (25.00 ml) and concentrated to a liquid: 3-chloropropanesulfonyl fluoride (A-2, 4.54 g, 28.2 mmol, 98% yield).
98%	With potassium hydrogen difluoride In water; acetonitrile at 20℃; for 3h;	1(E) Sulfonyl Fluorides Made with Potassium Bifluoride (see FIG. 19) General procedure: Representative procedure for the synthesis of sulfonyl fluorides using saturated aqueous KHF2 and CH3CN. 4-Bromobenzene-1-sulfonyl fluoride (5-1). KHF2 (71 g; 2.3 equiv) was dissolved in H2O (200 mL) to make a saturated solution (endothermic reaction), which was treated with a solution of 4-bromobenzene-1-sulfonyl chloride (100 g, 1 equiv) in acetonitrile (400 mL). The reaction mixture was stirred at room temperature for 3 h, monitored by GC-MS. After that time, the reaction mixture was transferred to a separatory funnel and the organic layer was collected. The aqueous phase was extracted with EtOAc (300 mL), and the combined organic extracts were washed with 10% aqueous NaCl (2×), saturated sodium chloride (lx), dried over sodium sulfate, and concentrated by rotary evaporation to give the desired product as a white solid (91.5 g, 98% yield). mp 63-64° C. 1H NMR: (400 MHz, CDCl3) δ 7.88 (dd, J=9.2 Hz, 2 Hz, 2H), 7.78 (dd, J=9.2 Hz, 2 Hz, 2H); 13C NMR: (101 MHz, CDCl3) δ 133.1, 131.9 (d, J=25.5 Hz), 131.3, 129.8; 19F NMR (376 MHz, CDCl3) δ +65.9; GC-MS: 4.68 min; EI (m/z): 240/238 [M]+.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2013/274463, 2013, A1 Location in patent: Paragraph 0194-0195
[2]Current Patent Assignee: SCRIPPS RESEARCH - US10117840, 2018, B2 Location in patent: Page/Page column 19; 20; 36; 45; 47

64
[ 78-83-1 ]
[ 1633-82-5 ]
C₇H₁₅ClO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In toluene at 3 - 8℃; for 4h; Inert atmosphere;	1.A Production of Compound Represented by Formula (2A) Under a nitrogen gas atmosphere, 242.2 g of toluene, 30.8 g of isobutyl alcohol (1.05 times by mol to 3-chloropropanesulfanyl chloride) and 41.2 g of triethylamine (1.03 times by mol to 3-chloropropanesulfonyl chloride) weremixed at room temperature, and the resulting mixture was cooled to 3°C. Thereto was added dropwise 70 g of 3-chloropropanesulfonyl chloride while keeping the temperature of the resulting mixture in a range from 3°C to 8°C. About3 hours were taken for the dropwise addition. After completion of the dropwise addition, 30.3 g of toluene was added tothe resulting mixture, and the resulting mixture was stirred at a temperature ranging from 2°C to 5°C for 1 hour. Aftercompletion of the reaction, 140 g of water was added dropwise to the resulting mixture while keeping the temperatureof the resulting mixture in a range from 0°C to 10°C, and 2.1 g of 35% by weight of hydrochloric acid was further addeddropwise. The temperature of the resulting mixture was adj usted within a range from 20°C to 25°C, the resulting mixturewas stirred at that temperature for 30 minutes, and then an organic layer obtained by separation was washed with anaqueous sodium bicarbonate solution. The separated organic layer was concentrated under reduced pressure to obtain90 g of a compound represented by formula (2A). The chemical purity of the compound represented by formula (2A)was 95.1%, and the yield was 100%. 1H-NMR (400MHz,CDCl3)δ: 4.02(2H,d), 3.70(2H,t), 3.30(2H,t), 2.34(2H,m), 2.05(1H,m), 0.99(6H,d)

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP2796455, 2014, A1 Location in patent: Paragraph 0104; 0105

65
[ 1633-82-5 ]
[ 6283-25-6 ]
3-chloro-N-(2-chloro-5-nitrophenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With pyridine In dichloromethane at 20℃; for 4h;	3-Chloro-N-(2-chloro-5-nitrophenyl)propane-1-sulfonamide To a solution of 2-chloro-5-nitroaniline (compound 3; 600 mg,3.48 mmol) in dichloromethane (7 ml) was added 3-chloropropanesulfonylchloride (0.47 ml, 3.82 mmol) and pyridine (2.81ml, 34.8 mmol). The reaction mixture was stirred at roomtemperature for 4 h, then diluted with EtOAc and washed withwater. The organic layer was separated and dried over Na2SO4.The drying agent was filtered, and the solvent was evaporatedunder reduced pressure. The product was recrystallized withEtOH/acetonitrile to afford yellowish solid compound 4 (750mg, 69%). Molecular formula: C9H10Cl2N2O4S; MS (ES)(m/z) [M1] 313; 1H NMR (300 MHz, CD3OD): 8.25-8.29(2H, m), 7.98 (H, s), 7.96 (2H, s), 7.64-7.67 (2H, m), 7.50 (H, s),7.23-7.27 (2H, m), 2.16 (3H, s).
69%	With pyridine In dichloromethane at 20℃; for 4h;	2 3-Chloro-N- (2-chloro-5-nitrophenyl)propane-1-sulfonamide (4). 3-Chloro-N- (2-chloro-5-nitrophenyl)propane-1-sulfonamide (4). To a solution of 2-chloro-5-nitroaniline 3 (600 mg, 3.48 mmol) in dichloromethane (7 mL) was added 3-chloropropanesulfonyl chloride (0.47 mL, 3.82 mmol) and pyridine (2.81 mL, 34.8 mmol). The reaction mixture was stirred at room temperature for 4 h then diluted with EtOAc and washed with water. The organic layer was separated and driedover Na2504. The drying agent was filtered and the solvent was evaporated under reduced pressure. The product was recrystallized with EtOH/acetonitrile to afford yellowish solid 4 (750 mg, 69 %). Molecular formula: C9Hi0C12N2O4S; MS (ES+) (m/z) [M+1] 313; ‘H NMR (300 MHz, CD3OD): ö 8.25-8.29 (2H, m), 7.98 (H, s), 7.96 (2H, s), 7.64-7.67 (2H, m), 7.50 (H, s), 7.23-7.27 (2H, m), 2.16 (3H, s).

Reference： [1]Esteva-Font, Cristina; Cil, Onur; Phuan, Puay-Wah; Su, Tao; Lee, Sujin; Anderson, Marc O.; Verkman [FASEB Journal, 2014, vol. 28, # 9, p. 3878 - 3890]
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2015/172065, 2015, A1 Location in patent: Page/Page column 48

66
[ 1633-82-5 ]
[ 393811-02-4 ]
3-(3-((3-chloropropyl)sulfonamido)benzyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	III.e Scheme III Synthesis of MEK binding Pharmacophore (MV3-61A) Reagents and conditions: (a) 3-nitrobenzyl bromide, THF, 0°C - RT, 64.5%; (b) resorcinol, cone. H2S04, 0°C - RT, 90%; (c) 1. NaH, THF, 2. (CH3)2NC0C1, DMAP (cat.), 93%; (d) SnCl2, EtOH, reflux, 90%; (e) C1S02(CH2)3C1, Hunigs base, DMAP, DCM, 0°C - RT, 85%; (f) CH3I, Cs2C03, DMF, 82.5%.
81%	With pyridine at 20℃; for 1h;	The preparation of 3-(3-((3-chloropropyl)sulfonamido)benzyl)-4-methyl-2-oxo-2H-chromen-7-yldimethylcarbamate (9) To a solution of 8 (1.5 g, 4.26 mmol) in pyridine (6mL) wasadded 3-chloropropane-1-sulfonyl chloride (0.83 g, 4.69mmol),and the resultant reaction mixture was stirred at room temperaturefor 1 h. Then, the reaction mixture was subjected toflash column chromatography (DCM/EA=10:1-8:1) to givethe title intermediate as a pale solid. Yield: 81%; 1H NMR(400 MHz, DMSO-d6): δ 9.79 (s, 1H), 7.85 (d, 8.8Hz, 1H),7.29-7.22 (m, 2H), 7.18 (dd, 2.4Hz, 8.8Hz, 1H), 7.12-7.04(m, 2H), 6.99 (d, 7.6Hz, 1H), 3.97 (s, 2H), 3.68 (t, 6.4Hz, 2H),3.23-3.14 (m, 2H), 3.07 (s, 3H), 2.94 (s, 3H), 2.47 (s, 3H),2.12-2.03 (m, 2H); ESI-MS: m/z=493 [M+H]+; m.p.162-165 °C.
1.7 g	With pyridine at 20℃; for 2h;	1.1.1 Synthesis of 3-(3-(3-chloropropylsulfonamide)benzyl)-4-methyl-2-oxo-2H-coumarin-7-dimethylcarbamate (2) In a round bottom flask,Add 3-(3-aminobenzyl)-4-methyl-2-oxo-2H-coumarin-7-dimethylcarbamate 1 (1.5g, 4.26mmol),3-chloropropylsulfonyl chloride (0.83g, 4.69mmol) and pyridine (8 mL),Stir the reaction at room temperature for 2h,Silica gel column chromatography with dichloromethane/ethyl acetate (10:1-8:1, V/V) as the eluent to obtain 1.7 g of white solid.

Reference： [1]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2014/164942, 2014, A1 Location in patent: Paragraph 0207-0208
[2]Fang, Fang; Li, Jiaming; Liang, Jingtai; Ma, Xiaodong; Tao, Qiangqiang; Wang, Hao; Wang, Yong; Zhao, Can [Medicinal Chemistry Research, 2020]
[3]Current Patent Assignee: HEFEI YUANZHI PHARMACEUTICAL R D; ANHUI UNIVERSITY OF CHINESE MEDICINE; USTC (in: CAS); CHINESE ACADEMY OF SCIENCES - CN111909139, 2020, A Location in patent: Paragraph 0013; 0031-0033

67
[ 1633-82-5 ]
[ 1465-25-4 ]
3-chloro-N-(2-(naphthalen-1-ylamino)ethyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N-(1-napthyl)ethylenediamine dihydrochloride (1 mmole) in 15 ml anhydrous DCM, TEA (3 equiv) was added at 0C and stirred for 15 minutes at RT. 3-chlorosulphonylchloride (1 equiv) was added dropwise and the resulting reaction mixture stirred at RT for 16 h under nitrogen. The reaction mixture was concentrated to obtain crude product, which was further purified by column chromatography to give pure intermediate 13. To 1 equiv. of 13 in acetonitrile, 2 equiv. of the appropriate amine was added and the reaction mixture was subjected to microwave irradiation 120C for 20-30 minutes. Then the reaction mixture was poured into water, and extracted with dichloromethane. The DCM layer was washed with water, brine, and dried over sodium sulphate. Solvent was removed under reduced pressure to give crude product which was further purified by column chromatography to give pure products 14-26.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 626 - 630

68
[ 1633-82-5 ]
[ 2915-84-6 ]
2,7-bis(1,1-dioxido-1,2-thiazolidin-2yl)-9H-fluoren-9-one [ No CAS ]

Reference： [1]MedChemComm,2015,vol. 6,p. 1278 - 1284

69
[ 1633-82-5 ]
[ 106-48-9 ]
C₉H₁₀Cl₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In dichloromethane at 0℃;	Compound 13 To a solution of 4-chlorophenol (255μL, 2.50 mmol) and Et3N (348μL, 2.50mmol) in CH2Cl2 (5 mL) was added 3-chloropropylsulfonyl chloride (443 mg, 2.50 mmol) at 0 °C. After work-up, the crude mixture was purified with silica gel column chromatography to obtain 13 as a colorless solid (645 mg, 96%).1H NMR (400 MHz, CDCl3/TMS): δ 7.93 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 3.46 (t, J = 7.4 Hz, 2H), 2.45 (tt, J = 6.0, 7.4 Hz, 2H).

Reference： [1]Hanaya, Kengo; Yoshioka, Shohei; Ariyasu, Shinya; Aoki, Shin; Shoji, Mitsuru; Sugai, Takeshi [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 545 - 550]

70
[ 402-45-9 ]
[ 1633-82-5 ]
C₁₀H₁₀ClF₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In dichloromethane at 0℃;	Compound 14 To a solution of 4-trifluoromethylphenol (406 mg, 2.50 mmol) and Et3N (348 μL, 2.50 mmol) in CH2Cl2 (5 mL) was added 3-chloropropylsulfonyl chloride (443 mg, 2.50 mmol) at 0 °C. After work-up, the crude mixture was purified with silica gel column chromatography and following washing with 2 M NaOH to obtain 14 as a colorless solid (719 mg, 95%).1H NMR (400 MHz, CDCl3/TMS): δ 7.71 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 7.4 Hz, 2H), 2.47 (tt, J = 6.1, 7.4 Hz, 2H).

Reference： [1]Hanaya, Kengo; Yoshioka, Shohei; Ariyasu, Shinya; Aoki, Shin; Shoji, Mitsuru; Sugai, Takeshi [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 545 - 550]

71
[ 1633-82-5 ]
[ 130-16-5 ]
C₁₂H₁₁Cl₂NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In dichloromethane at 20℃; for 1.75h;	Compound 11a To a solution of chloropropylsulfonyl chloride (886 mg, 5.00 mmol) and Et3N (710 μL, 5.09 mmol) in CH2Cl2 (20 mL) was added 5-chloroquinolin-8-ol (899 mg, 5.01 mmol). After stirring for 1.5 hr at room temperature, an additional amount of chloropropylsulfonyl chloride (354 mg, 2.00 mmol) and Et3N (307 μL, 2.20 mmol) were added to the reaction mixture, and the resulting mixture was stirred for further 15 min. After work-up, the crude mixture was purified by Isolera One system (hexane/AcOEt) to obtain 11a as a pale yellow solid (1542 mg, 96%). 1H NMR (500 MHz, CDCl3/TMS): δ9.00 (dd, J = 1.7,4.2Hz, 1H), 8.59 (dd, J= 1.7, 8.6 Hz, 1H), 7.65 (d, J = 8.3Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.60 (dd, J = 4.2,8.6 Hz, 1H), 3.81 (t, J = 7.4Hz, 2H), 3.79 (t, J = 6.3 Hz, 2H), 2.65 (tt, J = 6.3, 7.4Hz, 2H); 13C NMR (125 MHz, CDCl3): δ151.5,144.4, 141.8, 133.4, 130.3, 127.5, 126.3, 123.6, 122.9, 49.6, 42.8, 27.0; IR (neat): 2967, 1587, 1565, 1495, 1464, 1368, 1350, 1160, 1145cm-1; HRMS (ESI+) calcd for C12H11Cl2NNaO3S (M+Na) 341.9734: Found 341.9733.

Reference： [1]Hanaya, Kengo; Yoshioka, Shohei; Ariyasu, Shinya; Aoki, Shin; Shoji, Mitsuru; Sugai, Takeshi [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 545 - 550]

72
[ 826-81-3 ]
[ 1633-82-5 ]
C₁₃H₁₄ClNO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dmap; triethylamine In dichloromethane at 0 - 20℃; for 0.416667h;	Compound 12a To a solution of 2-methylquinolin-8-ol (476 mg, 2.99 mmol), Et3N (502 μL, 3.60 mmol), and DMAP (39 mg, 0.319 mmol) in CH2Cl2 (10mL) were added chloropropylsulfonyl chloride (401 μL, 3.30 mmol) at 0 °C. The reaction mixture was stirred for 25 min at room temperature. After work-up, the crude mixture was recrystallized from hexane/AcOEt to obtain 12a as a pale orange solid (818 mg, 91%). 1H NMR (500 MHz, CDCl3/TMS): δ 8.07(d, J = 8.4Hz, 1H), 7.72 (dd, J = 1.3,8.2Hz, 1H), 7.66 (dd, J = 1.3,7.6 Hz, 1H), 7.46 (dd, J = 7.6, 8.2Hz, 1H), 7.34 (d, J = 8.4Hz, 1H), 3.85 (t, J = 7.4Hz, 2H), 3.78 (t, J = 6.3 Hz, 2H), 2.74(s, 3H), 2.68 (tt, J = 6.3,7.4Hz, 2H); 13C NMR (125MHz, CDCl3): δ 160.0, 144.9,140.7, 136.3, 128.1, 127.0, 125.4, 123.8, 123.0, 49.5, 42.9, 27.0, 25.5; IR(neat): 2990, 2975, 2924, 1603, 1499, 1431, 1346, 1313, 1171, 1155 cm-1.

Reference： [1]Hanaya, Kengo; Yoshioka, Shohei; Ariyasu, Shinya; Aoki, Shin; Shoji, Mitsuru; Sugai, Takeshi [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 545 - 550]

73
[ 1633-82-5 ]
N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide [ No CAS ]
N-((1R,3r,5S)-8-(3-chloropropylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In dichloromethane at 0 - 25℃;	13.1 Step 1: Synthesis of N-((1R,3r,5S)-8-(3-chloropropylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide Into a 25-mL round-bottom flask was placed N-[(1 R,3r,5S)-8- azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide (200 mg, 0.62mmol, 1.00 equiv), dichloromethane (5mL), TEA (189 mg, 1.87mmol, 3.00 equiv). This was followed by the added of 3-chloropropane-1-sulfonyl chloride (143 mg, 0.81mmol, 1.30 equiv) dropwise at 0oC. The resulting solution was stirred overnight at 25oC. The solution was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 240 mg (96%) of N- [(1R,3r5S)-8-[(3-chloropropane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl- 1,2-oxazole-3-carboxamide as yellow oil. LCMS (method D, ESI): RT=0.97min, m/z =402.0 [M+H]+.

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2016/40515, 2016, A1 Location in patent: Paragraph 0320

74
[ 1633-82-5 ]
[ 951914-08-2 ]
N-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)-3-chloropropylsulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In tetrahydrofuran at 20℃; for 16h; Cooling with ice;	4.2 (2) Preparation of N-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)-3-chloropropylsulfonamide 2-(4-bromo-3,5-dimethylphenoxy)ethylamine (1.7 g, 7.0 mmol) was dissolved in tetrahydrofuran (50 mL)triethylamine (2.1 g, 21 mmol) was added, 3-chloropropyl-1-sulfonyl chloride (1.77 g, 10 mmol) was added dropwise under ice-cooling, after dropping, the reaction was allowed to proceed to room temperature for 16 h. Water (100 mL) was added, ethyl acetate extraction (100 mL x 3), the organic phases were combined, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, the crude product was isolated by silica gel column chromatography (ethyl acetate / petroleum ether = 0 to 1/5) to give the product (2.0 g, 74% yield).

Reference： [1]Current Patent Assignee: BOHAI WATER INDUSTRY CO., LTD. - CN104250239, 2016, B Location in patent: Paragraph 0367; 0368; 0369

75
[ 1633-82-5 ]
[ 421-85-2 ]
potassium 3-chloropropanesulfonyltrifluoromethanesulfonylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.79%		Potassium 3-chloropropanesulfonyltrifluoromethanesulfonylimide has been synthesized according to the previous literature with minor modifications.[25] 6.72g (45.1mmol) of trifluromethanesulfonamide was taken in a clean 500mL flask containing 100mL of anhydrous acetonitrile. To the above solution, 5g (90mmol) of potassium hydroxide was added in the presence of argon atmosphere under cold conditions and stirred for 30minutes. Later, 8g (45.1mmol) of 3-chloropropanesulfonyl chloride dissolved in 100mL of anhydrous acetonitrile was added drop-wise to the reaction mixture under cold conditions and stirred for 13h at room temperature. Then, the reaction mixture was filtered and the residue was washed with 50mL of anhydrous acetonitrile. The filtrate was dried with sodium sulfate, filtered, rotary evaporated and vacuum dried. The resultant solids were washed with excess of dichloromethane and ether for two times to remove the starting materials and then, vacuum dried to afford a fine white solid (11.35g, 76.79% yield). 1H NMR (400MHz, DMSO-d6): delta 3.74 (t, 2H, CH2-SO2), 3.24-2.94 (t, 2H, CH2-Cl), 2.24-1.97 (m, 2H, CH2-CH2-CH2). 13C NMR (101MHz, DMSO-d6): delta 124.98-118.54 (CF3), 52.00 (CH2-SO2), 43.72 (CH2-Cl), 27.38 (CH2-CH2-CH2).

Reference： [1]Electrochimica Acta,2017,vol. 241,p. 526 - 534
[2]ChemCatChem,2016,vol. 8,p. 3394 - 3401

76
[ 367-21-5 ]
[ 1633-82-5 ]
3-chloro-N-(3-chloro-4-fluorophenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.5%	With pyridine In dichloromethane at 20℃; for 18h;	221.1 [Step 1] 3-chloro-N-(3-chloro-4-fluorophenyl)propane- 1-sulfonamide A solution of 3-chloro-4-fluoroaniline (5.000 g, 34.350 mmol) and pyridine (5.534 mL, 68.700 mmol) in dichloromethane (50 mL) was mixed at the room temperature with 3-chloropropane-1-sulfonyl chloride (4.594 mL, 37.785 mmol). The reaction mixture was stirred at the same temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 80 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give3-chloro-N-(3-chloro-4-fluorophenyl)propane- 1- sulfonamide as brown solid (8.700 g,88.5 %).

Reference： [1]Current Patent Assignee: CHONGKUNDANG HOLDINGS CORP. - WO2017/18803, 2017, A1 Location in patent: Paragraph 2858; 2859; 2860

77
[ 1633-82-5 ]
N⁴-((3R,6S)-6-aminohexahydrofuro[3,2-b]furan-3-yl)-5-chloro-N²-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine [ No CAS ]
3-chloro-N-((3S,6R)-6-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.2%	With triethylamine In dichloromethane at 0 - 20℃;	12.1 To a solution of ~-((3R,6S)-6-aminohexahydrofuro[3,2-b]furan-3-yl)-5-chloro-N2 -(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (198.8 mg, 0.57 mmol) and TEA (94.6 mg,0.94 mmol) in DCM (5 mL) was added 3-chloropropane-1-sulfonyl chloride (132.1 mg, 0.75 mmol) at 0 °C. The mixture was stirred at 0 oc for 30 min, and then the reaction mixture wasallowed to warm to room temperature and stirred overnight. The reaction mixture was quenchedwith water (1 mL) and concentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v) = 1/50) to afford the title compound as a white solid (134.0mg, yield 48.2%).MS (ESI, pos. ion) m/z: 492.1 [M+Ht.
48.2%	With triethylamine In dichloromethane at 0 - 20℃;	12.1 Step 1) 3-chloro-N-((3S,6R)-6-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl)propane-1-sulfonamide 0 ° C,To a solution of N4 - ((3R, 6S) -6-aminohexahydrofuro [3,2-b] furan-3-yl) -5-chloro-N2- (1-methyl- Yl) pyrimidine-2,4-diamine (198.8 mg, 0.57 mmol) and triethylamine (94.6 mg, 0.94 mmol) in dichloromethane (5 mL) was added 3-chloropropane-1-sulfonyl chloride (132.1 mg , 0.75 mmol).The reaction mixture was stirred at 0 & lt; 0 & gt; C for 30 min,Then allowed to stand overnight at room temperature.After the reaction,Add water (1mL) quenching,Dry the solvent.The resulting residue was purified by silica gel column chromatography (MeOH / DCM (v / v) = 1/50) to afford the title compound as a white solid (134.0 mg, yield 48.2%).

Reference： [1]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2017/48675, 2017, A1 Location in patent: Paragraph 0410
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN106478651, 2017, A Location in patent: Paragraph 0767; 0768; 0769

78
[ 1633-82-5 ]
2-(4-bromo-3-vinylphenoxy)ethylamine [ No CAS ]
N-(2-(4-bromo-3-vinylphenoxy)ethyl)-3-chloropropane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In tetrahydrofuran at 20℃; for 16h; Cooling with ice;	3.5 (5) Preparation of N- (2- (4-bromo-3-vinylphenoxy) ethyl) -3-chloropropane-1-sulfonamide A solution of 2- (4-bromo-3-vinylphenoxy) ethylamine (2 g, 8.3 mmol) in tetrahydrofuran (20 mL)Triethylamine (2.5 g, 24.7 mmol) was added,Solution of 3-chloropropyl-sulfonyl chloride (1.62g, 9.1mmol) under ice-cooling,After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 16 hours.Add water (100mL),Ethyl acetate extraction (100 mL x 3),Organic synthesis,Saturated aqueous sodium chloride solution,Dried over anhydrous sodium sulfate,concentrate,Crude silica gel column chromatography (eluent ethyl acetate: petroleum ether = 1: 10) to give the title compound 5.5 g, yield 70%.

Reference： [1]Current Patent Assignee: BOHAI WATER INDUSTRY CO., LTD. - CN104788412, 2017, B Location in patent: Paragraph 0328; 0329; 0330; 0361; 0362; 0363

79
[ 149423-77-8 ]
[ 1633-82-5 ]
benzyl (trans-4-(3-chloropropylsulfonamido)cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h;	A A. Benzyl (frans-4-(3-chloropropylsulfonamido)cyclohexyl)carbamate Benzyl (frans-4-aminocyclohexyl)carbamate (1 .01 g, 4.07 mmol) was dissolved in DMF (8 mL) and N,N-diisopropylethylamine (1 .04 g, 8.02 mmol) was added. 3-Chloropropane-1 - sulfonyl chloride (0.786 g, 4.44 mmol) was added slowly, and the resulting mixture was stirred at room temperature for 3 hours. Water (50 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried to afford the title compound (1 .42 g, 90% yield) as a white solid. 1H NMR (400 MHz, CDCI3) δ 1 .14-1 .30 (m, 2 H), 1 .30-1 .45 (m, 2 H), 1 .99-2.14 (m, 4 H), 2.20-2.33 (m, 2 H), 3.12-3.21 (m, 2 H), 3.21 -3.33 (m, 1 H), 3.41 -3.53 (m, 1 H), 3.67 (t, J = 6 Hz, 2 H), 4.22 (d, J = 8 Hz, 1 H), 4.60 (d, J = 7 Hz, 1 H), 5.07 (s, 2 H), 7.27- 7.41 (m, 5 H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2018/69863, 2018, A1 Location in patent: Page/Page column 163

80
[ 1633-82-5 ]
[ 106-40-1 ]
N-(4-bromophenyl)-N-(3-chloropropyl)sulfamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With pyridine In dichloromethane at 20℃; for 4h; Cooling with ice;	55.1 Step 1: N-(4-bromophenyl)-N-(3-chloropropyl)sulfamide To a solution of 4-bromoaniline (0.86 g, 5 mmol) and pyridine (0.5 mL) in anhydrous dichloromethane (15 mL) was added 3-chloropropanesulfonyl chloride (0.6 mL, 5.0 mmol) in an ice-bath. After the addition, the mixture was stirred at rt for 4 h, then extracted with DCM (20 mL3). The combined organic layers were washed with water (15 mL) and hydrochloric acid (10 mL1, 2 mol/L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica-gel column chromatography (PE:EtOAc=6:1, V/V)to give a yellow solid (1.8 g, 99%). MS (ESI, pos.ion) m/z: 312.9 (M+2);

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - EP3342765, 2018, A1 Location in patent: Paragraph 0432

81
[ 1633-82-5 ]
[ 1198223-51-6 ]
(R)-3-chloro-N-(1-(3-(cyclopentyloxy)-4-fluorophenyl)ethyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine In dichloromethane at 0 - 20℃; for 5h;	85.4 Step-4: Synthesis of (R)-3-chloro-N-(l-(3-(cyclopentyloxy)-4- fluorophenyl)ethyl)propane-l-sulfonamide To a stirred solution of (R)-l-(3-(cyclopentyloxy)-4-fluorophenyl)ethan-l-amine (1474) hydrochloride 24 (1.5 g, 5.77 mmol) in DCM (25 mL) was added triethylamine (3.2 mL, 23.07 mmol) followed by 3-chloropropane-l-sulfonyl chloride (1 mL, 8.65 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 5h. Progress of the reaction was monitored by LC-MS. Reaction mixture was quenched by adding water (50 mL), and aqueous phase was extracted with DCM (50 mL x 2). Combined organic layer was washed with water (50 mL x 2) and brine (50 mL), dried over sodium sulphate and evaporated under reduced pressure to get the crude residue which was purified by combiflash column chromatography eluting with 30 % ethyl acetate in hexane to yield (R)-3-chloro-N-(l-(3- (cyclopentyloxy)-4-fluorophenyl)ethyl)propane-l -sulfonamide 25 (1.9 g, 91 %) as a colourless liquid. 1H NMR (400 MHz, DMSO-d6) δ 1.38 (d, J=6.85 Hz, 3H) 1.56 - 1.64 (m, 2H) 1.68 - 1.78 (m, 4H) 1.86 - 2.04 (m, 4H) 2.67 - 2.79 (m, 1H) 2.86 - 2.96 (m, 1H) 3.56 - 3.61 (m, 2H) 4.39 - 4.48 (m, 1H) 4.81 - 4.88 (m, 1H) 6.88-6.92 (m, 1 H) 7.13 (dd, J=l 1.74, 8.31 Hz, 1H) 7.18 (dd, J=8.31, 1.96 Hz, 1H) 7.85 (d, J=8.80 Hz, 1H).

Reference： [1]Current Patent Assignee: CV6 THERAPEUTICS - WO2018/98206, 2018, A1 Location in patent: Paragraph 0813

82
[ 1633-82-5 ]
benzyl (S)-2-amino-3-(3-(benzyloxy)phenyl)propanoate hydrochloride [ No CAS ]
C₂₆H₂₈ClNO₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine In dichloromethane at 0 - 15℃; for 1h;	26 [0320] To a solution of 3-04-2 (14.5 g, 36.4 mmol, HCl salt) and triethylamine (15.2 mL, 109 mmol) in dichloromethane (150 mL) was added 3-chloropropane-l-sulfonyl chloride (5.3 mL, 44 mmol) at 0 °C. The mixture was stirred for 1 hour at 15 °C. The reaction mixture was poured into water, the pH of the mixture adjusted to pH = 4 with IN hydrochloric acid aqueous, then extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to provide 1-87-1 (15 g, 79%) as yellow gum.

Reference： [1]Current Patent Assignee: TRI-INSTITUTIONAL THERAPEUTICS DISCOVERY INSTITUTE; CORNELL UNIVERSITY - WO2019/75259, 2019, A1 Location in patent: Paragraph 0320

83
[ 863504-84-1 ]
[ 1633-82-5 ]
tert-butyl 3-(3-chloropropanesulfonamido)-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 2h; Cooling with ice;	2.5.A Intermediate 2.5.A (0282) tert-Butyl 3-(3-chloropropanesulfonamido)-1 H-pyrazole-1 -carboxylate

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2019/149658, 2019, A1 Location in patent: Page/Page column 47

84
[ 1633-82-5 ]
[ 84228-48-8 ]
C₁₁H₁₁Cl₂NO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; dichloromethane; at 0 - 65℃; for 15.0h;	To a solution of methyl 5-amino-2,4-dichloro-benzoate (160 mg, 727.1 mpio, 1 eq) in 2 mL of dichloromethane was added TEA (220.7 mg, 2.2 mmol, 303.6 pL, 3 eq) and 3- chloropropane-l-sulfonyl chloride (193.1 mg, 1.1 mmol, 132.3 pL, 1.5 eq) at 0C. The mixture was stirred at 25C for 12 hours. Then it was concentrated under reduced pressure to give a residue. The residue was dissolved in 2 mL of methanol and TEA (220.7 mg, 2.2 mmol, 303.6 pL, 3 eq) was added. The mixture was stirred at 65C for 3 hours. Then it was concentrated under reduced pressure to remove methanol. The residue was diluted with 3 mL of ethyl acetate, washed three times with 3 mL of sat. NH4CI, dried over Na2SC>4, filtered and concentrated under reduced pressure to give 230 mg of crude compound 4 as a yellow solid, which was used into the next step directly.

Reference： [1]Patent: WO2020/117877,2020,A1 .Location in patent: Page/Page column 69-71

85
[ 1633-82-5 ]
[ 1240301-24-9 ]
tert-butyl 4-({6-[5-(1,1-dioxido-1,2-thiazolidin-2-yl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 3-chloro-n-propanesulfonyl chloride; tert-butyl 4-[6-(5-amino-2,3-dihydro-1H-indol-1-yl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate In tetrahydrofuran at 20℃; for 16h; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 3h;	tert-Butyl 4-({6-[5-(1,1-dioxido-1,2-thiazolidin-2-yl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (23d). To a solution of compound 21 (5.00g, 12.2mmol) and triethylamine (2.79mL, 20.0mmol) in THF (220mL) was added dropwise 3-chloropropanesulfonyl chloride (2.58g, 14.6mmol), and the mixture was stirred at room temperature for 16h. The mixture was diluted with AcOEt, successively washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residual solid was dissolved in DMF (100mL). Sodium hydride (60% oil dispersion, 583mg, 14.6mmol) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 3h. The reaction was quenched by addition of water and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. The solvent was removed by evaporation to give the title compound as a brown solid (5.10g, 81% over 2 steps). MS (ESI/APCI) m/z 516 [M+H]+. 1H NMR (300MHz, DMSO-d6) δ 1.41 (9H, s), 1.47-1.69 (2H, m), 1.87-2.06 (2H, m), 2.30-2.45 (2H, m), 3.06-3.27 (4H, m), 3.46 (2H, t, J=7.4Hz), 3.62-3.80 (4H, m), 3.98 (2H, t, J=8.7Hz), 5.13-5.35 (1H, m), 6.07 (1H, s), 7.02 (1H, dd, J=8.9, 2.5Hz), 7.17 (1H, d, J=2.3Hz), 8.33 (1H, d, J=8.7Hz), 8.45 (1H, s). Anal. Calcd for C25H33N5O5S: C, 58.23; H, 6.45; N, 13.58. Found: C, 58.12; H, 6.43; N, 13.68.

Reference： [1]Kamaura, Masahiro; Kubo, Osamu; Sugimoto, Hiromichi; Noguchi, Naoyoshi; Miyashita, Hirohisa; Abe, Shinichi; Matsuda, Kae; Tsujihata, Yoshiyuki; Odani, Tomoyuki; Iwasaki, Shinji; Murata, Toshiki; Sato, Kenjiro [Bioorganic and Medicinal Chemistry, 2021, vol. 34]

86
[ 5192-03-0 ]
[ 1633-82-5 ]
3-chloro-N-(1H-indol-5-yl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In dichloromethane at 20℃;	4.1.3. General procedure of 1-(1H-indol-5-yl) sulfonamide and amidederivatives (4a-f and 5) General procedure: To a dry round-bottom flask containing (88 mg, 0.66 mmol) ofcompound 1 (5-aminoindole) and 1 mmol of TEA (0.14 mL) dissolved in4 mL of DCM, one equivalent (0.66 mmol) of the appropriate isocyanatewas added and the reaction mixture was stirred overnight at roomtemperature. The mixture was evaporated, and the residue was partitionedbetween EA and water using aqueous NaHCO3. The organic layerwas dried over anhydrous Na2SO4, concentrated, and purified by columnchromatography (SiO2, EA/n-Hex) to afford the correspondingtarget compound.

Reference： [1]Elkamhawy, Ahmed; Kim, Hyeon Jeong; Elsherbeny, Mohamed H.; Paik, Sora; Park, Jong-Hyun; Gotina, Lizaveta; Abdellattif, Magda H.; Gouda, Noha A.; Cho, Jungsook; Lee, Kyeong; Nim Pae, Ae; Park, Ki Duk; Roh, Eun Joo [Bioorganic Chemistry, 2021, vol. 116]

87
[ 1633-82-5 ]
C₂₃H₂₆FN₅ [ No CAS ]
C₂₆H₃₁ClFN₅O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine In dichloromethane at 20℃; for 2h; Cooling with ice; Inert atmosphere;	10 Compound A21: 100 mg of compound 3 was dissolved in 20 ml of dichloromethane, and then triethylamine (78 mg, 0.77 mmol) and compound A20 (54 mg, 0.31 mmol) were added under ice bath conditions.After stirring for 2 hours at room temperature under nitrogen protection, the solvent was removed under reduced pressure, and the residue was diluted with water (30 mL), and then extracted with dichloromethane (50 mL).The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 120 mg of compound A21 with a yield of 79%, which was directly used in the next step.

Reference： [1]Current Patent Assignee: BEIJING DEEP INTELLIGENT PHARMA - CN113666934, 2021, A Location in patent: Paragraph 0169-0171

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	1633-82-5	MDL No. :	MFCD00007463
Formula :	C₃H₆Cl₂O₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GPKDGVXBXQTHRY-UHFFFAOYSA-N
M.W :	177.05	Pubchem ID :	15410
Synonyms :

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	35.09
TPSA :	42.52 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.44 cm/s

[ CAS No. 1633-82-5 ] {[proInfo.proName]}

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Medicinal Chemistry

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Application In Synthesis of [ 1633-82-5 ]

[ 1633-82-5 ] Synthesis Path-Upstream 1~2

[ 1633-82-5 ] Synthesis Path-Downstream 1~87

Related Functional Groups of
[ 1633-82-5 ]

Aliphatic Chain Hydrocarbons

Sulfonyl Chlorides

Chlorides

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Log Po/w (iLOGP) :	1.25
Log Po/w (XLOGP3) :	1.33
Log Po/w (WLOGP) :	2.26
Log Po/w (MLOGP) :	0.79
Log Po/w (SILICOS-IT) :	1.29
Consensus Log Po/w :	1.39

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

Log S (ESOL) :	-1.58
Solubility :	4.68 mg/ml ; 0.0264 mol/l
Class :	Very soluble
Log S (Ali) :	-1.82
Solubility :	2.65 mg/ml ; 0.015 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.25
Solubility :	0.998 mg/ml ; 0.00564 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.6

Signal Word:	Danger	Class:	8
Precautionary Statements:	P261-P280-P305+P351+P338-P310	UN#:	3265
Hazard Statements:	H314-H335	Packing Group:	Ⅱ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
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

[ CAS No. 1633-82-5 ] {[proInfo.proName]}

Quality Control of [ 1633-82-5 ]

Related Doc. of [ 1633-82-5 ]

Product Details of [ 1633-82-5 ]

Calculated chemistry of [ 1633-82-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1633-82-5 ]

Application In Synthesis of [ 1633-82-5 ]

[ 1633-82-5 ] Synthesis Path-Upstream 1~2

[ 1633-82-5 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 1633-82-5 ]

Aliphatic Chain Hydrocarbons

Sulfonyl Chlorides

Chlorides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1633-82-5 ]