[ CAS No. 141699-57-2 ] {[proInfo.proName]}

Name: 141699-57-2|tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate|95%
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Product Details of [ 141699-57-2 ]

CAS No. :	141699-57-2	MDL No. :	MFCD04116219
Formula :	C₁₀H₁₉NO₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	265.33	Pubchem ID :	-
Synonyms :

Safety of [ 141699-57-2 ]

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

Application In Synthesis of [ 141699-57-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 141699-57-2 ]
Downstream synthetic route of [ 141699-57-2 ]

[ 141699-57-2 ] Synthesis Path-Upstream 1~8

1
[ 83220-73-9 ]
[ 124-63-0 ]
[ 141699-57-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 0 - 20℃; for 2.5 h;	To a stirred solution of fert-butyl 3-hydroxypyrrolidine-l-carboxylate (16 g, 85.4 mmol) and triethylamine (19 mL, 129 mmol) in 130 mL CH₂CI₂ was added methanesulfonyl chloride (10 mL, 129 mmol) in 20 mL CH₂CI₂ dropwise at 0 °C. After addition, the reaction was stirred for 2.5 h at rt, then quenched with sat. NaHCC>3 (aq.), and extracted with CH₂CI₂. The extract was dried and concentrated to give the desired product (22.7 g, 100percent yield) as a yellow solid.
100%	With triethylamine In dichloromethane at 0 - 20℃; for 2 h;	To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.34 mmol) in DCM (17 mL) was added TEA (0.962 mL, 6.94 mmol) followed by MsCl (0.499 mL, 6.41 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with water, 2 N aq. HCl, saturated aq. NaHCO₃, and brine successively, dried over Na₂SO₄, filtered and concentrated in vacuo to afford tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (1.42 g, 100percent) as a colorless oil, which was used for the next reaction without further purification. ¹H-NMR (CDCl₃, Varian, 400 MHz): δ 1.47 (9H, s), 2.06-2.20 (1H, m), 2.21-2.36 (1H, m), 3.05 (3H, s), 3.44-3.54 (1H, m), 3.54-3.72 (3H, m), 5.27 (1H, br. s).
100%	With triethylamine In dichloromethane at 0 - 20℃; for 0.5 h; Inert atmosphere	tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (515 mg, 2.75 mmol) was dissolved in methylene chloride (4.2 mL) and stirred at 0 ° C. Methanesulfonyl chloride (234 μL, 3.00 mmol) and triethylamine (0.42 mL, 3.00 mmol) were added and the mixture was stirred at room temperature for 30 minutes under argon. After the reaction was completed, the organic solvent layer extracted with water and ethyl acetate was dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain tert-butyl 3 - ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 737 mg, 2.78 mmol) in a yield of 100percent.

100%	With triethylamine In dichloromethane at 20℃; for 1 h;	Methanesulfonyl chloride (1.12 g, 10 mmol) was added dropwise to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate(1.87 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in 20 ml of dichloromethane and reacted at room temperature for 1 hour. The reaction was quenched by adding cold saturated aqueous sodium bicarbonate to the system. The organic phase was separated, washed with water, dried and concentrated to give the title compound (2.65 g, 100percent).
100%	With triethylamine In dichloromethane at 0℃; for 3 h;	Triethylamine (35 g, 346 mmol, 2.1 eq.) and methanesulfonyl chloride (36.6 g, 321 mmol, 1.9 eq.) were added subsequently to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (30.0 g, 163 mmol, 1.0 eq.) in dichloromethane (200 mL) at 0° C. The reaction was stirred at 0° C. for 3 hours, quenched with water (20 mL), washed with water (100 mL*2) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title compound (45.6 g, yield: 100percent).
99%	Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: at 0 - 20℃;	Et₃N (5.58 mL, 40 mmol) was added to a solution of terf-butyl 3- hydroxypyrrolidine-1-carboxylate (3 g, 16.02 mmol) in dry DCM (35 mL). The solution was cooled to 0 °C, stirred for 10 min and then, methanesulfonyl chloride (2.1 mL, 27.24 mmol) was added and the reaction mixture was stirred at 0 °C. After 1 h the reaction mixture was allowed to warm to rt and stirred for 0.5 h. The mixture was poured into ice-water and diluted with DCM. The organic layer was washed with water, dried over Na₂SO₄, filtered and evaporated to dryness to afford the title compound as yellow oil (4.25 g, yield 99percent) that was used in the next step without further purification. ¹H NMR (400 MHz, CDC13) δ ppm 1.49 (s, 9 H) 2.08 - 2.21 (m, 1 H) 2.29 (br. s., 1 H) 3.07 (s, 3 H) 3.36 - 3.64 (m, 3 H) 3.65 - 3.75 (m, 1 H) 5.28 (tt, J=4.23, 2.08 Hz, 1 H))
99%	With triethylamine In dichloromethane at 20℃; for 4 h;	The compound tert-butyl 3-hydroxypyrrolidine-1-carboxylate 7a (561 mg, 3.0 mmol), methylsulfonyl chloride(410 mg, 3.6 mmol), triethylamine (606 mg, 6.0 mmol) and dichloromethane (50 mL) were added and stirred at room temperature for 4 hours.The mixture was diluted with 50 mL of methylene chloride and washed successively with saturated ammonium chloride solution (20 mL) and saturated brine (20 mL x 2)Polyester. The organic phase was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration and depressurized under reduced pressure to give the desired productTert-butyl 3 - ((methylsulfonyl) oxo) pyrrolidine-1-carboxylate 7b (790 mg) in 99percent yield. The product was used directly in the next step without purification
99%	With triethylamine In dichloromethane at 0 - 20℃; for 1 h;	To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1 -carboxylate(mixture of isomers, 5.1 g, 27.2 mmol) in DCM (75 mL), TEA (5.9 mL,42.7 mmol) was added at room temperature. The mixture was cooled to000 then methane sulfonyl chloride (2.62 mL, 32.7 mmol) was addeddropwise. The resulting solution was stirred at room temperature for 1 hthen was diluted with DCM (100 mL) and washed with water (50 mL)and brine (50 mL). The organic layer was dried over sodium sulfate andconcentrated to afford the title compound (7.15 g, 99percent yield) as a mixture of isomers, that was progressed without any further purification.1HNMR (CDCI3): 6 5.30-5.27 (m, 1H), 3.60-3.58 (m, 4H), 3.05 (5, 3H),2.19-2.16 (m, 1H), 2.13-2.12 (m, 1H), 1.39 (5, 9H).
98%	With triethylamine In dichloromethane at 20℃; for 1 h;	To a solution of compound 45-1 (10 g, 53.5 mmol) and TEA (6.5 g, 64.2 mmol) in DCM (100 mL) was added dropwise mesyl chloride (7.35 g, 64.2 mmol), and the reaction solution was reacted at r.t. for 1 h. To this solution, water (80 mL) was added and the resulting solution was extracted with DCM (100 mL×2). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to give compound 45-2-1 (13.86 g, 98percent) as colourless oil. ¹H NMR (400 MHz, CDCl₃): δ ppm 5.27 (s, 1H), 3.72-3.57 (m, 3H), 3.49 (s, 1H), 3.05 (s, 3H), 2.29 (s, 1H), 2.15 (s, 1H), 1.47 (s, 9H).
95%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16 h;	Preparation Example 1-55-13-Methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester 3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.94 g, 5.0 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C., and then diisopropylethylamine (0.97 g, 7.5 mmol) and methanesulfonylchloride (0.63 g, 5.5 mmol) were added thereto. The mixture was stirred at room temperature for 16 hours, distilled under reduced pressure to remove the solvent, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure, and purified by column chromatography using 2:1 mixture solvent of hexane and ethyl acetate to obtain the title compound (1.27 g, 95percent).
90%	With pyridine; dmap In dichloromethane at 0℃; for 18.1667 h;	Step A: 3-Methanesulfonyloxy-pyrrolidme-l-carboxyric acid tert-butγl esterTo a solution of the fert-butyl 3 -hydroxy- 1 -pyrrolidinecarboxylate (5.00 g, 26.7 mmol) in dichloromethane (50 mL) is added pyridine (10 mL, 122.6 mmol) and DMAP (0.56 g, 4.6 mmol). The mixture is then cooled to 0 ⁰C and methanesulfonyl chloride (3 mL, 38.8 mmol) is added over 10 minutes. The reaction mixture is then stirred for 18 hours, evaporated in vacuo, and the solid residue obtained triturated with ethyl acetate (500 mL) and filtered. The filterate is evaporated in vacuo and the residue is purified by flash chromatography to obtain the title compound (6.35 g, 90 percent).
77%	With triethylamine In dichloromethane at 0 - 20℃; for 18 h;	Step 1: tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate; To a solution of tert-butyl 3-hydroxypyrrolidine-i-carboxylate (Aldrich; 7.42 g, 39.6 mmol), in DCM (20 ml.) was added, at 0 ⁰C, triethylamine (8.44 mL; 48.5 mmol) and then mesylchloride (3.13 mL; 40 mmol). The mixture was stirred for 18 hours at RT and then water was added and the product was extracted with DCM (3 x 20 mL). The combined organic fractions were dried (MgSO₄), filtered and the solvent removed in vacuo to give tert- butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (8.26 g; 77 percent) as a brown oil. ¹H NMR: (CDCI3, 400MHz) δ 5.27-5.20 (1 H, m), 3.70-3.49 (4 H, m), 3.04 (3 H, s), 2.90-2.05 (2 H, m), 1.46 (9 H, s).
71.4%	Stage #1: With dmap; triethylamine In dichloromethane at 20℃; for 0.25 h;	To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.34 mmol, 1.0 eq) in DCM (10 ml) were added TEA (1.08 g, 10.68 mmol, 2.0 eq) and DMAP (65 mg, 0.53 mmol). The mixture was stirred at RT for 15 min. Then methanesulfonyl chloride (0.730 g 6.41 mmol 1.2 eq) was added and the mixture was stirred for overnight. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 71.4percent yield (1.0 g).
1.2 g	With triethylamine In chloroform at 0 - 20℃; for 1 h;	N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 μl) were added thereto at 0°C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z[M+H]⁺ 266.1
1.2 g	With triethylamine In chloroform at 0 - 20℃; for 1 h;	N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 μl) were added thereto at 0° C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z[M+H]⁺266.1
1.2 g	With triethylamine In chloroform at 0 - 20℃; for 1 h;	N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 μl) were added thereto at 0° C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z [M+H]⁺266.1
6.63 g	With dmap; triethylamine In dichloromethane at 0 - 20℃; for 4 h;	The compound, tert-butyl 3-hydroxypyrrolidine-1-carboxylate (4.00 g, 21.36 mmol)Dissolved in DCM (50 mL)Cooled to 0 ° C and then Et3N (4.7 mL, 32.04 mmol) was added slowly to the reaction followed by addition of MsCl (2.0 mL, 25.64 mmol) and DMAP (26.1 mg, 0.214 mmol) in DCM ) Solution,Warmed to room temperature, stirred for 4 hours,The reaction was quenched by the addition of water (50 mL) and the resulting mixture was extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound as a yellow oil (6.63 g, 117.0percent).

Reference： [1] Patent: WO2013/97773, 2013, A1, . Location in patent: Paragraph 0150
[2] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0494; 0495
[3] Patent: KR2016/103390, 2016, A, . Location in patent: Paragraph 0099; 0102
[4] Patent: CN107474024, 2017, A, . Location in patent: Paragraph 0385; 0389; 0390; 0391
[5] Patent: US2016/200730, 2016, A1, . Location in patent: Paragraph 0278; 0279
[6] Patent: WO2017/16668, 2017, A1, . Location in patent: Page/Page column 132; 133
[7] Patent: CN107226805, 2017, A, . Location in patent: Paragraph 0169; 0170; 0171; 0172; 0173
[8] Patent: WO2017/211759, 2017, A1, . Location in patent: Page/Page column 59
[9] Patent: US2017/313683, 2017, A1, . Location in patent: Paragraph 0874-0875
[10] Patent: US2011/166121, 2011, A1, . Location in patent: Page/Page column 42-43
[11] Patent: WO2007/106705, 2007, A1, . Location in patent: Page/Page column 89
[12] Tetrahedron, 2006, vol. 62, # 24, p. 5763 - 5774
[13] Journal of Organic Chemistry, 2008, vol. 73, # 14, p. 5397 - 5409
[14] Patent: WO2010/142628, 2010, A1, . Location in patent: Page/Page column 169-170
[15] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0183
[16] Nucleosides, Nucleotides and Nucleic Acids, 2005, vol. 24, # 5-7, p. 805 - 808
[17] Patent: US2005/165005, 2005, A1, . Location in patent: Page/Page column 58
[18] Patent: WO2005/75420, 2005, A2, . Location in patent: Page/Page column 19
[19] Patent: WO2010/3048, 2010, A1, . Location in patent: Page/Page column 84
[20] Patent: US2011/212102, 2011, A1, . Location in patent: Page/Page column 29
[21] Patent: WO2013/40059, 2013, A1, . Location in patent: Page/Page column 111
[22] Patent: EP2657233, 2013, A1, . Location in patent: Paragraph 0193
[23] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 406 - 418
[24] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7499 - 7508
[25] Patent: WO2014/193647, 2014, A2, . Location in patent: Paragraph 0271
[26] Patent: WO2016/57924, 2016, A1, . Location in patent: Page/Page column 113
[27] Patent: WO2016/86200, 2016, A1, . Location in patent: Page/Page column 210
[28] Organic and Biomolecular Chemistry, 2014, vol. 12, # 47, p. 9674 - 9682
[29] Patent: US2016/136168, 2016, A1, . Location in patent: Paragraph 0284
[30] Patent: US2016/193210, 2016, A1, . Location in patent: Paragraph 0286
[31] Patent: CN104119331, 2018, B, . Location in patent: Paragraph 0763; 0769; 0770
[32] Chemistry - A European Journal, 2018, vol. 24, # 33, p. 8343 - 8349
[33] Patent: EP1500643, 2005, A1, . Location in patent: Page 67

2
[ 124-63-0 ]
[ 101385-93-7 ]
[ 141699-57-2 ]

Yield	Reaction Conditions	Operation in experiment
63.5%	With triethylamine In dichloromethane at 0℃; for 3.5 h;	ter^-Butyl 3-[(methyIsulfonyl)oxy]pyrrolidine-l-carboxylate; 5 tert-Butyl 3-hydroxypyrrolidine-l-carboxylate (3.0Og, 16.02mmol) was dissolved in dry DCM (5OmL) and cooled in an ice-water bath. Methanesulfonyl chloride (2.38g, 20.83mmol) was added followed by TEA (2.43g, 24.03mmol) and the reaction mixture was stirred at 0°C for 3.5h. The reaction mixture was washed with water (25OmL) and dried with MgSO₄, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system 10 (40+M column, isocratic run heptane/EtOAc (50:50)) affording the title compund (2.7Og, 63.5percent). ¹H NMR (500MHz, CDCl₃): 6 1.38 (s, 9H), 2.07 (bs, IH), 2.18 (bs, IH), 2.97 (s, 3H), 3.35-3.61 (m, 4H), 5.16-5.18 (m, IH); ¹³C NMR (125MHz, CDCl₃): δ 28.59, 31.84, 32.76, 38.80, 43.61, 52.16, 80.12, 154.30.

Reference： [1] Patent: WO2006/73366, 2006, A1, . Location in patent: Page/Page column 185

3
[ 24424-99-5 ]
[ 124-63-0 ]
[ 141699-57-2 ]

Reference： [1] Patent: WO2011/104337, 2011, A1, . Location in patent: Page/Page column 73-74

4
[ 24424-99-5 ]
[ 141699-57-2 ]

Reference： [1] Patent: US2011/212102, 2011, A1,
[2] Patent: WO2014/193647, 2014, A2,
[3] Patent: CN107474024, 2017, A,
[4] Patent: CN104119331, 2018, B,
[5] Patent: EP1500643, 2005, A1,

5
[ 101385-93-7 ]
[ 141699-57-2 ]

Reference： [1] Patent: WO2017/211759, 2017, A1,

6
[ 141699-57-2 ]
[ 186550-13-0 ]

Reference： [1] Patent: EP1500643, 2005, A1,

7
[ 773837-37-9 ]
[ 141699-57-2 ]
[ 476493-40-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	at 100℃; for 16 h;	A solution of tert-butyl 3- (methanesulfonyloxy) pyrrolidine-1-carboxylate (2.65 g, 10 mmol) and sodium cyanide (2.5 g, 50 mmol) in N, N- dimethylformamide (100 mL) The solution was reacted at 100 ° C for 16 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic phases were combined, washed, dried and the resulting residue was concentrated by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the title compound (1.92 g, 98percent).
69%	at 100℃; for 16 h;	To a stirred solution of tert-butyl 3-[(methanesulfonyl)oxy]pyrrolidine-1-carboxylate (mixture of isomers, 6.1 g, 23.0 mmol) in DMF (40 mL)NaCN (3.38 g, 69.0 mmol) was added. The reaction mixture was stirredat 10000 for 1 6 h then was cooled to room temperature and diluted withEtOAc (75 mL). The organic layer was washed with water (2 x 40 mL), dried over sodium sulfate and concentrated. The resulting crude was purified by column chromatography (silica gel: 230-400, 25percent EtOAc in pet. ether) to afford the title compound (3.1 g, 15.8 mmol, 69percent yield, colorless liquid) as a mixture of isomers. 1HNMR (CDCI3): 6 3.69-3.59(m, 4H), 3.12-3.09 (m, 1H), 2.27-2.25 (m, 2H), 1.48 (5, 9H).

Reference： [1] Patent: CN107474024, 2017, A, . Location in patent: Paragraph 0385; 0392; 0393; 0394
[2] Patent: WO2017/211759, 2017, A1, . Location in patent: Page/Page column 59; 60

8
[ 788104-34-7 ]
[ 141699-57-2 ]
[ 476493-40-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	at 80℃; for 16 h;	Preparation Example 1-55-23-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester The compound obtained in Preparation Example 1-55-1 (1.27 g, 4.79 mmol) was dissolved in N,N-dimethylformamide (15 mL), and lithium cyanide (0.47 g, 14.37 mmol) was added thereto. The mixture was stirred at 80° C. for 16 hours, cooled to room temperature, distilled under reduced pressure to remove the solvent, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure, and purified by column chromatography using 2:1 mixture solvent of hexane and ethyl acetate to obtain the title compound (0.66 g, 70percent).¹H NMR (400 MHz, CDCl₃); δ 3.67 (1H, br s), 3.58 (2H, br s), 3.45 (1H, br s), 3.09 (1H, m), 2.25 (2H, m), 1.47 (9H, s)

Reference： [1] Patent: US2011/166121, 2011, A1, . Location in patent: Page/Page column 43

[ 141699-57-2 ] Synthesis Path-Downstream 1~87

1
[ 141699-57-2 ]
[ 113451-52-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium azide; In N,N-dimethyl-formamide; at 100℃; for 4h;	To a solution of tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (1.42 g, 5.35 mmol) in DMF (26 mL) was added sodium azide (1.04 g, 16.0 mmol). The reaction mixture was heated at 100 C. for 4 hours with stirring, while a white solid was formed. After concentration in vacuo, the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=10:1 to 5:1) to afford tert-butyl 3-azidopyrrolidine-1-carboxylate (1.07 g, 94%) as a colorless oil. 1H-NMR (CDCl3, Varian, 400 MHz): delta 1.47 (9H, s), 2.02-2.08 (2H, m), 3.35-3.54 (4H, m), 4.14-4.16 (1H, m).
85%	With sodium azide; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;	The obtained tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (737 mg, 2.78 mmol) was dissolved in dimethylformamide (14 mL) and sodium azide (451 mg, mmol). The mixed solution was stirred under argon at 80 DEG C for 3 hours. After completion of the reaction, water and ethyl acetate (3 x 20 mL) were added to the organic solvent layer, and the organic solvent layer was dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound (0.49 g, 2.35 mmol) Was obtained in 85% yield.
	With sodium azide; In 1-methyl-pyrrolidin-2-one; at 0 - 80℃; for 3h;	Triethylamine (0.75 mL, 5.34 mmol) and methanesulfonyl chloride (0.31 mL, 4.00 mmol) were added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol) in tetrahydrofuran (20 mL) at 0C and stirred at the same temperature for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was dried over anhydrous magnesium sulfate. The concentration residue was dissolved in N-methylpyrrolidinone (20 mL), followed by adding thereto sodium azide (520.8 mg, 8.01 mmol) at 0C, and the resulting mixture was stirred with heating at 80C for 3 hours. After the reaction mixture was cooled to 0C, water and diethyl ether were added thereto, followed by two runs of extraction with diethyl ether, and the extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an azide. To a solution of this azide in methanol (50 mL) was added palladium-carbon (250 mg) under a nitrogen atmosphere, and the resulting mixture was stirred for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered by the use of Celite and the filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel chromatography to obtain tert-butyl 3-aminopyrrolidine-1-carboxylate (365.6 mg, 73%).

Reference： [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0496; 0497
[2]Organic and Biomolecular Chemistry,2014,vol. 12,p. 9674 - 9682
[3]Patent: KR2016/103390,2016,A .Location in patent: Paragraph 0099-0101; 0103
[4]Journal of Organic Chemistry,1988,vol. 53,p. 1580 - 1582
[5]Patent: EP1500643,2005,A1 .Location in patent: Page 67

2
[ 141699-57-2 ]
[ 194787-34-3 ]
[ 197525-84-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 853 - 856

3
[ 71-30-7 ]
[ 141699-57-2 ]
(RS)-2-O-(N-tert-butoxycarbonyl-3-pyrrolidinyl)cytosine [ No CAS ]
[ 898828-79-0 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5763 - 5774

4
[ 83220-73-9 ]
[ 124-63-0 ]
[ 141699-57-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;	To a stirred solution of fert-butyl 3-hydroxypyrrolidine-l-carboxylate (16 g, 85.4 mmol) and triethylamine (19 mL, 129 mmol) in 130 mL CH2CI2 was added methanesulfonyl chloride (10 mL, 129 mmol) in 20 mL CH2CI2 dropwise at 0 C. After addition, the reaction was stirred for 2.5 h at rt, then quenched with sat. NaHCC>3 (aq.), and extracted with CH2CI2. The extract was dried and concentrated to give the desired product (22.7 g, 100% yield) as a yellow solid.
100%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;	To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.34 mmol) in DCM (17 mL) was added TEA (0.962 mL, 6.94 mmol) followed by MsCl (0.499 mL, 6.41 mmol) at 0 C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with water, 2 N aq. HCl, saturated aq. NaHCO3, and brine successively, dried over Na2SO4, filtered and concentrated in vacuo to afford tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (1.42 g, 100%) as a colorless oil, which was used for the next reaction without further purification. 1H-NMR (CDCl3, Varian, 400 MHz): delta 1.47 (9H, s), 2.06-2.20 (1H, m), 2.21-2.36 (1H, m), 3.05 (3H, s), 3.44-3.54 (1H, m), 3.54-3.72 (3H, m), 5.27 (1H, br. s).
100%	With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;Inert atmosphere;	tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (515 mg, 2.75 mmol) was dissolved in methylene chloride (4.2 mL) and stirred at 0 C. Methanesulfonyl chloride (234 muL, 3.00 mmol) and triethylamine (0.42 mL, 3.00 mmol) were added and the mixture was stirred at room temperature for 30 minutes under argon. After the reaction was completed, the organic solvent layer extracted with water and ethyl acetate was dried over magnesium sulfate, filtered and distilled under reduced pressure to obtain tert-butyl 3 - ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 737 mg, 2.78 mmol) in a yield of 100%.

100%	With triethylamine; In dichloromethane; at 20℃; for 1h;	Methanesulfonyl chloride (1.12 g, 10 mmol) was added dropwise to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate(1.87 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in 20 ml of dichloromethane and reacted at room temperature for 1 hour. The reaction was quenched by adding cold saturated aqueous sodium bicarbonate to the system. The organic phase was separated, washed with water, dried and concentrated to give the title compound (2.65 g, 100%).
100%	With triethylamine; In dichloromethane; at 0℃; for 3h;	Triethylamine (35 g, 346 mmol, 2.1 eq.) and methanesulfonyl chloride (36.6 g, 321 mmol, 1.9 eq.) were added subsequently to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (30.0 g, 163 mmol, 1.0 eq.) in dichloromethane (200 mL) at 0 C. The reaction was stirred at 0 C. for 3 hours, quenched with water (20 mL), washed with water (100 mL*2) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title compound (45.6 g, yield: 100%).
99%		Et3N (5.58 mL, 40 mmol) was added to a solution of terf-butyl 3- hydroxypyrrolidine-1-carboxylate (3 g, 16.02 mmol) in dry DCM (35 mL). The solution was cooled to 0 C, stirred for 10 min and then, methanesulfonyl chloride (2.1 mL, 27.24 mmol) was added and the reaction mixture was stirred at 0 C. After 1 h the reaction mixture was allowed to warm to rt and stirred for 0.5 h. The mixture was poured into ice-water and diluted with DCM. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as yellow oil (4.25 g, yield 99%) that was used in the next step without further purification. 1H NMR (400 MHz, CDC13) delta ppm 1.49 (s, 9 H) 2.08 - 2.21 (m, 1 H) 2.29 (br. s., 1 H) 3.07 (s, 3 H) 3.36 - 3.64 (m, 3 H) 3.65 - 3.75 (m, 1 H) 5.28 (tt, J=4.23, 2.08 Hz, 1 H))
99%	With triethylamine; In dichloromethane; at 20℃; for 4h;	The compound tert-butyl 3-hydroxypyrrolidine-1-carboxylate 7a (561 mg, 3.0 mmol), methylsulfonyl chloride(410 mg, 3.6 mmol), triethylamine (606 mg, 6.0 mmol) and dichloromethane (50 mL) were added and stirred at room temperature for 4 hours.The mixture was diluted with 50 mL of methylene chloride and washed successively with saturated ammonium chloride solution (20 mL) and saturated brine (20 mL x 2)Polyester. The organic phase was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration and depressurized under reduced pressure to give the desired productTert-butyl 3 - ((methylsulfonyl) oxo) pyrrolidine-1-carboxylate 7b (790 mg) in 99% yield. The product was used directly in the next step without purification
99%	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;	To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1 -carboxylate(mixture of isomers, 5.1 g, 27.2 mmol) in DCM (75 mL), TEA (5.9 mL,42.7 mmol) was added at room temperature. The mixture was cooled to000 then methane sulfonyl chloride (2.62 mL, 32.7 mmol) was addeddropwise. The resulting solution was stirred at room temperature for 1 hthen was diluted with DCM (100 mL) and washed with water (50 mL)and brine (50 mL). The organic layer was dried over sodium sulfate andconcentrated to afford the title compound (7.15 g, 99% yield) as a mixture of isomers, that was progressed without any further purification.1HNMR (CDCI3): 6 5.30-5.27 (m, 1H), 3.60-3.58 (m, 4H), 3.05 (5, 3H),2.19-2.16 (m, 1H), 2.13-2.12 (m, 1H), 1.39 (5, 9H).
98%	With triethylamine; In dichloromethane; at 20℃; for 1h;	To a solution of compound 45-1 (10 g, 53.5 mmol) and TEA (6.5 g, 64.2 mmol) in DCM (100 mL) was added dropwise mesyl chloride (7.35 g, 64.2 mmol), and the reaction solution was reacted at r.t. for 1 h. To this solution, water (80 mL) was added and the resulting solution was extracted with DCM (100 mL×2). The organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated to give compound 45-2-1 (13.86 g, 98%) as colourless oil. 1H NMR (400 MHz, CDCl3): delta ppm 5.27 (s, 1H), 3.72-3.57 (m, 3H), 3.49 (s, 1H), 3.05 (s, 3H), 2.29 (s, 1H), 2.15 (s, 1H), 1.47 (s, 9H).
95%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h;	Preparation Example 1-55-13-Methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester 3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.94 g, 5.0 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 C., and then diisopropylethylamine (0.97 g, 7.5 mmol) and methanesulfonylchloride (0.63 g, 5.5 mmol) were added thereto. The mixture was stirred at room temperature for 16 hours, distilled under reduced pressure to remove the solvent, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure, and purified by column chromatography using 2:1 mixture solvent of hexane and ethyl acetate to obtain the title compound (1.27 g, 95%).
90%	With pyridine; dmap; In dichloromethane; at 0℃; for 18.1667h;	Step A: 3-Methanesulfonyloxy-pyrrolidme-l-carboxyric acid tert-butgammal esterTo a solution of the fert-butyl 3 -hydroxy- 1 -pyrrolidinecarboxylate (5.00 g, 26.7 mmol) in dichloromethane (50 mL) is added pyridine (10 mL, 122.6 mmol) and DMAP (0.56 g, 4.6 mmol). The mixture is then cooled to 0 0C and methanesulfonyl chloride (3 mL, 38.8 mmol) is added over 10 minutes. The reaction mixture is then stirred for 18 hours, evaporated in vacuo, and the solid residue obtained triturated with ethyl acetate (500 mL) and filtered. The filterate is evaporated in vacuo and the residue is purified by flash chromatography to obtain the title compound (6.35 g, 90 %).
77%	With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;	Step 1: tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate; To a solution of tert-butyl 3-hydroxypyrrolidine-i-carboxylate (Aldrich; 7.42 g, 39.6 mmol), in DCM (20 ml.) was added, at 0 0C, triethylamine (8.44 mL; 48.5 mmol) and then mesylchloride (3.13 mL; 40 mmol). The mixture was stirred for 18 hours at RT and then water was added and the product was extracted with DCM (3 x 20 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo to give tert- butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (8.26 g; 77 %) as a brown oil. 1H NMR: (CDCI3, 400MHz) delta 5.27-5.20 (1 H, m), 3.70-3.49 (4 H, m), 3.04 (3 H, s), 2.90-2.05 (2 H, m), 1.46 (9 H, s).
71.4%		To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.34 mmol, 1.0 eq) in DCM (10 ml) were added TEA (1.08 g, 10.68 mmol, 2.0 eq) and DMAP (65 mg, 0.53 mmol). The mixture was stirred at RT for 15 min. Then methanesulfonyl chloride (0.730 g 6.41 mmol 1.2 eq) was added and the mixture was stirred for overnight. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 71.4% yield (1.0 g).
	With triethylamine; In dichloromethane; at -10 - 20℃; for 2.08333h;	A solution of 0.33 cm3 of methanesulfonyl chloride in 3.2 cm3 of dichloromethane is added dropwise to a solution of 710 mg of 1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 0.62 cm3 of triethylamine in 14.2 cm3 of dichloromethane, stirred under a nitrogen atmosphere at -10 C. The reaction medium is stirred at -10 C. for 5 min, and then at a temperature in the region of 20 C. for 2 h, before being concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with water and ethyl acetate. The solution is stirred for 5 min and is then separated by settling out. The aqueous phase is extracted three times with ethyl acetate. The organic phases are pooled, washed successively with an aqueous solution of sodium bicarbonate at 5% and of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa) to give 938 mg of methanesulfonic acid (1-tert-butoxycarbonylpyrrolidin-3-yl) ester in the form of a pale yellow oil. LCMS (electrospray): m/z 266 (MH+), m/z 210 [MH+-tBu].
	In pyridine; at -5 - 20℃; for 0.666667h;	3-Methanesulphonvloxy-pyrrolidine-1-carboxylic acid tert-butyl ester; 3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester is dissolved in dry pyridine (20 ml) and cooled to-5 C. Methanesulphonyl chloride is added over a period of 10 minutes keeping the temperature between-5 C and 0 C after which the yellow solution is allowed to warm up to room temperature over a period of 30 minutes. Water (20 ml) is added and the mixture is then extracted using DCM (2 x 30ml), the organic washings being combined and washed with 2N potassium hydrogen sulphate solution (2 x 30 ml). The organic phase is dried (using MgS04), filtered and evaporated to give the title compound as a colourless oil.
	With triethylamine; In dichloromethane; at 20℃; for 18h;	To a solution of N-Boc-3-hydroxypyrrolidine (28; 2 g, 10.7 mmol) and Et3N (2.2 ml, 16.0 mmol) in CH2Cl2 (5 mL) was added a solution of methanesulfonyl chloride (1.84 g, 2.52 ml, 16.0 mmol) in CH2Cl2 (5 mL) dropwise in an ice-water bath. The mixture was stirred at room temperature for 18 h. It was then diluted with 50 mL of CH2Cl2, washed with saturated Na2CO3 (20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to afford N-Boc-3-(methylsulfonyloxy)pyrrolidine 29 (2.6 g, 92%). This material was used in the following step without further purification.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;	4-[4-Fluoro-2-(pyrrolidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester To a solution of 3-hydroxypyrrolidine HCl (5.0 g) in dry MeOH (40.0 ml) was added triethylamine (8.45 ml) and the solution was cooled to 0 C. in an ice bath. Di t-butyl dicarbonat (8.80 g) was added portionwise over a period of 30 min. The reaction was allowed to warm to room temperature and stirred for 5 h. The solvent was removed and the residue was dissolved in dichloromethane (50.0 ml) and washed with water. The organic phase was passed through a PTFE separation frit and the solvent was evaporated in vacuum. The residue was used without further purification. Dichloromethane (20.0 ml) was added to the residue and the solution was cooled to 0 C. in an ice bath. Triethylamine (8.4 ml) was than added followed by dropwise addition of methansulfonyl chloride (3.13 ml. The solution was allowed to warm to room temperature and was stirred for 18 h. The reaction was portioned between water and dichloromethane and the organic layer was separated, dried, filtered and evaporated. Yield: 8.26 g
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	Step 1: 3-Methanesulfonyloxy-pyrrolidine- 1-carboxylic acid tert-butyl esterTo a solution of 3-hydroxy-pyrrolidine-1 -carboxylic acid tert-butyl ester (2000.00 mg; 10.68 mmol; 1 .00 eq.) in DCM 10ml added ethyl-diisopropyl-amine (2.49 ml; 13.89 mmol; 1 .30 eq.), then added dropwise methanesulfonyl chloride (0.89 ml; 1 1 .22 mmol; 1 .05 eq.) at 0C, the reaction mixture was stirred for overnight at RT. TLC (EA/HEX=7:3) showed staring material converted to desired completed.Diluted the reaction solution with EA, washed with brine, organic layer was dried, filtered through silica gel 10g, most color material was absorbed on silica gel, the filtrate was evaporated off solvent, got residue as title compound directly using for the next step reaction, TLC was clean.
1.2 g	With triethylamine; In chloroform; at 0 - 20℃; for 1h;	N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 mul) were added thereto at 0C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z[M+H]+ 266.1
	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h;	To a solution of tert- vXy 3-hydroxypyrrolidine-l-carboxylate (4.00 g, 21.36 mmol) in DCM (50 mL) was added Et3N (4.7 mL, 32.04 mmol) slowly at 0 C, followed by the addition of MsCl (2.0 mL, 25.64 mmol) and a solution of DMAP (26.1 mg, 0.214 mmol) in DCM (4 mL). The mixture was stirred at rt for 4 hours, then quenched with water (50 mL), and extracted with DCM (50 mL x 3). The combined organic layers was dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as yellow oil (6.63 g, 117.0%). MS (ESI, pos. ion) m/z: 210.0 (M-56+1); 'H NMR (400 MHz, CDC13): delta 5.10 (s, 1H), 3.55-3.29 (m, 4H), 2.92 (s, 3H), 2.11-2.01 (m, 2H), 1.32 (s, 9H).
	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;	Step 1 tert-bulyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylateTo a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5 g, 27 mrnol) in DCM (20 mL) was added triethylamine (8.1 g, 80 inmol) at room temperature. The mixture was cooled to 0C and then methanesulfonyl chloride (3.9 g, 34 mmol) was added dropwise into the mixture. The resulting mixture was slowly warmed to room temperature over 2 hrs under N2 atomsphere. Themixture was diluted with DCM (80 mL) and washed with 1120 (80 mL), hydrochloric acid (80 ml x2, 1 N), saturated NaHCO3 (80 mL). The organic phase was dried over anhydrous Na2SO4, filtered arid concentrated to give the crude desired product (3.8 g, 54% yield) as colourless oil which was used in the next step without ftrther purification.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2 g, 10.68 mmol) and triethylamine (3.24 g, 32.05 mmol) in DCM (10 mL) at 0 C was added mesyl chloride (1.47 g, 12.82 mmol) dropwise. The mixture was stirred at room temperature for 3 h. The mixturewas diluted with DCM (20 mL) and the mixtutre was washed with brine (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.1 g, crude) as colorless oil that required no ifirther purification.
1.2 g	With triethylamine; In chloroform; at 0 - 20℃; for 1h;	N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 mul) were added thereto at 0 C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z[M+H]+ 266.1
1.2 g	With triethylamine; In chloroform; at 0 - 20℃; for 1h;	N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 mul) were added thereto at 0 C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z [M+H]+ 266.1
6.63 g	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h;	The compound, tert-butyl 3-hydroxypyrrolidine-1-carboxylate (4.00 g, 21.36 mmol)Dissolved in DCM (50 mL)Cooled to 0 C and then Et3N (4.7 mL, 32.04 mmol) was added slowly to the reaction followed by addition of MsCl (2.0 mL, 25.64 mmol) and DMAP (26.1 mg, 0.214 mmol) in DCM ) Solution,Warmed to room temperature, stirred for 4 hours,The reaction was quenched by the addition of water (50 mL) and the resulting mixture was extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound as a yellow oil (6.63 g, 117.0%).
	With triethylamine; In tetrahydrofuran; at 0℃; for 1.5h;	(b) Synthesis of tert-butyl 3-aminopyrrolidine-1-carboxylate Triethylamine (0.75 mL, 5.34 mmol) and methanesulfonyl chloride (0.31 mL, 4.00 mmol) were added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol) in tetrahydrofuran (20 mL) at 0C and stirred at the same temperature for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was dried over anhydrous magnesium sulfate. The concentration residue was dissolved in N-methylpyrrolidinone (20 mL), followed by adding thereto sodium azide (520.8 mg, 8.01 mmol) at 0C, and the resulting mixture was stirred with heating at 80C for 3 hours. After the reaction mixture was cooled to 0C, water and diethyl ether were added thereto, followed by two runs of extraction with diethyl ether, and the extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an azide. To a solution of this azide in methanol (50 mL) was added palladium-carbon (250 mg) under a nitrogen atmosphere, and the resulting mixture was stirred for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered by the use of Celite and the filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel chromatography to obtain tert-butyl 3-aminopyrrolidine-1-carboxylate (365.6 mg, 73%).
190 mg	With triethylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice;	136 mg of tert-butyl 3-hydroxypyrrolidine-1-formate was dissolved in 1 ml of dichloromethane, 0.15 ml of triethylamine was added, and 67 mul of methanesulfonyl chloride was added dropwise under ice cooling. Upon addition, the mixture was stirred at room temperature for 2 hours and then the reaction was quenched. Water was added, and then the mixture was extracted with EtOAc, and the organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration, 190 mg of oil matter was obtained. 1H NMR (300 MHz, CDCl3) delta 5.25-5.28 (m, 1H), 3.49-3.68 (m, 4H), 3.05 (s, 3H), 2.12-2.28 (m, 2H), 1.47 (s, 9H).

Reference： [1]Patent: WO2013/97773,2013,A1 .Location in patent: Paragraph 0150
[2]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0494; 0495
[3]Patent: KR2016/103390,2016,A .Location in patent: Paragraph 0099; 0102
[4]Patent: CN107474024,2017,A .Location in patent: Paragraph 0385; 0389; 0390; 0391
[5]Patent: US2016/200730,2016,A1 .Location in patent: Paragraph 0278; 0279
[6]Patent: WO2017/16668,2017,A1 .Location in patent: Page/Page column 132; 133
[7]Patent: CN107226805,2017,A .Location in patent: Paragraph 0169; 0170; 0171; 0172; 0173
[8]Patent: WO2017/211759,2017,A1 .Location in patent: Page/Page column 59
[9]Patent: US2017/313683,2017,A1 .Location in patent: Paragraph 0874-0875
[10]Patent: US2011/166121,2011,A1 .Location in patent: Page/Page column 42-43
[11]Patent: WO2007/106705,2007,A1 .Location in patent: Page/Page column 89
[12]Tetrahedron,2006,vol. 62,p. 5763 - 5774
[13]Journal of Organic Chemistry,2008,vol. 73,p. 5397 - 5409
[14]Patent: WO2010/142628,2010,A1 .Location in patent: Page/Page column 169-170
[15]Patent: US2015/11548,2015,A1 .Location in patent: Paragraph 0183
[16]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808
[17]Patent: US2005/165005,2005,A1 .Location in patent: Page/Page column 58
[18]Patent: WO2005/75420,2005,A2 .Location in patent: Page/Page column 19
[19]Patent: WO2010/3048,2010,A1 .Location in patent: Page/Page column 84
[20]Patent: US2011/212102,2011,A1 .Location in patent: Page/Page column 29
[21]Patent: WO2013/40059,2013,A1 .Location in patent: Page/Page column 111
[22]Patent: EP2657233,2013,A1 .Location in patent: Paragraph 0193
[23]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 406 - 418
[24]Journal of Medicinal Chemistry,2014,vol. 57,p. 7499 - 7508
[25]Patent: WO2014/193647,2014,A2 .Location in patent: Paragraph 0271
[26]Patent: WO2016/57924,2016,A1 .Location in patent: Page/Page column 113
[27]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 210
[28]Organic and Biomolecular Chemistry,2014,vol. 12,p. 9674 - 9682
[29]Patent: US2016/136168,2016,A1 .Location in patent: Paragraph 0284
[30]Patent: US2016/193210,2016,A1 .Location in patent: Paragraph 0286
[31]Patent: CN104119331,2018,B .Location in patent: Paragraph 0763; 0769; 0770
[32]Chemistry - A European Journal,2018,vol. 24,p. 8343 - 8349
[33]Patent: EP1500643,2005,A1 .Location in patent: Page 67
[34]Patent: EP3486244,2019,A1 .Location in patent: Paragraph 0141; 0142

5
[ 66-22-8 ]
[ 141699-57-2 ]
[ 898828-77-8 ]
(RS)-2,4-bis-O-(N-tert-butoxycarbonyl-3-pyrrolidinyl)uracil [ No CAS ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5763 - 5774

6
[ 65-71-4 ]
[ 141699-57-2 ]
[ 898828-76-7 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5763 - 5774
[2]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808

7
[ 66224-66-6 ]
[ 141699-57-2 ]
[ 898828-73-4 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5763 - 5774
[2]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808
[3]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 406 - 418

8
2,6-diamino-purine [ No CAS ]
[ 141699-57-2 ]
[ 898828-75-6 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5763 - 5774

9
[ 141699-57-2 ]
2-amino-6-chloro-purine [ No CAS ]
[ 898828-72-3 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5763 - 5774

10
[ 71-30-7 ]
[ 141699-57-2 ]
[ 898828-79-0 ]
3-(4-amino-pyrimidin-2-yloxy)-pyrrolidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808
[2]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808

11
[ 66-22-8 ]
[ 141699-57-2 ]
[ 898828-77-8 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808

12
[ 141699-57-2 ]
[ 1904-98-9 ]
[ 898828-75-6 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808

13
[ 141699-57-2 ]
[ 898828-74-5 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5763 - 5774

14
[ 141699-57-2 ]
[ 113451-56-2 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 1580 - 1582

15
[ 141699-57-2 ]
3-benzyloxy-1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-4-phenyl-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		129 mg of sodium hydride (at 50% in oil) are added to a solution of 450 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 9 cm3 of dimethylformamide, stirred under a nitrogen atmosphere at 0 C. After stirring at a temperature in the region of 20 C. for 30 min, 621 mg of methanesulfonic acid (1-tert-butoxycarbonylpyrrolidin-3-yl) ester are added. The reaction medium is stirred for 1 h at 80 C. and then poured into a water/ethyl acetate mixture. After stirring for 5 min, the medium is separated by settling out and the aqueous phase is extracted three times with ethyl acetate. The organic phases are pooled, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered through an Iena filter, rinsed with ethyl acetate and evaporated under reduced pressure (2.7 kPa) to give 998 mg of an oil which is purified by chromatography on a column of 70 g of silica (irregular 15-40 mum Merck) [eluent: dichloromethane/methanol (98/2 by volume); flow rate: 15 cm3/min; detection: 250 nm]. After concentration of the fractions under reduced pressure, 956 mg of a product are obtained, which is again purified by chromatography on a column of 90 g of silica (irregular 15-40 mum Merck) [eluent: dichloromethane/ethyl acetate (98/2 by volume); flow rate: 15 cm3/min; detection: 250 nm]. After concentration of the fractions under reduced pressure, 575 mg of 3-benzyloxy-1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-4-phenyl-1H-pyrazole are recovered in the form of a colorless foam. LCMS (electrospray): m/z 420 (MH+), m/z 364 [MH+-tBu], m/z 320 [MH+-Boc]. The methanesulfonic acid (1-tert-butoxycarbonylpyrrolidin-3-yl) ester can be prepared in the following way:

Reference： [1]Patent: US2005/165005,2005,A1 .Location in patent: Page/Page column 57-58

16
[ 371-41-5 ]
[ 141699-57-2 ]
[ 950648-92-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate; In acetonitrile; at 85℃; for 120h;	Step B: 3-(4-Fluoro-phenoxy)-pyrrolidine-l-carboxylic acid tert-butyl esterTo a solution of the product from Step A (1.06 g, 8.60 mmol) in acetonitrile (25 mL) is added 4-fluorophenol (0.55 g, 8.98 mmol) and potassium carbonate (0.86 g, 6.23 mmol). The mixture is heated at 85 0C for 5 days. Analysis of the reaction by TLC shows the formation of the product. The mixture is then diluted with water and extracted with ethyl acetate. Organic layer is then condensed in vacuo and purified by flash chromatography (20-100% ethyl acetate in heptanes) to give the product (0.72 g, 64 %).
	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20 - 60℃; for 18h;	3- (4-fluoro-phenoxy)-pyrrolidine-l-carboxylic acid ter-butyl ester; Sodium hydride (554 mg, 13. 84 mmol) is added to a solution of 4-fluorophenol (1.60 g, 14.20 mmol) in DMF (20 ml) and the mixture is stirred at room temperature for 2 minutes. 3-Methanesulphonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester is added and the mixture heated at 60 C for 18 hours. Water (50 ml) is then added and the resulting product is extracted using diethyl ether (3 x 30 ml). The organic extracts are dried (using MgS04), filtered and evaporated to give a white solid, which is purified using column chromatography over silica gel (ethyl acetate/isohexane 1: 9 v/v) to give the title compound.

Reference： [1]Patent: WO2007/106705,2007,A1 .Location in patent: Page/Page column 89
[2]Patent: WO2005/75420,2005,A2 .Location in patent: Page/Page column 19

17
[ 124-63-0 ]
[ 101385-93-7 ]
[ 141699-57-2 ]

Yield	Reaction Conditions	Operation in experiment
63.5%	With triethylamine; In dichloromethane; at 0℃; for 3.5h;	ter^-Butyl 3-[(methyIsulfonyl)oxy]pyrrolidine-l-carboxylate; 5 tert-Butyl 3-hydroxypyrrolidine-l-carboxylate (3.0Og, 16.02mmol) was dissolved in dry DCM (5OmL) and cooled in an ice-water bath. Methanesulfonyl chloride (2.38g, 20.83mmol) was added followed by TEA (2.43g, 24.03mmol) and the reaction mixture was stirred at 0C for 3.5h. The reaction mixture was washed with water (25OmL) and dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system 10 (40+M column, isocratic run heptane/EtOAc (50:50)) affording the title compund (2.7Og, 63.5%). 1H NMR (500MHz, CDCl3): 6 1.38 (s, 9H), 2.07 (bs, IH), 2.18 (bs, IH), 2.97 (s, 3H), 3.35-3.61 (m, 4H), 5.16-5.18 (m, IH); 13C NMR (125MHz, CDCl3): delta 28.59, 31.84, 32.76, 38.80, 43.61, 52.16, 80.12, 154.30.

Reference： [1]Patent: WO2006/73366,2006,A1 .Location in patent: Page/Page column 185

18
[ 141699-57-2 ]
cis-tert-butyl 3-(acetylthio)pyrrolidine-1-carboxylate [ No CAS ]
trans-tert-butyl 3-(acetylthio)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		tert-Butyl 3-(acetylthio)pyrrolidine-l-carboxylate; Potassium carbonate (4.42g, 31.96mmol) was suspended in dry MeOH (2OmL) and thioacetic acid (2.28g, 29.96mmol) was added. The mixture was stirred vigorously for 10 mins, concentrated and diluted in dry DMF (3OmL). tert-Butyl 3-[(methylsulfonyl)oxy]pyrrolidine- 1-carboxylate (2.65g, 9.99mmol) dissolved in dry DMF (2OmL) was added and the reaction20 mixture was heated to 60C for 3.5h. The reaction mixture was diluted with water (35OmL) and extracted with EtOAc (2x15OmL) The organic phases were dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system (25+M column, isocratic run heptane/EtOAc (60:40)) affording the title compund (0.592g, 24.2%) (the product is a mixture of cis and trans isomers).1H NMR (500MHz, CDCl3): delta 1.41 (d,25 18H), 1.66 (d, IH), 1.74-1.86 (m, 2H), 2.20-2.26 (m, 2H), 2.29 (s, 3H), 3.10-3.26 (m, 2H), 3.30-3.43 (m, 4H), 3.46-3.54 (m, IH), 3.66-3.74 (m, 2H); 13C NMR (125MHz, CDCl3): delta 28.68, 30.82, 31.25, 32.34, 36.16, 41.09, 44.88, 51.60, 55.37, 79.67, 154.43; Mass Spectrum: M+H+ 241.

Reference： [1]Patent: WO2006/73366,2006,A1 .Location in patent: Page/Page column 185

19
[ 211494-48-3 ]
[ 141699-57-2 ]
3-[3-(6-Amino-pyridin-2-yl)4-cyclobutyl-phenoxy]-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%		A. 3-[3-(6-Amino-pyridin-2-yl)4-cyclobutyl-phenoxy]-pyrrolidine-1-carboxylic acid tert-butyl ester Prepared as in Example 29 using 4-(6-amino-pyridin-2-yl)-3-cyclobutyl-phenol and <strong>[141699-57-2]3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester</strong>, (88% yield). 1H NMR (CDCl3)delta: 1.45 (s, 9H), 1.70-1.79 (m, 1H), 1.82-1.87 (m, 1H), 2.00-2.09 (m, 5H), 2.17-2.22 (m, 1H), 3.45-3.60 (m, 4H), 3.79 (q, J=9 Hz, 1H), 4.52 (bs, 2H), 4.92 (bs, 1H), 6.43 (d, J=8 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 6.90 (bs, 1H), 7.20-7.24 (m, 1H), 7.44 (t, J=8 Hz, 1H).

Reference： [1]Patent: US2001/7873,2001,A1

20
[ 2627-86-3 ]
[ 141699-57-2 ]
[ 1039632-28-4 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 5397 - 5409

21
[ 3886-69-9 ]
[ 141699-57-2 ]
[ 1039632-26-2 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 5397 - 5409

22
[ 63493-81-2 ]
[ 141699-57-2 ]
[ 1143025-13-1 ]

Yield	Reaction Conditions	Operation in experiment
49%		Intermediate 49: tert-Bntyl 3-(2-aminobenzothiazol-6-yl)sulfanylpyrrolidine-l- carboxylate; To a solution of tert-butyl 3-methylsulfonyloxypyrrolidine-l -carboxylate (1.7 g, 6.4 mmol) in MeCN (100 mL) was added 2-aminobenzothiazole-6-thiol (1.2 g, 6.4 mmol) and potassium carbonate (1.2 g, 8.3 mmol). The reaction mixture was stirred overnight, then heated at reflux for 24 hours. The reaction mixture was cooled to 60 C, then MeOH (10 mL) and sodium borohydride (0.3 g) were added and the reaction mixture was heated for 3 hours. The reaction mixture was cooled and then concentrated in vacuo and the residue partitioned between DCM (100 mL) and H2O (100 mL). The aqueous phase was <n="152"/>extracted with DCM (50 mL) and the combined organic phases were dried, then concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with EtOAc/isohexane (0 - 80%) to give the title compound as an off-white solid (1.1 g, 49%): 1H NMR deltal .38 (9H, s), 1.77 (IH, s), 2.14 (IH, s), 3.12 - 3.17 (IH, m), 3.35 - 3.41 (IH, m), 3.48 - 3.54 (IH, m), 3.76 (IH, s), 7.27 (2H, s), 7.56 (2H, s), 7.77 (IH, s);MS (M-^Bu)+ 296.

Reference： [1]Patent: WO2009/47558,2009,A1 .Location in patent: Page/Page column 150-151

23
[ 90-02-8 ]
[ 141699-57-2 ]
[ 1203486-46-7 ]

Yield	Reaction Conditions	Operation in experiment
	With tetra-(n-butyl)ammonium iodide; potassium carbonate; In dichloromethane; at 70 - 80℃; for 18h;	2-Hydroxybenzaldehyde (25; 1.2 g, 9.8 mmol), N-Boc-3-(methylsulfonyloxy)pyrrolidine (29; 2.6 g, 9.8 mmol), K2CO3 (2.0 g, 14.7 mmol) and tetrabutyl ammonium iodide (300 mg, cat) in CH2Cl2 (20 mL) was stirred at 70-80 0C for 18 h. DMF was removed by concentration under reduced pressure. The resulting residue was diluted with EtOAc (100 mL), washed with water (50 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (pentane: EtOAc = 1:10) to afford 676 mg oftert-butyl 3-(2- formylphenoxy)pyrrolidine-l-carboxylate 30 as an oil (yield: 23%).

Reference： [1]Patent: WO2010/3048,2010,A1 .Location in patent: Page/Page column 84

24
[ 141699-57-2 ]
[ 108-59-8 ]
[ 1196044-24-2 ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 16525 - 16528

26
[ 1258010-49-9 ]
[ 141699-57-2 ]
[ 1258010-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;	Step 2: tert-butyl 3-(4-(5-(1 -cyclohexylS-fmethoxymethyl)- 1 H-pyrazol-4-yl)-1 , 2, 4-oxadiazol-3- yl)phenoxy)pyrrolidine- 1 -carboxylate; To a solution of tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1 -carboxylate, obtained from step 1 , (0.15 g; 0.56 mmol), in DMF (2 mL) was added Example 123 (0.10 g; 0.28 mmol) and potassium carbonate (42 mg; 0.31 mmol) and the mixture stirred at 60 0C for 16 hours. The mixture was diluted with water (10 mL), the product extracted with EtOAc (3 x 10 mL) and the combined organic fractions dried (MgSO4), filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on an lsolute Flash Si Il 20 g column, eluting with petrol containing increasing amounts of EtOAc to give tert-butyl 3-(4-(5-(1- cyclohexyl-5-(methoxymethyl)-1 H-pyrazol-4-yl)-1 ,2,4-oxadiazol-3-yl)phenoxy)pyrrolidine-1 - carboxylate as a colourless oil. 1H NMR: (CDCI3, 400MHz) delta 8.13 (1 H, s), 8.08 (2 H, d, J = 8.2 Hz), 6.97 (2 H, d, J = 8.6 Hz), 5.03 (2 H, s), 4.97 (1 H, s), 4.35-4.27 (1 H, m), 3.72-3.47 (4 H, m), 3.42 (3 H, s), 2.30-2.07 (2 H, m), 2.08-1.89 (5 H, m), 1.80-1.70 (1 H, m), 1.47 (9 H, s), 1.44-1.25 (4 H, m). LC/MS: 524 (M+H)+. HPLC (Method C) Rt = 23.0 min (Purity: 98.2 %).

Reference： [1]Patent: WO2010/142628,2010,A1 .Location in patent: Page/Page column 170

27
[ 1268486-44-7 ]
[ 141699-57-2 ]
[ 1268486-45-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 865 - 868

28
[ 788104-34-7 ]
[ 141699-57-2 ]
[ 476493-40-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	In N,N-dimethyl-formamide; at 80℃; for 16h;	Preparation Example 1-55-23-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester The compound obtained in Preparation Example 1-55-1 (1.27 g, 4.79 mmol) was dissolved in N,N-dimethylformamide (15 mL), and lithium cyanide (0.47 g, 14.37 mmol) was added thereto. The mixture was stirred at 80 C. for 16 hours, cooled to room temperature, distilled under reduced pressure to remove the solvent, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried with anhydrous magnesium sulfate, distilled under reduced pressure, and purified by column chromatography using 2:1 mixture solvent of hexane and ethyl acetate to obtain the title compound (0.66 g, 70%).1H NMR (400 MHz, CDCl3); delta 3.67 (1H, br s), 3.58 (2H, br s), 3.45 (1H, br s), 3.09 (1H, m), 2.25 (2H, m), 1.47 (9H, s)

Reference： [1]Patent: US2011/166121,2011,A1 .Location in patent: Page/Page column 43

29
[ 24424-99-5 ]
[ 141699-57-2 ]

Reference： [1]Patent: US2011/212102,2011,A1
[2]Patent: WO2014/193647,2014,A2
[3]Patent: CN107474024,2017,A
[4]Patent: CN104119331,2018,B
[5]Patent: EP1500643,2005,A1

30
[ 24424-99-5 ]
[ 124-63-0 ]
3-hydroxypyrrolidine hydrochloride [ No CAS ]
[ 141699-57-2 ]

Yield	Reaction Conditions	Operation in experiment
		XV 111.1 tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1 -carboxylate To a solution of 3-hydroxypyrrolidine HCI (5.0 g) in dry MeOH (40.0 ml) was added triethylamine (8.45 ml) and the solution was cooled to 0C in an ice bath. Di t-butyl dicarbonat (8.80 g) was added portionwise over a period of 30 min. The reaction was allowed to warm to room temperature and stirred for 5h. The solvent was removed and the residue was dissolved in dichloromethane (50.0 ml) and washed with water. The organic phase was passed through a PTFE separation frit and the solvent was evaporated in vacuum .The residue was used without further purification.Dichloromethane (20.0 ml) was added to the residue and the the solution was cooled to 0C in an ice bath. Triethylamine (8.4 ml) was than added followed by dropwise addition of methansulfonyl chloride (3.13 ml. The solution was allowed to warm to room temperature and was stirred for 18h. The reaction was portioned between water and dichloromethane and the organic layer was separated, dried, filtered and evaporated.Yield: 8.26g

Reference： [1]Patent: WO2011/104337,2011,A1 .Location in patent: Page/Page column 73-74

31
[ 141699-57-2 ]
[ 1428253-07-9 ]

Reference： [1]Patent: WO2013/40059,2013,A1

32
[ 141699-57-2 ]
[ 1428253-09-1 ]

Reference： [1]Patent: WO2013/40059,2013,A1

33
[ 141699-57-2 ]
[ 1428253-08-0 ]

Reference： [1]Patent: WO2013/40059,2013,A1

34
[ 1428252-98-5 ]
[ 141699-57-2 ]
[ 1428253-06-8 ]

Yield	Reaction Conditions	Operation in experiment
16%		Step 2: Benzyl 4-(1 -(1 -(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-fluoro-3- (trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylateTo a solution of 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1 H-imidazol-2-yl]-piperidine- 1 -carboxylic acid benzyl ester (1000.00 mg; 2.24 mmol; 1 .00 eq.) in DMF 8ml added NaH (107.27 mg; 2.68 mmol; 1 .20 eq.), stirred at RT for 20mins, added 3- methanesulfonyloxy-pyrrolidine-1 -carboxylic acid tert-butyl ester (1 186.02 mg; 4.47 mmol; 2.00 eq.) , the reaction mixture was stirred 85 C for 5hr, Ic-ms showed around 40% desired, continued stirring for over night, no big changed, purified the product by HPLC (basic) with 30-100% acetonitrile /water, collected title compound 220mg, yield 16%.

Reference： [1]Patent: WO2013/40059,2013,A1 .Location in patent: Page/Page column 111

35
[ 611-99-4 ]
[ 141699-57-2 ]
[ 1388825-75-9 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.5h;	A mixture of fert-butyl 3 -(methylsulfonyloxy)pyrrolidine-l -carboxylate (0.6 g, 2.26 mmol), bis(4-hydroxyphenyl)methanone (2.15 g, 10.0 mmol) and K2CO3 (313 mg, 2.26 mmol) in 12 mL DMF was heated at 100 C for 3.5 h, then quenched with water, and extracted with EtOAc. The extract was washed with water, dried, and concentrated to give a residue, to which was added CH2C12 and the white suspension thus formed removed and filtration. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether/CH2Cl2/acetone = 4/2/1) to give the desired product (400 mg, 46% yield).

Reference： [1]Patent: WO2013/97773,2013,A1 .Location in patent: Paragraph 0151

36
[ 1448315-53-4 ]
[ 141699-57-2 ]
[ 1448315-58-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 25 N-{4-Methyl-3-[6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]phenyl}-3-(pentafluoro-lambda6-sulphanyl)-5-(pyrrolidin-3-yloxy)benzamide 150 mg (0.28 mmol) of the compound of Example 20, 89 mg (0.34 mmol) of <strong>[141699-57-2]tert-butyl 3-[(methyl-sulphonyl)oxy]pyrrolidine-1-carboxylate</strong> [lit. e.g.: P. Kocalka et al., Tetrahedron 2006, 62 (24), 5763-5774] and 201 mg (0.62 mmol) of caesium carbonate in 3 ml of DMF were heated at 90 C. for 6 h. The reaction was then stirred into 15 ml of 0.1 M aqueous sodium hydroxide solution and the mixture was stirred at RT for another 10 min. The precipitate formed was filtered off, washed with water and dried under reduced pressure.

Reference： [1]Patent: US2013/190290,2013,A1 .Location in patent: Paragraph 1439; 1440; 1441; 1442

37
[ 141699-57-2 ]
[ 151266-23-8 ]
[ 461701-17-7 ]

Yield	Reaction Conditions	Operation in experiment
57%	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere;	110 mg of 3-iodo-1H-pyrazole [3,4-d]pyrimidine-4-amine and 110 mg of tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-formate were dissolved in 2 ml of N,N-dimethylformamide, then 270 mg of cesium carbonate was added, and heated to 90 C overnight under argon atmosphere. The next day, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was isolated by column chromatography (dichloromethane: methanol= 97:3) to obtain 100 mg of yellow solids in a yield of 57%. 1H NMR (300 MHz, CDCl3) delta 8.32 (s, 1H), 6.05 (s, 2H), 5.40-5.39 (m, 1H), 3.90-3.68 (m, 3H), 3.58-3.47 (m, 1H), 2.58-2.26 (m, 2H), 1.48 (s, 9H).

Reference： [1]Patent: EP3486244,2019,A1 .Location in patent: Paragraph 0143; 0144

38
3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
[ 141699-57-2 ]
tert-butyl 3-{4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.2 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1h;	A suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62 mg) obtained in Step 1, tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (217 mg) obtained in Step 2, and potassium carbonate (221 mg) in DMF (2.0 ml) was stirred at 70C for 1 hour. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (36.2 mg). Physical properties: m/z[M+H]+ 465.1
36.2 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1h;	A suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62 mg) obtained in Step 1, tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (217 mg) obtained in Step 2, and potassium carbonate (221 mg) in DMF (2.0 ml) was stirred at 70 C. for 1 hour. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (36.2 mg). Physical properties: m/z[M+H]+ 465.1
36.2 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1h;	A suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62 mg) obtained in Step 1, tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (217 mg) obtained in Step 2, and potassium carbonate (221 mg) in DMF (2.0 ml) was stirred at 70 C. for 1 hour. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (36.2 mg). Physical properties: m/z [M+H]+ 465.1

Reference： [1]Patent: EP2657233,2013,A1 .Location in patent: Paragraph 0194
[2]Patent: US2016/136168,2016,A1 .Location in patent: Paragraph 0285
[3]Patent: US2016/193210,2016,A1 .Location in patent: Paragraph 0287

39
[ 141699-57-2 ]
[ 151266-23-8 ]
tert-butyl (S)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
354 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 6h;	(Step 2) Synthesis of (S)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (446 mg), (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (450 mg), potassium carbonate (692 mg) in DMF (5.0 ml) was stirred at 85C for 6 hours. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (354 mg). Physical properties: m/z[M+H]+ 431.1

Reference： [1]Patent: EP2657233,2013,A1 .Location in patent: Paragraph 0329

40
[ 141699-57-2 ]
tert-butyl (S)-3-(4-amino-3-((3,5-diisopropylphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: EP2657233,2013,A1

41
[ 645391-89-5 ]
[ 141699-57-2 ]
[ 1620690-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;	Example V (R)-ferf-Butyl 3-(4-((S)-1 -(benzyloxycarbonylamino)ethyl)phenoxy)pyrrolidine-1 - carboxylate 6.00 g (22.6 mmol) <strong>[141699-57-2]3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester</strong>*, 6.14 g (22.6 mmol) of example IV and 14.7 g (45.2 mmol) Cs2C03 are added to 80 ml_ DMF and stirred at 80 C over night. The reaction mixture is filtered, washed with MeOH and the solvent is removed in vacuo. The crude product is purified by HPLC (MeOH/H2O/NH3). ESI-MS: 439 [M-H]" Rt (HPLC):1.22 min (method C)

Reference： [1]Patent: WO2014/170197,2014,A1 .Location in patent: Page/Page column 82

42
[ 1104442-05-8 ]
[ 141699-57-2 ]
C₂₁H₂₆N₂O₆S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7499 - 7508

43
[ 141699-57-2 ]
isopropyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7499 - 7508

44
[ 141699-57-2 ]
C₁₇H₁₈N₂O₆S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7499 - 7508

45
[ 3469-69-0 ]
[ 141699-57-2 ]
3-(4-iodo-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.7%		To a stirred solution of 4-iodo-lH-pyrazole (4.08 g, 21.00 mmol) in DMF (320 mL) was added NaH (0.79 g, 26.25 mmol) portion-wise at 4 C. The mixture was stirred at 4 C for 1 hour, then tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate (4.64 g, 17.50 mmol) was added. The mixture was heated to 100 C and stirred further for 17 hours, then cooled to rt, quenched with H20 (5 mL), and concentrated in vacuo. The residue was washed with H20 (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers was dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =5/1) to give the title compound as a white solid (6.28 g, 98.7%). MS (ESI, pos. ion) m/z: 308.0 (M-56+1); NMR (400 MHz, CDCb): delta 7.53 (s, 1H), 7.46 (s, 1H), 4.89-4.86 (m, 1H), 3.85-3.52 (m, 4H), 2.38- 2.33 (m, 2H), 1.47 (s, 9H).
98.7%		he compound 4-iodo-1H-pyrazole (4.08 g, 21.00 mmol)Dissolved in DMF (320 mL), cooled to 4 C,Then NaH (0.79 g, 26.25 mmol) was added portionwise to the reaction,After stirring the reaction at 4 C for 1 hour,Tert-Butyl 3 - ((methylsulfonyl) oxy) pyrrolidine-1-carboxylate (4.64 g, 17.50 mmol)The reaction was heated to 100 C,After stirring for 17 hours,The reaction mixture was cooled to room temperature, quenched by adding water (5 mL), concentrated under reduced pressure and the residue washed with water (80 mL). The resulting mixture was extracted with EtOAc (80 mL × 3) and the combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure , And the residue was purified by silica gel column chromatography (PE / Et0Ac (v / v) = 5/1) to give the title compound as a white solid (6.28 g, 98.7%).
		NaH, 60% in oil (0.113 g, 2.84 mmol) was suspended in 3 mL DMF under argon, and the mixture was cooled in an ice bath with stirring while a solution of 4-iodo- 1H-pyrazole (0.50 g, 2.6 mmol) in 10 mL DMF was added dropwise. Stirring was continued at ice bath temperature for 10-15 mm, followed by dropwise addition of tert20 butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (0.68 g, 2.6 mmol). Stirring wascontinued overnight allowing the ice to melt, and the reaction to assume a The reaction mixture was diluted with water and extracted with EtOAc. The extract was washed with water and brine, then dried over Na2504, filtered and evaporated. The residue was purified by silica gel chromatography to provide the product. MS(ESI) m/z 363.8 (M+H) 307.8 (M+H-tBu)t

Reference： [1]Patent: WO2014/193647,2014,A2 .Location in patent: Paragraph 0272
[2]Patent: CN104119331,2018,B .Location in patent: Paragraph 0763; 0773; 0774
[3]Patent: WO2017/40449,2017,A1 .Location in patent: Paragraph 00285

46
[ 141699-57-2 ]
[ 1359974-18-7 ]

Reference： [1]Patent: US2015/11548,2015,A1

47
[ 2075-45-8 ]
[ 141699-57-2 ]
[ 1201657-89-7 ]

Yield	Reaction Conditions	Operation in experiment
61.5%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	To a solution of 4-bromo-1H-pyrazole (0.65 g, 4.42 mmol) in DMF were added sodium hydride at 0 C. (0.159 g, 6.6 mmol, 1.5 eq.) and the compound of Intermediate Example 30(a) (1.1 g, 4.42 mmol, 1.0 eq.). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 1% methanol in DCM) to yield the product in 61.5% yield (0.85 g).

Reference： [1]Patent: US2015/11548,2015,A1 .Location in patent: Paragraph 0184

48
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
[ 141699-57-2 ]
tert-butyl-3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate [ No CAS ]
tert-butyl-3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18h;	step 1: 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.19 g, 3.01 mmol), tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate (1.7 equiv., 5.11 mmol, 1360 mg) and cesium carbonate (2.5 equiv., 7.51 mmol, 2450 mg) were mixed in DMF (17.4 mL), and the reaction was stirred at 90 C. for 18 h. The mixture was diluted with EtOAc and 10% citric acid was added to adjust the pH to 9, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford 1307 mg (77% yield) off-white foam. LCMS and NMR analysis indicated a mixture of two regioisomers (i.e., tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate). The mixture was used in the next step without further purification. MS (ESI) m/z: 565 [M+1]+.

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0487

49
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
[ 75-04-7 ]
[ 141699-57-2 ]
tert-butyl-3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate [ No CAS ]
tert-butyl-3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		step 1: 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.19 g, 3.01 mmol), tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate (1.7 equiv., 5.11 mmol, 1360 mg) and cesium carbonate (2.5 equiv., 7.51 mmol, 2450 mg) were mixed in DMF (17.4 mL), and the reaction was stirred at 90 C. for 18 h. The mixture was diluted with EtOAc and 10% citric acid was added to adjust the pH to 9, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford 1307 mg (77% yield) off-white foam. LCMS and NMR analysis indicated a mixture of two regioisomers (i.e., tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate). The mixture was used in the next step without further purification. MS (ESI) m/z: 565 [M+1]+. step 2: The mixture from step 1 was dissolved in DCM (15 mL) and HOAc (1.05 equiv., 2.429 mmol, 0.1392 mL). MCPBA (1.05 equiv., 2.429 mmol, 544.3 mg) was added in one portion at 0 C., and the reaction was stirred at 0 C. for 1 h. The reaction mixture was evaporated, and the yellow gel was dissolved in a solution of ethylamine (2 mol/L) in THF (17.0 equiv., 39.32 mmol, 19.66 mL). The yellow solution was kept at 25 C. for 18 h. Na2SO3 (1 teaspoon) was added, and the suspension was stirred at 25 C. for 45 min. The mixture was diluted with EtOAc. After filtration and evaporation, the crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford a mixture of tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate (1.00 g, 77% yield overall) as off-white solid. The mixture was used without in the next step without further purification. MS (ESI) m/z: 562 [M+1]+.

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0487; 0488

50
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
[ 75-04-7 ]
[ 141699-57-2 ]
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-8-(pyrrolidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-ethyl-7-(pyrrolidin-3-yl-oxy)pyrido[2,3-d]pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		step 1: 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.19 g, 3.01 mmol), tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate (1.7 equiv., 5.11 mmol, 1360 mg) and cesium carbonate (2.5 equiv., 7.51 mmol, 2450 mg) were mixed in DMF (17.4 mL), and the reaction was stirred at 90 C. for 18 h. The mixture was diluted with EtOAc and 10% citric acid was added to adjust the pH to 9, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford 1307 mg (77% yield) off-white foam. LCMS and NMR analysis indicated a mixture of two regioisomers (i.e., tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate). The mixture was used in the next step without further purification. MS (ESI) m/z: 565 [M+1]+. step 2: The mixture from step 1 was dissolved in DCM (15 mL) and HOAc (1.05 equiv., 2.429 mmol, 0.1392 mL). MCPBA (1.05 equiv., 2.429 mmol, 544.3 mg) was added in one portion at 0 C., and the reaction was stirred at 0 C. for 1 h. The reaction mixture was evaporated, and the yellow gel was dissolved in a solution of ethylamine (2 mol/L) in THF (17.0 equiv., 39.32 mmol, 19.66 mL). The yellow solution was kept at 25 C. for 18 h. Na2SO3 (1 teaspoon) was added, and the suspension was stirred at 25 C. for 45 min. The mixture was diluted with EtOAc. After filtration and evaporation, the crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford a mixture of tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate (1.00 g, 77% yield overall) as off-white solid. The mixture was used without in the next step without further purification. MS (ESI) m/z: 562 [M+1]+. step 3: The mixture obtained in step 2 (450 mg, 0.8006 mmol) was mixed with HCl (4 mol/L) in 1,4-dioxane (44.0 equiv., 35.23 mmol, 8.806 mL) and maintained at 25 C. for 4 h. The reaction mixture was diluted with EtOAc and NaHCO3 (s, aq) to pH 9 and the layers separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The product was obtained as a mixture of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-8-(pyrrolidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one and 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-ethyl-7-(pyrrolidin-3-yloxy)pyrido[2,3-d]pyrimidin-2-amine (335 mg, 84% yield), which was used in the next step without further purification. MS (ESI) m/z: 462 [M+1]+.

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0487; 0488; 0489

51
[ 4530-20-5 ]
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
[ 75-04-7 ]
[ 141699-57-2 ]
tert-butyl-(2-(3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidin-1-yl)-2-oxoethyl)carbamate [ No CAS ]
tert-butyl-(2-(3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidin-1-yl)-2-oxoethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63 mg; 44 mg		step 1: 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.19 g, 3.01 mmol), tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate (1.7 equiv., 5.11 mmol, 1360 mg) and cesium carbonate (2.5 equiv., 7.51 mmol, 2450 mg) were mixed in DMF (17.4 mL), and the reaction was stirred at 90 C. for 18 h. The mixture was diluted with EtOAc and 10% citric acid was added to adjust the pH to 9, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford 1307 mg (77% yield) off-white foam. LCMS and NMR analysis indicated a mixture of two regioisomers (i.e., tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate). The mixture was used in the next step without further purification. MS (ESI) m/z: 565 [M+1]+. step 2: The mixture from step 1 was dissolved in DCM (15 mL) and HOAc (1.05 equiv., 2.429 mmol, 0.1392 mL). MCPBA (1.05 equiv., 2.429 mmol, 544.3 mg) was added in one portion at 0 C., and the reaction was stirred at 0 C. for 1 h. The reaction mixture was evaporated, and the yellow gel was dissolved in a solution of ethylamine (2 mol/L) in THF (17.0 equiv., 39.32 mmol, 19.66 mL). The yellow solution was kept at 25 C. for 18 h. Na2SO3 (1 teaspoon) was added, and the suspension was stirred at 25 C. for 45 min. The mixture was diluted with EtOAc. After filtration and evaporation, the crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford a mixture of tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate (1.00 g, 77% yield overall) as off-white solid. The mixture was used without in the next step without further purification. MS (ESI) m/z: 562 [M+1]+. step 3: The mixture obtained in step 2 (450 mg, 0.8006 mmol) was mixed with HCl (4 mol/L) in 1,4-dioxane (44.0 equiv., 35.23 mmol, 8.806 mL) and maintained at 25 C. for 4 h. The reaction mixture was diluted with EtOAc and NaHCO3 (s, aq) to pH 9 and the layers separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The product was obtained as a mixture of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-8-(pyrrolidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one and 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-ethyl-7-(pyrrolidin-3-yloxy)pyrido[2,3-d]pyrimidin-2-amine (335 mg, 84% yield), which was used in the next step without further purification. MS (ESI) m/z: 462 [M+1]+. step 4: Boc-Gly-OH (4.0 equiv., 0.8745 mmol, 153.2 mg) and HATU (4.0 equiv., 0.8745 mmol, 339.3 mg) were mixed in 1,4-dioxane (1.0 mL) at 25 C. for 20 min. The white suspension was transferred into a solution of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-N-ethyl-7-pyrrolidin-3-yloxy-pyrido[2,3-d]pyrimidin-2-amine and 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-8-pyrrolidin-3-yl-pyrido[2,3-d]pyrimidin-7-one (101 mg, 0.2186 mmol) in 1,4-dioxane (1.0 mL) and DIPEA (5.0 equiv., 1.093 mmol, 0.191 mL). The reaction was kept at 25 C. for 4 h. The crude was diluted with EtOAc and the pH was adjusted to 9 by addition of 10% citric acid. The layers were separated, and the aqueous layer was extracted by EtOAc. The organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to give the two isomers: tert-butyl (2-(3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidin-1-yl)-2-oxoethyl)carbamate: 63 mg, 46% yield, MS (ESI) m/z: 619 [M+1]+. tert-butyl (2-(3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidin-1-yl)-2-oxoethyl)carbamate: 44 mg, 33% yield, MS (ESI) m/z: 619 [M+1]+.

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0487; 0488; 0489; 0490; 0491; 0492

52
[ 1003-56-1 ]
[ 141699-57-2 ]
tert-butyl 3-(3-methyl-2-oxopyridin-1(2H)-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere;	Step 2 tert-Butyl 3-(3-methyl-2-oxopyridiu-1 (2H)-yi)pyrrolidine-1-carboxylateTo a solution of tert-Butyl 3 -((methylsulfonyfloxy)pyrrolidine- I -carboxylate (1.0 g, 3.77 mmol), K2C03 (781.3 mg, 5.70 mmol) in DMF (7 mL) was added 3-Methylpyriclin-2(1H)-one (493.6 mg,4.52 mmol) at room temperature. The mixture was stined at 100 C for 16 hrs under a N2atmosphere. After cooling to room temperature, it was diluted with EtOAc (120 mL), washed with H20 (80 mL x 2) and brine (80 mL). The organic phase was dried over Na2SO4, filtered andconcentrated to dryness to afford the crude title compounds (800 mg) as yellow oil which was used to the next step directly without further purification.

Reference： [1]Patent: WO2016/57924,2016,A1 .Location in patent: Page/Page column 113

53
[ 141699-57-2 ]
tert-butyl 3-(4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/168156,2016,A1

54
C₁₁H₇BrFN₅ [ No CAS ]
[ 141699-57-2 ]
C₂₀H₂₂BrFN₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 20h;	Example A4 a) Preparation of intermediate 25 A stirred mixture of intermediate 17 (3.00 g, 9.74 mmol), CS2CO3 (9.5 g, 29.2 mmol) and DMF (45 ml) at ambient temperature was treated with 3-methanesulfonyloxy- pyrrolidine-l-carboxylic acid tert-bvXy ester (3.87 g, 14.6 mmol), and the resulting mixture was heated at 80 C for 20 hours. The mixture was cooled to ambient temperature and partitioned between water and 2-methyltetrahydrofuran. The organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was triturated with Et20 to afford the desired product as a brown solid (3.60 g, 77%).

Reference： [1]Patent: WO2016/62792,2016,A1 .Location in patent: Page/Page column 28-29

55
[ 141699-57-2 ]
pyrrolidin-3-yl methanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In water; ethyl acetate; at 20℃; for 1h;	4M HCl/EtOAc (10 mL) was added to a solution of tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (4.0 g, 15 mmol) in ethyl acetate (40 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to give the title compound hydrochloride (2.5 g, yield: 100%).

Reference： [1]Patent: US2016/200730,2016,A1 .Location in patent: Paragraph 0355; 0356

56
[ 141699-57-2 ]
1-acryloylpyrrolidin-3-yl methanesulfonate [ No CAS ]

Reference： [1]Patent: US2016/200730,2016,A1

57
1-(3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone [ No CAS ]
[ 141699-57-2 ]
tert-butyl 3-(5-acetyl-3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
680 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;	g, 5.33 mmol) in DMF (10 mL) was added Cs2CO3 (19.5 g, 59.6 mmol) and tert-butyl 3- ((methylsulfonyl)oxy)pyrrolidine- I -carboxylate (2.1 g, 7.99 mniol), The mixture was heated to 80 C for 12 h. After cooling the reaction to room temperature, the reaction was filteredand concentrated in vacuo. The residue was dissolved in EtOAc (40 mL) and the mixture was washed with brine (20 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether tert-butyl methyl ether I THF from 10: 1: 1 to 1: 10: 10) to give the title compound (680 mg, 31%) as colorless oil. ?H NMR (400 MHz, CD3OD) 8 4.41 -4.39(m, 2H), 3.92 - 3.87 (m, 1H), 3.82 - 3.70 (m, 2H), 3.66 - 3.43 (m, 4H), 2.88 - 2.76 (m, 4H),2.33 - 2.31 (m, 211), 2.20 - 2.17 (m, 3H), 1.48 (s, 9H).

Reference： [1]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 210; 211

58
1-(3-bromo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone [ No CAS ]
[ 141699-57-2 ]
tert-butyl 3-(5-acetyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/86200,2016,A1

59
[ 141699-57-2 ]
potassium (1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)trifluoroborate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 9674 - 9682
[2]Patent: KR2016/103390,2016,A

60
[ 141699-57-2 ]
tert-butyl 3-(4-(5-fluoro-2-(3,4-dichlorobenzyloxy)phenyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-carboxylate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 9674 - 9682
[2]Patent: KR2016/103390,2016,A

61
[ 141699-57-2 ]
tert-butyl 3-(4-(5-chloro-2-(3,4-dichlorobenzyloxy)phenyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-carboxylate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 9674 - 9682

62
[ 141699-57-2 ]
(3R)-tert-butyl 3-(4-amino-3-(2-fluoro-4-(2,3,5,6-tetrafluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/200730,2016,A1

63
[ 141699-57-2 ]
(3R)-tert-butyl 3-(4-amino-3-(2-fluoro-4-(4-fluorobenzoyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/200730,2016,A1

64
[ 141699-57-2 ]
(3R)-tert-butyl 3-(4-amino-3-(2-fluoro-4-(2-fluorobenzoyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/200730,2016,A1

65
[ 141699-57-2 ]
(3R)-tert-butyl 3-(4-amino-3-(2-fluoro-4-(3-fluorobenzoyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/200730,2016,A1

66
[ 141699-57-2 ]
(3R)-tert-butyl 3-(4-amino-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/200730,2016,A1

67
[ 141699-57-2 ]
(3R)-tert-butyl 3-(4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/200730,2016,A1

68
[ 141699-57-2 ]
[ 151266-23-8 ]
[ 1422827-96-0 ]

Yield	Reaction Conditions	Operation in experiment
44%	With caesium carbonate; In N,N-dimethyl-formamide; at 85℃; for 12h;	Cesium carbonate (37 g, 115 mmol, 3.0 eq.) and 3-iodo-1H-pyrazolo[3,4-d] pyrimidin-4-amine (10 g, 38 mmol, 1.0 eq.) were added to a solution of 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (35 g, 134 mmol, 3.5 eq.) in DMF (300 mL). The reaction was stirred at 85 C. for 12 h, cooled to room temperature and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=1:1) to give the title compound (7.0 g, yield: 44%).

Reference： [1]Patent: US2016/200730,2016,A1 .Location in patent: Paragraph 0280; 0281

69
[ 103-67-3 ]
[ 141699-57-2 ]
[ 862906-27-2 ]

Yield	Reaction Conditions	Operation in experiment
63%	at 100℃; for 3h;Inert atmosphere;	A mixture of terf-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (INT 1 , 4.25 g, 16.02 mmol)) and N-Methyl-1-phenylmethanamine (6.20 mL, 48.07 mmol) was stirred and heated at 100 C for 3 h, under nitrogen. The residue was portioned between DCM/water. The aqueous phase was further extracted with dichloromethane. The combined extracts were washed with brine and dried (Na2S04) filtered and evaporated. The crude product thus obtained was purified by flash chromatography on silica gel, gradient CH:AcOEt from (100:0) to (70:30) to give the title compound as yellow oil (2.93 g, 63% yield). HPLC-MS (Method A): Ret, 2.20 min; ESI+-MS m/z, 291 (M+1 ).

Reference： [1]Patent: WO2017/16668,2017,A1 .Location in patent: Page/Page column 133

70
[ 141699-57-2 ]
1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: CN107226805,2017,A

71
[ 141699-57-2 ]
tert-butyl 3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: CN107226805,2017,A

72
[ 1558038-00-8 ]
[ 141699-57-2 ]
ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With caesium carbonate; at 100℃; for 16h;	The compound 3- (4-phenoxyphenyl) -1H-pyrazole-4-carboxylate 7f (308 mg, 1.0 mmol)3-((Methylsulfonyl) oxo) tert-butyl 3 - ((methylsulfonyl) oxo) pyrrolidine-1-carboxylate7b (477 mg, 1.8 mmol),Cesium carbonate (650 mg, 2.0 mmol) andAnhydrous N, N-dimethylformamide (20 mL), heated to 100 C, and stirred for 16 hours. Cool to room temperature, minusThe residue was washed with saturated sodium bicarbonate (30 mL) and extracted with dichloromethane (50 mL x 3). The organic phase is combined with anhydrousDried over sodium sulfate, the desiccant was removed by filtration, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate =10/1) to obtain the target productEthyl 1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -3- (4-phenoxyphenyl)Pyrazole-4-carboxylate 7 g (334 mg), yield: 70%

Reference： [1]Patent: CN107226805,2017,A .Location in patent: Paragraph 0169; 0186; 0187; 0188; 0189

73
ethyl 3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylate [ No CAS ]
[ 141699-57-2 ]
C₂₇H₃₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 120℃; for 12h;	To a solution of compound 20-4 (7 g, 22.6 mmol) and compound 45-2-1 (12 g, 45.3 mmol) in DMF (70 mL) was added DBU (6.9 g, 45.3 mmol), and the reaction solution was stirred at 120 C. for 12 h, followed by concentration to give a crude product which was purified by column chromatography to afford compound 45-3 (10.41 g, 96%) as coloueless oil. LCMS (ESI) m/z: 478 (M+1). 1H NMR (400 MHz, CDCl3): delta ppm 7.79-7.768 (d, 2H), 7.38-7.34 (t, 2H), 7.1427.11 (t, 2H), 7.05-7.03 (d, 4H), 4.39-4.37 (d, 2H), 3.86-3.7 (m, 3H), 3.582-3.54 (m, 1H), 3.41 (s, 1H), 2.59-2.53 (m, 1H), 2.37-2.32 (m, 1H), 1.48 (s, 9H), 1.44-1.40 (t, 3H).

Reference： [1]Patent: US2017/313683,2017,A1 .Location in patent: Paragraph 0877-0879

74
[ 141699-57-2 ]
C₂₇H₃₀IN₃O₅ [ No CAS ]

Reference： [1]Patent: US2017/313683,2017,A1

75
[ 141699-57-2 ]
C₂₈H₃₀N₄O₅ [ No CAS ]

Reference： [1]Patent: US2017/313683,2017,A1

76
[ 141699-57-2 ]
C₂₆H₂₈N₆O₄ [ No CAS ]

Reference： [1]Patent: US2017/313683,2017,A1

77
[ 101385-93-7 ]
[ 141699-57-2 ]

Reference： [1]Patent: WO2017/211759,2017,A1

78
[ 773837-37-9 ]
[ 141699-57-2 ]
[ 476493-40-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	In N,N-dimethyl-formamide; at 100℃; for 16h;	A solution of tert-butyl 3- (methanesulfonyloxy) pyrrolidine-1-carboxylate (2.65 g, 10 mmol) and sodium cyanide (2.5 g, 50 mmol) in N, N- dimethylformamide (100 mL) The solution was reacted at 100 C for 16 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic phases were combined, washed, dried and the resulting residue was concentrated by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the title compound (1.92 g, 98%).
69%	In N,N-dimethyl-formamide; at 100℃; for 16h;	To a stirred solution of <strong>[141699-57-2]tert-butyl 3-[(methanesulfonyl)oxy]pyrrolidine-1-carboxylate</strong> (mixture of isomers, 6.1 g, 23.0 mmol) in DMF (40 mL)NaCN (3.38 g, 69.0 mmol) was added. The reaction mixture was stirredat 10000 for 1 6 h then was cooled to room temperature and diluted withEtOAc (75 mL). The organic layer was washed with water (2 x 40 mL), dried over sodium sulfate and concentrated. The resulting crude was purified by column chromatography (silica gel: 230-400, 25% EtOAc in pet. ether) to afford the title compound (3.1 g, 15.8 mmol, 69% yield, colorless liquid) as a mixture of isomers. 1HNMR (CDCI3): 6 3.69-3.59(m, 4H), 3.12-3.09 (m, 1H), 2.27-2.25 (m, 2H), 1.48 (5, 9H).

Reference： [1]Patent: CN107474024,2017,A .Location in patent: Paragraph 0385; 0392; 0393; 0394
[2]Patent: WO2017/211759,2017,A1 .Location in patent: Page/Page column 59; 60

79
[ 141699-57-2 ]
[ 270912-72-6 ]

Reference： [1]Patent: WO2017/211759,2017,A1

80
[ 141699-57-2 ]
tert-butyl 3-([(benzyloxy)carbonyl]amino}methyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/211759,2017,A1

81
[ 141699-57-2 ]
pyrrolidin-3-yl methanesulfonate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; diethyl ether;	3-Methanesulfonyloxy-pyrrolidine- 1 -carboxylic acid tert-butyl ester (CAS 141699-57-2,768 mg, 2.89 mmol, 1.00 equiv) was dissolved in Et20 (8.7 mL) and HC1 (4 M in dioxane,8.68 mL, 17.4 mmol, 6 equiv) was added. The mixture was stuffed overnight, concentrated and the residue was used without further purification.

Reference： [1]Patent: WO2017/220517,2017,A1 .Location in patent: Page/Page column 31

82
[ 141699-57-2 ]
tert-butyl 3-(chlorosulfonyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 8343 - 8349

83
[ 141699-57-2 ]
tert-butyl 3-(fluorosulfonyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 8343 - 8349

84
[ 141699-57-2 ]
[ 10387-40-3 ]
tert-butyl 3-(acetylthio)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 8343 - 8349

85
6-bromo-3-butyl-1H-pyrrolo[3,2-c]pyridine [ No CAS ]
[ 141699-57-2 ]
tert-butyl 3-(6-bromo-3-butyl-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.8%		To a stirred solution of 6-bromo-3-butyl-1H-pyrrolo[3,2-c]pyridine (500 mg, 01.975mmol) in DMF (50 mL) was added CS2CO3 (2.24g, 6.9mmol) at RT. Resulting reaction mixture was allowed to stir at 100C for 1 h, then was added tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1 -carboxylate in DMF (1.04g, 3.95mmol), then heated for 2 h. The reaction was monitored by LCMS. The reaction mixture was cooled, 20 mi ice cold water was added and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate. The crude was purified by flash column chromatography in devisal silica using 25-30% EtOAc/pet ether to get tert-butyl 3-(6- bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)pyrrolidine-1 -carboxyiate (0.39 g, 46.8 %) as pale yellow gum. LC-MS (method 23): Rt = 2.43 min; m/z = 423.55 (M+H+).

Reference： [1]Patent: WO2018/149986,2018,A1 .Location in patent: Page/Page column 92-93

86
[ 141699-57-2 ]
1-(tert-butoxycarbonyl)-3-(4-cyanophenylamino)pyrrolidine [ No CAS ]

Reference： [1]Patent: EP1500643,2005,A1

87
[ 141699-57-2 ]
[ 186550-13-0 ]

Reference： [1]Patent: EP1500643,2005,A1

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Precautionary Statements-General
Code	Phrase
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Prevention
Code	Phrase
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P322
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P378
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Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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H316	Causes mild skin irritation
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H319	Causes serious eye irritation
H320	Causes eye irritation
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H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 141699-57-2 ] {[proInfo.proName]}

Quality Control of [ 141699-57-2 ]

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Application In Synthesis of [ 141699-57-2 ]

[ 141699-57-2 ] Synthesis Path-Upstream 1~8

[ 141699-57-2 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 141699-57-2 ]

Amides

Sulfonates

Related Parent Nucleus of [ 141699-57-2 ]

Aliphatic Heterocycles

Pyrrolidines

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[ 141699-57-2 ]

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[ 141699-57-2 ]