Name: 1226781-80-1|2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole|95%
Brand: Ambeed
SKU: A287627
Price: 47.0 USD
Availability: InStock
Rating: 90 (40 reviews)

1
[ 657428-42-7 ]
[ 124-63-0 ]
[ 1226781-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester With sodium hydride In acetonitrile; mineral oil at 20℃; for 2h; Inert atmosphere; Stage #2: methanesulfonyl chloride In acetonitrile; mineral oil at 20℃; Cooling with ice;	5.A; 5.B Intermediate 5; 2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole; Step A: tert-Butyl 1-(methylsulfonyl)]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (A) and tent-butyl 2-(methylsulfonyl)]-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (B); A suspension of N-Boc-pyrazolopyrrolidine (Intermediate 3, Step B) (27.16 g, 130 mmol) in anhydrous acetonitrile (1.0 L) was charged in a 2.0 L three-neck flask fitted with a thermometer and an addition funnel and then treated with sodium hydride (60% dispersion in oil, 6.23 g, 156 mmol) while under nitrogen atmosphere in one portion. The reaction mixture was stirred at room temperature for 2 h. The resulting white suspension was then cooled in an ice bath and methanesulfonyl chloride (25.2 mL, 324 mmol) was slowly added via addition funnel The ice bath was then removed and the mixture was stirred 1 h at room temperature. The reaction mixture was quenched with water (500 mL) and the layers were separated. The aqueous layer was then extracted with 2×500 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a mixture of products A and B as colorless syrups. NMR in CD3OD indicated a 1:1 mixture of two products, in which the proton on the pyrazole ring in product A appeared at 7.70 ppm while the proton in product B appeared at 7.95 pm. LC-MS: 288.08 (M+1).; Step B: 2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole; Trifluoroacetic acid (200 mL) was added slowly to a solution containing intermediates A and B prepared in the previous step (48.4 g, 168 mmol) in dichloromethane (400 mL) at 0° C. After addition, the cooling bath was removed and the reaction was allowed to stir at room temperature for 2 h. Solvent was removed under reduced pressure and the resulting trifluoroacetate salt was then neutralized with 500 mL of 25% methanol and 2.5% ammonium hydroxide in dichloromethane. After removal of solvent, the desired Intermediate 5 was obtained after chromatography on a Biotage column (2×340 g) eluting with 2.5-12.5% methanol and 0.25-1.25% ammonium hydroxide in dichloromethane. LC-MS: 109.85 (M+1).

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2010/120863, 2010, A1 Location in patent: Page/Page column 23

2
[ 951127-24-5 ]
[ 1226781-80-1 ]
[ 1226781-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl ((2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate; 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole In methanol for 0.5h; Stage #2: With decaborane In methanol at 20℃; for 18h;	2.A Example 2; (2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine; Step A: tert-Butyl {(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate; A mixture of Intermediate 1 (516 mg, 1.5 mmol) and 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (Intermediate 5) (280 mg, 1.5 mmol) in anhydrous methanol (70 ml) was stirred for 30 min before adding decaborane (54.8 mg, 0.45 mmol). The reaction was stirred at room temperature for 18 h. The reaction was concentrated and purified on 40M Biotage silica column eluting with 0-10% ethyl acetate in dichloromethane to wash out the minor isomer and 1.25% methanol in dichloromethane to elute the title compound which was obtained as a white solid. LC/MS: 517.05 (M+1).

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2010/120863, 2010, A1 Location in patent: Page/Page column 24-25

3
[ 951127-25-6 ]
[ 1226781-80-1 ]
[ 1226781-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic acid 1,1-dimethylethyl ester; 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole In methanol at 20℃; for 2h; Stage #2: With decaborane In methanol at 20℃;	1.A Example 1; (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine; Step A: tert-Butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5 (4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate; A mixture of Intermediate 2 (26.3 g, 80 mmol) and 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (Intermediate 5) (15.07 g, 80 mmol) in anhydrous methanol (1.5 L) was stirred at room temperature for 2 h. To the resulting white suspension was added decaborane (2.95 g, 24.15 mmol) and the mixture was stirred at room temperature overnight. Methanol was removed and the residue was purified on two 65i Biotage columns eluting with 5-50% ethyl acetate in dichloromethane to afford the title compound as a white solid. LC-MS: 499.10 (M+1).

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2010/120863, 2010, A1 Location in patent: Page/Page column 24

4
[ 1226781-80-1 ]
[ 1350652-30-0 ]
C₂₃H₃₀F₂N₄O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-oxothiepan-3-yl]carbamate With titanium(IV) isopropylate In dichloromethane; dimethyl sulfoxide at 0℃; for 0.166667h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran; dichloromethane; dimethyl sulfoxide at 50℃; for 3h;	4.A To a solution of fer/-butyl [(2J,3S)-2-(2,5-difluorophenyl)-5-oxothiepan-3- yljcarbamate (mtermediate 3) (55 mg, 0.1.5 mmols) and 2-(methylsulfonyl)-2,4>5,6- te1iahydropyrrolo[3,4-c]pyra2ole (Intermediate 19) (35 mg, 0.19 mmol) in DCM (1.5 mL) and DMSO (100 μL) was added titanium(IV) isopropoxide (135 μ, 0.46 mmol). The reaction was stirred for 10 min at 0 °C, then sodium cyanoborohydride (462 μ, 0.46 mmol, 1M in THF) was added and the reaction was heated to 50 °C for 3 h. The reaction mixture was concentrated to approximately 0.5 mL and purified by preparative thin layer chromatography (2 x 1000 micron PTLC plates using 10% MeOH (containing 2 N N) in DCM as a developing solvent). The major band was removed, eluted with 1:1 methanol/DCM and evaporated. Examination of the oil by .H NMR showed an approximately 4: 1 mixture of diastereomeric amines at C-5.

Reference： [1]Current Patent Assignee: MERCK & CO INC; SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2011/146358, 2011, A1 Location in patent: Page/Page column 64-65

5
[ 1226781-80-1 ]
[ 1350652-34-4 ]
C₃₇H₃₆F₂N₄O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; (6S,7R)-7-(2,5-difluorophenyl)-6-(tritylamino)oxepan-4-one With titanium(IV) isopropylate In dichloromethane at 0℃; for 0.166667h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran; dichloromethane at 20 - 50℃; for 19h;	1.A To a 0 °C solution of (65,7ii)-7-(2,5-diiluorophenyl)^-(tritylamino)oxepan-4-one(Intermediate 5) (150 mg, 0.31 mmol) and 2-(memylsulfonylV2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazole (Intermediate 19) (64 mg, 0.34 mmol) in DCM (3 mL) was added titanium(TV) isopropoxide (91 μ, 0.31 mmol). The reaction was stirred for 10 min at 0 °C, then sodium cyanoborohydride (3 0 μ,, 0. 1 mmol, 1M in THF) was added. The reaction was heated to 50 °C for 1 h, then cooled to rt for 18 h and concentrated to approximately 1 mL. The resulting solution was purified by preparative thin layer chromatography (4 x 1000 micron FTLC plates using 10% methanol (containing 2N N) in DCM as a developing solvent). The major band was removed, eluted with 1:1 methanol/DC and evaporated. Examination of the oil by 1H NMR showed an approximately 4:1 mixture of diastereomeric amines at C-5.

Reference： [1]Current Patent Assignee: MERCK & CO INC; SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2011/146358, 2011, A1 Location in patent: Page/Page column 62

6
[ 1226781-80-1 ]
C₁₄H₁₈FNO₄S [ No CAS ]
C₂₀H₂₇FN₄O₅S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole With triethylamine In N,N-dimethyl acetamide for 0.166667h; Stage #2: C₁₄H₁₈FNO₄S With acetic acid In N,N-dimethyl acetamide at 20℃; for 0.5h; Stage #3: With sodium tris(acetoxy)borohydride In N,N-dimethyl acetamide at 0 - 20℃; for 2h;	1.9 Step 9. Preparation of Compound 9 To a mixture of amine (0.053 g, 0.152 mmol, 1.2 equiv) in dimethylacetamide (2 mL) was added triethylamine (0.038 g, 0.380 mmol, 3 equiv) and stirred for 10 min. Then compound 8 (0.040 g, 0.126 mmol, 1 equiv) and acetic acid (0.038 g, 0.634 mmol, 5 equiv) were added and the mixture was stirred for 30 min at room temperature. To the resulting solution, sodiumtriacetoxy borohydride (0.032 g, 0.152 mmol, 1.2 equiv) was added at 0 °C and allowed to stir at room temperature for 2 h. The mixture was poured into water and then extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash chromatography (60- 65 % ethyl acetate in hexane) to obtain compound 9 as white solid. 1H NMR (400 MHz, CDCI3): δ 7.75 (s, IH), 7.19 (dd, J= 3.92 Hz, J= 5.40 Hz, IH), 6.74 (d, J=5.52 Hz, IH), 4.57-4.49 (m, 2H), 4.27 (d, J=11.6 Hz, IH), 3.96-3.80 (m, 5H), 3.31 (s, 3H), 2.54-2.50 (m, IH), 1.34 (s, 9H). Mol. formula C2oH27FN405S2, calcd. mol. wt.486.58).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/122920, 2013, A1 Location in patent: Page/Page column 41; 42

7
[ 1226781-80-1 ]
C₁₅H₁₈F₂N₂O₄ [ No CAS ]
C₂₁H₂₇F₂N₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole With triethylamine In tetrahydrofuran; methanol for 0.166667h; Stage #2: C₁₅H₁₈F₂N₂O₄ With titanium(IV) tetraethanolate In tetrahydrofuran; methanol at 20℃; for 12h; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran; methanol at 0 - 20℃; for 3h;	2.8 Step 8: Synthesis of Compound 9 To a solution of amine (0.526 g, 1.52 mmol, 2.5 equiv) in methanohtetrahydrofuran (3 mL:5 mL) was added triethylamine (0.254 mL, 1.8 mmol, 3 equiv) and stirred for 10 min. To this, 8 (0.200 g, 0.6 mmol, 1 equiv) was added followed by titaniumtetraethoxide (0.306 mL, 1.46 mmol, 2.4 equiv) and the mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated and diluted with methanol (lOmL). Sodium triacetoxyborohydride (0.308 g, 1.46 mmol, 2.4 equiv) was added at 0 °C and the mixture was stirred at room temperature for 3 h and concentrated. The reaction mixture was neutralized with aqueous ammonia (3 mL) and then extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous Na2S04, filtered and concentrated. The residue obtained was purified by flash chromatography (70- 80 % ethyl acetate in hexane) to obtain 9 as white solid. Mol. formula C2iH27F2N505S, calcd. mol. wt. 499.53. Observed mass : 500.3 (M+l).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/122920, 2013, A1 Location in patent: Page/Page column 45

8
[ 773837-37-9 ]
[ 951127-25-6 ]
[ 1226781-80-1 ]
[ 1548337-32-1 ]
[ 1548337-36-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic acid 1,1-dimethylethyl ester With sodium metabisulfite In water at 20℃; for 1h; Stage #2: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole In ethanol; water for 4h; Stage #3: sodium cyanide In ethanol; water at 50℃; for 48h;	2.1; 3.1 Synthesis of Compound 1 & 2 (Step 1) To a suspension ofM2 (0.95 g, 2.8 mmol) in water (8.67 mL) was added sodiummetabisulfite (0.55 g, 2.8 mmol) and stirred a room temperature for 1hour. A solution ofM3(0.52 g, 2.8 mmol) in ethanol (8.67 mL) was added to the above reaction mixture and continuedthe stirring for further 4 hours. Neat NaCN (0.14 g, 2.8 mmol) was added to the above reaction mixture in one portion and heated the reaction mixture at 50 °C for 2 days. Reaction mixture wasconcentrated under vacuum to remove most of the ethanol. The crude mixture was extracted withCHCh (50 x 3 mL ). The combined organic layer was washed with water, dried over N a2S04,filtered, concentrated and purified by flash chromatography to obtain 1 and 2 as solids. Compound 1: 1H NMR (300 MHz, CDCh): o 7.77 (s, 1H), 7.26- 7.35 (m, 1H), 7.00 (t, J = 5.76 Hz, 2H), 4.57 (t, J = 9.88 Hz, 2H), 4.32 - 4.39 (m, 1H), 3.85 - 4.09 (m, 5H), 3.60 ( d, J = 11.34Hz, 1H), 3.34 (s, 3H), 2.63-2.74 (m, 1H), 2.02-2.15 (m, 1H), 1.31 (s, 9H).Compound 2: 1H NMR (300 MHz, CDCh): o 7.28- 7.36 (m, 2H), 7.00 (t, J = 5.85 Hz, 2H),4.55 (d, J = 8.97 Hz, 2H), 4.37 (dd, J= 2.65, 11.25 Hz, 1H), 3.88-4.07 (m, 5H), 3.60 (d, J =11.34 Hz, 1H), 2.71 (td, J = 3.45, 12.49 Hz, 1H), 1.97- 2.12 (m, 1H), 1.31 (s, 9H).; Molecular Formula: CzzHzsFzNs03; LCMS purity: 94.48%; Expected: 445.2; Observed: 446.0 (M+ 1 ).(Preparation ofM3: M3.PhS03H (1.0 g, 2.8 mmol) was dissolved in minimum volume ofMeOH:CHCh (1: 1) and passed through a column [Orochem 5 g, 10 ml, Amino (NH2)] usingMeOH as eluent. Organics were concentrated under vacuum to get free M3, which was useddirectly without further purification.)

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/18355, 2014, A1 Location in patent: Page/Page column 32; 34

9
[ 1226781-80-1 ]
C₁₇H₂₀F₂N₄O*3C₂HF₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium metabisulfite / water / 1 h / 20 °C 1.2: 4 h 1.3: 48 h / 50 °C 2.1: methylmagnesium bromide / tetrahydrofuran; diethyl ether / 1 h / -78 - 20 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/18355, 2014, A1

10
[ 1226781-80-1 ]
C₁₈H₂₂F₂N₄O₃S*2C₂HF₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium metabisulfite / water / 1 h / 20 °C 1.2: 4 h 1.3: 48 h / 50 °C 2.1: methylmagnesium bromide / diethyl ether / 1 h / -78 - 20 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C / Inert atmosphere 2.3: 1 h / 0 °C 3.1: dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/18355, 2014, A1

11
[ 1226781-80-1 ]
[ 1544022-38-9 ]
C₂₇H₂₈F₂N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C₂₁H₁₉F₂NO₃ With N,N-dimethyl acetamide; triethylamine for 0.333333h; Stage #2: With acetic acid for 0.333333h; Stage #3: With sodium tris(acetoxy)borohydride	2.15 Synthesis of 16 To a solution of 15 (200 mg, 0.53 mmol) in DMAc (2 mL) was added Ml (555 mg, 1.6 mmol) followed by EtsN (0.22 mL, 1.6 mmol) and stirred it for 20 minutes. AcOH (0.15 mL, 2.7 mmol) was added to the reaction mixture and continued the stirring for 20 minutes. NaBH(OAc)3 (341 mg, 1.6 mmol) was added to the reaction mixture and continued the stirring for over night. The reaction mixture was quenched with NH4OH and extracted with EtOAc. Combined organics were concentrated under vacuum. Crude mixture was purified by silica gel chromatography afforded 16. XH NMR (400 MHz, CDC13): δ 7.75 (s, 1H), 7.38 - 7.18 (m, 5 H), 7.09 - 6.95 (m, 2 H), 6.91 (br. s., 1 H), 5.03 - 4.90 (m, 2 H), 4.71 - 4.60 (m, 1H), 4.20 - 3.90 (m, 4 H), 3.78 - 3.57 (m, 2 H), 3.30 (s, 3 H), 2.94 - 2.84 (m, 1 H), 2.16 (br. s., 1 H), 1.59 - 1.41 (m, 3 H), 1.00 - 0.85 (m, 2 H).; Molecular Formula: C27H28F2 404S; LCMS purity: 96.47%; Expected: 542.2; Observed: 543.0 (M+l).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/18350, 2014, A1 Location in patent: Page/Page column 44

12
[ 1226781-82-3 ]
[ 1226781-80-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With benzenesulfonic acid; In Isopropyl acetate; for 48h;Large scale;	Step (4) The distilled pale yellow wet product IV was dissolved in isopropyl acetate 35kg, and then added dropwise with acid solution at roomtemperature (benzenesulfonic acid 7.7kg and 14kg isopropyl acetate), stirring2d, suction filtration to give a pale gray solid, at 40 deg. C vacuum dried togive a pale gray solid after 10h 7.78kg, 95% yield, purity 98.2%.
80.5%	With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h;	3a (2.1 g, 7.3 mmol) was dissolved in dichloromethane (25 ml), and trifluoroacetic acid (5 ml) was added thereto at 0C, followed by reaction at 0C for 2 hours. The reaction solution was dried by rotary evaporation, and the reaction was quenched by addition of aqueous ammonia (2 ml), followed by purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 50:1) to obtain a white solid 3b (1.1 g, yield 80.5%). 1H NMR (400 MHz, MeOD): delta 7.85 (s, 1H), 4.01-3.94 (m, 4H), 3.36 (s, 3H).
80.5%	With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h;	3a(2.1g, 7.3mmol) dissolved in dichloromethane (25 ml) in, at 0 C added to trifluoroacetic acid (5 ml), the reaction of the 0 C under 2 hours. The reaction the fluid turns on lathe stem, plus ammonia water (2 ml) quenching the reaction, silica gel column chromatography for purification (dichloromethane/methanol (v/v)=50:1), to obtain white solid3b(1.1g, 80.5% yield).

With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h;

A solution of 2E (2.1 g, 7.3 mmol)Was dissolved in dichloromethane (25 mL)Cooled to 0 C, trifluoroacetic acid (5 mL) was added,Reaction for 2 hours.The reaction solution was concentrated, quenched by addition of aqueous ammonia (2 mL), and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50: 1) to give intermediate 2 as a white solid.

Reference： [1]Patent: CN105348286,2016,A .Location in patent: Paragraph 0052
[2]Patent: EP3159344,2017,A1 .Location in patent: Paragraph 0132; 0134
[3]Patent: TW2017/8222,2017,A .Location in patent: Page/Page column 54; 55
[4]Patent: TW2017/8223,2017,A .Location in patent: Page/Page column 43

13
[ 1226781-80-1 ]
C₁₁H₉F₂NO₄ [ No CAS ]
C₁₇H₁₈F₂N₄O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.9%	With lithium borohydride In N,N-dimethyl-formamide at -15℃; for 1h; Inert atmosphere; Large scale;	4 Preparation of Compound (8) General procedure: Under nitrogen, at room temperature to 50L reactor was added 1.8kg (7.0mol) of the compound (6) and 1.57kg (8.4mol) of the compound (7) in 20L of anhydrous DMA.After stirring for one hour cooled to -10 deg.] C, sodium borohydride was slowly added 114g (3.0mol), keeping the temperature below -10°C, TLC monitoring completion of the reaction, water was slowly added aqueous ammonia 2.0kg and 10kg, warmed to room temperature, filtered to give compound (8) crude, the crude product was recrystallized from methanol to give compound (8) masterwork 2.87kg (6.7mol), a yield of 95.7%. Purity by HPLC: 99.2%. According to the method of Example 1, the reaction of DMF anhydrous solvent substitution; the reaction temperature was -15°C ; reducing agent used in replace of lithium borohydride, the final compound (8) purified product yield was 94.9%.Purity by HPLC: 99.8%.

Reference： [1]Current Patent Assignee: HUANG YANGE; HUANG, YANGE - CN105399744, 2016, A Location in patent: Paragraph 0037; 0073; 0074

14
[ 1280210-79-8 ]
[ 1226781-80-1 ]

Reference： [1]Patent: EP3159344,2017,A1
[2]Patent: TW2017/8222,2017,A
[3]Patent: TW2017/8223,2017,A

15
6a-hydroxy-3a,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylic acid tert-butyl ester [ No CAS ]
[ 1226781-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / dichloromethane; methanol / 0 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 2.2: 1 h / 20 - 30 °C 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 °C

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - EP3159344, 2017, A1

16
[ 1226781-80-1 ]
tert-butyl ((2R,3S)-2-(2,3,5-trifluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.6%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-2-(2,3,5-trifluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate In toluene at 140℃; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20 - 30℃; for 3h; Inert atmosphere;	4.1 Step 1: tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(triflu oromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (4a) Intermediate 3 (3 g, 7.26 mmol) and 3b (1.76 g, 9.44 mmol) were added to 100 ml toluene, and the reaction was allowed to proceed in an open round-bottom flask in a 140°C oil bath until the solvent was evaporated to dryness. In a N2 atmosphere, the residue was cooled to room temperature and re-dissolved in 1,2-dichloroethane (30 ml), and tri(acetoxy)sodium borohydride (4.62 g, 21.8 mmol) and acetic acid (0.87 g, 14.5 mmol) were added sequentially, followed by reaction at room temperature for 3 hours. The reaction was quenched by addition of a saturated sodium bicarbonate solution (30 ml) to the reaction solution, which was allowed to be partitioned. The aqueous phase was extracted with ethyl acetate (30 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain a white oily liquid 4a (1.3 g, yield 30.6%).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - EP3159344, 2017, A1 Location in patent: Paragraph 0096; 0138; 0139

17
[ 1226781-80-1 ]
(2R,3S,5R,6S)-2-(2,5 difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: toluene / 140 °C 1.2: 3 h / 20 - 30 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 - 30 °C
	Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / toluene; 1,2-dichloro-ethane / 3 h / 20 - 140 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
	Multi-step reaction with 2 steps 1.1: chloroform / 3 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - EP3159344, 2017, A1
[2]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8222, 2017, A
[3]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

18
[ 1226781-80-1 ]
(2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: toluene / 140 °C 1.2: 3 h / 20 - 30 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 - 30 °C
	Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / toluene; 1,2-dichloro-ethane / 3 h / 20 - 140 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
	Multi-step reaction with 4 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - EP3159344, 2017, A1
[2]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8222, 2017, A
[3]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

19
[ 1226781-80-1 ]
tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl ((2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 60% 2: 5.9%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate In toluene at 140℃; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20 - 30℃; for 3h; Inert atmosphere;	3.3 Step 3: tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5( 2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (3c) Intermediate 1 (490 mg, 1.24 mmol) and 3b (254 mg, 1.36 mmol) were added to 10 ml toluene, and the reaction was allowed to proceed in an open round-bottom flask in a 140°C oil bath until the solvent was evaporated to dryness. In a N2 atmosphere, the residue was cooled to room temperature and re-dissolved in 1,2-dichloroethane (15 ml), and tri(acetoxy)sodium borohydride (1.05 mg, 4.96 mmol) and acetic acid (149 mg, 2.48 mmol) were added sequentially, followed by reaction at room temperature for 3 hours. The reaction was quenched by addition of a saturated sodium bicarbonate solution (20 ml) to the reaction solution, which was allowed to be partitioned. The aqueous phase was extracted with ethyl acetate (20 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain a white oily liquid 3c (455 mg, yield 60%) and a white solid 3d (45 mg, yield 5.9%).
1: 60% 2: 5.9%	With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane; toluene at 20 - 140℃; for 3h; Inert atmosphere;	3.3 tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (3c) Intermediate 1(490 mg, 1.24 mmol) and 3b (254 mg, 1.36mmol) in toluene is added to the 10 ml, 140 °C oil bath temperature in the round bottom flask open reaction to the solvent to dryness. in the nitrogen atmosphere, the remainder of the cooling to the room temperature, re-dissolved in 1,2- dichloroethane (15 ml), is added in sodium triacetoxyborohydride (1.05 mg, 4.96mmol) and acetic acid (149 mg, 2.48mmol), react at room temperature for 3 hours. To add saturated sodium bicarbonate solution in the reaction solution (20 ml) quenching the reaction, layered, ethyl acetate (20mL × 2) extracting the aqueous phase, combined with the organic phase, dried with anhydrous sodium sulfate, concentrated. Silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3:1) separation and purification, to obtain white oily liquid3c(455 mg, yield 60%) and the white solid3d (45 mg, 5.9% yield).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - EP3159344, 2017, A1 Location in patent: Paragraph 0096; 0132; 0135
[2]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8222, 2017, A Location in patent: Page/Page column 54; 55; 56

20
tert-butyl 6a-hydroxy-2,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate [ No CAS ]
[ 1226781-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / dichloromethane; methanol / 0 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 1 h 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 °C
	Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / dichloromethane; methanol / 0 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 2.2: 1 h 3.1: trifluoroacetic acid / dichloromethane / 2 h / 0 °C

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8222, 2017, A
[2]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8223, 2017, A

21
[ 1226781-80-1 ]
tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate In chloroform for 4h; Reflux; Dean-Stark; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 5 - 20℃; for 5h; Inert atmosphere;
30.6%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate In toluene at 140℃; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 3h; Inert atmosphere;	4.1 tert-butyl ((2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (4a) Intermediate 3 (3 g, 7.26 mmol) and 3b (1.76 g, 9.44 mmol) were added 20 to 100 mL of toluene, and the round bottom flask was exposed to a solvent at a 140 ° C oil bath temperature Evaporated to dry. In a nitrogen atmosphere, the residue was cooled to room temperature and the residue was redissolved in 1,2_ Dichloroethane (30 mL), followed by the addition of tris (acetoxy) borohydride (4.62 g, 21.8 mmol) and acetic acid (0.87 g, 14.5 mmol) were added and reacted at room temperature for 3 hours. to The reaction solution by adding saturated sodium bicarbonate solution (30 mL) quenching reaction, stratification, with B 25 acid ethyl ester (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. Sand column chromatography (petroleum ether / ethyl acetate (ν / ν) = 3: 1) was isolated and purified to give A white oily liquid 4a (1.3 g, yield 30.6%).

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]
[2]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8222, 2017, A Location in patent: Page/Page column 58; 59

22
[ 1226781-80-1 ]
tert-butyl ((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
(2R,3S,5R,6S)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: toluene / 140 °C 1.2: 3 h / 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
	Multi-step reaction with 2 steps 1.1: chloroform / 4 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8222, 2017, A
[2]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

23
[ 1226781-80-1 ]
tert-butyl ((2R,3R,4R)-2-(2,5-difluorophenyl)-4-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl ((2R,3R,4R,5S)-2-(2,5-difluorophenyl)-4-fluoro-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42.6%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3R,4R)-2-(2,5-difluorophenyl)-4-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate With benzenesulfonic acid In N,N-dimethyl acetamide at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl acetamide at 20℃; for 24h;	1 Step 2:(2R, 3R, 4R, 5S) -2- (2,5-difluorophenyl) -4-fluoro-5- (2- (methylsulfonyl) pyrrolo [3,4-c] Azo-5 (2H, 4H, 6H) -yl) tetrahydro-2H-pyran-3-yl) carbamate (1c) Under nitrogen protection,A mixture of 1b (345 mg, 1 mmol) and intermediate 2 (206 mg, 1.1 mmol)Was dissolved in N, N-dimethylacetamide (6 mL)A mixture of hydrobenzene sulfonic acid (222 mg, 1.2 mmol)The mixture was stirred at room temperature for 1 hour,Sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added and the reaction was stirred at room temperature for 24 hours.Water (60 mL) and aqueous ammonia (6 mL) were added to the reaction system to precipitate a solid which was isolated by filtration and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2: 1) , Yield 1c (220 mg, yield 42.6%).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - TW2017/8223, 2017, A Location in patent: Page/Page column 44; 45

24
[ 1226781-80-1 ]
C₁₄H₁₄F₂O₄ [ No CAS ]
C₂₀H₂₃F₂N₃O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.1%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C₁₄H₁₄F₂O₄ In N,N-dimethyl acetamide at 20℃; for 1h; Inert atmosphere; Large scale; Stage #2: With sodium tetrahydroborate In N,N-dimethyl acetamide; water at -10℃; Large scale;	Preparation of compound (5) Under nitrogen protection,Add to the 50L reactor at room temperature2.56 kg (9.0 mol) Compound (3)And 1.85 kg (9.9 mol) of compound (4) in 20 L of anhydrous DMA.After stirring for one hour, the temperature was lowered to -10 ° C,Slowly add sodium borohydride 114 g (3.0 mol)And 0.2 L of water, keeping the temperature below -10 ° C, After TLC monitoring reaction is complete,Slowly add ammonia 2.0kg and water 10kg,Warmed to room temperature and filtered to give crude compound (5)The crude product was recrystallized from methanol to give 3.73 kg (8.2 mol) of product (5)Yield 91.1%. Purity by HPLC: 98.2%.

Reference： [1]Current Patent Assignee: SUZHOU XINEN MEDICINE TECH - CN107235983, 2017, A Location in patent: Paragraph 0012; 0013

25
[ 1226781-80-1 ]
C₁₇H₁₈F₅NO₄ [ No CAS ]
tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C₁₇H₁₈F₅NO₄ In chloroform for 5h; Dean-Stark; Reflux; Stage #2: With acetic acid; sodium triacetoxyborodeuteride In chloroform; 1,2-dichloro-ethane at 20 - 35℃; for 3h;	2.1 First Step: tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol- 5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate (2B) Compound 2A and Compound 1C were synthesized by referring to WO2015192701 method. Compound 1A (395mg, 1.00mmol) and Compound 1C (281mg, 1.50mmol) were added to a reaction flask containing chloroform (10mL),Heat and stir to reflux, Dean-Starks water separation reaction for 5 hours. The heating was stopped at the end of the reaction, and after the reaction solution stopped boiling, 1,2-dichloroethane (5 mL) was added to dilute the reaction solution. Under nitrogen atmosphere, the reaction system was stirred and cooled to 515, and sodium deuterated triacetoxyborohydride (333mg, 1.50mmol) and acetic acid (0.026mL, 1.5mmol) were added in sequence. After the addition, the temperature was raised to 20 ~35°C, react for 3 hours. After the reaction was completed, water (5 mL) was slowly added, stirred for 5 minutes, left to stand for separation, and the aqueous layer was extracted with dichloromethane (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography of the residue (petroleum ether/ethyl acetate (v/v)=4:1) to obtain N-[(2R, 3S, 5R, 6S)-5-deutero-2-(2,5-di Fluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-C]pyrazopyrimidin-5-yl)-6-(trifluoromethyl)tetrahydropyridinepyran-3-yl] tert-butyl carbamate (2B), white solid (400 mg, yield: 71%).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111253403, 2020, A Location in patent: Paragraph 0152-0158

26
[ 1226781-80-1 ]
C₁₇H₁₇F₆NO₄ [ No CAS ]
tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydropyran-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.3%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; C₁₇H₁₇F₆NO₄ In chloroform for 5h; Reflux; Dean-Stark; Stage #2: With acetic acid; sodium triacetoxyborodeuteride In chloroform; 1,2-dichloro-ethane at 20 - 35℃; for 3h; Inert atmosphere;	3.1 First step: tert-butyl N-[(2R,3S,5R,6S)-5-deuterio-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl) -2-(2,4,5-trifluorophenyl)tetrahydropyran-3-yl]carbamate (3B) Compound 2A and Compound 1C were synthesized by referring to WO2015192701 method. Compound 3A (413mg, 1.00mmol) and Compound 1C (281mg, 1.50mmol) were added to a reaction flask containing chloroform (10mL), Heat and stir to reflux, Dean-Starks water separation reaction for 5 hours. The heating was stopped at the end of the reaction, and after the reaction solution stopped boiling, 1,2-dichloroethane (5 mL) was added to dilute the reaction solution. Under nitrogen atmosphere, the reaction system was stirred and cooled to 515, and sodium deuterated triacetoxyborohydride (333mg, 1.50mmol) and acetic acid (0.026mL, 1.5mmol) were added in sequence. After the addition, the temperature was raised to 20 ~35°C, react for 3 hours. After the reaction was completed, water (5 mL) was slowly added, stirred for 5 minutes, left to stand for separation, and the aqueous layer was extracted with dichloromethane (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography of the residue (petroleum ether/ethyl acetate (v/v)=4:1) to obtain N-[(2R, 3S, 5R, 6S)-5-deutero-5-(2-methylsulfonate) Acyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro Pyran-3-yl] tert-butyl carbamate (3B),White solid (300 mg, yield: 51.3%).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111253403, 2020, A Location in patent: Paragraph 0165-0171

27
[ 1226781-80-1 ]
tert-butyl N-[(2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111253403, 2020, A

28
[ 1226781-80-1 ]
tert-butyl N-[(2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(1-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111253403, 2020, A

29
[ 1226781-80-1 ]
tert-butyl N-[(2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111253403, 2020, A

30
[ 1226781-80-1 ]
(2R,3S)-4,4,5,6-tetradeuterio-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: deuteromethanol; water-d2 / 2 h / 75 - 80 °C / Microwave irradiation 2.1: chloroform-d1 / 5 h / Dean-Stark; Reflux 2.2: 3 h / 20 - 35 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 6.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111253403, 2020, A

31
[ 1226781-80-1 ]
5-deuterio-2-(trideuteriomethylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In deuteromethanol; water-d2 at 75 - 80℃; for 2h; Microwave irradiation;	1.2 Second Step: 5-deuterio-2-(trideuteriomethylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole Compound 1C was synthesized with reference to the method of WO2015192701. Compound 1C (1.4 g, 7.49 mmol) was dissolved in a mixed solvent of heavy water (12 mL) and deuterated methanol-d1 (6 mL), and reacted in a microwave at 80° C. for 1 hour. After the reaction was stopped, it was concentrated, and the residue was added with a mixed solvent of heavy water (14 mL) and deuterated methanol-d1 (6 mL). The reaction was carried out at 75° C for 1 hour in a microwave, and the reaction was monitored by LC-MS. After the reaction, the reaction solution was concentrated to obtain crude 5-deutero-2-(deuterated methanesulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (1D), used directly in the next reaction.

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111253403, 2020, A Location in patent: Paragraph 0116-0117; 0123-0127

32
[ 1226781-80-1 ]
C₁₂H₁₀F₅NO₂ [ No CAS ]
tert-butyl N-((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium tris(acetoxy)borohydride; acetic acid In chloroform; 1,2-dichloro-ethane at 20 - 90℃; for 3h; Inert atmosphere;	1.1 Combine compound 1a (340mg, 1.7mmol) and compound 1b(680mg, 1.7mmol) was added to 20mL chloroform,React at 90°C for 1 hour until the solvent evaporates to dryness.The remainder was redissolved in 1,2-dichloroethane (15mL),In a nitrogen atmosphere,Add sodium tris(acetoxy)borohydride (1.1g, 5.2mmol) and acetic acid (150mg, 2.5mmol) in sequence,React at room temperature for 3 hours.Add saturated sodium bicarbonate solution (20 mL) to the reaction solution to quench the reaction,Stratification,Extract the aqueous phase with ethyl acetate (20mL×2), combine the organic phases,Dry with anhydrous sodium sulfate,concentrate.Separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-1/1),To obtain compound 1c,White solid (500mg, yield 50%).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111269218, 2020, A Location in patent: Paragraph 0158-0168

33
[ 1226781-80-1 ]
C₁₂H₉F₆NO₂ [ No CAS ]
C₂₆H₂₈F₆N₂O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium tris(acetoxy)borohydride In chloroform; 1,2-dichloro-ethane at 20 - 90℃; for 3h; Inert atmosphere;	2.1 Compound 1a (320 mg, 1.6 mmol) and compound 2b (670 mg, 1.6 mmol) were added to 20 mL of chloroform, and reacted at 90° C. for 1 hour until the solvent was evaporated. The residue was redissolved in 1,2-dichloroethane (15mL), and in a nitrogen atmosphere, sodium tris(acetoxy)borohydride (1.0g, 4.9mmol) and acetic acid (150mg, 2.5mmol) were added sequentially, React at room temperature for 3 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL) to the reaction solution, the layers were separated, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-1/1) gave compound 2c as a white solid (500 mg, yield 52%).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN111269218, 2020, A Location in patent: Paragraph 0175-0185

34
[ 1226781-80-1 ]
tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-4-fluoro-5-oxotetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl ((2R,3R,4R,5S)-2-(2,5-difluorophenyl)-4-fluoro-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-4-fluoro-5-oxotetrahydro-2H-pyran-3-yl)carbamate With benzenesulfonic acid In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

35
[ 1226781-80-1 ]
(2R,3S,5R,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

36
[ 1226781-80-1 ]
(2R,3S,5S,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 5 °C / Inert atmosphere 4.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

37
[ 1226781-80-1 ]
tert-butyl ((2R,3S,6R)-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: chloroform / 5 h / Reflux; Dean-Stark 2: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

38
[ 1226781-80-1 ]
tert-butyl ((2R,3S,5R,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

39
[ 1226781-80-1 ]
tert-butyl ((2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 20 °C / Inert atmosphere

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

40
[ 1226781-80-1 ]
tert-butyl ((2R,3S,6S)-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: chloroform / 5 h / Reflux; Dean-Stark 2: samarium diiodide / tetrahydrofuran / 7 h / 20 °C / Inert atmosphere

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

41
[ 1226781-80-1 ]
tert-butyl ((2R,3S,5S,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: chloroform / 5 h / Reflux; Dean-Stark 2.1: samarium diiodide / tetrahydrofuran / 7 h / 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 3.2: 2 h / -10 - 5 °C / Inert atmosphere

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

42
[ 1226781-80-1 ]
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine 2,2,2-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: chloroform / 3 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.1: ethyl acetate / 3 h / 20 °C

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

43
[ 1226781-80-1 ]
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2,6 dihydropyrrolo[3,4-c]pyrazol-5(4H)yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: chloroform / 3 h / Reflux; Dean-Stark 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 5 h / 20 °C

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

44
[ 1226781-80-1 ]
tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate In chloroform for 3h; Reflux; Dean-Stark; Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 5 - 20℃; for 5h; Inert atmosphere;

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

45
[ 1226781-80-1 ]
tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
tert-butyl N-[(2R,3S,6R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate [ No CAS ]
tert-butyl N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 85% 2: 6%	In chloroform for 5h; Reflux; Dean-Stark;

Reference： [1]Zhang, Chen; Ye, Fei; Wang, Jianmin; He, Ping; Lei, Ming; Huang, Longbin; Huang, Anbang; Tang, Pingming; Lin, Hongjun; Liao, Yuting; Liang, Yong; Ni, Jia; Yan, Pangke [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7108 - 7126]

46
[ 36082-50-5 ]
[ 1226781-80-1 ]
C₁₀H₉BrClN₅O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In ethanol at 0℃; for 2h; Inert atmosphere;	1 Synthesis of compound 7: Take a 100ml three-necked flask, add 1.23g 5-bromo-2,4-dichloropyrimidine, add 5ml ethanol to dissolve it,Put it in a refrigerator under the protection of nitrogen, add 0.54g of triethylamine at 0,Take 1.5g of 2,4,5,6-tetrahydro-2-(methylsulfonyl)pyrrolo[3,4-C]pyrazole, add 20ml of ethanol to dissolve it,Add dropwise to the above reaction solution at 0°C, and solids will precipitate in the reaction solution. After the dropwise addition, continue the low-temperature reaction for 2h.TLC detected that the reaction of the raw materials was complete, the reaction was stopped, and 1.74 g of off-white solid was obtained by suction filtration with a yield of 85%.

Reference： [1]Current Patent Assignee: NANJING HUAWE MEDICAL TECH DEVELOPMENT - CN108017639, 2020, B Location in patent: Paragraph 0108-0111

47
[ 1226781-80-1 ]
C₁₄H₁₂ClN₅O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / ethanol / 2 h / 0 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl acetamide; water / 1 h / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NANJING HUAWE MEDICAL TECH DEVELOPMENT - CN108017639, 2020, B

48
[ 1226781-80-1 ]
C₂₁H₁₅F₄N₅O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / ethanol / 2 h / 0 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl acetamide; water / 1 h / 80 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / water; 1,2-dimethoxyethane / 1 h / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NANJING HUAWE MEDICAL TECH DEVELOPMENT - CN108017639, 2020, B

49
[ 1226781-80-1 ]
C₁₇H₁₂ClF₄N₅O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / ethanol / 2 h / 0 °C / Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / N,N-dimethyl acetamide; water / 2 h / Inert atmosphere

Reference： [1]Current Patent Assignee: NANJING HUAWE MEDICAL TECH DEVELOPMENT - CN108017639, 2020, B

50
[ 1226781-80-1 ]
tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-6-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate [ No CAS ]
((2R,3S,5R,6R)-2-(2,5-difluorophenyl)-6-fluoro-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole-5(4H)-yl)tetrahydro-2H-pyran-3-yl)tert-butyl carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: 2-methylsulfonic acid-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole; tert-butyl ((2R,3R)-2-(2,5-difluorophenyl)-6-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate With benzenesulfonic acid In N,N-dimethyl acetamide at 20℃; for 1h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In N,N-dimethyl acetamide at 20℃; for 24h; Inert atmosphere;	1.2 tert-butyl((2R,3S,5R,6R)-2-(2,5-difluorophenyl)-6-fluoro-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol -5(4H)-yl)tetrahydro-2H-pyran-3-yl)carbamate Under the protection of nitrogen, the tert-butyl((2R,3R)-2-(2,5-difluorophenyl)-6-fluoro-5-carbonyltetrahydro-2H-pyran-3-yl)carbamic acid Ester 1b (345mg, 1mmol) and 2-methanesulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (206mg, 1.1mmol, synthesized with reference to WO2017031918A1), dissolved in N,N-dimethylacetamide (6mL), add benzenesulfonic acid hydrate (222mg, 1.2mmol), stir at room temperature for 1 hour, add sodium triacetoxyborohydride (276mg, 1.3mmol), stir at room temperature for reaction 24 Hour. Water (60mL) and ammonia (6mL) were added to the reaction system, the solid was precipitated, and the crude product was filtered out. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain ( (2R,3S,5R,6R)-2-(2,5-difluorophenyl)-6-fluoro-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazole -5(4H)-yl)tetrahydro-2H-pyran-3-yl)tert-butyl carbamate 1c (103 mg, yield 20.0%).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN113387989, 2021, A Location in patent: Paragraph 0054; 0064-0069

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	1226781-80-1	MDL No. :	MFCD20687608
Formula :	C₆H₉N₃O₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BUJWKBIFOTURDW-UHFFFAOYSA-N
M.W :	187.22	Pubchem ID :	57518503
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.99
TPSA :	72.37 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.24 cm/s

Log Po/w (iLOGP) :	0.67
Log Po/w (XLOGP3) :	-1.12
Log Po/w (WLOGP) :	-0.31
Log Po/w (MLOGP) :	-0.13
Log Po/w (SILICOS-IT) :	-0.5
Consensus Log Po/w :	-0.28

[ CAS No. 1226781-80-1 ] {[proInfo.proName]}

Quality Control of [ 1226781-80-1 ]

Related Doc. of [ 1226781-80-1 ]

Product Details of [ 1226781-80-1 ]

Calculated chemistry of [ 1226781-80-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1226781-80-1 ]

Application In Synthesis of [ 1226781-80-1 ]

[ 1226781-80-1 ] Synthesis Path-Downstream 1~50

Related Functional Groups of
[ 1226781-80-1 ]

Sulfamides

Related Parent Nucleus of
[ 1226781-80-1 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Log S (ESOL) :	-0.54
Solubility :	54.3 mg/ml ; 0.29 mol/l
Class :	Very soluble
Log S (Ali) :	0.09
Solubility :	231.0 mg/ml ; 1.23 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-1.33
Solubility :	8.82 mg/ml ; 0.0471 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.48

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 1226781-80-1 ] {[proInfo.proName]}

Quality Control of [ 1226781-80-1 ]

Related Doc. of [ 1226781-80-1 ]

Product Details of [ 1226781-80-1 ]

Calculated chemistry of [ 1226781-80-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1226781-80-1 ]

Application In Synthesis of [ 1226781-80-1 ]

[ 1226781-80-1 ] Synthesis Path-Downstream 1~50

Related Functional Groups of [ 1226781-80-1 ]

Sulfamides

Related Parent Nucleus of [ 1226781-80-1 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1226781-80-1 ]

Related Parent Nucleus of
[ 1226781-80-1 ]