Name: 1009071-34-4|tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate|97%
Brand: Ambeed
SKU: A188857
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1
1-[3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-4-({2-[4-(trifluoromethyl)phenyl]cyclopropyl}-carbonyl)piperazine [ No CAS ]
[ 1009071-34-4 ]
1-[3-(3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl]sulfonyl}-4-({2-[4-(trifluoromethy)phenyl]cyclopropyl}carbonyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-[3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-4-({2-[4-(trifluoromethyl)phenyl]cyclopropyl}-carbonyl)piperazine; tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate With sodium carbonate In 1-methyl-pyrrolidin-2-one; water; isopropyl alcohol for 0.333333h; Stage #2: With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1-methyl-pyrrolidin-2-one; water at 100℃; for 3h;	147 To a solution of l-[3-bromo-5- (trifluoromethyl)phenyl]sulfonyl} -4-( {2-[4-(trifluoromethyl)phenyl]cyclopropyl} - carbonyl)piperazine (80mg, 0.14 mmol, prepared by the method described in Example 5 substituting l-(4-trifluoromethylphenylacetyl)piperazine for 1-benzoylpiperazine and 3-bromo-5- trifluoromethylphenylsulfonyl chloride for 3,5-bis(trifluoromethyl)phenylsulfonyl chloride) in N- methyl-2-pyrrolidone (2 mL) are sequentially added water (2 mL), isopropyl alcohol (ImL), 1- (erf-butyloxycarbonyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxoboralan-2-yl)-pyrazole (100 mg, 0.32 mmol) and sodium carbonate (21 mg, 0.20 mmol). The reaction mixture is degassed with nitrogen for 20 min after which tetrakis(triphenylphosphine)palladium is added. The reaction mixture is heated to 1000C for 3h and then cooled to ambient temperature, concentrated and purified using mass triggered preparative reverse phase ηPLC system (Method C). The reaction is purified using the preparative ηPLC. LCMS (Method B) m/z (MH)+ = 587 (at) 2.19 min.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/24284, 2008, A2 Location in patent: Page/Page column 69

2
[ 936250-20-3 ]
[ 24424-99-5 ]
[ 1009071-34-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	With triethylamine; In 1,4-dioxane; at 20℃; for 48h;	C. tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyI-l,3,2-dioxaboroIan-2-yl)- lH-pyrazole-1-carboxylate. 3-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (0.2 g, 0.96 mmol), di-t-butyldicarbonate (0.4 g, 1.8 mmol) and triethylamine (0.18 g, 1.79 mmol) were placed in 1 ,4-dioxane (5 mL) and stirred, under nitrogen, at rt for two days. The solvent was removed and the desired product isolated using silica gel chromatography (25 % ethyl acetate in hexanes) to afford the title compound (0.175 g, 59 % yield). MS (ESI) m/z 309.4 [M+l]+.

Reference： [1]Patent: WO2008/51493,2008,A2 .Location in patent: Page/Page column 184

3
[ 1009071-34-4 ]
[ 1021918-82-0 ]
[ 1021917-07-6 ]

Yield	Reaction Conditions	Operation in experiment
22%	With potassium phosphate In water; N,N-dimethyl-formamide at 100℃;	5.1.141.D C. tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyI-l,3,2-dioxaboroIan-2-yl)- lH-pyrazole-1-carboxylate. 3-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (0.2 g, 0.96 mmol), di-t-butyldicarbonate (0.4 g, 1.8 mmol) and triethylamine (0.18 g, 1.79 mmol) were placed in 1 ,4-dioxane (5 mL) and stirred, under nitrogen, at rt for two days. The solvent was removed and the desired product isolated using silica gel chromatography (25 % ethyl acetate in hexanes) to afford the title compound (0.175 g, 59 % yield). MS (ESI) m/z 309.4 [M+l]+. [00614] D. 6-(3-Methyl-lH-pyrazol-4-yl)-l-((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-b]pyrazin-2(3H)-one. 6-Bromo- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 101. B) (0.16 g, 0.51 mmol), tert-butyl 3-methyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole- 1 -carboxylate (0.175 g, 0.56 mmol), dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.04 g, 0.05 mmol) and potassium phosphate (0.43 g, 2.05 mmol) were combined in DMF (3 mL) and water (0.2 mL), the mixture purged with nitrogen and heated in a sealed tube at 100 °C overnight. The solvent was removed and the crude purified on silica gel chromatography (100 % ethyl acetate) to afford the title compound as a white solid (0.036 g, 22% yield). 1H NMR (400 MHz, DMSO-J6) δ 12.77 (s, IH), 1 1.87 (s, IH), 8.17 (s,lH), 7.92 (s,lH), 3.82 (d, J= 12, 2H),3.72 (d, J=7.2, 2H), 3.23 (t, J= 10, 2H), 2.54 (s, 3H), 2.13 (m, IH), 1.54 (d, J=72, 2H), 1.26(m, 2H); MS (ESI) m/z 315.1 [M+l]+; mp 222-224 °C.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2008/51493, 2008, A2 Location in patent: Page/Page column 184

4
[ 1021919-24-3 ]
[ 73183-34-3 ]
[ 1009071-34-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate In dimethyl sulfoxide at 20 - 80℃; for 5.08333h;	35.B Step B: N-Boc-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole. To the product of Step A (3.30 g 12.6 mmol) was added bis(pinacolato)diboron (3.53 g, 13.9 mmol), potassium acetate (3.72 g, 37.9 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.457 g, 0.632 mmol) and DMSO (15 mL). The reaction vessel was purged with N2 for 5 min at rt prior to heating to 80° C. for about 5 hours. The reaction was cooled to rt, diluted with EtOAc and filtered through Celite. The solution was then washed with brine 5 times and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-21% EtOAc in hexane affording the title compound. HPLC/MS: 309.3 (M+1); Rt=3.48 min.
	With potassium acetate In 1,2-dimethoxyethane at 90℃; Inert atmosphere;	108.3 A mixture of tert-butyl 4-bromo-3-methyl-lH-pyrazole- 1-carboxylate (9.2 g, 35.2 mmol), 4, 4, 4' , 4' , 5, 5, 5' , 5' - octamethyl-2, 2' -bi-1, 3, 2-dioxaborolane (9.39 g, 37.0 mmol), potassium acetate (10.4 g, 106 mmol) and 1,2-dimethoxyethane (100 itiL) was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (2.88 g, 3.52 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 900C overnight. After cooled to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was suspended in 1:1 EtOAc/hexane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to afford the crude title compound (7.0 g, 65%) as a colorless oil:1H NMR (300 MHz, CDCl3) δ 1.32 (12H, s) , 1.62 (9H, s) , 2.42 (3H, s), 8.26 (IH, s) . This material included some impurities and was used in next reaction without further purification

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2008/269279, 2008, A1 Location in patent: Page/Page column 39
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 203-204

5
[ 1009071-34-4 ]
[ 1072708-49-6 ]
[ 1072709-38-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1-methyl-pyrrolidin-2-one; water; iso-butanol at 100℃; for 4h;	3 6-[2-chloro-4-(3-methyl-1H-pyrazol-4-yl)phenyl]-5-(4-chlorophenyl)-2-(2,2-dimethylpropanoyl)furo[2,3-b]pyridine-3-carboxamide. To the product of Reference Example 8 (4.34 g, 7.95 mmol) was added the product of Reference Example 35 (4.41 g, 14.30 mmol), tetrakis(triphenylphosphine)palladium (0) (413 mg, 0.358 mmol), NMP (40 mL), water (3.2 mL) 2-butanol (30 mL) and aq Na2CO3 (2 M, 6.75 mL). The reaction vessel was purged with N2 for 4 min at rt prior to heating to 100° C. for about 4 hours. The reaction was cooled and then concentrated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. Brine has been used instead of NaHCO3. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane. Further purification was achieved by suspension of the product in 2-propanol (heated to 80° C.), followed by filtration of the cooled mixture to afford the title compound.HPLC/MS: 547.0 (M+1), 549.0 (M+3); Rt=3.73 min. 1H NMR (500 MHz, DMSO-d6): δ 12.73 (bd, J=33.27 Hz, 1H); 8.36 (s, 1H); 8.21 (s, 1H); 8.11 (bs, 0.4H); 7.92 (s, 1H); 7.81 (bs, 0.6H); 7.50-7.42 (m, 3H); 7.36 (d, J=8.38 Hz, 2H); 7.26 (d, J=8.37 Hz, 2H); 2.38 (s, 3H); 1.38 (s, 9H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2008/269279, 2008, A1 Location in patent: Page/Page column 41

6
[ 1009071-34-4 ]
[ 1244027-58-4 ]
[ 1244027-03-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one With caesium carbonate In 1,2-dimethoxyethane; water for 2h; Inert atmosphere; Reflux; Stage #2: With water; sodium hydroxide In 1,2-dimethoxyethane for 3h;	108.4 A mixture of 6-bromo-2,2-dimethyl-2, 3- dihydrothieno [3, 2-d]pyrimidin-4 (IH) -one (522 mg, 2 mmol) , tert-butyl 3-methyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) -lH-pyrazole-1-carboxylate (1.85 g, 6.00 mmol), cesium carbonate (3.26 g, 10.0 mmol), 1,2- dimethoxyethane (20 itiL) and water (5 mL) was purged with argon. Then, 1, lf -bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (163 mg, 0.20 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 2 h. Then, sodium carbonate (636 mg, 6.00 mmol) was added. After 30 min, 8 M NaOH (1.5 mL, 12 mmol) was added. After 3 h, the mixture was cooled to room temperature, and poured into water (100 mL) and EtOAc (200 mL) . The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) , then triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (312 mg, 60%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.40 (6H, s) , 2.37 (3H, br s) , 6.53 (IH, s), 6.96 (IH, br s) , 7.34 (IH, br s) , 7.70 (0.6H, br s), 8.06 (0.4H, br s) , 12.85 (IH, m) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 204-205

7
[ 1009071-34-4 ]
[ 1244027-69-7 ]
[ 1244026-99-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-1,2-dimethyl-2-(2,2,2-trifluoroethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere; Stage #2: With water; sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 1h;	104.2 A flask was charged with 6-bromo-l, 2-dimethyl-2-(2, 2, 2-trifluoroethyl) -2, 3-dihydrothieno [3, 2-d]pyrimidin- 4 (IH) -one (420 mg, 1.22 mmol) , tert-butyl 3-methyl-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -lH-pyrazole-1- carboxylate (1.13 g, 3.7 mmol), sodium carbonate (366 mg, 6.1 mmol), 1, 2-dimethoxyethane (6 mL) and water (3 ml). The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (98 mg, 0.12 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 1000C for 2 h, 8 M aqueous NaOH (1 mL) was added. After stirring at 1000C for 1 h, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc) , then crystallized from MeOH/EtOAc/heptane) to give the title compound (212 mg, 50%) as a pale yellow solid:1H NMR (300 MHz, DMSO-d6) δ 1.59 (3H, s) , 2.40 (3H, br s), 2.55-2.79 (IH, m) , 2.84-3.06 (IH, m) , 2.93 (3H, s) , 6.88 (IH, s), 7.71 (IH, s), 7.79 (0.6H, br s) , 8.12 (0.4H, br s) , 12.87 (IH, br s) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 199

8
[ 1009071-34-4 ]
[ 1244027-80-2 ]
[ 1244027-04-0 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6'-bromo-1'-ethyl-1'H-spiro[cyclopentane-1,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-one With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere; Stage #2: With water; sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 1h;	109.4 A flask was charged with 6' -bromo-1' -ethyl-1'H- spiro[cyclopentane-l,2f -thieno [3, 2-d]pyrimidin] -4' (3'H) -one (158 mg, 0.50 mmol), tert-butyl 3-methyl-4- (4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) -lH-pyrazole-1- carboxylate (463 mg, 1.5 mmol), sodium carbonate (150 mg, 2.5 mmol), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) . The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (41 mg, 0.050 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 1000C for 1 h, 8 M aqueous NaOH (0.5 mL) was added. After stirring at 1000C for 1 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc) , then crystallized from MeOH/EtOAc/hexane to give the title compound (86 mg, 54%) as a yellow solid:1H NMR (300 MHz, DMSO-d6) δ 1.13 (3H, t, J = 7.0 Hz), 1.54- 1.79 (4H, m) , 1.79-2.03 (4H, m) , 2.40 (3H, br s) , 3.30 (2H, q, J = 7.0 Hz), 6.85 (IH, s) , 7.60 (IH, s) , 7.79 (0.6H, br s), 8.13 (0.4H, br s) , 12.85 (IH, br s) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 207-208

9
[ 1009071-34-4 ]
C₁₁H₁₂BrF₃N₂OS [ No CAS ]
[ 1244027-05-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1,2-dimethoxyethane; water at 110℃; for 6h; Inert atmosphere;	110 A mixture of 5-bromo-3- (ethylamino) thiophene-2- carboxamide (250 mg, 1.0 mmol) , 4, 4, 4-trifluorobutan-2-one (1.0 mL), CSA (23 mg, 0.10 mmol), MgSO4 (192 mg, 2.0 mmol) and DMA (0.5 mL) was microwave-irradiated at 1500C for 1 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a brown crystalline solid. A flask was charged with this solid, 1, 2-dimethoxyethane (3 mL) , tert- butyl 3-methyl-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) -lH-pyrazole-1-carboxylate (555 mg, 1.8 mmol), sodium carbonate (180 mg, 3.0 mmol) and water (1.5 mL) . The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (49 mg, 0.060 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 1000C for 6 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc) , then crystallized from MeOH/EtOAc/heptane) to give the title compound (37 mg, 10%) as a pale brown solid:1H NMR (300 MHz, DMSO-d6) δ 1.16 (3H, t, J = 7.0 Hz), 1.69 (3H, s), 2.40 (3H, br s) , 2.53-2.71 (IH, m) , 2.74-3.00 (IH, m) , 3.32-3.50 (2H, m) , 6.83 (IH, s) , 7.66 (IH, s) , 7.80 (0.6H, br s), 8.14 (0.4H, br s) , 12.85 (IH, br s) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 208-209

10
[ 1009071-34-4 ]
C₁₀H₁₁BrF₂N₂OS [ No CAS ]
[ 1244027-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; C₁₀H₁₁BrF₂N₂OS With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere; Stage #2: With water; sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 1h;	115.3 A mixture of 5-bromo-3- [ (2, 2- difluoroethyl) amino] thiophene-2-carboxamide (130 mg, 0.456 mmol), 2, 2-dimethoxypropane (1 mL) , CSA (11 mg, 0.046 mmol), MgSO4 (110 mg, 0.912 itimol) and DMA (1 mL) was stirred at 90°C for 2 h. Then, saturated aqueous NaHCC>;3 and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, a colorless crystalline solid was obtained. A flask was charged with the solid, 1,2- dimethoxyethane (3.0 mL) , tert-butyl 3-methyl-4- (4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) -lH-pyrazole-1- carboxylate (422 mg, 1.37 mmol) , sodium carbonate (137 mg, 2.28 mmol) and water (1.5 mL) . The flask was purged with argon. Then, 1, 1' -bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (37 mg, 0.046 mmol) was added to the mixture. The flask was purged with argon. After stirring at 1000C for 2 h, 8 M aqueous NaOH (0.5 mL) was added. After stirring at 1000C for 1 h, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc), then crystallized from EtOAc/hexane to give the title compound (78 mg, 52%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) 6 1.44 (6H, s) , 2.39 (3H, br s) , 3.78 (2H, td, J = 15.1, 3.8 Hz), 5.95-6.44 (IH, m) , 6.88 (IH, s), 7.58 (IH, s), 7.78 (0.6H, br s) , 8.11 (0.4H, br s), 12.88 (IH, br s)

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 217-218

11
[ 1009071-34-4 ]
C₁₅H₁₄BrN₃O₃S [ No CAS ]
[ 1244027-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; C₁₅H₁₄BrN₃O₃S With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 2h;	119.3 A mixture of 5-bromo-3- [ (3- nitrobenzyl) amino] thiophene-2-carboxamide (260 mg, 0.730 mmol), 2,2-dimethoxypropane (2.0 mL) , CSA (17 mg, 0.073 mmol), MgSO4 (200 mg) and DMA (2 mL) was microwave-irradiated at 1200C for 1 h. Then, saturated aqueous sodium hydrogen carbonate was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, a yellow crystalline solid was obtained. A flask was charged with this solid, 1, 2-dimethoxyethane (4 mL) , tert-butyl 3- methyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -IH- pyrazole-1-carboxylate (675 mg, 2.19 mmol), sodium carbonate (219 mg, 3.65 mmol) and water (2 mL) . The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (60 mg, 0.073 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 1000C for 2 h, 8 M aqueous NaOH (1.0 mL) was added. After stirring at 1000C for 1 h, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (124 mg, 43%) as a yellow solid:1H NMR (300 MHz, DMSO-d6) δ 1.45 (6H, s) , 2.30 (3H, br s) , 4.74 (2H, s), 6.70 (IH, s) , 7.54-7.77 (2.6H, m) , 7.81 (IH, d, J = 7.9 Hz), 8.01 (0.4H, br s) , 8.13 (IH, d, J = 7.9 Hz),8.20 (IH, s), 12.85 (IH, br s) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 229-230

12
[ 1009071-34-4 ]
C₁₀H₁₃BrN₂O₂S [ No CAS ]
[ 1244027-18-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; C₁₀H₁₃BrN₂O₂S With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere; Stage #2: With water; sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 1.5h;	123.2 A mixture of 5-bromo-3- [ (2- hydroxyethyl) amino] thiophene-2-carboxamide (100 mg, 0.377 mmol), acetone (1.0 mL) , PTSA (6.5 mg, 0.038 mmol) and acetic acid (1.0 mL) was stirred at 700C for 1 h. The mixture was poured into saturated aqueous NaHCC>;3. The organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, a pale brown amorphous solid was obtained. A flask was charged with the amorphous, 1,2-dimethoxyethane (3.0 mL) , tert-butyl 3-methyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) -lH-pyrazole-1-carboxylate (349 mg, 1.13 mmol), sodium carbonate (113 mg, 1.89 mmol) and water (1.5 mL) . The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (31 mg, 0.038 mmol) was added to the mixture. The flask was purged with argon. After stirring at 1000C for 1 h, 8 M aqueous NaOH (1.0 mL) was added. After stirring at 1000C for 1.5 h, the organic materials were extracted with EtOAc/THF. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH) , then crystallized from MeOH/EtOAc/hexane) to give the title compound (40 mg, 35%) as a pale brown solid:1H NMR (300 MHz, DMSO-d6) δ 1.43 (6H, s) , 2.29-2.45 (3H, m) , 3.24-3.40 (2H, m) , 3.45-3.62 (2H, m) , 4.80 (IH, t, J = 5.6 Hz), 6.79 (IH, s), 7.40 (IH, s) , 7.75 (0.6H, br s) , 8.09 (0.4H, br s), 12.55-13.06 (IH, m) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 237

13
[ 1009071-34-4 ]
[ 1244028-01-0 ]
[ 1244027-19-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; C₁₂H₁₃BrF₂N₂OS With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere; Stage #2: With water; sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 0.5h;	124 A mixture of 5-bromo-3- [ (2, 2- difluoroethyl) amino] thiophene-2-carboxamide (150 mg, 0.53 mmol) , cyclopentanone (2.0 mL) , CSA (12 mg, 0.053 mmol) , MgSO4 (100 mg) and DMA (1 mL) was stirred at 1100C for 20 h. The mixture was poured into saturated aqueous NaHCU3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 80:20 hexane/EtOAc) to give a brown crystalline solid. A flask was charged with this solid, 1,2-dimethoxyethane (4 mL) , tert-butyl 3-methyl-4- (4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) -lH-pyrazole-1- carboxylate (370 mg, 1.20 mmol), sodium carbonate (120 mg, 2.00 mmol) and water (2 mL) . The flask was purged with argon. Then, 1, 1' -bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (33 mg, 0.040 mmol) was added to the mixture. The flask was purged with argon. After stirring at 1000C for 2 h, 8 M aqueous NaOH (1.0 mL) was added. After stirring at 1000C for 30 min, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc), then crystallized from heptanes/EtOAc to give the title compound (29 mg, 16%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.54-2.06 (8H, m) , 2.41 (3H, br s), 3.63-3.84 (2H, m) , 5.91-6.41 (IH, m) , 6.93 (IH, s) , 7.68-7.89 (1.6H, m) , 8.11 (0.4H, br s) , 12.88 (IH, br s) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 238-239

14
[ 1009071-34-4 ]
[ 1244028-04-3 ]
[ 1244027-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; C₁₄H₁₄BrN₃OS With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 1h;	127.3 Preparation of 2 , 2 -dimethyl- 6- (5-methyl-lH-pyrazol-4-yl) -1- (pyridin-2-ylmethyl) -2 , 3-dihydrothieno [3 , 2-d] pyrimidin- 4 (IH) -one A mixture of 5-bromo-3- [ (pyridin-2- ylmethyl) amino] thiophene-2-carboxamide (160 mg, 0.51 mmol) , 2,2-dimethoxypropane (1.5 mL) , CSA (12 mg, 0.051 mmol), MgSO4 (150 mg) and DMA (1.5 mL) was microwave-irradiated at 1200C for 1 h. The mixture was poured into saturated aqueous NaHCC>;3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, a brown solid was obtained. A flask was charged with this solid, 1,2-dimethoxyethane (5 mL) , tert- butyl 3-methyl-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) -lH-pyrazole-1-carboxylate (472 mg, 1.53 mmol), sodium carbonate (153 mg, 2.55 mmol) and water (2.5 mL) . The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (42 mg, 0.051 mmol) was added to the mixture. The flask was purged with argon. After stirring at 1000C for 0.5 h, 8 M aqueous NaOH (1.0 mL) was added. After stirring at 1000C for 1 h, the organic materials were extracted with EtOAc/THF. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc) to give the title compound (59 mg, 33%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.44 (6H, s) , 2.31 (3H, br s) , 4.64 (2H, s), 6.72 (IH, br s) , 7.23-7.33 (IH, m) , 7.39 (IH, d, J = 7.7 Hz), 7.56 (IH, s) , 7.67 (0.6H, br s) , 7.73-7.83 (IH, m), 8.03 (0.4H, br s) , 8.50-8.61 (IH, in), 12.59-13.16 (IH, m) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 243-244

15
[ 1009071-34-4 ]
[ 1244028-07-6 ]
[ 1244027-23-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; C₁₄H₁₄BrN₃OS With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 1h;	128.3 A mixture of 5-bromo-3- [ (pyridin-3- ylmethyl) amino] thiophene-2-carboxamide (175 mg, 0.56 mmol) , 2,2-dimethoxypropane (1.5 mL) , CSA (13 mg, 0.056 mmol), MgSO4 (150 mg) and DMA (1.5 mL) was microwave-irradiated at 1200C for 1 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, a brown solid was obtained. A flask was charged with this solid, 1, 2-dimethoxyethane (5.0 mL) , tert- butyl 3-methyl-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) -lH-pyrazole-1-carboxylate (518 mg, 1.68 mmol), sodium carbonate (168 mg, 2.80 mmol) and water (2.5 mL) . The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (41 mg, 0.056 mmol) was added to the mixture. The flask was purged with argon. After stirring at 1000C for 1 h, 8 M aqueous NaOH (1.0 mL) was added. After stirring at 1000C for 1 h, the organic materials were extracted with EtOAc/THF. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc) to give the title compound (64 mg, 32%, 3 steps) as a pale yellow solid:1H NMR (300 MHz, DMSO-d6) δ 1.44 (6H, s) , 2.31 (3H, br s), 4.63 (2H, s), 6.72 (IH, br s) , 7.33-7.43 (IH, m) , 7.58 (IH, s), 7.63-7.78 (1.6H, m) , 8.04 (0.4H, br s) , 8.41-8.51 (IH, m) , 8.58 (IH, d, J = 2.1 Hz), 12.85 (IH, br s) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 246

16
[ 1009071-34-4 ]
[ 1244028-10-1 ]
[ 1244027-24-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; C₁₄H₁₄BrN₃OS With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane at 100℃; for 1h;	129.3 A mixture of 5-bromo-3- [ (pyridin-4- ylmethyl) amino] thiophene-2-carboxamide (167 mg, 0.53 mmol), 2,2-dimethoxypropane (1.5 mL) , CSA (12 mg, 0.053 mmol), MgSO4 (150 mg) and DMA (1.5 mL) was microwave-irradiated at 1200C for 1 h. The mixture was poured into saturated aqueous NaHCθ3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, a brown solid was obtained. A flask was charged with the solid, 1,2-dimethoxyethane (5 mL) , tert- butyl 3-methyl-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) -lH-pyrazole-1-carboxylate (490 mg, 1.59 iranol) , sodium carbonate (159 mg, 2.65 iranol) and water (2.5 mL) . The flask was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (43 mg, 0.053 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 1000C for 0.5 h, 8 M aqueous NaOH (1.0 mL) was added. After stirring at 1000C for 1 h, the organic materials were extracted with EtOAc/THF. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH) , then crystallized from MeOH/EtOAc) to give the title compound (38 mg, 20%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.43 (6H, s) , 2.16-2.38 (3H, m) , 4.62 (2H, br s) , 6.56-6.71 (IH, m) , 7.34 (2H, d, J = 5.9 Hz), 7.60 (IH, s), 7.66 (0.6H, br s) , 8.02 (0.4H, br s) , 8.52 (2H, d, J = 5.9 Hz), 12.71-12.93 (IH, m) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/101302, 2010, A1 Location in patent: Page/Page column 248-249

17
[ 123-75-1 ]
[ 494833-79-3 ]
[ 1009071-34-4 ]
2-chloro-3-phenylpropanoic acid chloride [ No CAS ]
[ 1330781-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-amino-5-bromothiophene-2-carboxyamide; 2-chloro-3-phenylpropanoic acid chloride With triethylamine In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: pyrrolidine In tetrahydrofuran at 70℃; Stage #3: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate	94.B B) Production of 6-(5-methyl-1H-pyrazol-4-yl)-2-(2-phenyl-1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.21 mL) and tetrahydrofuran (5.0 mL) was added 2-chloro-3-phenylpropanoyl chloride (305 mg) with stirring at room temperature. The reaction mixture was stirred for 10 min, and pyrrolidine (0.42 mL) was added. The reaction mixture was stirred with heating at 70°C for 2 hr, sodium iodide (2.0 mg) was added, and the reaction mixture was stirred with heating at 70°C for 18 hr. The mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give a pale-yellow solid (285 mg). The obtained pale-yellow solid (285 mg) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (435 mg), sodium carbonate (126 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (57 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100°C for 30 min, extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give two kinds of pale-yellow solids. The solid eluted earlier was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product (5.0 mg) of tert-butyl 3-methyl-4-{4-oxo-2-[(E)-2-phenylethenyl]-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-1H-pyrazole-1-carboxylate as a yellow solid. The solid eluted later was purified by silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (18 mg) as a colorless solid. 1H-NMR(DMSO-d6) δ 1.54-1.72(4H,m), 2.24-2.49(7H,m), 2.85-3.03(1H,m), 3.33-3.40(1H,m), 3.91-4.00(1H,m), 7.14-7.30(5H,m), 7.32(1H,s), 7.77-8.38(1H,m), 12.21(1H,brs), 12.96(1H,brs).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 86

18
[ 1009071-34-4 ]
[ 1330782-99-4 ]
[ 76-05-1 ]
[ 1330781-14-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine-1-carboxylate With caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 2h; Stage #2: trifluoroacetic acid at 20℃; for 1h;	11.B B) Production of 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-pyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one monotrifluoroacetate tert-Butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine-1-carboxylate (173 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (266 mg), cesium carbonate (282 mg), 1,2-dimethoxyethane (5 mL) and water (0.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1, 71 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 80°C for 2 hr. Ethyl acetate (20 mL) and water (5 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mLx2). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give a mixture of tert-butyl 4-{2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylate and tert-butyl (2S)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]pyrrolidine-1-carboxylate. A solution of the mixture of tert-butyl 4-{2-[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylate and tert-butyl (2S)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]pyrrolidine-1-carboxylate produced above in trifluoroacetic acid (10 mL) was stirred at room temperature for 1 hr, and the mixture was concentrated under reduced pressure. The residue was crystallized from methanol/ethyl acetate (1 mL/4 mL) to give the title compound (129 mg) as a pale-brown solid. 1H-NMR(DMSO-d6) δ 1.93-2.15(3H,m), 2.38-2.44(1H,m), 2.46(3H,brs), 3.35-3.50(2H,m), 4.66(1H,t,J=7.2Hz), 7.37(1H,s), 7.85-8.48(1H,m), 8.99(1H,brs), 9.52(1H,brs), 12.80(1H,brs), 13.06(1H,brs). MS(ESI+):[M+H]+302. MS(ESI+),found:302.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 49

19
[ 1009071-34-4 ]
[ 1330783-77-1 ]
[ 1330782-11-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	106.B B) Production of tert-butyl (3S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.2]octane-2-carboxylate tert-Butyl (3S)-3-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate (190 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (266 mg), sodium carbonate (78 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (35 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100°C for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (146 mg) as a pale-yellow solid. 1H-NMR(DMSO-d6) δ 1.08-1.85(16H,m), 2.06-2.22(2H,m), 2.39-2.48(3H,m), 3.97-4.09(1H,m), 4.52-4.56(1H,m), 7.39(0.4H,s), 7.42(0.6H,s), 7.92(0.6H,brs), 8.27(0.4H,brs), 12.24-12.46(1H,m), 12.96(1H,brs).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 91-92

20
[ 1009071-34-4 ]
[ 1330783-90-8 ]
[ 1330783-91-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere;	116.I I) Production of 2-(7-azabicyclo[2.2.1]hept-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one monohydrochloride Benzyl 1-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (313 mg) produced above, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (419 mg), cesium carbonate (1.33 g), 1,2-dimethoxyethane (8 mL) and water (2.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (25 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 100°C for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with 3:1 ethyl acetate/tetrahydrofuran mixture. The obtained organic layer was dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give benzyl 1-{6-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-7-azabicyclo[2.2.1]heptane-7-carboxylate (240 mg). The benzyl 1-{6-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-7-azabicyclo[2.2.1]heptane-7-carboxylate (240 mg) produced above was dissolved in methanol (10 mL), 10% palladium-carbon (100 mg, 50% wet) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 2 hr. The reaction system was filtered through a celite pat, and formic acid was passed through the celite pat until the compound was sufficiently eluted. The filtrate was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with 3:1 ethyl acetate/tetrahydrofuran mixture. The organic layer was dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added 10% hydrochloric acid/methanol solution (5.0 mL), and the mixture was stirred at 50°C for 1 hr. The mixture was concentrated under reduced pressure, to the residue was added heated 20:1 ethanol/water (15 mL), and the insoluble material was filtered off. The filtrate was left standing at room temperature for 1 hr, and the precipitate was collected by filtration to give the title compound (103 mg) as a white solid. 1H-NMR(DMSO-d6) δ 1.79-2.14(6H,m), 2.37-2.47(5H,m), 4.16-4.25(1H,m), 7.38(1H,s), 7.91-8.40(1H,m), 9.71(2H,brs), 12.66-13.15(2H,m). MS(ESI+):[M+H]+328. MS(ESI+),found:328.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane; water at 90℃; for 1h; Inert atmosphere;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 98
[2]Kurasawa, Osamu; Miyazaki, Tohru; Homma, Misaki; Oguro, Yuya; Imada, Takashi; Uchiyama, Noriko; Iwai, Kenichi; Yamamoto, Yukiko; Ohori, Momoko; Hara, Hideto; Sugimoto, Hiroshi; Iwata, Kentaro; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Nomura, Toshiyuki; Cho, Nobuo [Journal of Medicinal Chemistry, 2020, vol. 63, # 3, p. 1084 - 1104]

21
[ 1009071-34-4 ]
[ 1330784-24-1 ]
C₂₆H₃₂FN₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	128.B B) Production of tert-butyl (1R,3S,4R,5S)-5-fluoro-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate tert-Butyl (1R,3S,4R,5S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylate (300 mg) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (416 mg), sodium carbonate (215 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1)(55 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100°C for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was purified by high performance liquid chromatography {column: L-column 2 ODS (20 mm i.d.*50 mm L), mobile phase: 0.1% aqueous trifluoroacetic acid solution/0.1% trifluoroacetic acid-acetonitrile solution}. The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. The residue was collected by filtration and washed with water (3 mL) to give the title compound (106 mg) as a colorless solid. 1H-NMR(DMSO-d6) δ 1.12-1.61(11H,m), 2.05-2.34(2H,m), 2.36-2.48(3H,m), 2.93-3.07(1H,m), 4.04-4.28(1H,m), 4.58-4.83(1H,m), 5.17-5.53(1H,m), 7.33-7.54(1H,m), 7.81-8.34(1H,m), 12.31-12.61(1H,m), 12.82-13.13(1H,m).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 106

22
[ 1009071-34-4 ]
[ 1330784-51-4 ]
[ 1330784-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In 1,2-dimethoxyethane; water at 90℃; for 1h; Inert atmosphere;	145.C C) Production of 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-1,2,3,6-tetrahydropyridin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride tert-Butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (900 mg) produced above, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.35 g), cesium carbonate (4.27 g), 1,2-dimethoxyethane (12 mL) and water (4 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1)(80 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 90°C for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with 3:1 ethyl acetate/tetrahydrofuran mixture. The obtained organic layer was successively washed with saturated aqueous sodium hydrogen carbonate and brine (20 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give tert-butyl (2S)-2-{6-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-3,6-dihydropyridine-1(2H)-carboxylate as a white solid. To a solution of tert-butyl (2S)-2-{6-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-3,6-dihydropyridine-1(2H)-carboxylate produced above in methanol (15 mL) was added 10% hydrochloric acid/methanol solution (14 mL), and the mixture was stirred at 50°C for 1 hr. After cooling to room temperature, the precipitated solid was collected by filtration to give the title compound (620 mg) as a white solid. 1H-NMR(DMSO-d6) δ 2.37-2.53(4H,m), 2.71-2.86(1H,m), 3.61-3.83(2H,m), 4.34-4.51(1H,m), 5.74-6.02(2H,m), 7.36(1H,s), 8.13(1H,brs), 9.74(1H,brs), 9.85-9.96(1H,m), 12.89(1H,brs). MS(ESI+):[M+H]+314. MS(ESI+),found:314
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 2h; Inert atmosphere;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 116
[2]Kurasawa, Osamu; Miyazaki, Tohru; Homma, Misaki; Oguro, Yuya; Imada, Takashi; Uchiyama, Noriko; Iwai, Kenichi; Yamamoto, Yukiko; Ohori, Momoko; Hara, Hideto; Sugimoto, Hiroshi; Iwata, Kentaro; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Nomura, Toshiyuki; Cho, Nobuo [Journal of Medicinal Chemistry, 2020, vol. 63, # 3, p. 1084 - 1104]

23
[ 1009071-34-4 ]
[ 1330782-88-1 ]
[ 1330781-03-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-2-(2-chlorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water at 100℃; for 0.5h;	1.F F) Production of 2-(2-chlorophenyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one 6-Bromo-2-(2-chlorophenyl)thieno[3.2-d]pyrimidin-4(3H)-one (157 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (425 mg), sodium carbonate (138 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (38 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100°C for 1 hr, 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 100°C for 30 min. After stirring, the mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (43 mg) as a yellow solid. 1H-NMR(DMSO-d6) δ 2.43(3H,brs), 7.43-7.69(5H,m), 7.92(0.6H,brs), 8.30(0.4H,brs), 12.78(1H,brs), 13.03(1H,brs).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 44-45

24
[ 1009071-34-4 ]
[ 1330782-89-2 ]
[ 1330781-46-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one With potassium carbonate; diethylamine; sodium iodide In ISOPROPYLAMIDE at 70℃; for 2.5h; Stage #2: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate With calcium carbonate In 1,2-dimethoxyethane at 100℃; for 4h; Inert atmosphere;	42 Production of 2-[(diethylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Example 42 Production of 2-[(diethylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one 0.57M Diethylamine/N,N-dimethylacetamide solution (0.7 mL), 0.15M sodium iodide/N,N-dimethylacetamide solution (0.2 mL), and 0.12 M 6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one/N,N-dimethylacetamide solution (1.0 mL) were successively added to potassium carbonate (33.2 mg), and the mixture was stirred at 70°C for 2.5 hr. Insoluble material was removed by filtration, and the filtrate was purified by high performance liquid chromatography {column: YMC CombiPrep Pro C18 RS (20 mm i.d.50 mm L), mobile phase: acetonitrile/10% aqueous ammonium formate solution}. The obtained compound was dissolved in 1,2-dimethoxyethane (0.5 mL), 0.48M tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate/DME solution (0.5 mL), 0.96M aqueous calcium carbonate solution (0.5 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (10 mg) were added, and the mixture was stirred at 100°C for 4 hr under a nitrogen atmosphere. Insoluble material was removed by filtration, and the filtrate was purified by high performance liquid chromatography {column: YMC CombiPrep Pro C18 RS (20 mm i.d.50 mm L), mobile phase: acetonitrile/10% aqueous ammonium formate solution} to give the title compound (8.5 mg). MS(ESI+):[M+H]+318. MS(ESI+),found:318.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 64

25
[ 1009071-34-4 ]
[ 1330782-90-5 ]
[ 1330781-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water at 100℃; for 0.5h;	2.C C) Production of 6-(5-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one 6-Bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (100 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (294 mg), sodium carbonate (95 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (26 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100°C for 3 hr, 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 100°C for 30 min. After stirring, the mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (44 mg) as a pale-yellow solid. 1H-NMR(DMSO-d6) δ 1.65-1.78(4H,m), 2.45(3H,s), 2.53-2.59(4H,m), 3.57(2H,s), 7.37(1H,s), 8.00(1H,brs), 11.84-13.16(2H,m). MS(ESI+):[M+H]+316. MS(ESI+),found:316.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 45

26
[ 1009071-34-4 ]
[ 1330783-51-1 ]
[ 1330783-54-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 1.5h; Inert atmosphere;	83.C C) Production of 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride tert-Butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (2.55 g) produced above, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (3.79 g), cesium carbonate (4.01 g), 1,2-dimethoxyethane (50 mL) and water (5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (502 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 80°C for 1.5 hr. Ethyl acetate (75 mL) and water (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (20 mLx2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give tert-butyl (2S)-2-{6-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate as a pale-yellow solid. To a solution of tert-butyl (2S)-2-{6-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylate produced above in methanol (50 mL) was added 4M hydrochloric acid/ethyl acetate solution (10 mL), and the mixture was stirred at 50°C for 4 hr and at room temperature for 1 hr. The precipitated solid was collected by filtration to give the title compound (1.18 g) as a pale-yellow solid. 1H-NMR(DMSO-d6) δ 1.48-1.92(5H,m), 2.23-2.35(1H,m), 2.46(3H,s), 2.94-3.12(1H,m), 3.29-3.41(1H,m), 4.16-4.29(1H,m), 7.34(1H,s), 8.12(1H,s), 9.07-9.25(1H,m), 9.46-9.60(1H,m), 12.84(1H,brs). MS(ESI+):[M+H]+316. MS(ESI+),found:316.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 2h; Inert atmosphere;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 77-78
[2]Kurasawa, Osamu; Miyazaki, Tohru; Homma, Misaki; Oguro, Yuya; Imada, Takashi; Uchiyama, Noriko; Iwai, Kenichi; Yamamoto, Yukiko; Ohori, Momoko; Hara, Hideto; Sugimoto, Hiroshi; Iwata, Kentaro; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Nomura, Toshiyuki; Cho, Nobuo [Journal of Medicinal Chemistry, 2020, vol. 63, # 3, p. 1084 - 1104]

27
[ 1009071-34-4 ]
[ 1330783-56-6 ]
[ 1330781-90-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-2-{1-[4-(methylsulfonyl)phenyl]pyrrolidin-2-yl}thieno[3,2-d]pyrimidin-4(3H)-one With caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 1.5h; Inert atmosphere; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water at 80℃; for 2h;	86.B B) Production of 6-(5-methyl-1H-pyrazol-4-yl)-2-{1-[4-(methylsulfonyl)phenyl]pyrrolidin-2-yl}thieno[3,2-d]pyrimidin-4(3H)-one 6-Bromo-2-{1-[4-(methylsulfonyl)phenyl]pyrrolidin-2-yl}thieno[3,2-d]pyrimidin-4(3H)-one (203 mg) produced above, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (275 mg), cesium carbonate (291 mg), 1,2-dimethoxyethane (5 mL) and water (0.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1)(73.0 mg) was added, the atmosphere in the flask was purged again with argon, and the mixture was stirred at 80°C for 1.5 hr. 2M Aqueous sodium hydroxide solution (1 mL) was added to the reaction mixture, and the mixture was further stirred at 80°C for 2 hr. Ethyl acetate (20 mL) and 1M hydrochloric acid (3 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the object fraction was concentrated under reduced pressure. The obtained residue was washed with methanol (5 mL) to give the title compound (130 mg) as a pale-yellow solid. 1H-NMR(DMSO-d6) δ 1.96-2.22(3H,m), 2.33-2.47(4H,m), 3.03(3H,s), 3.37-3.48(1H,m), 3.73-3.85(1H,m), 4.77(1H,dd,J=8.4,1.6Hz),6.61(2H,d,J=8.9Hz),7.34(1H,s), 7.63(2H,d,J=8.9Hz),7.80-8.34(1H,m), 12.47(1H,brs), 12.83-13.09(1H,m).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 79-80

28
[ 1009071-34-4 ]
[ 1330785-58-4 ]
[ 1330785-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	91.B B) Production of tert-butyl (1R,3S,4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate tert-Butyl (1R,3S,4S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.03 g) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.49 g), sodium carbonate (768 mg), 1,2-dimethoxyethane (8.0 mL) and water (4.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (197 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100°C for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (690 mg) as a pale-yellow solid. 1H-NMR(DMSO-d6) δ 1.04-1.86(14H,m), 2.04-2.20(1H,m), 2.33-2.48(3H,m), 2.60-2.67(1H,m), 4.11-4.17(1H,m), 4.18-4.26(1H,m), 7.34-7.54(1H,m), 7.88(0.6H,brs), 8.23(0.4H,brs), 12.23-12.48(1H,m), 12.82-13.09(1H,m).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2540728, 2013, A1 Location in patent: Page/Page column 83

29
[ 1009071-34-4 ]
C₁₂H₁₅BrN₂O [ No CAS ]
C₂₁H₂₈N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium carbonate In 1,2-dimethoxyethane; water

Reference： [1]Katoh, Taisuke; Takai, Takafumi; Yukawa, Takafumi; Tsukamoto, Tetsuya; Watanabe, Etsurou; Mototani, Hideyuki; Arita, Takeo; Hayashi, Hiroki; Nakagawa, Hideyuki; Klein, Michael G.; Zou, Hua; Sang, Bi-Ching; Snell, Gyorgy; Nakada, Yoshihisa [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 11, p. 2466 - 2475]

30
[ 1009071-34-4 ]
2-(3-amino-3-oxopropyl)-3’-hydroxy-[1,1‘-biphenyl]-4-yl trifluoromethansulfonate [ No CAS ]
3-[3’-hydroxy-4-(3-methyl-1H-pyrazol-4-yl)biphenyl-2-yl]propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In 1,4-dioxane; water at 80℃; for 12h; Inert atmosphere; Microwave irradiation; Sealed tube;	7 3-f3’-Hydrwcy-4-(3-methyl- iH-pyrazo1-4-ybiphanyI-2-yIjpropanamide (P45) A 20 mL microwave vial was charged with 2-(3-amino-3-oxopropyl)-3’- hydroxybi phenyl-4-yl trifluoromethanesu lfonate(0.25 g, 0.642 mmol), tert-butyt 3-methyl- 4-(boronic acid pinacol ester)-1 H-pyrazole-1-carboxylate (030 g, 096 mmol) and caesium carbonate (0.42 9,128 mmol) in a softiUon of water (1 mL) and 1,4-dioxane (10 mL). Nitrogen was bubbled through the mixture for 5 mm before [1,1 ‘- bis(diphenylphosphino)ferrocene] dichloropalladium(l I), complex with dichloromethane(0) (10 mol%, 0.052 g, 0.064 mrnol) was added and the reaction vial sealed and placed in a microwave reactor for 12 h at 80 °O. On coollng, water (10 mL) was added and the mixture extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and concentrated. The crude residue was taken up in ethyl acetate and washed with 2M hydrochloric acid (20 mL). The aqueous acidic layer was set aside and a precipitate formed which was isolated by filtration to give the title compound(0.060 g, 29%) as fine pale yellow crystals. 1H NMR (400MHz, DMSO-d6) 5 7.86 (s, I H), 7.39 (d, J = 1.7 Hz, I H), 7.31 (dd, J 1 .9, 7.9 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.14 (d, J = 7.9 Hz, 1H), 6,79-6.69 (m, 4H), 2.82 -275 (m, 2H),2.41 (s, 3H), 2.28 (dd. J = 7.1, 8.9 Hz, 2H), NH and OH not seen; HPLC(water/ACN +0.1% TFA gradient) 97.39% at 220 nm; LCMS [M+H] = 322.20.

Reference： [1]Current Patent Assignee: VECTUS BIOSYSTEMS LIMITED; ACCUGEN - WO2016/145478, 2016, A1 Location in patent: Paragraph 0147

31
[ 1009071-34-4 ]
[ 1244027-58-4 ]
2,2-dimethyl-6-(3-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; water for 18h; Inert atmosphere; Reflux; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water Inert atmosphere;	General procedure: A mixture of 11b (138 mg,0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole(291 mg, 1.50 mmol), Na2CO3 (265 mg, 2.50 mmol),DME (5 mL) and water (2.5 mL) was purged with argon gas. Then,PdCl2(dppf) (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon gas again. This mixture was refluxed for18 h. Then, the mixture was poured into saturated NaHCO3 aq.(100 mL), and EtOAc (100 mL), and the mixture was stirred vigorously.An insoluble materials were filtered off. The organic layerwas separated from the filtrate, washed with brine, dried overMgSO4, filtered and concentrated under reduced pressure. Thisresidue was purified by column chromatography on silica gel (nhexane/EtOAc, 95:5 to 0:100, v/v, then EtOAc/MeOH, 100:0 to90:10, v/v) to afford a white solid (60 mg). This solid was trituratedwith EtOAc/hexane and collected by filtration to afford 12a

Reference： [1]Kurasawa, Osamu; Oguro, Yuya; Miyazaki, Tohru; Homma, Misaki; Mori, Kouji; Iwai, Kenichi; Hara, Hideto; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Yoshida, Sei; Ishikawa, Tomoyasu; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2133 - 2147]

32
[ 1009071-34-4 ]
[ 1244027-65-3 ]
1,2,2-trimethyl-6-(3-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; water for 18h; Inert atmosphere; Reflux; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water Inert atmosphere;	General procedure: A mixture of 11b (138 mg,0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole(291 mg, 1.50 mmol), Na2CO3 (265 mg, 2.50 mmol),DME (5 mL) and water (2.5 mL) was purged with argon gas. Then,PdCl2(dppf) (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon gas again. This mixture was refluxed for18 h. Then, the mixture was poured into saturated NaHCO3 aq.(100 mL), and EtOAc (100 mL), and the mixture was stirred vigorously.An insoluble materials were filtered off. The organic layerwas separated from the filtrate, washed with brine, dried overMgSO4, filtered and concentrated under reduced pressure. Thisresidue was purified by column chromatography on silica gel (nhexane/EtOAc, 95:5 to 0:100, v/v, then EtOAc/MeOH, 100:0 to90:10, v/v) to afford a white solid (60 mg). This solid was trituratedwith EtOAc/hexane and collected by filtration to afford 12a

Reference： [1]Kurasawa, Osamu; Oguro, Yuya; Miyazaki, Tohru; Homma, Misaki; Mori, Kouji; Iwai, Kenichi; Hara, Hideto; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Yoshida, Sei; Ishikawa, Tomoyasu; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2133 - 2147]

33
[ 1009071-34-4 ]
[ 1244027-69-7 ]
1,2-dimethyl-6-(3-methyl-1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-1,2-dimethyl-2-(2,2,2-trifluoroethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; water for 18h; Inert atmosphere; Reflux; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water Inert atmosphere;	General procedure: A mixture of 11b (138 mg,0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole(291 mg, 1.50 mmol), Na2CO3 (265 mg, 2.50 mmol),DME (5 mL) and water (2.5 mL) was purged with argon gas. Then,PdCl2(dppf) (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon gas again. This mixture was refluxed for18 h. Then, the mixture was poured into saturated NaHCO3 aq.(100 mL), and EtOAc (100 mL), and the mixture was stirred vigorously.An insoluble materials were filtered off. The organic layerwas separated from the filtrate, washed with brine, dried overMgSO4, filtered and concentrated under reduced pressure. Thisresidue was purified by column chromatography on silica gel (nhexane/EtOAc, 95:5 to 0:100, v/v, then EtOAc/MeOH, 100:0 to90:10, v/v) to afford a white solid (60 mg). This solid was trituratedwith EtOAc/hexane and collected by filtration to afford 12a

Reference： [1]Kurasawa, Osamu; Oguro, Yuya; Miyazaki, Tohru; Homma, Misaki; Mori, Kouji; Iwai, Kenichi; Hara, Hideto; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Yoshida, Sei; Ishikawa, Tomoyasu; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2133 - 2147]

34
[ 1009071-34-4 ]
[ 1330782-90-5 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	35 6.1.32. 6-(3-Methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (10c) A mixture of 9c (100 mg, 0.318 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(294 mg, 0.954 mmol), Na2CO3 (95 mg, 1.59 mmol),PdCl2(dppf) (26 mg, 0.032 mmol), DME (3.0 mL) and water(1.5 mL) was stirred for 3 h at 100 C under Ar. Then 8 M NaOH(1.0 mL) was added, and the mixture was stirred further 30 minat same temperature. The mixture was extracted with EtOAc-THF. The combined extracts were dried over Na2SO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (n-hexane/EtOAc, 80:20 to 0:100, v/v, thenEtOAc/MeOH, 100:0 to 90:10, v/v). The residue was triturated withEtOAc-MeOH, and the precipitate was collected by filtration toafford 10c (44 mg, yield 44%) as a pale yellow solid. 1H NMR(300 MHz, DMSO-d6) d 1.65-1.78 (4H, m), 2.45 (3H, s), 2.53-2.59(4H, m), 3.57 (2H, s), 7.37 (1H, s), 8.00 (1H, br s), 11.84-13.16(2H, m). Anal. Calcd for C15H17N5OS: C, 57.12; H, 5.43; N, 22.21.Found: C, 56.96; H, 5.24; N, 22.04.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

35
[ 1009071-34-4 ]
[ 1330782-97-2 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-(piperidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere;	36 6.1.33. 6-(3-Methyl-1H-pyrazol-4-yl)-2-(piperidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (10d) A mixture of 9d (175 mg, 0.533 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(361 mg, 1.17 mmol), Na2CO3 (128 mg, 2.13 mmol),PdCl2(dppf) (44 mg, 0.053 mmol), DME (4.0 mL) and water(2.0 mL) was stirred at 100 C for 1 h under Ar. The mixture wasextracted with EtOAc-THF. The combined extracts were dried overNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on amino silica gel (EtOAc/MeOH, 100:0 to90:10, v/v). The residue was triturated with EtOAc-MeOH-n-hexane,and the precipitate was collected by filtration to afford 10d(56 mg, yield 32%) as a pale brown solid. 1H NMR (300 MHz,DMSO-d6) d 1.30-1.44 (2H, m), 1.44-1.60 (4H, m), 2.40-2.48 (7H,m), 3.42 (2H, s), 7.38 (1H, s), 8.04 (1H, br s), 12.61 (1H, br s),12.61 (1H, br s). Anal. Calcd for C16H19N5OS0.2H2O: C, 57.71; H,5.87; N, 21.03. Found: C, 58.02; H, 5.89; N, 20.67.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

36
[ 1009071-34-4 ]
[ 1330783-16-8 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	38 6.1.35. 6-(3-Methyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one (10f) General procedure: A mixture of 9c (100 mg, 0.318 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(294 mg, 0.954 mmol), Na2CO3 (95 mg, 1.59 mmol),PdCl2(dppf) (26 mg, 0.032 mmol), DME (3.0 mL) and water(1.5 mL) was stirred for 3 h at 100 C under Ar. Then 8 M NaOH(1.0 mL) was added, and the mixture was stirred further 30 minat same temperature. The mixture was extracted with EtOAc-THF. The combined extracts were dried over Na2SO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (n-hexane/EtOAc, 80:20 to 0:100, v/v, thenEtOAc/MeOH, 100:0 to 90:10, v/v). The residue was triturated withEtOAc-MeOH, and the precipitate was collected by filtration toafford 10c

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

37
[ 1009071-34-4 ]
[ 1330783-17-9 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-[(3S)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	39 6.1.36. 6-(3-Methyl-1H-pyrazol-4-yl)-2-[(3S)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one (10g) General procedure: A mixture of 9c (100 mg, 0.318 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(294 mg, 0.954 mmol), Na2CO3 (95 mg, 1.59 mmol),PdCl2(dppf) (26 mg, 0.032 mmol), DME (3.0 mL) and water(1.5 mL) was stirred for 3 h at 100 C under Ar. Then 8 M NaOH(1.0 mL) was added, and the mixture was stirred further 30 minat same temperature. The mixture was extracted with EtOAc-THF. The combined extracts were dried over Na2SO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (n-hexane/EtOAc, 80:20 to 0:100, v/v, thenEtOAc/MeOH, 100:0 to 90:10, v/v). The residue was triturated withEtOAc-MeOH, and the precipitate was collected by filtration toafford 10c

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

38
[ 1009071-34-4 ]
[ 1330783-48-6 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-[(3-phenylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere;	41 6.1.38. 6-(3-Methyl-1H-pyrazol-4-yl)-2-[(3-phenylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one (10i) General procedure: A mixture of 9d (175 mg, 0.533 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(361 mg, 1.17 mmol), Na2CO3 (128 mg, 2.13 mmol),PdCl2(dppf) (44 mg, 0.053 mmol), DME (4.0 mL) and water(2.0 mL) was stirred at 100 C for 1 h under Ar. The mixture wasextracted with EtOAc-THF. The combined extracts were dried overNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on amino silica gel (EtOAc/MeOH, 100:0 to90:10, v/v). The residue was triturated with EtOAc-MeOH-n-hexane,and the precipitate was collected by filtration to afford 10d.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

39
[ 1009071-34-4 ]
[ 1330783-08-8 ]
2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 6-bromo-2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere; Stage #2: With hydrogenchloride In methanol; ethyl acetate	42 6.1.39. 2-[(2R)-2-(Hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-onedihydrochloride (10j0) General procedure: A mixture of 9c (100 mg, 0.318 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(294 mg, 0.954 mmol), Na2CO3 (95 mg, 1.59 mmol),PdCl2(dppf) (26 mg, 0.032 mmol), DME (3.0 mL) and water(1.5 mL) was stirred for 3 h at 100 C under Ar. Then 8 M NaOH(1.0 mL) was added, and the mixture was stirred further 30 minat same temperature. The mixture was extracted with EtOAc-THF. The combined extracts were dried over Na2SO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (n-hexane/EtOAc, 80:20 to 0:100, v/v, thenEtOAc/MeOH, 100:0 to 90:10, v/v). The residue was triturated withEtOAc-MeOH, and the precipitate was collected by filtration toafford 10c

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

40
[ 1009071-34-4 ]
[ 1330782-92-7 ]
2-[(3S)-3-fluoropyrrolidin-1-yl]methyl}-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	43 6.1.40. 2-[(3S)-3-Fluoropyrrolidin-1-yl]methyl}-6-(3-methyl-1Hpyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (10k) General procedure: A mixture of 9c (100 mg, 0.318 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(294 mg, 0.954 mmol), Na2CO3 (95 mg, 1.59 mmol),PdCl2(dppf) (26 mg, 0.032 mmol), DME (3.0 mL) and water(1.5 mL) was stirred for 3 h at 100 C under Ar. Then 8 M NaOH(1.0 mL) was added, and the mixture was stirred further 30 minat same temperature. The mixture was extracted with EtOAc-THF. The combined extracts were dried over Na2SO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (n-hexane/EtOAc, 80:20 to 0:100, v/v, thenEtOAc/MeOH, 100:0 to 90:10, v/v). The residue was triturated withEtOAc-MeOH, and the precipitate was collected by filtration toafford 10c

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

41
[ 1009071-34-4 ]
[ 1330782-89-2 ]
[ 506-59-2 ]
2-[(dimethylamino)methyl]-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	Stage #1: 6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one; N,N-dimethylammonium chloride In N,N-dimethyl-formamide at 100℃; for 1h; Sealed tube; Stage #2: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water for 1h; Inert atmosphere; Reflux; Stage #3: With hydrogenchloride In methanol	34 6.1.31. 2-[(Dimethylamino)methyl]-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride (10b0) A mixture of 8 (140 mg, 0.50 mmol), dimethylamine hydrochloride(200 mg, 1.54 mmol) and DMF (3 mL) was stirred at 100 C for1 h in a sealed tube by using microwave reactor. The mixture wasconcentrated under reduced pressure. The residue was extractedwith EtOAc-THF. The combined extracts were washed with saturatedNaHCO3 aq., dried over MgSO4 and concentrated in vacuoto give crude product of 9b. A mixture of the crude product of9b, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (380 mg, 1.23 mmol),Na2CO3 (265 mg, 2.50 mmol), PdCl2(dppf) (41 mg, 0.050 mmol),DME (4.0 mL) and water (2.0 mL) was stirred at reflux for 1 h underAr. The mixture was diluted with brine and extracted with EtOAc-THF. The combined extracts were dried over MgSO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (EtOAc/MeOH, 100:0 to 80:20, v/v). Theresidue was dissolved with MeOH (3 mL) and 10% HCl in MeOH(1 mL). The mixture was concentrated under reduced pressure.The residue was triturated with EtOAc-MeOH and the precipitatewas collected by filtration to afford 10b0 (24 mg, yield 13%) as acolorless solid. 1H NMR (300 MHz, DMSO-d6) d 2.47 (3H, s), 2.95(6H, s), 4.40 (2H, s), 7.40 (1H, s), 8.10 (1H, s), 10.40 (1H, br s),12.82 (1H, br s). HRMS: Calcd for C13H16N5OS [M-2HCl+H]+:290.1070. Found: 290.1058.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

42
[ 1009071-34-4 ]
[ 1330783-04-4 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-(2-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere;	19 6.1.18. 6-(3-Methyl-1H-pyrazol-4-yl)-2-(2-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one (7g) General procedure: A mixture of 6d (111 mg, 0.358 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(492 mg, 1.60 mmol), Na2CO3 (331 mg, 1.07 mmol),PdCl2(dppf) (29 mg, 0.036 mmol), DME (3.0 mL) and water(1.5 mL) was stirred at 100 C for 2 h under Ar. Then 8 M NaOH(1.0 mL) was added. After stirring at 100 C for 0.5 h, the organic materials were extracted with EtOAc/THF. The combined extractswere dried over Na2SO4 and concentrated in vacuo. The residuewas purified by column chromatography on amino silica gel (nhexane/EtOAc, 80:20 to 0:100, v/v). The residue was trituratedwith MeOH-EtOAc and the precipitate was collected by filtrationto afford 7d (51 mg, yield 46%) as a pale yellow solid. 1H NMR(300 MHz, DMSO-d6) d 2.49 (3H, br s), 7.49 (1H, s), 7.51-7.65(3H, m), 7.94 (0.6H, br s), 8.10-8.20 (2H, m), 8.29 (0.4H, br s),12.65 (1H, br s), 13.02 (1H, br s). Anal. Calcd for C16H12N4OS0.1H2-O: C, 61.96; H, 3.96; N, 18.06. Found: C, 61.82; H, 3.97; N, 17.97.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

43
[ 1009071-34-4 ]
[ 1330783-11-3 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-(1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere;	36 6.1.45. 6-(3-Methyl-1H-pyrazol-4-yl)-2-(1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one (14a) General procedure: A mixture of 9d (175 mg, 0.533 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(361 mg, 1.17 mmol), Na2CO3 (128 mg, 2.13 mmol),PdCl2(dppf) (44 mg, 0.053 mmol), DME (4.0 mL) and water(2.0 mL) was stirred at 100 C for 1 h under Ar. The mixture wasextracted with EtOAc-THF. The combined extracts were dried overNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on amino silica gel (EtOAc/MeOH, 100:0 to90:10, v/v). The residue was triturated with EtOAc-MeOH-n-hexane,and the precipitate was collected by filtration to afford 10d.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

44
[ 1009071-34-4 ]
[ 1330783-39-5 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-[phenyl(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Inert atmosphere;	36 6.1.46. 6-(3-Methyl-1H-pyrazol-4-yl)-2-[phenyl(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one (14b) General procedure: A mixture of 9d (175 mg, 0.533 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(361 mg, 1.17 mmol), Na2CO3 (128 mg, 2.13 mmol),PdCl2(dppf) (44 mg, 0.053 mmol), DME (4.0 mL) and water(2.0 mL) was stirred at 100 C for 1 h under Ar. The mixture wasextracted with EtOAc-THF. The combined extracts were dried overNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on amino silica gel (EtOAc/MeOH, 100:0 to90:10, v/v). The residue was triturated with EtOAc-MeOH-n-hexane,and the precipitate was collected by filtration to afford 10d.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

45
[ 1009071-34-4 ]
[ 1330782-89-2 ]
[ 136725-54-7 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one; (3S)-3-fluoropyrrolidine In N,N-dimethyl-formamide at 100℃; for 1h; Sealed tube; Stage #2: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water for 1h; Inert atmosphere; Reflux; Stage #3: With hydrogenchloride In deuteromethanol	40 6.1.37. 6-(3-Methyl-1H-pyrazol-4-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride (10h0) General procedure: A mixture of 8 (140 mg, 0.50 mmol), dimethylamine hydrochloride(200 mg, 1.54 mmol) and DMF (3 mL) was stirred at 100 C for1 h in a sealed tube by using microwave reactor. The mixture wasconcentrated under reduced pressure. The residue was extractedwith EtOAc-THF. The combined extracts were washed with saturatedNaHCO3 aq., dried over MgSO4 and concentrated in vacuoto give crude product of 9b. A mixture of the crude product of9b, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (380 mg, 1.23 mmol),Na2CO3 (265 mg, 2.50 mmol), PdCl2(dppf) (41 mg, 0.050 mmol),DME (4.0 mL) and water (2.0 mL) was stirred at reflux for 1 h underAr. The mixture was diluted with brine and extracted with EtOAc-THF. The combined extracts were dried over MgSO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (EtOAc/MeOH, 100:0 to 80:20, v/v). Theresidue was dissolved with MeOH (3 mL) and 10% HCl in MeOH(1 mL). The mixture was concentrated under reduced pressure.The residue was triturated with EtOAc-MeOH and the precipitatewas collected by filtration to afford 10b0 (24 mg, yield 13%) as acolorless solid. 1H NMR (300 MHz, DMSO-d6) d 2.47 (3H, s), 2.95(6H, s), 4.40 (2H, s), 7.40 (1H, s), 8.10 (1H, s), 10.40 (1H, br s),12.82 (1H, br s). HRMS: Calcd for C13H16N5OS [M-2HCl+H]+:290.1070. Found: 290.1058.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

46
[ 109-97-7 ]
[ 1009071-34-4 ]
[ 1330782-89-2 ]
2-((1H-pyrrol-1-yl)methyl)-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: pyrrole; 6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one In N,N-dimethyl-formamide at 100℃; for 1h; Sealed tube; Stage #2: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water for 1h; Inert atmosphere; Reflux; Stage #3: With hydrogenchloride In methanol	37 6.1.34. 2-((1H-pyrrol-1-yl)methyl)-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one(10e) General procedure: A mixture of 8 (140 mg, 0.50 mmol), dimethylamine hydrochloride(200 mg, 1.54 mmol) and DMF (3 mL) was stirred at 100 C for1 h in a sealed tube by using microwave reactor. The mixture wasconcentrated under reduced pressure. The residue was extractedwith EtOAc-THF. The combined extracts were washed with saturatedNaHCO3 aq., dried over MgSO4 and concentrated in vacuoto give crude product of 9b. A mixture of the crude product of9b, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (380 mg, 1.23 mmol),Na2CO3 (265 mg, 2.50 mmol), PdCl2(dppf) (41 mg, 0.050 mmol),DME (4.0 mL) and water (2.0 mL) was stirred at reflux for 1 h underAr. The mixture was diluted with brine and extracted with EtOAc-THF. The combined extracts were dried over MgSO4 and concentratedin vacuo. The residue was purified by column chromatographyon amino silica gel (EtOAc/MeOH, 100:0 to 80:20, v/v). Theresidue was dissolved with MeOH (3 mL) and 10% HCl in MeOH(1 mL). The mixture was concentrated under reduced pressure.The residue was triturated with EtOAc-MeOH and the precipitatewas collected by filtration to afford 10b0 (24 mg, yield 13%) as acolorless solid. 1H NMR (300 MHz, DMSO-d6) d 2.47 (3H, s), 2.95(6H, s), 4.40 (2H, s), 7.40 (1H, s), 8.10 (1H, s), 10.40 (1H, br s),12.82 (1H, br s). HRMS: Calcd for C13H16N5OS [M-2HCl+H]+:290.1070. Found: 290.1058.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

47
[ 1009071-34-4 ]
[ 1330785-55-1 ]
C₁₉H₁₇N₅OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1.5h;	32 A mixture of 11 (100 mg, 0.276 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(255 mg, 0.828 mmol), PdCl2(dppf) (23 mg, 0.028 mmol),Na2CO3 (66 mg, 1.10 mmol), DME (3.0 mL) and water (1.5 mL)was stirred at 100 C for 1.5 h. The mixture was diluted with waterand extracted with EtOAc. The combined extracts were washedwith brine, dried over Na2SO4 and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (n-hexane/EtOAc, 85:15 to 0:100, v/v) to give a crude product of 12 as apale yellow solid (89 mg). A mixture of the crude product of 12(80 mg), MeOH (2 mL) and TFA (2 mL) was stirred with heatingat 70 C for 5 h. The reaction mixture was concentrated underreduced pressure, and the residue was triturated with MeOH-EtOAc. The precipitate was collected by filtration to afford 10a(43 mg, yield 44%) as a yellow solid. 1H NMR (300 MHz, DMSOd6)d 2.46 (3H, br s), 4.20 (2H, s), 4.31 (2H, s), 7.40 (1H, s), 7.42-7.58 (5H, m), 8.05 (1H, br s), 9.15-10.22 (2H, m), 13.04 (1H, brs). Anal. Calcd for C20H18N5O3SF30.25H2O: C, 51.11; H, 3.97; N,14.90. Found: C, 51.10; H, 3.81; N, 14.89.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

48
[ 1009071-34-4 ]
6-bromo-2-methylthieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]
2-methyl-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 3h; Inert atmosphere;	12 6.1.12. 2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (7a) A mixture of 6a (130 mg, 0.53 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(327 mg, 1.06 mmol), Na2CO3 (169 mg, 1.59 mmol),PdCl2(dppf) (43.3 mg, 0.053 mmol), DME (3.0 mL) and water(1.5 mL) was stirred at 100 C for 3 h under Ar. The organic materialswere extracted with EtOAc, dried over MgSO4 and concentratedin vacuo. The residue was purified by columnchromatography on amino silica gel (EtOAc/MeOH, 100:0 to90:10, v/v) to give pale yellow solid. The solid was triturated withMeOH, and the precipitate was collected by filtration to afford 7a(74.0 mg, yield 57%) as a colorless solid. 1H NMR (300 MHz,DMSO-d6) d 2.36 (3H, s), 2.44 (3H, s), 7.31 (1H, s), 7.98 (1H, br s),12.30 (1H, br s), 12.96 (1H, br s). HRMS: Calcd for C11H11N4OS [M+H]+: 247.0648. Found: 247.0625.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

49
[ 1009071-34-4 ]
[ 1330784-59-2 ]
2-(cyclopentylmethyl)-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water for 3h; Inert atmosphere;	13 6.1.13. 2-(Cyclopentylmethyl)-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (7b) General procedure: A mixture of 6a (130 mg, 0.53 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(327 mg, 1.06 mmol), Na2CO3 (169 mg, 1.59 mmol),PdCl2(dppf) (43.3 mg, 0.053 mmol), DME (3.0 mL) and water(1.5 mL) was stirred at 100 C for 3 h under Ar. The organic materialswere extracted with EtOAc, dried over MgSO4 and concentratedin vacuo. The residue was purified by columnchromatography on amino silica gel (EtOAc/MeOH, 100:0 to90:10, v/v) to give pale yellow solid. The solid was triturated withMeOH, and the precipitate was collected by filtration to afford 7a(74.0 mg, yield 57%) as a colorless solid. 1H NMR (300 MHz,DMSO-d6) d 2.36 (3H, s), 2.44 (3H, s), 7.31 (1H, s), 7.98 (1H, br s),12.30 (1H, br s), 12.96 (1H, br s). HRMS: Calcd for C11H11N4OS [M+H]+: 247.0648. Found: 247.0625.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

50
[ 1009071-34-4 ]
6-bromo-2-cyclohexylthieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]
2-cyclohexyl-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water for 3h; Inert atmosphere;	14 6.1.14. 2-Cyclohexyl-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (7c) General procedure: A mixture of 6a (130 mg, 0.53 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(327 mg, 1.06 mmol), Na2CO3 (169 mg, 1.59 mmol),PdCl2(dppf) (43.3 mg, 0.053 mmol), DME (3.0 mL) and water(1.5 mL) was stirred at 100 C for 3 h under Ar. The organic materialswere extracted with EtOAc, dried over MgSO4 and concentratedin vacuo. The residue was purified by columnchromatography on amino silica gel (EtOAc/MeOH, 100:0 to90:10, v/v) to give pale yellow solid. The solid was triturated withMeOH, and the precipitate was collected by filtration to afford 7a(74.0 mg, yield 57%) as a colorless solid. 1H NMR (300 MHz,DMSO-d6) d 2.36 (3H, s), 2.44 (3H, s), 7.31 (1H, s), 7.98 (1H, br s),12.30 (1H, br s), 12.96 (1H, br s). HRMS: Calcd for C11H11N4OS [M+H]+: 247.0648. Found: 247.0625.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

51
[ 1009071-34-4 ]
[ 1330782-91-6 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-phenylthieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere;	15 6.1.15. 6-(3-Methyl-1H-pyrazol-4-yl)-2-phenylthieno[3,2-d]pyrimidin-4(3H)-one (7d) A mixture of 6d (111 mg, 0.358 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(492 mg, 1.60 mmol), Na2CO3 (331 mg, 1.07 mmol),PdCl2(dppf) (29 mg, 0.036 mmol), DME (3.0 mL) and water(1.5 mL) was stirred at 100 C for 2 h under Ar. Then 8 M NaOH(1.0 mL) was added. After stirring at 100 C for 0.5 h, the organic materials were extracted with EtOAc/THF. The combined extractswere dried over Na2SO4 and concentrated in vacuo. The residuewas purified by column chromatography on amino silica gel (nhexane/EtOAc, 80:20 to 0:100, v/v). The residue was trituratedwith MeOH-EtOAc and the precipitate was collected by filtrationto afford 7d (51 mg, yield 46%) as a pale yellow solid. 1H NMR(300 MHz, DMSO-d6) d 2.49 (3H, br s), 7.49 (1H, s), 7.51-7.65(3H, m), 7.94 (0.6H, br s), 8.10-8.20 (2H, m), 8.29 (0.4H, br s),12.65 (1H, br s), 13.02 (1H, br s). Anal. Calcd for C16H12N4OS0.1H2-O: C, 61.96; H, 3.96; N, 18.06. Found: C, 61.82; H, 3.97; N, 17.97.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

52
[ 1009071-34-4 ]
[ 1330783-25-9 ]
2-(ethoxymethyl)-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere;	16 6.1.16. 2-(Ethoxymethyl)-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (7e) General procedure: A mixture of 6d (111 mg, 0.358 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(492 mg, 1.60 mmol), Na2CO3 (331 mg, 1.07 mmol),PdCl2(dppf) (29 mg, 0.036 mmol), DME (3.0 mL) and water(1.5 mL) was stirred at 100 C for 2 h under Ar. Then 8 M NaOH(1.0 mL) was added. After stirring at 100 C for 0.5 h, the organic materials were extracted with EtOAc/THF. The combined extractswere dried over Na2SO4 and concentrated in vacuo. The residuewas purified by column chromatography on amino silica gel (nhexane/EtOAc, 80:20 to 0:100, v/v). The residue was trituratedwith MeOH-EtOAc and the precipitate was collected by filtrationto afford 7d (51 mg, yield 46%) as a pale yellow solid

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

53
[ 1009071-34-4 ]
[ 1330784-32-1 ]
C₁₇H₂₁N₅O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In 1,2-dimethoxyethane; water at 80℃;	17 A mixture of 6f (400 mg, 1.07 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(659 mg, 2.14 mmol), Cs2CO3 (696 mg, 2.14 mmol),PdCl2(dppf) (44.0 mg, 0.054 mmol), DME (5.0 mL) and water(0.5 mL) was stirred at 80 C overnight. The mixture was dilutedwith water and extracted with EtOAc. The combined extracts werewashed with brine, dried over MgSO4 and concentrated in vacuo.The residue was purified by column chromatography on silica gel(n-hexane/EtOAc, 9:1 to 1:1, v/v). The residue was dissolved inMeOH (4.0 mL) and 4 M HCl in EtOAc (1.0 mL, 4.00 mmol). Themixture was stirred at room temperature for 3 h. The resultingsolid was collected and washed with EtOAc to give 7f0 (50.0 mg,yield 13%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) d2.47 (3H, s), 2.69 (3H, br s), 4.23 (2H, br s), 7.31-8.30 (5H, m),9.54 (2H, br s). Anal. Calcd for C12H15N5OSCl20.15H2O: C, 41.07;H, 4.39; N, 19.96. Found: C, 41.29; H, 4.58; N, 19.67.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

54
[ 1009071-34-4 ]
[ 1330783-22-6 ]
6-(3-methyl-1H-pyrazol-4-yl)-2-morpholin-4-ylthieno[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,2-dimethoxyethane; water at 100℃; for 2h; Inert atmosphere;	20 6.1.19. 6-(3-Methyl-1H-pyrazol-4-yl)-2-morpholin-4-ylthieno[3,2-d]pyrimidin-4(3H)-one (7h) General procedure: A mixture of 6d (111 mg, 0.358 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(492 mg, 1.60 mmol), Na2CO3 (331 mg, 1.07 mmol),PdCl2(dppf) (29 mg, 0.036 mmol), DME (3.0 mL) and water(1.5 mL) was stirred at 100 C for 2 h under Ar. Then 8 M NaOH(1.0 mL) was added. After stirring at 100 C for 0.5 h, the organic materials were extracted with EtOAc/THF. The combined extractswere dried over Na2SO4 and concentrated in vacuo. The residuewas purified by column chromatography on amino silica gel (nhexane/EtOAc, 80:20 to 0:100, v/v). The residue was trituratedwith MeOH-EtOAc and the precipitate was collected by filtrationto afford 7d (51 mg, yield 46%) as a pale yellow solid. 1H NMR(300 MHz, DMSO-d6) d 2.49 (3H, br s), 7.49 (1H, s), 7.51-7.65(3H, m), 7.94 (0.6H, br s), 8.10-8.20 (2H, m), 8.29 (0.4H, br s),12.65 (1H, br s), 13.02 (1H, br s). Anal. Calcd for C16H12N4OS0.1H2-O: C, 61.96; H, 3.96; N, 18.06. Found: C, 61.82; H, 3.97; N, 17.97.

Reference： [1]Kurasawa, Osamu; Homma, Misaki; Oguro, Yuya; Miyazaki, Tohru; Mori, Kouji; Uchiyama, Noriko; Iwai, Kenichi; Ohashi, Akihiro; Hara, Hideto; Yoshida, Sei; Cho, Nobuo [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3658 - 3670]

55
[ 1009071-34-4 ]
[ 1562339-49-4 ]
tert-butyl 4-(3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-3-methyl-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 16h; Schlenk technique; Inert atmosphere;	2.1 Step 1: 3-Methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phe trifluoromethanesulfonate (80 mg, 0.16 mmol), (tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (59 mg, 0.19 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol), K2CO3 (66 mg, 0.48 mmol) were mixed in a Schlenk tube. The reaction was degassed with N2 for 15 min and dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature, partitioned between EtOAc and water. The organic layers were dried over Na2S04, concentrated under vacuum, then purified via column chromatography: eluting with gradient CH2Cl2/MeOH (0% to 30% MeOH), column: silica 4g to provide tert-butyl 4-(3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino)pyridazin-3-yl)phenyl)-3-methyl-lH-pyrazole-l-carboxylate (46 mg, 54%) as light brown solid .

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2017/100726, 2017, A1 Location in patent: Page/Page column 157

56
[ 1009071-34-4 ]
tert-butyl 4-bromo-7-[5-[[(2R*,4S*)-1-tert-butoxycarbonyl-2-methyl-4-piperidyl]-methyl-amino]thiazolo[5,4-d]thiazol-2-yl]pyrrolo[2,3-c]pyridine-1-carboxylate [ No CAS ]
tert-butyl 7-[5-[[(2R*,4S*)-1-tert-butoxycarbonyl-2-methyl-4-piperidyl]-methyl-amino]thiazolo[5,4-d]thiazol-2-yl]-4-(1-tert-butoxycarbonyl-3-methyl-pyrazol-4-yl)pyrrolo[2,3-c]pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	28 A mixture of tert-butyl 4-bromo-7-[5-[[(2R,4S)-l-tert-butoxycarbonyl-2-methyl-4- piperidyl]-methyl-amino]thiazolo[5,4-d]thiazol-2-yl]pyrrolo[2,3-c]pyridine-l-carboxylate (100 mg, 0.15 mmol), prepared based on the chemistry described in Example 27, tert-butyl 3-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-l-carboxylate (56 mg, 0.18 mmol), PdCl2(dppf) (12.5 mg, 0.015 mmol), and K2CO3 (0.15 mL, 0.30 mmol, 2.0 M) in DMF (1.0 mL) was stirred at 80 °C under argon overnight and then cooled and concentrated. The residue was chromatographed (ethyl acetate in dichloromethane, 0-100%) to provide tert-butyl 7-[5- (1787) [[(2R,4S)- l-tert-butoxycarbonyl-2-methyl-4-piperidyl] -methyl-amino] thiazolo [5, 4-d]thiazol-2- yl]-4-(l-tert-butoxycarbonyl-3-methyl-pyrazol-4-yl)pyrrolo[2,3-c]pyridine-l-carboxylate, which was treated with HC1 in dioxane (3.0 mL, 4.0 M)) at room temperature for 4 h and diluted with diethyl ether. The precipitate was collected by filtration and washed with diethyl ether then dried under a N2 stream to provide N-methyl-N- [(2R,4S)-2-methyl-4-piperidyl] -2- [4-(3 -methyl- 1H- pyrazol-4-yl)-lH-pyrrolo[2,3-c]pyridin-7-yl]thiazolo[5,4-d]thiazol-5-amine;hydrochloride (13 mg, 17%). (1788) LC-MS 465.6 [M+H]+, RT 0.91 min. 1H NMR (methanol-^) d: 7.99-8.19 (m, 3H), 6.93-7.01 (m, 1H), 3.92-4.07 (m, 1H), 3.37-3.58 (m, 3H), 3.18 (s, 3H), 2.47 (s, 3H), 2.11-2.40 (m, 3H), 1.94- 2.08 (m, 1H), 1.57 (br d, 7=6.7 Hz, 3H); 3NHs not observed.

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2020/5882, 2020, A1 Location in patent: Page/Page column 176-177

57
[ 1009071-34-4 ]
3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl) (hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile [ No CAS ]
3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate; 3-(8-(bis(4-methoxybenzyl)amino)-5-bromo-2-((2,6-difluorophenyl) (hydroxy)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile With potassium phosphate; dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphino-(2′-aminobiphenyl-2-yl)(chloro)palladium In 1,4-dioxane; water at 110℃; for 1h; Stage #2: With trifluoroacetic acid at 80℃; for 0.333333h;	102 Example 102. 3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(3-methyl-1H-pyrazol-4-yl)- jl,2,4j triazolo jl,5-aj pyrazin-6-yl)benzonitrile, Peak 1 To a solution of 3 -(8-(bis(4-methoxybenzyl)amino)-5 -bromo-2-((2,6-difluorophenyl)(hydroxy)methyl)- [1 ,2,4jtriazolo [1,5 -ajpyrazin-6-yl)benzonitrile (0.43g, 0.062 mmol) (from example 92, step 2), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole- 1 -carboxylate (0.076 g, 0.246 mmol), and dicyclohexyl(2’,4’,6’-triisopropylbiphenyl-2-yl)phosphine-(2’-aminobiphenyl-2- yl)(chloro)palladium (1:1) (0.010 g, 0.012 mmol) in dioxane (0.5 mL) and water (0.1 mL) was added potassium phosphate tribasic (0.065 g, 0.308 mmol). The reactionnMxture was stirred at 100 0Q for 1 hour. The reaction mixture was then diluted with water and DCM. The layers were separated, the aqueous layer was extracted with DCM, and the combined organic fractions were dried over MgSO4, filtered and concentrated. The cmde material was dissolved in TFA (2 mL) and heated to 80 °C for 20 minutes. The reaction mixture was then cooled to room temperature,concentrated, and basified by adding aqueous NaHCO3 solution. The crude material was directly purified by a silica gel column to afford the desired product (8 mg, 29%) as a racemic mixture. The product was then separated with chiral HPLC using a chiral column (Phenomenex Lux Sum Cellulose-4, 21. lx2SOmm) and 40% EtOH in Hexanes (20 mL/min) solvent system. Peak 1 was isolated, and further purified usingpreparative LC/MS (pH = 2, acetonitrile/water with TFA) to give the desired product as a TFA salt. LC-MS calculated for C23H17F2N80 (M+H): mlz = 459.1; found459.2.

Reference： [1]Current Patent Assignee: INCYTE CORP - WO2020/10197, 2020, A1 Location in patent: Page/Page column 234-235

58
[ 1009071-34-4 ]
[ 1330783-41-9 ]
C₂₆H₃₅N₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 2h; Inert atmosphere;

Reference： [1]Kurasawa, Osamu; Miyazaki, Tohru; Homma, Misaki; Oguro, Yuya; Imada, Takashi; Uchiyama, Noriko; Iwai, Kenichi; Yamamoto, Yukiko; Ohori, Momoko; Hara, Hideto; Sugimoto, Hiroshi; Iwata, Kentaro; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Nomura, Toshiyuki; Cho, Nobuo [Journal of Medicinal Chemistry, 2020, vol. 63, # 3, p. 1084 - 1104]

59
[ 1009071-34-4 ]
[ 1330783-61-3 ]
C₂₅H₃₃N₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 2h; Inert atmosphere;

Reference： [1]Kurasawa, Osamu; Miyazaki, Tohru; Homma, Misaki; Oguro, Yuya; Imada, Takashi; Uchiyama, Noriko; Iwai, Kenichi; Yamamoto, Yukiko; Ohori, Momoko; Hara, Hideto; Sugimoto, Hiroshi; Iwata, Kentaro; Skene, Robert; Hoffman, Isaac; Ohashi, Akihiro; Nomura, Toshiyuki; Cho, Nobuo [Journal of Medicinal Chemistry, 2020, vol. 63, # 3, p. 1084 - 1104]

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CAS No. :	1009071-34-4	MDL No. :	MFCD12407274
Formula :	C₁₅H₂₅BN₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CQZGWEHXOJJYPA-UHFFFAOYSA-N
M.W :	308.18 g/mol	Pubchem ID :	53216815
Synonyms :

Signal Word:	Warning	Class:	N/A
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Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
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[ CAS No. 1009071-34-4 ]

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[ 1009071-34-4 ] Synthesis Path-Downstream 1~59

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[ 1009071-34-4 ]

Organoboron

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[ 1009071-34-4 ]

Pyrazoles

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Quality Control of [ 1009071-34-4 ]

Related Doc. of [ 1009071-34-4 ]

Product Details of [ 1009071-34-4 ]

Safety of [ 1009071-34-4 ]

Application In Synthesis of [ 1009071-34-4 ]

[ 1009071-34-4 ] Synthesis Path-Downstream 1~59

Related Functional Groups of [ 1009071-34-4 ]

Organoboron

Amides

Esters

Related Parent Nucleus of [ 1009071-34-4 ]

Pyrazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1009071-34-4 ]

Related Parent Nucleus of
[ 1009071-34-4 ]