Name: 1065010-87-8|Potassium cyclopropyltrifluoroborate|97%
Brand: Ambeed
SKU: A172269
Price: 5.0 USD
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1
[ 21508-19-0 ]
[ 1065010-87-8 ]
[ 39763-81-0 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7481 - 7485

2
[ 7283-96-7 ]
[ 1065010-87-8 ]
[ 29481-26-3 ]

Yield	Reaction Conditions	Operation in experiment
50%	With palladium diacetate; caesium carbonate; catacxium A; In water; toluene; at 100℃;Sealed tube; Inert atmosphere;	Intermediate 25 -Cyclopropylthiophene-2-carbaldehyde Intermediate 2. 5 -Cyclopropylthiophene-2-carbaldehyde: A sealed reaction vial was charged with palladium(II) acetate (9.19 mg, 0.041 mmol), butyldi-1- adamantylphosphine (0.022 g, 0.06 1 mmol), potassium cyclopropyl trifluoroborate (0.306g, 2.067 mmol) and Cs2CO3 (2.000 g, 6.14 mmol). The vessel was purged and back filled with Ar. A solution of 5-chlorothiophene-2-carbaldehyde (0.3 g, 2.046 mmol) in a mixture of toluene (degassed) (8.0 mL) and water (degassed) (0.800 mL) was added and the reaction mixture stirred at 100 °C. The reaction mixture was heated at this temperature overnight. The reaction mixture was cooled to rt, diluted with water and extracted withDCM. The combined organic layers were washed with brine, dried over anhydrousNa2SO4, filtered and concentrated. The crude product was purified by chromatography toyield Intermediate 2 (156 mg, 50percent) as a yellow oil. ?H NMR (400 MHz, CDC13) oe 9.77(s, 1H), 7.57 (d, J= 3.7 Hz, 1H), 6.86 (dd, J = 3.9, 0.6 Hz, 1H), 2.16 (s, 1H), 1.36 - 1.23(m, 2H), 0.91 - 0.79 (m, 2H).

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7481 - 7485
[2]Patent: WO2015/191681,2015,A2 .Location in patent: Page/Page column 54

3
[ 6310-09-4 ]
[ 1065010-87-8 ]
[ 893738-59-5 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7481 - 7485
[2]Patent: WO2015/134701,2015,A1 .Location in patent: Page/Page column 55; 56

4
[ 13473-01-3 ]
[ 1065010-87-8 ]
[ 1063960-83-7 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7481 - 7485

5
[ 72990-37-5 ]
[ 1065010-87-8 ]
[ 1063960-86-0 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7481 - 7485

6
[ 1065010-87-8 ]
[ 2905-65-9 ]
[ 148438-02-2 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7481 - 7485

7
[ 1065010-87-8 ]
[ 7051-16-3 ]
[ 1063960-56-4 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7481 - 7485

8
[ 1065010-87-8 ]
[ 126325-50-6 ]
[ 1211399-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 80℃;Inert atmosphere; Sealed tube;	PREPARATIVE EXAMPLE 6; 2-Cvclopropyl-4-methylpyridin-3-amine (FFl); Following a modified synthetic procedure reported in J. Org. Chem. 2003, 68, 5534, a mixture of <strong>[126325-50-6]2-bromo-4-methylpyridin-3-amine</strong> (1.0 eq.), potassium cyclopropyltrifluoroborate (2.0 eq.), Cs2CO3 (3.0 eq.) and PdCl2(dppf)-CH2Cl2 adduct (0.1 eq.) in 10:1 solution THF:H2O (0.14M) was put in a 10-mL glass vial equipped with a small magnetic stirring bar. The reaction vessel was fitted with a rubber septum, was evacuated and back-filled with argon and sealed with an aluminum/Teflon crimp top. The reaction mixture was then heated for O/N at 80 0C. After completion of the reaction, the vial was cooled to RT before it was opened. The reaction mixture was diluted with EtOAc and filtered on a pad of Solca Floc200FCC. The crude product was purified by flash chromatography eluting with 10-100% EtO Ac/petroleum ether affording the titled compound as brown oil. 1H-NMR (400 MHz, DMSO-d6, 300K) delta 7.55 (IH, d, J = 4.7 Hz), 6.75 (IH, d, J = 4.7 Hz), 4.89 (2H, br. s), 2.13-2.04 (4H, m), 0.85-0.68 (4H, m). MS (ES) C9Hi2N2 requires: 148, found: 149 (M+H)+.

Reference： [1]Patent: WO2010/23480,2010,A1 .Location in patent: Page/Page column 43

9
[ 1065010-87-8 ]
[ 1142191-57-8 ]
[ 1241752-52-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium phosphate In touluene; water for 18.1667h; Reflux; Inert atmosphere;	6 As shown in step 6-v of Scheme 6, Compound 1020 (3.6 g, 13.5 mmol), potassium cyclopropyl-trifluoro-boron (2.5 g, 16.9 mmol), and potassium phosphate (8.6 g, 40.5 mmol) were taken up in about 80 mL of a toluene/water mixture. The reaction mixture was flushed with nitrogen gas for 10 minutes and Pd(PPtLs)4 (1.4 g, (1,21 mmol) was added. The reaction mixture was refluxed for 18 hours, resulting in a mixture of products by HPLC analysis. The reaction was cooled, diluted with EtOAc and saturated NaCl. The organics were separated, dried (MgSO4), and concentrated under reduced pressure to provide a solid, which was purified by medium pressure silica gel chromatography (0-8% EtOAc/hexanes gradient) to give 5-bromo-2-cyclopropyl-3-methoxypyridine (Compound 1022, 0.54 g, 70% pure): ESMS (M+H) 227.9/229.9. This compound was used as is in subsequent reactions.
55%	With potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ In water; toluene at 100℃; for 16h; Inert atmosphere;	10.c c) 5-bromo-2-cyclopropyl-3-methoxypyridine To a stirred solution of 2,5-dibromo-3-methoxypyridine (3.5 g, 13.11 mmol) in toluene (40 mL) and water (10 mL) tripotassium phosphate (8.35 g, 39.34 mmol). potassium cyclopropyltrifluoroborate (2.426 g, 16.39 mmol) were added and purged with argon. Then tetrakis(triphenylphosphine)palladium(0) (1.364 g, 1.18 mmol) was added, purged with argon and heated at 100°C for 16h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel to afford the desired product as a light yellow liquid (700 mg, 55%). MS (m/z)=227.6 [M+H]+;
	With potassium phosphate In water; toluene for 18h; Reflux;	6.v [00112] As shown in step 6-v of Scheme 6, Compound 1020 (3.6 g, 13.5 mmol), potassium cyclopropyl-trifluoro-boron (2.5 g, 16.9 mmol), and potassium phosphate (8.6 g, 40.5 mmol) were taken up in about 80 mL of a toluene/water mixture. The reaction mixture was flushed with nitrogen gas for 10 minutes and Pd(PPtLs)4 (1.4 g, (1,21 mmol) was added. The reaction mixture was refluxed for 18 hours, resulting in a mixture of products by HPLC analysis. The reaction was cooled, diluted with EtOAc and saturated NaCl. The organics were separated, dried (MgSO4), and concentrated under reduced pressure to provide a solid, which was purified by medium pressure silica gel chromatography (0-8% EtOAc/hexanes gradient) to give 5-bromo-2-cyclopropyl-3-methoxypyridine (Compound 1022, 0.54 g, 70% pure): ESMS (M+H) 227.9/229.9. This compound was used as is in subsequent reactions.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2010/135014, 2010, A1 Location in patent: Page/Page column 53-55
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2017/76931, 2017, A1 Location in patent: Page/Page column 21
[3]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2010/96389, 2010, A1 Location in patent: Page/Page column 47; 48

10
[ 1065010-87-8 ]
[ 1246081-93-5 ]
[ 1246085-54-0 ]

Yield	Reaction Conditions	Operation in experiment
55.2%	With potassium phosphate In water; toluene at 23 - 110℃; for 14h;	[0669] 8-Cyclopropyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[6] [l,4]oxazine-6- carbaldehyde (346A): To a suspension of potassium phosphate, tribasic (0.141 g, 0.665 mmol), potassium cyclopropyltrifluoroborate (0.049 g, 0.332 mmol), 8-chloro-2-methyl-3-oxo- 3,4-dihydro-2H-benzo[δ][l,4]oxazine-6-carbaldehyde 15 (0.05 g, 0.222 mmol) in toluene (Ratio: 5.00, 5mL) and water (Ratio: 1.000, 1.0 mL) was added PdOAc2 (3.73 mg, 0.017 mmol) and dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphine (0.016 g, 0.033 mmol) at 23 0C. The reaction was stirred at 110 0C for 14 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3 x 5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (0.25 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOΗ:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The late eluting fractions were dried in vacuo to provide the title compound as an off-white solid (0.0283 g, 0.122 mmol, 55.2 % yield). 1H NMR (400 MHz, DMSO-J6) δ ppm 0.69 - 0.81 (m, 2 H) 0.91 - 1.04 (m, 2 H) 1.48 (d, J=6.57 Hz, 3 H) 2.15 (tt, J=8.49, 5.15 Hz, 1 H) 4.85 (q, J=6.82 Hz, 1 H) 7.13 (d, J=1.77 Hz, 1 H) 7.19 (d, J=1.77 Hz, 1 H) 9.79 (s, 1 H) 10.89 (s, 1 H). ESI-MS: m/z 232.1 (M+H)+.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/111626, 2010, A2 Location in patent: Page/Page column 200-201

11
[ 23056-36-2 ]
[ 1065010-87-8 ]
[ 1255311-63-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With caesium carbonate In water; toluene at 98℃; for 48h; Inert atmosphere;	52 To a mixture of potassium cyclopropyltrifluoroborate (0.943 g, 6.37 mmol), palladium (II) acetate (0.0285 g, 0.126 mmol), di-1-adamantylbutylphosphine [CAS 321921-71-5] (0.0678 g, 0.189 mmol) and Cs2CO3 (6.165 g, 18.922 mmol) in toluene (20 ml) and water (4 ml) under a nitrogen atmosphere was added 2-chloro-4-nitropyridine (I g, 6.307 mmo). The reaction mixture was heated at 98 0C for 2 days. After cooling, the mixture was washed with water. The organic phase was separated and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel; Heptane/DCM from 100/0 to 50/50 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D52 (0.800 g, 77%) as yellow oil which crystallized upon standing

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC; ADDEX THERAPEUTICS SA - WO2010/130423, 2010, A1 Location in patent: Page/Page column 72

12
[ 1065010-87-8 ]
[ 1254981-79-7 ]
[ 1254981-96-8 ]

Yield	Reaction Conditions	Operation in experiment
48.7%	With caesium carbonate In toluene at 100℃; Inert atmosphere;	82 To a mixture of D70 (0.6 g, 1.8 mmol) in toluene (14 ml) under a nitrogen atmosphere were added potassium cyclopropyltrifluoroborate (0.799 g, 5.4 mmol), bis(adamantan- l-yl)(butyl)phosphine (0.019 g, 0.054 mmol), palladium(II) acetate (8.15 mg, 0.036 mmol) and Cs2CO3 (1.758 g, 5.4 mmol). The reaction mixture was heated at 100 0C overnight. After cooling, additional potassium cyclopropyltrifluoroborate (0.7 g, 4.71 mmol), bis(adamantan-l-yl)(butyl)phosphine (0.019 g, 0.054 mmol) and palladium(II) acetate (8.15 mg, 0.036 mmol) were added to the reaction mixture, which was then heated at 100 0C for 48 h. After cooling, more potassium cyclopropyltrifluoroborate (0.35 g, 2.37 mmol) was added and heated at 1000C for 3 days. After cooling, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/EtOAc from 100/0 to 60/40 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D82 (0.217 g, 48.7%) as a yellow solid.

Reference： [1]Current Patent Assignee: ADDEX THERAPEUTICS SA; JOHNSON & JOHNSON INC - WO2010/130424, 2010, A1 Location in patent: Page/Page column 131

13
[ 1065010-87-8 ]
[ 1190235-90-5 ]
[ 1190235-98-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate; catacxium A In water; toluene at 100℃; Inert atmosphere;	84a ethyl 1-({4-[3-cyclopropyl-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-1H-pyrazole-4-carboxylate ethyl 1-({4-[3-cyclopropyl-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)-1H-pyrazole-4-carboxylate Under a nitrogen atmosphere, to a mixed solution of the compound (400 mg, 0.87 mmol) obtained in Example 77e, potassium cyclopropyltrifluoroborate (140 mg, 0.96 mmol), cesium carbonate (850 mg, 2.6 mmol) and di-(1-adamantyl)-n-butylphosphine (20 mg, 0.050 mmol) in toluene/water (v/v = 10/1, 11 mL) was added palladium acetate (II) (8 mg, 0.030 mmol), and the mixture was stirred at 100°C overnight. The palladium catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane - hexane/ethyl acetate=70/30) to give the title compound (240 mg, 65%) as a pale-brown solid. 1H NMR (300 MHz, CHLOROFORM-d) δppm 0.74 - 0.88 (2 H, m), 1.00 - 1.14 (2 H, m), 1.34 (3 H, t, J=7.0 Hz), 1.94 - 2.12 (1 H, m), 4.30 (2 H, q, J=7.2 Hz), 5.68 (2 H, s), 7.28 (1 H, s), 7.54 (1 H, s), 7.77 (1 H, s), 7.89 (1 H, s), 8.00 (1 H, s), 8.09 (1 H, s) LCMS (ESI+) M+H+: 422.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2264017, 2010, A1 Location in patent: Page/Page column 194-195

14
[ 4316-97-6 ]
[ 1065010-87-8 ]
[ 21741-40-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; catacxium A;palladium diacetate; In toluene; at 100℃; for 24h;Inert atmosphere;	To a stirred solution of <strong>[4316-97-6]4,6-dichloro-5-methylpyrimidine</strong> (1 g, 6.13 mmol) in toluene (38.2 ml) was added potassium cyclopropyl(trifluoro)borate (0.999 g, 6.75 mmol), di(1- adamantyl)-n-butylphosphine (0.066 g, 0.184 mmol), palladium(ll) acetate (0.028 g, 0.123 mmol), cesium carbonate (6.00 g, 18.40 mmol) and the reaction mixture stirred under argon at 100 C for 24 hours. The reaction mixture was washed with water and extracted with ethyl acetate (3 x 25 mL). The organic layers were collected, dried under magnesium sulphate and evaporated under reduced pressure. Crude residues were purified by Si SP4 column chromatography eluting with a gradient of 0-15% ethyl acetate-isohexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (491 mg);m/z (ES+) 169 (M+1 ); 1H NMR (400 MHz, CDCI3) delta ppm 8.59 (1 H, s), 2.49 (3H, s), 2.03 - 2.22 (1 H, m), 1.16 - 1.28 (2H, m), 1.1 1 (2H, dt).

Reference： [1]Patent: WO2011/45353,2011,A1 .Location in patent: Page/Page column 61

15
[ 1065010-87-8 ]
[ 1301612-83-8 ]
[ 1301612-88-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate In α,α,α-trifluorotoluene; water at 120℃; for 1h; Sealed tube; Microwave irradiation;	138.1 Step 1: tert-Butyl 1-(4-(2-cyclopropyl-7-phenylfuro[2,3-b]pyrazin-6- yl)phenyl)cyclobutylcarbamate: Palladium(ll) acetate (0.5 mg, 0.002 mmol) was added to a pre-degassed solution of ferf-butyl 1-(4-(2-chloro-7-phenylfuro[2,3-6]pyrazin-6- yl)phenyl)cyclobutylcarbamate (50.0 mg, 0.105 mmol), di(1 -adamantyl)-n-butylphosphine (1.1 mg, 0.003 mmol), potassium cyclopropyltrifluoroborate (17.1 mg, 0.1 16 mmol), and cesium carbonate (103 mg, 0.315 mmol) in α,α,α-trifluorotoluene (1.0 ml)/water (0.1 ml) in a microwave vial. The vessel was sealed and irradiated at 120 °C for 20 minutes. Analysis by LCMS showed incomplete reaction and therefore, the reaction was further heated under microwave conditions at 120 °C for 40 minutes. LCMS indicated complete reaction. The reaction mixture was partitioned between EtOAc and 1 :1 water/brine, separated, dried (Phase Separator), solvents removed in vacuo and remaining residue purified by flash chromatography (Si02, 0-20%, EtOAc in cyclohexane) to give the title compound (50.6 mg, 0.1 18 mmol, quantitative) as a yellow oil. LCMS (Method A): RT = 8.73 min, M+H+ = 482.2.

Reference： [1]Current Patent Assignee: THE MCCLAY FOUNDATION - WO2011/55115, 2011, A1 Location in patent: Page/Page column 202

16
[ 1065010-87-8 ]
[ 1309831-15-9 ]
[ 1309833-20-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In water; toluene at 90℃; Inert atmosphere;	30 Alternative Suzuki Conditions for Synthesis of 1-(2-Cyclopropyl-4-fluoro-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-oneToluene (140 mL) then H2O (50 mL) was added to a mixture of 1-(2-bromo-4-fluoro-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (14.5 g, 45.6 mmol), potassium cyclopropyltrifluoroborate (7.42 g, 50.1 mmol), palladium(II) acetate (205 mg, 0.91 mmol), tricyclohexylphosphine (511 mg, 1.82 mmol) and K2CO3 (12.6 g, 91.1 mmol) under N2. The mixture was sparged with N2 for 10 mins then heated to 90° C. and stirred overnight. TLC did not indicate complete reaction, so more palladium(II) acetate (103 mg, 0.45 mmol), tricyclohexylphosphine (255 mg, 0.91 mmol) and potassium cyclopropyltrifluoroborate (3.7 g, 25.5 mmol) were added. The mixture was sparged with N2 once again and heated to 90° C. under N2 overnight. TLC only indicated a little further reaction, so after allowing to cool to room temperature, the mixture was filtered through a small plug of celite and the filter cake washed with EtOAc (5×50 mL). The filtrate was partitioned and the organic layer was dried (MgSO4), filtered and the solvent removed under vacuum to leave a solid residue. To the solid residue was added potassium cyclopropyltrifluoroborate (3.7 g, 25.5 mmol), palladium(II) acetate (103 mg, 0.45 mmol), tricyclohexylphosphine (255 mg, 0.91 mmol) and K2CO3 (6.3 g, 91.1 mmol). The mixture was placed under N2 and toluene (140 mL) and H2O (50 mL) were added. The mixture was sparged with N2 for 10 min then the mixture heated to 90° C. under N2 overnight. TLC indicated complete reaction. After allowing to cool to room temperature, the mixture was partitioned and the organic layer dried (MgSO4), filtered and the solvent removed under vacuum. The mixture was purified by filtration through a 4-to-5 inch plug of silica (the residue was dry-loaded on to silica) eluting with EtOAc/hexane (3:7 to 4:6; fractions collected in conical flasks) to give the product (11.0 g, 86%) as a solid.

Reference： [1]Current Patent Assignee: RIGEL PHARMACEUTICALS INC - US2011/130415, 2011, A1 Location in patent: Page/Page column 46

17
[ 1065010-87-8 ]
[ 1435-51-4 ]
[ 1311265-74-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; toluene; at 90.0℃; for 18.0h;Inert atmosphere;	Example 78 2'-amino-6-(3-cyclopropyl-5-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5(l'H)-oneStep A: A mixture of l ,3-dibromo-5-fluorobenzene (248 mu, 1.97 mmol), potassiumcyclopropyltrifluoroborate (321 mg, 2.17 mmol), K2CO3 (816.5 mg, 5.91 mmol), PdCl2(dppf)dcm (32 mg, 0.039 mmol), and toluene/water (3: 1, 8 mL) was sparged with N2 for 5 minutes. The mixture was stirred at 90C for 18 hours and allowed to cool to room temperature. The reaction mixture was then diluted with EtOAc (50 mL) and washed with brine (3 X 20 mL). The organic layer was separated, dried (MgS04), filtered and concentrated in vacuo. A portion of the crude product obtained was purified by preparative TLC eluting with hexane to provide l-bromo-3-cyclopropyl-5-fluorobenzene as a liquid.

Reference： [1]Patent: WO2011/72064,2011,A1 .Location in patent: Page/Page column 92

18
[ 1065010-87-8 ]
[ 39890-95-4 ]
[ 1321517-92-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;palladium diacetate; catacxium A; In water; toluene; at 100℃; for 18h;Inert atmosphere; Sealed tube;	2-Chloro-6-trifluoromethyl pyridine (451 mg, 2.5 mmol), cyclopropyltrifluoroborate potassium salt (373 mg, 2.52 mmol), palladium acetate (1 1 mg, 0.05 mmol), di(1- adamantyl)-n-butylphosphine (27 mg, 0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in a mixture of toluene and water (10:1 , 10 mL). After flushing the vessel under a stream of nitrogen gas for 5 minutes, the reaction tube was sealed and then heated at 100 C for 18 hours. On cooling, the mixture was partitioned between DCM (15 mL) and water (15 mL). The separated aqueous phase was extracted with DCM (2 x 15 mL) and the combined organic phases were passed through a phase separator and concentrated in vacuo, affording a yellow oil which was used without further purification (423 mg, crude).LCMS: major peak observed at 1.77 min; poor ionisation (method A)TLC Rf: 0.6 (EtOAc/hexane, 1 :9).

Reference： [1]Patent: WO2011/95625,2011,A1 .Location in patent: Page/Page column 110

19
[ 1092513-18-2 ]
[ 1065010-87-8 ]
[ 1332365-30-6 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 8126 - 8130

20
[ 1065010-87-8 ]
[ 38262-42-9 ]
[ 25033-19-6 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 8126 - 8130

21
[ 1065010-87-8 ]
[ 1354807-23-0 ]
[ 1354807-41-2 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium phosphate monohydrate In water; toluene at 100℃;	16 Example 16(E)-3-(4-Cyclopropyl-phenyl)-3-phenyl-l-pyridin-4-yl-propan-l-one oximeTo a solution of (E)-3-(4-bromo-phenyl)-3-phenyl-l-pyridin-4-yl-propan-l-one oxime (example 5, 100 mg) in toluene (0.9 mL) and water (0.1 mL) was added potassiumcyclopropyltrifluoroborate (47 mg), tri-potassium phosphate monohydrate (199 mg) and tetrakis(triphenylphosphine) palladium (0) (6 mg). The mixture was heated to 100°C overnight. After cooling to rt a saturated aqueous solution of NaHC03 was added, the phases were separated and the inorganic one was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc / w-heptane 1: 1) to yield (E)- 3-(4-cyclopropyl-phenyl)-3-phenyl-l-pyridin-4-yl-propan-l-one oxime (43 mg, 49%) as a white foam, MS (ESI+): m/z = 343.3 ([M+H]+).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2012/7365, 2012, A1 Location in patent: Page/Page column 110-111

22
[ 957345-85-6 ]
[ 1065010-87-8 ]
[ 1361941-18-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 2-bromo-4H,5H,6H-thieno[2,3-c]pyrrol-6-one; potassium cyclopropyltrifluoroborate With caesium carbonate In water for 0.5h; Reflux; Inert atmosphere; Stage #2: With di-(1-adamantyl)-n-butylphosphine at 100℃; for 14h;	116g Example 116g 2-Cyclopropyl-4H-thieno[2,3-c]pyrrol-6(5H)-one 116g CGIPHARM60WOA 100-mL single-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 116f (900 mg, 4.12 mmol), potassium cyclopropyltrifluoroborate (733 mg, 4.95 mmol), cesium carbonate (4.03 g, 12.4 mmol), toluene (18 mL), water (1 mL). After bubbling nitrogen through the resulting suspension for 30 min, palladium(II) acetate (279 mg, 0.412 mmol) and n-butyldi-l-adamantylphosphine (222 mg, 0.618 mmol) were added, and the reaction mixture was heated at 100 °C for 14 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 5% methanol/methylene chloride) to afford a 35% yield (254 mg) of 116g as an off-white solid: mp 109-110 °C; ]H NMR (300 MHz, CDC13) δ 6.72 (s, 1H), 6.08 (br s, 1H), 4.28 (s, 2H), 2.16 (m, 1H), 1.09 (m, 2H), 0.84 (m, 1H); MS (ESI+) m/z 180.1 (M+H).

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC; ROCHE HOLDING AG - WO2012/31004, 2012, A1 Location in patent: Page/Page column 97-98

23
[ 1065010-87-8 ]
[ 1373845-46-5 ]
[ 1373844-63-3 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium phosphate In water; toluene at 110℃; for 1h; Inert atmosphere; Microwave irradiation;	A A degassed suspension of 5-bromo-2-[6-(4-fluorophenoxy)pyridin-3-yl]-A-methyl-6-nitro-2H- indazole-3-carboxamide (10 mg, 0.021 mmol), potassium phosphate (35 mg, 0.16 mmol), potassium cyclopropyltrifluoroborate (19 mg, 0.13 mmol) and Pd(dppf)CI2.CH2Cl2 (3 mg, 0.004 mmol) in toluene (1 mL) and water (0.1 ml_) was heated under microwave irradiation at 110 °C for 1 h. The reaction mixture was diluted with EtOAc (3 mL), washed with water (1 mL) and brine (1 mL), then dried (MgS04) and concentrated to dryness. The residue was purified by flash column chromatography eluting with MeOH/DCM (0-10 %) to give 5- cyclopropyl-2-[6-(4-fluorophenoxy)pyridin-3-yl]-A/-methyl-6-nitro-2/-/-indazole-3-carboxamide as a tan solid (7 mg, 73 %).

Reference： [1]Current Patent Assignee: VAXART INC - WO2012/51659, 2012, A1 Location in patent: Page/Page column 57

24
[ 1065010-87-8 ]
[ 197376-41-3 ]
[ 1214911-59-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium phosphate;palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 24h;	Example 31A A Schlenk tube was charged with 244 mg (1 mmol) of Example 12AA, 192.37 mg (1.3 mmol) of potassium cyclopropyltrifluoroborate, 742.93 mg (3.5 mmol) of tri-potassium phosphate, 11.23 mg (0.05 mmol) of palladium(II)acetate, 28.04 mg (0.1 mmol) of tricyclohexylphosphine in toluene (4 ml) and water (200 mul) and heated to 100 C. for 24 hours. After cooling a solid was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 using n-hexane/ethyl acetate mixture of increasing polarity (from 100% n-hexane to 100% ethyl acetate) as eluant. 160 mg (78%) of the title compound were obtained.GC-MS (Method 3A): Rt: 11.08 minMS: 205 [M]+.

Reference： [1]Patent: US2012/115863,2012,A1 .Location in patent: Page/Page column 52-53

25
[ 1065010-87-8 ]
[ 1263375-39-8 ]
[ 1263375-17-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium phosphate In water; toluene at 115℃; for 0.416667h; Inert atmosphere; Microwave irradiation;	35.1 Example 35 (Compound 240)trans- A/ -(5-chloro-4-(5-cyclopropyl-6-((tetrahydro-2/-/-pyran-4-yl)methyl)aminopyrazin-2- yl)pyridin-2-yl)cyclohexane-1 ,4-diamineStep 1. Preparation of 6-(5-chloro-2-fluoropyridin-4-tl)-3-cyclopropyl-/V-((tetrahydro-2/-/- pyran-4-yl)methyl)pyrazin-2-amine: 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-//-((tetrahydro-2/-/-pyran-4- yl)methyl)pyrazin-2-amine (0.0316 g, 0.088 mmol), potassium cyclopropyltrifluoroborate (0.026 g, 0.177 mmol), and potassium phosphate (0.1 13 g, 0.531 mmol) were dissolved in a mixture of toluene (1 ml) and H20 (0.170 ml). The solution was then degassed by sparging with argon for 5 min. At this time it was treated with PdCl2(dppf).CH2Cl2 adduct (0.014 g, 0.018 mmol). The reaction mixture was then heated in the microwave at 1 15°C for 25 min. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to give 0.0445 g of the crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 20 EtOAc / 80 heptane to 70 EtOAc / 30 heptane gave 0.0271 g (84%) of 6-(5-chloro-2-fluoropyridin-4-tl)-3- cyclopropyl-/V-((tetrahydro-2/-/-pyran-4-yl)methyl)pyrazin-2-amine. LCMS (m/z): 363.1 (MH+), retention time = 1.06 min.
	With potassium phosphate In toluene at 115℃; for 0.416667h; Microwave irradiation; Inert atmosphere;	35.1 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-/V-((tetrahydro-2/-/-pyran-4- yl)methyl)pyrazin-2-amine (0.0316 g, 0.088 mmol), potassium cyclopropyltnfluoroborate (0.026 g, 0.177 mmol), and potassium phosphate (0.1 13 g, 0.531 mmol) were dissolved in a mixture of toluene (1 ml) and H20 (0.170 ml). The solution was then degassed by sparging with argon for 5 min. At this time it was treated with PdCl2(dppf).CH2Cl2 adduct (0.014 g, 0.018 mmol). The reaction mixture was then heated in the microwave at 1 15°C for 25 min. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to give 0.0445 g of the crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 20 EtOAc / 80 heptane to 70 EtOAc / 30 heptane gave 0.0271 g (84%) of 6-(5-chloro-2-fluoropyridin-4-tl)-3- cyclopropyl-/V-((tetrahydro-2/-/-pyran-4-yl)methyl)pyrazin-2-amine. LCMS (m/z): 363.1 (MH+), retention time = 1.06 min.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2012/101066, 2012, A1 Location in patent: Page/Page column 177-178
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2012/101065, 2012, A2 Location in patent: Page/Page column 194

26
[ 1065010-87-8 ]
[ 1400702-26-2 ]
[ 1400698-63-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate In water; toluene for 3h; Inert atmosphere; Reflux;	9.2 A mixture of the above compound (100 mg, 160 μηιο), potassium cyclopropyltrifluoroborate (45.9 mg, 321 μιηο), palladium acetate (3.7 mg, 16.0 μιηο), di(l- adamantyl)butylphosphine (9.1 mg, 24.1 μηιοι), cesium carbonate (105 mg, 321 μη ο), water (80 μ) and toluene (802 μ) was heated to reflux under argon atmosphere for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered through diatomite column, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 19: 1→17:3) to give ethyl 4-({(l-cyclopropyl- 4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (93.0 mg, 99%) as a pale yellow solid.APCI-MS m/z:585[M+H]+.1H-NMR (DMSO-d6) δ 0.25-0.95 (4H, m), 1.37 (3H, t, J= 7.3Hz), 2.38 (3H, s), 2.73-2.82 (1H, m), 4.40 (2H, q, J = 7.3Hz), 4.46-5.12 (2H, m), 7.20 (2H, d, J - 8.2Hz), 7.26 (2H, d, J = 8.8Hz), 7.69-7.75 (1H, m), 7.77-7.84 (3H, m), 8.01 (1H, d, J= 8.2Hz), 8.14 (2H, d, J= 8.5Hz), 8.49 (lH, d, J= 8.2Hz).
99%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene for 3h; Inert atmosphere; Reflux;	5.2 (2) Synthesis of ethyl 4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)(4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate A mixture of the compound obtained in ( 1) (100 mg, 160 µmol), cyclopropyltrifluoroborate potassium salt (45.9 mg, 321 µmol), palladium acetate (3.7 mg, 16.0 µmol), di(1-adamantyl)butylphosphine (9.1 mg, 24.1 µmol), and cesium carbonate (105 mg, 321 µmol) in water (80 µL) and toluene (802 µL) was heated under reflux for 3 hours under argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane:ethyl acetate = 19:1→17:3) to give ethyl 4-({(1-cyclopropyl-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (93.0 mg, 99%) as a pale yellow solid. APCI-MS m/z: 585 [M+H]+, 1H-NMR (DMSO-d6) δ 0.25-0.95 (4H, m), 1.37 (3H, t, J = 7.3 Hz), 2.38 (3H, s), 2.73-2.82 (1H, m), 4.40 (2H, q, J = 7.3 Hz), 4.46-5.12 (2H, m), 7.20 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.69-7.75 (1H, m), 7.77-7.84 (3H, m), 8.01 (1H, d, J = 8.2 Hz), 8.14 (2H, d, J = 8.5 Hz), 8.49 (1H, d, J = 8.2 Hz).
99%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene for 3h; Inert atmosphere; Reflux;	5.2 Synthesis of ethyl 4-({(1-cyclopropyl-4-methyl-isoquinolin-3-yl)[4-(trifluoromethoxy) l3enzyl]amino } sulfonyl)benzoate A mixture ofthe compound obtained in (1) (100mg, 160 jtmol), cyclopropyltrifluoroborate potassium salt (45.9 mg, 321 jtmol), palladium acetate (3.7 mg, 16.0 jtmol), di(1- adamantyl)butylphosphine (9.1 mg, 24.1 tmol), and cesium carbonate (105 mg, 321 tmol) in water (80 tL) and toluene (802 IL) was heated under reflux for 3 hours under argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated under reduced pressure. The obtained residue was purified by a silica gel colunm chromatography (hexane:ethyl acetate=1 9:1 - 17:3) to give ethyl 4-({(1 -cyclopropyl4-methylisoquinolin-3-yl)[4-(trifluoromethoxy) benzyl] amino}sulfonyl)benzoate (93.0 mg, 99%) as a pale yellow solid.APCI-MS mlz: 585 [M+H].10527] ‘H-NMR (DMSO-d5) ö 0.25-0.95 (4H, m), 1.37(3H, t, J=7.3 Hz), 2.38 (3H, s), 2.73-2.82 (1H, m), 4.40 (2H,q, J=7.3 Hz), 4.46-5.12 (2H, m), 7.20 (2H, d, J=8.2 Hz), 7.26(2H, d, J=8.8 Hz), 7.69-7.75 (1H, m), 7.77-7.84 (3H, m), 8.01(1H, d, J=8.2 Hz), 8.14 (2H, d, J=8.5 Hz), 8.49 (1H, d, J=8.2Hz).

Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - WO2012/124825, 2012, A1 Location in patent: Page/Page column 58; 59
[2]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP2896613, 2015, A1 Location in patent: Paragraph 0325; 0326
[3]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US2015/307454, 2015, A1 Location in patent: Paragraph 0523; 0525; 0526; 0527

27
[ 1065010-87-8 ]
[ 1413281-17-0 ]
[ 1413281-26-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In tetrahydrofuran; water at 85℃; for 24h; Inert atmosphere;	72.i Ethyl 2-amino-5-cyclopropyl-6-(trifluoromethyl)nicotinate A mixture of intermediate I.i (0.5 g, 1.6 mmol), potassium cyclopropyltrifluoroborate (0.249 g, 1.68 mmol), Cs2C03 (1.46 g, 4.5 mmol) in THF -water (10-1, 9 mL) was degassed with argon. Dichloro-1,1'-bis(diphenlyphosphino)ferrocene]dichloropalladium(II).CH2Cl2 complex (0.122 g, 0.150 mmol) was added. The reaction mixture was heated at +85°C for 1 day. After cooling to rt, the reaction mixture was partitioned between EA (50 mL) and water (40 mL). The two layers were separated and the aq. layer was extracted once more with EA (50 mL). The combined org. layers were dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hex 1:9) affording the title ester as a white powder (0.376 g, 86% yield).1H NMR (? 6-DMSO) ?: 7.83 (s, 1H); 7.31 (br. s, 2H); 4.30 (q, J = 7.1 Hz, 2H); 1.94 (m, 1H); 1.30 (t, J = 7.1 Hz, 3H); 0.88-0.95 (m, 2H); 0.57-0.64 (m, 2H).MS (ESI, m/z): 275.2 [M+H+] for C12H13N2O2F3
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; caesium carbonate In tetrahydrofuran Heating;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2013/72882, 2013, A1 Location in patent: Page/Page column 112-113
[2]Surivet, Jean-Philippe; Lange, Roland; Hubschwerlen, Christian; Keck, Wolfgang; Specklin, Jean-Luc; Ritz, Daniel; Bur, Daniel; Locher, Hans; Seiler, Peter; Strasser, Daniel Stefan; Prade, Lars; Kohl, Christopher; Schmitt, Christine; Chapoux, Gaëlle; Ilhan, Eser; Ekambaram, Nadia; Athanasiou, Alcibiade; Knezevic, Andreja; Sabato, Daniela; Chambovey, Alain; Gaertner, Mika; Enderlin, Michel; Boehme, Maria; Sippel, Virginie; Wyss, Pierre [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6705 - 6711]

28
[ 1065010-87-8 ]
[ 1214353-79-3 ]
[ 1415898-27-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With butyl-1-adamantylphosphine; caesium carbonate;palladium diacetate; In water; toluene; at 100℃; for 20h;Inert atmosphere;	To a mixture of palladium(II)acetate (17.9 mg, 79.8 mumol), butyl-1-adamantylphosphine (42.9 mg, 120 mumol), potassium cyclopropyltrifluoroborate (597 mg, 4.03 mmol) and cesium carbonate (3.9 g, 12.0 mmol) under an argon atmosphere was added a solution of <strong>[1214353-79-3]5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester</strong> (CAN 1214353-79-3, 1 g, 3.99 mmol) in toluene (25.2 ml) and water (2.8 mL) under an argon atmosphere. The reaction mixture was heated to 100 C. for 20 h, diluted with water (17.5 ml), poured onto 100 ml ice/brine and extracted with i-PrOAc (2×100 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow liquid. This crude material was purified by column chromatography (70 g SiO2, n-heptane/i-PrOAc 0-10% over 120 min) to give the title compound (497 mg, 59%) as yellow solid, MS (EI): m/e=212.0 [M+H]+.
59%	With caesium carbonate;butyl-1-adamantylphosphine; palladium diacetate; In water; toluene; at 100℃; for 20h;Inert atmosphere;	To a mixture of palladium(II)acetate (17.9 mg, 79.8 muiotaetaomicron), butyl- 1-adamantylphosphine (42.9 mg, 120 muiotaetaomicron), potassium cyclopropyltrifluoroborate (597 mg, 4.03 mmol) and cesium carbonate (3.9 g, 12.0 mmol) under an argon atmosphere was added a solution of <strong>[1214353-79-3]5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester</strong> (CAN 1214353-79-3, 1 g, 3.99 mmol) in toluene (25.2 ml) and water (2.8 mL) under an argon atmosphere. The reaction mixture was heated to 100C for 20 h, diluted with water (17.5 ml), poured onto 100 ml ice / brine and extracted with z'-PrOAc (2 x 100 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow liquid. This crude material was purified by column chromatography (70 g Si02, n-heptane / z'-PrOAc 0-10% over 120 min) to give the title compound (497 mg, 59%) as yellow solid, MS (EI): m/e = 212.0 [M+H]+.

Reference： [1]Patent: US2012/316147,2012,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2012/168350,2012,A1 .Location in patent: Page/Page column 69; 70

29
[ 1065010-87-8 ]
[ 1415899-56-7 ]
[ 1415899-57-8 ]

Yield	Reaction Conditions	Operation in experiment
36%	With caesium carbonate; catacxium A In water; toluene at 120℃; for 20h; Inert atmosphere;	166.b Palladium(II)acetate (1.19 mg, 5.3 μmol), butylbis(tricyclo[3.3.1.13,7]dec-1-yl)-phosphine (2.85 mg, 7.94 μmol, CAN 321921-71-5), potassium cyclopropyltrifluoroborate (39.6 mg, 267 μmol) and cesium carbonate (259 mg, 794 μmol) were combined to give a white solid. To this solid a degassed solution of 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (80 mg, 265 μmol) in toluene (2.02 mL)/water (224 μL) was added through a septum cap. The reaction mixture was heated to 120° C. and stirred for 20 h. After cooling to ambient temperature the reaction mixture was diluted with water (2 mL), poured onto 20 mL ice water/brine/1 N HCl, extracted with isopropyl acetate (2×40 mL), and washed with 20 mL ice water/brine. The organic layers were dried with Na2SO4 and concentrated in vacuo to give a light brown oily residue which was purified by preparative TLC (silica gel, 2.0 mm, DCM/MeOH, 49:1). The title compound (25 mg, 36%) was isolated as light yellow liquid; MS (ESI): 262.0 [M-H]-.
36%	Stage #1: potassium cyclopropyltrifluoroborate; 5-bromo-6-(tetrahydrofuran-2-ylmethoxy)pyridine-2-carboxylic acid With caesium carbonate In water; toluene at 120℃; for 20h; Inert atmosphere; Stage #2: With hydrogenchloride In water; toluene Cooling with ice;	166.b Palladium(II)acetate (1.19 mg, 5.3 μιηο), butylbis(tricyclo[3.3.1.13,7]dec-l-yl)-phosphine (2.85 mg, 7.94 μιηο, CAN 321921-71-5), potassium cyclopropyltrifluoroborate (39.6 mg, 267 μιηο) and cesium carbonate (259 mg, 794 μιηο) were combined to give a white solid. To this solid a degassed solution of 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2- carboxylic acid (80 mg, 265 μηιο) in toluene (2.02 mL) / water (224 μ,) was added through a septum cap. The reaction mixture was heated to 120°C and stirred for 20 h. After cooling to ambient temperature the reaction mixture was diluted with water (2 mL), poured onto 20 mL ice water/brine/1 N HC1, extracted with isopropyl acetate (2 x 40 mL), and washed with 20 mL ice water/brine. The organic layers were dried with Na2S04 and concentrated in vacuo to give a light brown oily residue which was purified by preparative TLC (silica gel, 2.0 mm, DCM/MeOH, 49: 1). The title compound (25 mg, 36%) was isolated as light yellow liquid; MS (ESI): 262.0 [M-H]~.
36%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 120℃; for 20h; Inert atmosphere;	4.b b) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid b) 5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid Palladium(II)acetate (1.19 mg, 5.3 μιηο), butylbis(tricyclo[3.3.1.13,7]dec-l-yl)-phosphine (2.85 mg, 7.94 μιηο, CAN 321921-71-5), potassium cyclopropyltrifluoroborate (39.6 mg, 267 μιηο) and cesium carbonate (259 mg, 794 μιηο) were combined to give a white solid. To this solid a degassed solution of 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2- carboxylic acid (80 mg, 265 μηιο) in toluene (2.02 mL) / water (224 μ^) was added through a septum cap. The reaction mixture was heated to 120 °C and stirred for 20 h. After cooling to ambient temperature the reaction mixture was diluted with water (2 mL), poured onto 20 mL ice water/brine/1 N HCl, extracted with isopropyl acetate (2 x 40 mL), and washed with 20 mL ice water/brine. The organic layers were dried with Na2S04 and concentrated in vacuo to give a light brown oily residue which was purified by preparative TLC (silica gel, 2.0 mm, DCM/MeOH, 49: 1). The title compound (25 mg, 36%) was isolated as light yellow liquid; MS (ESI): 262.0 [M-H]~.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/316147, 2012, A1 Location in patent: Page/Page column 99
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2012/168350, 2012, A1 Location in patent: Page/Page column 200; 201
[3]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1 Location in patent: Page/Page column 48-49

30
[ 1065010-87-8 ]
[ 1266118-30-2 ]
[ 1266118-38-0 ]

Yield	Reaction Conditions	Operation in experiment
55%	With caesium carbonate In tetrahydrofuran; water at 80℃; for 72h; Inert atmosphere;	179 Example 179: l-[6-(trans-4-ter/-Butyl-cyclohexyloxy)-4-cyclopropyl-quinolin-2-ylmethyl]- azetidine-3-carboxylic acid methyl ester THFl-[4-Bromo-6-(trans-4-fer?-butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-azetidine-3- carboxylic acid methyl ester (0.100 g, 0.000204 mol), cyclopropyl trifluoroborate potassium salt (0.050 g, 0.00034 mol), [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (0.019 g, 0.000023 mol), Cesium Carbonate (0.215 g, 0.000660 mol), Tetrahydrofuran (2.50 niL) and Water (0.25 rnL) were added to a 4OmL vial equipped with a magnetic stir bar. The vial was degassed by stirring under a flow of Ar. The reaction was stirred under Ar for 3d at 80 0C. The reaction was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using 0- 10% methanol in DCM as eluent (Rf =0.44 in 10% methanol/DCM). The product was further purified by preparative HPLC. Appropriate fractions were combined to give the product in 76 mg yield (55%) as bis-TFA salt. ESI-MS(M+H+): 451.30.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2011/17561, 2011, A1 Location in patent: Page/Page column 103-104

31
[ 1065010-87-8 ]
[ 14203-25-9 ]
[ 1299473-95-2 ]

Yield	Reaction Conditions	Operation in experiment
82%	With caesium carbonate In water; toluene at 100℃; for 2h; Industry scale;	1.C Step C: 2-Cvclopropyl-3-methoxycyclopent-2-en-l-one (1-4)2-Bromo-3-methoxycyclopent-2-en-l-one 3 (3.55 g, 18.58 mmol), potassium cycloproyltrifluoroborate (2.89 g, 19.51 mmol), l5 -bis(di-tert-butylphosphino)ferrocene palladium dichioride (0.363 g, 0.558 mmol), and CS2CO3 (18.17 g, 55.8 mmol) in Toluene (45.1 miyWater (4.51 ml) (degassed with N2 bubbling) were heated at 100 °C for 2 h. The reaction was diluted with ethyl acetate and dried (MgS04), then filtered through a pad of florisil, rinsing with ethyl acetate and the solvent was evaporated under reduced pressure. Purification by Kugelohr distillation (150°C (at) 5 Torr) afforded 14 (2.33 g, 82 %) as a light yellow oil. MS (ESI): m/z = 153.10 (MH+).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/53574, 2011, A1 Location in patent: Page/Page column 23

32
[ 358-23-6 ]
[ 1065010-87-8 ]
[ 36138-76-8 ]
[ 1421253-24-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 145-Cyclopropyl-2-methylphenyl trifluoromethanesulfonate.A solution of <strong>[36138-76-8]5-bromo-2-methylphenol</strong> (2.00 g, 10.7 mmol), potassium cyclopropyltrifluoroborate (2.85 g, 19.2 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.379 g, 0.535 mmol) and K3P04 (5.67 g, 26.7 mmol) in toluene (40 mL) and water (10 mL) was allowed to stir at 100 C for 17 h under nitrogen. The reaction was monitored by LH NMR. The mixture was cooled to rt, and diluted with 1 M HC1 aq (100 mL), brine and EtOAc. The products were extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated to give crude as red oil (1.73 g). The crude was used without further purification.To a solution of the crude product (1.73 g) and pyridine (1.21 mL, 15.0 mmol) in DCM (15 mL), Tf20 (2.17 mL, 12.8 mmol) was added at 0 C under nitrogen. The mixture was allowed to stir for 1 h. The reaction was monitored by TLC (25% EtO Ac/heptane). The mixture was diluted with brine and DCM. The organic layer was separated and concentrated. The residue was purified by flash columnchromatography on 40 g silica gel (with 15 g pre-column of silica gel; eluent: heptane/EtOAc =100:0 to 85: 15) to give 5-cyclopropyl-2-methylphenyl trifluoromethanesulfonate. LH NMR (400 MHz, CDC13) delta ppm 7.16 (d, J = 7.87 Hz, 1 H), 6.96 (dd, J= 1.64, 7.87 Hz, 1 H), 6.92 (d, J= 1.64 Hz, 1 H), 2.32 (s, 3 H), 1.85 - 1.92 (m, 1 H), 0.97 - 1.01 (m, 2 H), 0.65 - 0.69 (m, 2 H).

Reference： [1]Patent: WO2013/16197,2013,A1 .Location in patent: Page/Page column 94

33
[ 1065010-87-8 ]
[ 288067-35-6 ]
[ 1421253-27-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In toluene; at 100℃;Inert atmosphere;	15-B. 2-cyano-5-cyclopropylphenyl trifluoromethanesulfonateStep 1 : A solution of <strong>[288067-35-6]4-bromo-2-hydroxybenzonitrile</strong> (1 g, 5.05 mmol), potassiumcyclopropyltrifluoroborate (1.495 g, 10.10 mmol), K3P04 (5.05 ml, 15.15 mmol) and PdCl2(Amphos)2 (0.358 g, 0.505 mmol) in toluene (25 mL) was allowed to stir at 100 C under nitrogen overnight. The mixture was then cooled to room temperature, diluted with EtOAc/NH4Cl (aq), and filtered through a pad of Celite. The organic layer was seperated, dried over Na2S04, filtered and concentrated. The residue was purifed by FCC (0-50%o EtO Ac/heptane) to provide 4-cyclopropyl-2-hydroxybenzonitrile, LH NMR (400 MHz, CH2C12) 8 12.17 (br. s., 1H), 7.23 (d, J= 8.34 Hz, 1H), 6.51 - 6.58 (m, 2H), 1.82 (tt, J = 5.02, 8.37 Hz, 1H), 0.94 - 1.00 (m, 2H), 0.68 - 0.73 (m, 2H).

Reference： [1]Patent: WO2013/16197,2013,A1 .Location in patent: Page/Page column 95

34
[ 20780-72-7 ]
[ 1065010-87-8 ]
[ 1428559-40-3 ]

Yield	Reaction Conditions	Operation in experiment
43%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In tetrahydrofuran; water at 130℃; for 4h; Microwave irradiation;	51 General procedure: 4-Bromoisatin (1 eq) was added to a solution of the potassium trifluoroborate salt (1.4 eq), K3P04 (3.6 eq) and degassed solvent. The reaction mixture was degassed and Pd(PPh3)2C12or Pd(dppf)2C12 (0.1 eq) was added. The reaction vessel was sealed and heated by microwave irradiation (Biotage Initiator) for 4 h at 130°C. The reaction mixture was cooled to rt, diluted with EtOAc (-10 mL/mmol substrate) and filtered through Celite. The organic solution was washed with brine (-10 mL/mmol substrate) and the resulting aqueous layer was further extracted with EtOAc (2 x). The combined organic layers were dried over MgSO4, filtered andconcentrated in vacuo to give the crude product which was purified as specified below.
43%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In tetrahydrofuran; water at 130℃; for 4h; Sealed tube; Microwave irradiation;	51 General Procedure 3 Suzuki Coupling of 4-bromoindoline-2,3-dione Derivatives with Trifluoroborate Potassium Salts [0344] 4-Bromoisatin (1 eq) was added to a solution of the potassium trifluoroborate salt (1.4 eq), K3PO4 (3.6 eq) and degassed solvent. The reaction mixture was degassed and Pd(PPh3)2Cl2 or Pd(dppf)2Cl2 (0.1 eq) was added. The reaction vessel was sealed and heated by microwave irradiation (Biotage Initiator) for 4 h at 130° C. The reaction mixture was cooled to rt, diluted with EtOAc (10 mL/mmol substrate) and filtered through Celite. The organic solution was washed with brine (10 mL/mmol substrate) and the resulting aqueous layer was further extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product which was purified as specified below. Example 51-preparation of 2″-(((9-Cyclopropyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)methyl)benzonitrile 4-Cyclopropylindoline-2,3-dione Following General Procedure 3,4-bromoisatin (300 mg, 1.33 mmol), potassium cyclopropyltrifluoroborate (275 mg, 1.86 mmol), K3PO4 (1.01 g, 14.8 mmol) and Pd(dppf)2Cl2 (93 mg, 0.13 mmol) in THF/ H2O (3:1, 4 mL) gave the crude reaction mixture, which was purified via flash column chromatography (eluent 30-40° C. petrol/acetone, 4:1) to afford the product as an orange solid. (36 mg, 43%). [0645] δH (500 MHz, DMSO-d6); 0.80-0.84 (2H, m), 1.06-1.15 (2H, m), 2.78-2.89 (1H, m), 6.49 (1H, d, J=7.8 Hz), 6.62 (1H, d, J=7.8 Hz), 7.40 (1H, app t, J=7.8 Hz), 10.98 (1H, br s) [0646] δC (125 MHz, DMSO-d6) 10.6, 10.9, 108.4, 116.8, 126.3, 138.2, 147.6, 150.4, 159.2, 176.7 [0647] mp 145-148° C.

Reference： [1]Current Patent Assignee: UNIVERSITY OF OXFORD; Oxford University Innovation (in: Oxford University) - WO2013/41859, 2013, A1 Location in patent: Paragraph 00156; 00397-00400
[2]Current Patent Assignee: UNIVERSITY OF OXFORD; Oxford University Innovation (in: Oxford University) - US2014/378451, 2014, A1 Location in patent: Paragraph 0344; 0643-0647

35
[ 1065010-87-8 ]
[ 152406-28-5 ]
[ 1449752-99-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 100℃; for 36h;
74%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 100℃; for 36h;	1 To a stirred solution of agelastatin A (1) (14.8 mg, 0.0434 mmol) in THF-H20 (4 mL; 3:1 v/v) were added potassium cyclopropyl trifluoroborate (7.4 mg, 0.0521 mmol), Cs2C03 (46.7 mg, 0.143 mmol), and PdCl2(dppf) (17.7 mg, 0.0217 mmol). After Stirling at 100 °C for 24 h, the mixture was cooled to room temperature and additional amounts of potassium cyclopropyl trifluoroborate (7.4 mg, 0.0521 mmol) and PdCl2(dppf) (17.7 mg, 0.0217 mmol) were added. After stirring for additional 12 h at 100 °C, the whole mixture was cooled to room temperature and transferred to a separatory funnel where it was partitioned between CH2C12 and 0. The aqueous layer was separated and concentrated. The residue was purified by flash silica gel column chromatography (MeOH/CH2Cl2 1 :7) to give cyclopropylagelastatin A (CPAA) (5) (9.7 mg, 74%) as a colorless solid. Compound 5: colorless solid; [a]25D-43.3 (c 0.065, MeOH); IR (KBr) v 3383, 1633 cm"1; 1H MR (400 MHz, CD3OD) δ 6.79 (d, 1H, J= 4.0 Hz), 5.86 (d, 1H, J= 4.0 Hz), 4.74 (ddd, 1H, J= 11.6, 6.4, 6.0 Hz), 4.04 (d, 1H, J= 5.2 Hz), 3.86 (s, 1H), 2.80 (s, 3H), 2.69 (dd, 1H, J= 13.2, 6.4 Hz), 2.12 (dd, HI, J= 12.8, 12.4 Hz), 1.81 (m, 1H), 0.96-0.92 (m, 2H), 0.70 (m, 1H), 0.60 (m, 1H); 13C MR (100 MHz, CD3OD) S 162.10, 161.51, 141.04, 121.88, 115.23, 107.50, 95.90, 67.53, 62.48, 52.99, 40.34, 24.20, 7.39, 7.19, 6.31; MS m/z 303 (M+H^), 93 (100%); HRMS (FAB) calcd for Ci5Hi9N403 (M+H+): 303.1457, found: 303.1482.

Reference： [1]Li, Zhimin; Shigeoka, Daisuke; Caulfield, Thomas R.; Kawachi, Takashi; Qiu, Yushi; Kamon, Takuma; Arai, Masayoshi; Tun, Han W.; Yoshimitsu, Takehiko [MedChemComm, 2013, vol. 4, # 7, p. 1093 - 1098]
[2]Current Patent Assignee: OSAKA UNIVERSITY; MAYO FOUNDATION - WO2014/59314, 2014, A1 Location in patent: Page/Page column 23; 43

36
[ 1065010-87-8 ]
[ 3038-48-0 ]
2-(trifluoromethyl)-6-(cyclopropyl)phenylacetic acid [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 17508 - 17513

37
[ 1065010-87-8 ]
[ 62778-19-2 ]
[ 1533425-16-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In tetrahydrofuran; water at 105℃; Inert atmosphere;	39 1,3-dichloro-2-cyclopropyl-5-nitrobenzene While purging a 50-mL seal tube with argon, added l,3-dichloro-2-iodo-5-nitrobenzene (1.0 g, 3.15 mmol, Eq: 1.00), potassium cyclopropyltrifluoroborate (584.3 mg, 3.95 mmol, Eq: 1.26), potassium carbonate (1.0 g, 7.24 mmol, Eq: 2.3), bis(triphenylphosphine)palladium(II) chloride (442 mg, 630 μηιο, Eq: 0.200), tetrahydrofuran (18 mL), and water (2.0 mL). Sealed the reaction mixture under argon and heated to 105 °C. After 16 h, cooled and carefully removed an aliquot while purging with argon. The HPLC showed starting material remaining. Added more potassium cyclopropyltrifluoroborate (100.0 mg, 0.676 mmol, Eq: 0.215), bis(triphenylphosphine)palladium(II) chloride (220.5 mg, 0.314 mmol, Eq: 0.10), and potassium carbonate (1.00 g, 7.24 mmol, Eq: 2.3) while purging with argon. Heated over weekend at 105 °C. HPLC after 64 h more showed all the starting material had been consumed. Diluted with ethyl acetate and washed with 1 N hydrochloric acid and saturated sodium chloride solution. Dried over magnesium sulfate, filtered, and concentrated onto silica gel. Purified using a 120 g silica gel column on an Intelliflash 280; collected peaks only in 28 mL fractions at 76 mL/min; equilibrated with heptane; dry loaded; eluted 4 min with heptane; increased from 0 - 15% dichlormethane/heptane over 20 min. Obtained 505 mg (69%) of l,3-dichloro-2-cyclopropyl-5- nitrobenzene as a white waxy solid.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/6066, 2014, A1 Location in patent: Paragraph 0260

38
[ 371-67-5 ]
[ 1065010-87-8 ]
potassium (1-cyclopropyl-2,2,2-trifluoroethyl)trifluoroborate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 2,2,2-trifluorodiazoethane; potassium cyclopropyltrifluoroborate With chloro-trimethyl-silane In toluene at 40℃; Inert atmosphere; Stage #2: With potassium hydrogen bifluoride In acetone; toluene at 0 - 20℃; for 0.5h; Inert atmosphere;
80%	Stage #1: 2,2,2-trifluorodiazoethane; potassium cyclopropyltrifluoroborate With chloro-trimethyl-silane In toluene at 40℃; Inert atmosphere; Sealed tube; Stage #2: With potassium hydrogen difluoride In acetone; toluene at 0 - 23℃; for 0.5h; Inert atmosphere;	III Potassium (1-cyclopropyl-2,2,2-trifluoroethyl)trifluoroborate General procedure: [0115] General procedure for the synthesis of trifluoromethylated potassium organ otrifluoroborates [0116] Potassium organotrifluoroborate (1 mmol) was added into a 20 mL Biotage microwave vial equipped with a stir bar. The vial was sealed and purged with argon three times. A solution of CF3CHN2 in CH2C12 (-0.5 M, 4 mL) or toluene (-0.5 M, 4 mL) was added under Ar. Then freshly distilled MesSiCl (120 mg, 1.1 mmol) or / tolylSiCi3 (248 mg, 1.1 mmol) was added, and the reaction was stirred at ambient room temperature ("RT," or about 20-23 °C) in CH2CI2 or about 40 °C in toluene overnight. The reaction was cooled to 0 °C, then a saturated solution of KHF2 (1 mL, 4.5 M) was added dropwise under Ar. Acetone (3 mL) was added to increase the solubility and improve the stirring of the reaction. The reaction was allowed to warm to RT and stirred for an additional 30 min under Ar. The solvent was evaporated from the crude reaction mixture, and the product was extracted into dry acetone to eliminate the inorganic salts. The acetone was evaporated and the desired product was recrystallized from the crude mixture.; [0129] Following the general procedure, starting from potassium 1- cyclopropyltrifluoroborate (148 mg, 1 mmol), using toluene (~1 M CF3CHN2, 2 mL) and TMS- Cl at RT, the desired product was obtained as a white solid (184 mg, 80%) after the unreacted 1- cyclopropyltrifluoroborate was removed by recrystallization in acetone/Et20, and the filtrate was evaporated; mp 224-227 °C; IR (neat) 1317, 1254, 1229, 1 163, 1120, 1054, 997, 966, 944, 848, 788, 750, 690, 620 cm'YH NMR (500 MHz, acetone-i/6) δ 0.78 - 0.76 (m, 1H), 0.40 - 0.28 (m, 3H), 0.14 - 0.09 (m, 2H); 13C NMR (126 MHz, acetone-i/6) δ 132.0 (q, J= 278.5 Hz), 39.8, 7.5 (d, J= 3.8 Hz), 4.31, 3.33; 19F NMR (471 MHz, acetone-i/6) δ -62.05, -142.36 (q, J = 51.8 Hz); nB NMR (128 MHz, acetone-i/6) δ 3.52 (q, J= 55.1 Hz); HRMS (ESI-TOF) m/z calcd. for C5H6BF6" [M-K]" 191.0467, found 191.0494.

Reference： [1]Argintaru, O. Andreea; Ryu, Daweon; Aron, Ioana; Molander, Gary A. [Angewandte Chemie - International Edition, 2013, vol. 52, # 51, p. 13656 - 13660][Angew. Chem., 2013, vol. 125, # 51, p. 13901 - 13905,5]
[2]Current Patent Assignee: UNIVERSITY OF PENNSYLVANIA - WO2014/126990, 2014, A1 Location in patent: Paragraph 0115; 0116; 0129

39
[ 1065010-87-8 ]
[ 1527525-21-8 ]
[ 1527525-24-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 105℃; for 72h; Inert atmosphere;	81.A tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate A mixture of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.2225 mmo 1; 115.9 mg), potassiumcyclopropyl trifluoroborate (0.3337 mmol; 50.90 mg), butyldi-1-adamantylphosphine (0.06674 mmol; 25.19 mg), cesium carbonate (0.6674 mmol; 217.4 mg) and palladium (II) acetate (0.04449 mmol; 9.994 mg) in water (0.5 mL) and Toluene (4.5 mL) was purged with Argon for 1 minute. The reaction mixture in a pressure tube was stirred at 105°C for 3 days. The layers were separated. The organic later was concentrated. The residue was purified on silica eluted with 0 to5% MeOH in DCM to afford tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (129 mg, 100%).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/1377, 2014, A1 Location in patent: Page/Page column 127

40
[ 1261606-45-4 ]
[ 1065010-87-8 ]
[ 1552290-28-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 80℃; for 19h; Inert atmosphere; Sealed tube;	4.3.18 Ethyl 2-(2-chloro-4-cyclopropylphenyl)acetate (4b) To a 5mL vial was added ethyl 2-(4-bromo-2-chlorophenyl)acetate (3a, 100mg, 0.36mmol), potassium cyclopropyltrifluoroborate (66mg, 1.2equiv), Pd(OAc)2 (8.1mg, 10mol%), butyl di-1-adamantylphosphine (20mg, 15mol%), Cs2CO3 (352mg, 3.0equiv), water (0.24mL) and toluene (2.2mL). The mixture was purged with nitrogen for 1min and heated at 80°C for 19h. The reaction mixture was cooled, diluted with water and DCM and the layers were separated. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to afford compound 4b as a yellow oil (73mg, 86%). FTIR (thin film, cm-1) 3083, 2982, 1734, 1158; 1H NMR (400MHz, CDCl3) δ 7.14 (d, J=7.9Hz, 1H), 7.07 (d, J=1.9Hz, 1H), 6.92 (dd, J=7.9, 1.9Hz, 1H), 4.16 (q, J=7.1Hz, 2H), 3.70 (s, 2H), 1.84 (dt, J=8.4, 5.1Hz, 1H), 1.29-1.21 (t, J=7.1Hz, 3H), 1.00-0.91 (m, 2H), 0.72-0.63 (m, 2H); 13C NMR (101MHz, CDCl3) δ 170.8, 145.1, 134.4, 131.4, 131.1, 129.3, 126.7, 124.4, 60.9, 38.8, 14.9, 14.2, 9.3; HRMS (ESI+) calcd for C13H16ClO2 ([M+H]+), 239.0839; found, 239.0827.

Reference： [1]Wong, Brian; Linghu, Xin; Crawford, James J.; Drobnick, Joy; Lee, Wendy; Zhang, Haiming [Tetrahedron, 2014, vol. 70, # 7, p. 1508 - 1515]

41
[ 552331-06-3 ]
[ 1065010-87-8 ]
[ 1578483-81-4 ]

Yield	Reaction Conditions	Operation in experiment
41%	With palladium diacetate; caesium carbonate; catacxium A; In water; toluene; at 100℃; for 2h;Microwave irradiation;	Preparation 2: 3-Chloro-6-cyclopropylisoquinoline Method D A suspension of <strong>[552331-06-3]6-bromo-3-chloroisoquinoline</strong> (50 mg, 0.21 mmol), potassium cyclopropyltrifluoroborate (40 mg, 0.27 mmol), Pd(OAc)2 (3.7 mg, 0.016 mmol), Cs2C03 (202 mg, 0.62 mmol) and di(1 -adamantyl)-n-butylphosphine (5.54 mg, 0.015 mmol) in toluene/water (4/0.4 mL) was stirred at 100 under microwave irradiation for 120 minutes. The reaction mixture was filtered, concentrated in vacuo and purified using Biotage silica gel column chromatography eluting with DCM to afford the title compound (17 mg, 41 %). 1 H NMR (500 MHz, CDCI3): delta 8.97 (s, 1 H), 7.85 (d, J = 8.6 Hz, 1 H), 7.61 (d, J = 1.0 Hz, 1 H), 7.46 - 7.38 (m, 1 H), 7.33 - 723 (m, 1 H), 2.05 - 2.01 (m, 1 H), 1 .19 - 1 .10 (m, 2H), 0.91 - 0.85 (m, 2H). LCMS (ESI) Rt = 2.77 minutes MS m/z 204 [M+H]+

Reference： [1]Patent: WO2014/37751,2014,A1 .Location in patent: Paragraph 00254-00256

42
[ 1065010-87-8 ]
[ 1357095-18-1 ]
[ 1613238-49-5 ]

Yield	Reaction Conditions	Operation in experiment
78.5%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 115℃; for 16h;	42.b 3-Cyclopropyl-4-cyclopropylmethoxy-pyridine 3-Cyclopropyl-4-cyclopropylmethoxy-pyridine To a solution of 3-Bromo-4-cyclopropylmethoxy-pyridine (Example 42a, 4.1 g, 18.0 mmol) in a mixture of toluene (55 ml) and water (6.5 ml) was added potassium cyclopropyltrifluoroborate (CAN 1065010-87-8, 2.79 g, 18.9 mmol), palladium(II) acetate (80.7 mg, 360 μιηο), butyldi-l-adamantylphosphine (CAN 321921-71-5, 193 mg, 539 μιηο) and cesium carbonate (14.6 g, 44.9 mmol). The reaction mixture was stirred at 115°C for 16h, cooled down to room temperature and filtered through a pad of celite. The filtrate was poured into a separatory funnel, diluted with ethylacetate and extracted with water. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude was purified by flash chromatography on silica eluting with a heptane/(solution 3% triethylamine in ethylacetate) gradient to yield the title compound (2.67gr, 78.5%) as a yellow oil. MS (ESI, m/z): 190.3 (M+H+).
68%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 125℃; for 7h;	1.b b) 3-cyclopropyl-4-(cyclopropylmethoxy)pyridine To a solution of 3-bromo-4-(cyclopropylmethoxy)pyridine (8.1 g, 35.5 mmol, Eq: 1.00) in a mixture of toluene (150 mL) and water (18 mL) was added potassium cyclopropyltrifluoroborate (CAS 1065010-87-8) (5.52 g, 37.3 mmol, Eq: 1.05), Cs2C03 (23.1 g, 71.0 mmol, Eq: 2.0), butyldi-l-adamantylphosphine (382 mg, 1.07 mmol, Eq: 0.03) and Pd(OAc)2 (159 mg, 710 μιηο, Eq: 0.02). The reaction mixture was stirred at 125°C for 7 h. Reaction mixture was cooled down and poured into a separatory funnel, ethyl acetate and water were added. After extraction of the mixture, the organic phase was collected, dried over Na2S04 and evaporated down to dryness. Flash chromatography with a 120 g Si02 column, and an eluent mixture of heptane and ethyl acetate gave 4.6 g of the desired product (Yield 68%). MS (ESI, m/z) 190.3 (MH+).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86805, 2014, A1 Location in patent: Page/Page column 69-70
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2014/154612, 2014, A1 Location in patent: Page/Page column 39; 40

43
[ 36953-42-1 ]
[ 1065010-87-8 ]
[ 1346544-23-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With palladium diacetate; caesium carbonate; catacxium A; In water; toluene; at 115℃;Inert atmosphere;	Example 48 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl- l-methylcarbamoyl-propyl)-amide a) 4-Chloro-3-cyclopropyl-pyridine To a solution of <strong>[36953-42-1]3-bromo-4-chloropyridine</strong> (CAN 36953-42-1, 4 g, 20.8 mmol) in a mixture of toluene (72 ml) and water (8.5 ml) under an argon atmosphere were added potassium cyclopropyltrifluoroborate (3.23 g, 21.8 mmol), palladium (II) acetate (93.3 mg, 416 muiotaetaomicron), butyldi-l-adamantylphosphine (224 mg, 624 muiotaetaomicron) and cesium carbonate (16.9 g, 52.0 mmol). The reaction mixture was stirred overnight at 115C, cooled down to room temperature and filtered through a pad of celite. The filtrate was poured into a separatory funnel, diluted with ethyl acetate and extracted with an aqueous solution 1.0M sodium bicarbonate. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/( solution 3% triethylamine in ethyl acetate) gradient to yield the title product (2.39g, 75%) as a yellow liquid. MS (ESI, m/z): 154.0 (M+H+).
67%	With palladium diacetate; caesium carbonate; catacxium A; In water; toluene; at 115℃;Inert atmosphere;	To a solution of <strong>[36953-42-1]3-bromo-4-chloropyridine</strong> (7.1 g, 36.9 mmol, Eq: 1.00) in toluene/water (153 mL/ 18 mL) was added Potassium Cyclopropyltrifluoroborate (CAS 1065010-87-8) (8.41 g, 38.7 mmol, Eq: 1.05), palladium (II) acetate (331 mg, 1.48 mmol, Eq: 0.04), cesium carbonate (30.1 g, 92.2 mmol, Eq: 2.5) and Butyldi-l-Adamantylphosphine (661 mg, 1.84 mmol, Eq: 0.05). Reaction was stirred at 1 15C overnight under argon. LC-MS showed product. Extraction with water/ethyl acetate (3 times). Organic layer was dried on MgS04 and evaporated. Column on Si02 with a gradient heptane/ethyl acetate gave 3.8 g of the desired compound as a yellow oil (Yield 67%). MS (ESI, m/z): 154.0 (MH+).

Reference： [1]Patent: WO2014/86805,2014,A1 .Location in patent: Page/Page column 74-75
[2]Patent: WO2014/154612,2014,A1 .Location in patent: Page/Page column 73

44
[ 1065010-87-8 ]
[ 1613238-91-7 ]
[ 1613236-27-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	With palladium diacetate; caesium carbonate; catacxium A In toluene at 125℃; for 18h; Inert atmosphere;	97.d d) 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1,3,3-trimethyl-l- (5-methyl-[l,2,4]oxadiazol-3-yl)-butyl]-amide d) 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1,3,3-trimethyl-l- (5-methyl-[l,2,4]oxadiazol-3-yl)-butyl]-amide To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-(N- hydroxycarbamimidoyl)-l,3,3-trimethyl-butyl]-amide (Example 97c, 0.175 g, 365 μmol) in toluene (2 ml) under an argon atmosphere was added potassium cyclopropytrifluoroborate (108 mg, 730 μιηο,), palladium (II) acetate (4.1 mg, 18.3 μιηο) , butyldi-1- adamantylphosphine (13.1 mg, 36.5 μιηο) and cesium carbonate (243 μ, 730 μιηο). The reaction was stirred at 125°C for 18hours. The reaction was filtered through a pad of celite.The filtrate was diluted with ethylacetate and was extracted with an 1.0M aqueous solution of sodium bicarbonate.The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (154mg, 96%) as a light yellow oil. MS (ESI, m/z): 441.7 (M+H+).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86805, 2014, A1 Location in patent: Page/Page column 120-121

45
[ 1065010-87-8 ]
[ 1616931-07-7 ]
[ 1616930-75-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 100℃; for 24h; Inert atmosphere;	34 Intermediate 34b Potassium cyclopropyltrifluoroborate (248 mg), palladium(II) acetate (26 mg), di(1-adamantyl)-n-butyl-phosphine (83 mg) and cesium carbonate (1.12 g) were consecutively added to a degassed solution of intermediate 34a (580 mg) in toluene (9 mL) and water (1 mL) and the mixture was stirred at 100° C. for 24 h. The mixture was chilled, the layers were separated and the organic layer was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by column chromatography (Interchim cartridge 30SiHP, 40 g, Cy/EtOAc) to yield the desired product (77% yield). [0670] LC-MS (Method 1): m/z [M+H]+=315.3 (MW calc.=314.38); Rt=3.9 min.
77%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 100℃; for 24h; Inert atmosphere;	34 Intermediate 34b) Potassium cyclopropyltrifluoroborate (248 mg), palladium(ll) acetate (26 mg), di(1 -adamantyl)-n-butyl- phosphine (83 mg) and cesium carbonate (1.12 g) were consecutively added to a degassed solution of intermediate 34a (580 mg) in toluene (9 mL) and water (1 mL) and the mixture was stirred at 100 °C for 24 h. The mixture was chilled, the layers were separated and the organic layer was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by column chromatography (Interchim cartridge30SiHP, 40 g, Cy / EtOAc) to yield the desired product (77%yield). LC-MS (Method 1): m/z [M+Hf = 315.3 (MW calc. = 314.38); R, = 3.9 min.

Reference： [1]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - US2014/194443, 2014, A1 Location in patent: Paragraph 0668-0670
[2]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - WO2014/108337, 2014, A1 Location in patent: Page/Page column 83; 84

46
[ 1065010-87-8 ]
[ 84459-33-6 ]
[ 1208078-38-9 ]

Yield	Reaction Conditions	Operation in experiment
39%		To a degassed mixture of toluene (60 mL) and water (9 mL) was added potassium cyclopropyl-trifluoroborate (0.91 g, 6.2 mmol) and tribasic potassium phosphate (6.37 g, 30 mmol). The resulting mixture was stirred for 15 min at rt, thereafter, <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.50 g, 6.84 mmol, WO2006044454), palladium(II) acetate (0.11 g, 0.5 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.48 g, 1.0 mmol) were added and the mixture was heated under reflux, overnight. After cooling to rt, water (50 mL) and ethyl acetate (50 mL) were added and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/hexanes 1:3) to give 4-chloro-2-cyclopropyl-benzaldehyde (0.48 g, 2.6 mmol, 39%) as a colorless semi solid: 1H-NMR (CDCl3, Bruker 400 MHz) delta 0.80 (2H, m), 1.08-1.17 (2H, m), 2.58 (1H, m), 7.10 (1H, d, J=2 Hz), 7.29 (1H, dd, J=8 Hz, 2 Hz), 7.75 (1H, d, J=8 Hz), 10.6 (1H, s).

Reference： [1]Patent: US2014/179676,2014,A1 .Location in patent: Paragraph 0735

47
[ 1065010-87-8 ]
(6-chloroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone [ No CAS ]
(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 100℃; for 3h;	63.A Example 63: Preparation of (6-Cyclopropylimidazo[1, 2-ib]pyridi oromethyl)phenyl)piperidiri-l-yl)methanone Example 63: Preparation of (6-Cyclopropylimidazo[1, 2-ib]pyridi oromethyl)phenyl)piperidiri-l-yl)methanone Step A: A mixture of ( 6-chloroimidazo [ 1 , 2-b] pyridazin-2-yl) ( 4- (2- (trifluoromethyl(phenyl) piperidin-l-yl) methanone (0.050 g, 0.122 mmol), potassium cyclopropyltrifluoroborate (0.026 g, 0.183 mmol), Pd(0Ac)2 (0.002 g, 0.0061 mmol), di- ( 1-admantyl ) -n-butylphosphine (0.004 a. 0.0122 mmolS , and Cs2COj (0.119 g, 0.366 rttmol) in toluene (2 mL) and 0 (0,2 mL) was heated at 100 °C for 3 hours. The mixture was concentrated under reduced pressure and the resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give (6- cyclopropylimidazo [1 , 2-b] pyridazin-2-yl) (4- (2- ( trifluoromethyl ) phenyl) piperidin-1-yl) raethanone as a white solid (0.035 g, 69%) : KMR (300 MHz, CDCI3) δ 8.30 (s, 1H) , 7.78 (m, 1H) , 7.63 (d, J = 7.8 Hz, 1H) , 7.54- 7.44 (m, 2H) , 7.30 (t, J = 7.8 Hz, 1H) , 6.88 (d, J = 9.6 Hz, 1H) , 5.30 (m, 1H) , 4.94 (m, 1H) , 3.27 (m, 2H), 2.89 (m, 1H) , 2.12-1.81 (m, 5H) , 1.14-1.08 (m, 4H) ; MS (ESI+) m/z 41S [M+H] * .
69%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 100℃; for 3h; Inert atmosphere;

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2014/152013, 2014, A1 Location in patent: Page/Page column 159; 160
[2]Cioffi, Christopher L.; Racz, Boglarka; Varadi, Andras; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Blaner, William S.; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2019, vol. 62, # 11, p. 5470 - 5500]

48
[ 849937-96-8 ]
[ 1065010-87-8 ]
[ 1613239-40-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	With palladium diacetate; caesium carbonate; catacxium A; In water; toluene; at 110℃;	To a solution of <strong>[849937-96-8]5-bromo-2,4-dichloropyridine</strong> (CAS 849937-96-8) (22.95 g, 96.1 mmol, Eq: 1.00) in Toluene (352 mL) and Water (48.0 mL) was added Pd(OAc)2 (431 mg, 1.92 mmol, Eq: 0.02), butyldi-l-adamantylphosphine (1.03 g, 2.88 mmol, Eq: 0.03), potassium cyclopropyltrifluoroborate (CAS 1065010-87-8) (14.9 g, 101 mmol, Eq: 1.05) and Cs2C03 (62.6 g, 192 mmol, Eq: 2.0). The resulting reaction mixture was stirred at 110C overnight and controlled by TLC. The reaction was found to be only partially complete so 0.5 more equivalents (7.5 g) of potassium cyclopropyltrifluororate were added (3 times). Reaction mixture concentrated in vacuo then diluted with ethyl acetate and the solution poured into a separatory funnel. Extraction with aqueous saturated NaHC03, organic phase dried over NaS04 and evaporated down to dryness. Flash chromatography with a 330 g Si02 column, eluent mixture of heptane and ethyl acetate giving 7.39 g of the desired product (Yield 40%). MS (ESI, m/z): 188.2 (M).

Reference： [1]Patent: WO2014/154612,2014,A1 .Location in patent: Page/Page column 70

49
[ 1065010-87-8 ]
C₁₅H₁₉BrFN₃O₂ [ No CAS ]
C₁₈H₂₄FN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 120℃; for 10h; Microwave irradiation; Inert atmosphere;	21ag Example 21 af (600 mg, 1 .61 mmol), potassium cyclopropyltrifluoroborate (477 mg,3.22 mmol), Potassium triphosphate (1 .20g mg, 5.64 mmol), tricyclohexylphosphine (90 mg, 0.32 mmol) and palladium (II) acetate (36 mg, 0.16 mmol) are suspended ina mixture of toluene (17 mL) and water (0.2 mL) in a microwave vial and degassedfor 5 minutes with a flow of nitrogen gas. The mixture is heated under microwaveirradiation for 2 x 5 hours at 120 00 then allowed to cool and diluted with ethylacetate and water. The phases are separated, the organic phase filtered throughdecal ite and the solvent removed under vacuum. The residue is purified by flashchromatography (0-20% ethyl acetate in cyclohexane) to give the title compound(170 mg, 30%).U PLC-MS (Method 2): R = 1 .34 mmMS (ESI pos): mlz = 334 (M+H)
30%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 120℃; for 10h; Inert atmosphere; Microwave irradiation;	21ag Example 21 ag Example 21 ag 10698] Example 21 af (600 mg, 1.61 mmol), potassium cyclopropyltrifluoroborate (477 mg, 3.22 mmol), Potassium triphosphate (1.20 g mg, 5.64 mmol), tricyclohexylphosphine (90 mg, 0.32 mmol) and palladium (II) acetate (36 mg, 0.16 mmol) are suspended in a mixture of toluene (17 mE) and water (0.2 mE) in a microwave vial and degassed for 5 minutes with a flow of nitrogen gas. The mixture is heated under microwave irradiation for 2x5 hours at 120° C. then allowed to cool and diluted with ethyl acetate and water. The phases are separated, the organic phase filtered through decalite and the solvent removed under vacuum. The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound (170 mg, 30%).10699] UPEC-MS (Method 2): R=1 .34 mm10700] MS (ESI pos): mlz=334 (M+H7
30%	With potassium triphosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 120℃; for 10h; Microwave irradiation; Inert atmosphere;	33r Example 33q (600 mg, 1 .61 mmol), potassium cyclopropyltrifluoroborate (477 mg, 3.22 mmol), Potassium triphosphate (1 .20g mg, 5.64 mmol), tricyclohexylphosphine (90 mg, 0.32 mmol) and palladium (II) acetate (36 mg, 0.16 mmol) are suspended in a mixture of toluene (17 ml_) and water (0.2 ml_) in a microwave vial and degassed for 5 minutes with a flow of nitrogen gas. The mixture is heated under microwave irradiation for 2 x 5 hours at 120 °C then allowed to cool and diluted with ethyl acetate and water. The phases are separated, the organic phase filtered through decalite and the solvent removed under vacuum. The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound (170 mg, 30%). UPLC-MS (Method 2): Rt = 1 .34 min MS (ESI+): m/z = 334 (M+H)+

30%

With potassium triphosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 120℃; for 10h; Microwave irradiation; Inert atmosphere;

34n Example 34n Example 34n Example 33m (600 mg, 1 .61 mmol), potassium cyclopropyltrifluoroborate (477 mg, 3.22 mmol), Potassium triphosphate (1 .20g mg, 5.64 mmol), tncyclohexylphosphine (90 mg, 0.32 mmol) and palladium (II) acetate (36 mg, 0.16 mmol) are suspended in a mixture of toluene (17 ml_) and water (0.2 ml_) in a microwave vial and degassed for 5 minutes with a flow of nitrogen gas. The mixture is heated under microwave irradiation for 2 x 5 hours at 120 °C then allowed to cool and diluted with ethyl acetate and water. The phases are separated, the organic phase filtered through decalite and the solvent removed under vacuum. The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound (170 mg, 30%). UPLC-MS (Method 2): Rt = 1 .34 min MS (ESI+): m/z = 334 (M+H)+

Reference： [1]Current Patent Assignee: CENTREXION THERAPEUTICS US - WO2014/184275, 2014, A1 Location in patent: Page/Page column 167; 168
[2]Current Patent Assignee: CENTREXION THERAPEUTICS US - US2014/343065, 2014, A1 Location in patent: Paragraph 0697; 0698; 0699; 0700
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2016/75239, 2016, A1 Location in patent: Page/Page column 117-118
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2016/75240, 2016, A1 Location in patent: Page/Page column 142; 143

50
[ 1065010-87-8 ]
C₂₁H₂₆ClN₃O₄ [ No CAS ]
C₂₄H₃₁N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With palladium diacetate; potassium carbonate; XPhos In water at 100℃;	44d Cyclopentyl methyl ether (2 mL) and water (0.2 mL) are added to example 44c (140mg, 0.32 mmol), potassium cyclopropyltrifluoroborate (47 mg, 0.32 mmol), palladium(II) acetate (2 mg, 0.01 mmol), X-Phos (9 mg, 0.02 mmol) and Potassium carbonate(13 mg, 0.10 mmol) and the reaction mixture is heated at 10000 overnight. Thereaction is diluted with EtOAc/brine. The organic layer is separated, dried andevaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-30% EtOAc/cyclohexane) to furnish the title compound (105 mg, 78%).UPLC-MS (Method 7a): R = 5.37 mmMS (APCI): mlz = 426 (M+H)
78%	With palladium diacetate; potassium carbonate; XPhos In water at 100℃;	44d Example 44d Example 44d [0959] [0960] Cyclopentyl methyl ether (2 mL) and water (0.2 mL) are added to example 44c (140 mg, 0.32 mmol), potassium cyclopropyltrifluoroborate (47 mg, 0.32 mmol), palladium (II) acetate (2 mg, 0.01 mmol), X-Phos (9 mg, 0.02 mmol) and Potassium carbonate (13 mg, 0.10 mmol) and the reaction mixture is heated at 100° C. overnight. The reaction is diluted with EtOAc/brine. The organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-30% EtOAc/cyclohexane) to furnish the title compound (105 mg, 78%). [0961] UPLC-MS (Method 7a): Rt=5.37 min [0962] MS (APCI): m/z=426 (M+H)+

Reference： [1]Current Patent Assignee: CENTREXION THERAPEUTICS US - WO2014/184275, 2014, A1 Location in patent: Page/Page column 217; 218
[2]Current Patent Assignee: CENTREXION THERAPEUTICS US - US2014/343065, 2014, A1 Location in patent: Paragraph 0959; 0960; 0961; 0962

51
[ 1065010-87-8 ]
C₂₁H₂₉BrN₂O₄ [ No CAS ]
C₂₄H₃₄N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 120℃; for 2h; Microwave irradiation;	15a Example 3e (150 mg, 0.330 mmol), potassium cyclopropyltrifluoroborate (122 mg, 0.827 mmol), palladium (II) acetate (22 mg, 0.099 mmol), tricyclohexylphosphine (56 mg, 0.199 mmol) and tn potassium posphate (246 mg, 1.16 mmol) are dissolved in Toluene (2 mL) and water (0.200 mL) and the reaction mixture is heated at 120°C for2h under microwave irradiation. The reaction is diluted with DCM/water. The organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by preparative HPLC (stationary phase: Xbridge 018 5 pm 19 x 100 mm. Mobile phase: ACN/ H20 + NH4000H 5mM). Fractions containing the title compound are combined, evaporated under reduced pressure and freeze-dried tofurnish the title compound (105 mg, 77%).UPLC-MS (Method 2): R = 1 .42 mmMS (ESI pos): m/z = 415 (M+H)+
77%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 120℃; for 2h; Microwave irradiation;	15a Example 15a Example iSa 10593] Example 3e (150 mg, 0.330 mmol), potassium cyclopropyltrifluoroborate (122 mg, 0.827 mmol), palladium (II) acetate (22 mg, 0.099 mmol), tricyclohexylphosphine (56 mg, 0.199 mmol) and tn potassium posphate (246 mg, 1.16 mmol) are dissolved in Toluene (2 mE) and water (0.200 mE) and the reaction mixture is heated at 120° C. for 2 h under microwave irradiation. The reaction is diluted with DCMJ water. The organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by preparative HPEC (stationary phase: Xbridge Cl 8 5 jtm 19x 100 mm. Mobile phase: ACN/H20+NH4COOH 5 mM). Fractions containing the title compound are combined, evaporated under reduced pressure and freeze-dried to furnish the title compound (105 mg, 77%).10594] UPEC-MS (Method 2): R=1 .42 mm10595] MS (ESI pos): mlz=415 (M+H)

Reference： [1]Current Patent Assignee: CENTREXION THERAPEUTICS US - WO2014/184275, 2014, A1 Location in patent: Page/Page column 146
[2]Current Patent Assignee: CENTREXION THERAPEUTICS US - US2014/343065, 2014, A1 Location in patent: Paragraph 0592; 0593; 0594; 0595

52
[ 1065010-87-8 ]
[ 113975-22-7 ]
[ 1227177-68-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 130.0℃; for 2.0h;Inert atmosphere; Microwave irradiation;	2-Fluoro-3-iodopyridine (300 mg, 1 .34 mmol), potassium cyclopropyltrifluoroborate (498 mg, 3.36 mmol), palladium (II) acetate (30 mg, 0.135 mmol) are dissolved in toluene (4 mL) under a nitrogen flow. Tricyclohexylphosphine (75 mg, 0.27 mmol), tn-potassium phosphate (1.1 g, 5.38 mmol) and water (0.4 mL) are added and the reaction mixture is heated under microwave irradation (1 30C) for 2h. At rt, water is added and the aqueous layer is extracted with DCM. Then the organic layer is washed with water and brine, separated and dried to furnish 3-cyclopropyl-2-fluoro- pyridine (200 mg, 97%).U PLC-MS (Method 2): R = 0.94 mmMS (ESI pos): mlz = 138 (M+H)
97%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 130.0℃; for 2.0h;Inert atmosphere; Microwave irradiation;	10449] 2-Fluoro-3-iodopyridine (300 mg, 1.34 mmol), potassium cyclopropyltrifluoroborate (498 mg, 3.36 mmol), palladium (II) acetate (30 mg, 0.135 mmol) are dissolvedtoluene (4 mE) under a nitrogen flow. Tricyclohexylphosphine (75 mg, 0.27 mmol), tri-potassium phosphate (1.15.38 mmol) and water (0.4 mE) are added and the reaction mixture is heated under microwave irradation (130 C.) forh. At it, water is added and the aqueous layer is extracted with DCM. Then the organic layer is washed with water and brine, separated and dried to thmish 3-cyclopropyl-2-fluoro-pyri- dine (200 mg, 97%).10450] UPEC-MS (Method 2): R=0.94 mm10451] MS (ESI pos): mlz=138 (M+H)

Reference： [1]Patent: WO2014/184275,2014,A1 .Location in patent: Page/Page column 107; 108
[2]Patent: US2014/343065,2014,A1 .Location in patent: Paragraph 0449; 0450; 0451

53
4-bromo-1-(4-methoxybenzyl)indoline-2,3-dione [ No CAS ]
[ 1065010-87-8 ]
4-cyclopropyl-1-(4-methoxybenzyl)indoline-2,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In tetrahydrofuran; water at 130℃; for 4h; Inert atmosphere; Sealed tube; Microwave irradiation;	3.34 4.3.34 4-Cyclopropyl-1-(4-methoxybenzyl)indoline-2,3-dione (44) Bromoisatin 30 (683 mg, 1.98 mmol), potassium cycloproplytrifluoroborate (410 mg, 2.77 mmol), K3PO4 (1.51 g, 7.13 mmol) were added sequentially to a microwave vial before addition of degassed THF/H2O (3:1, 9 mL). The reaction mixture was further degassed before addition of Pd(dppf)Cl2 (141 mg, 0.193 mmol). The reaction vessel was sealed and heated by microwave irradiation for 4 h at 130 °C. The reaction mixture was cooled to room temperature, filtered through Celite, using EtOAc as an eluent. The solution was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the crude compound as a black green oil. Purification on silica gel (CH2Cl2) afforded the title compound (44) as an orange solid (586 mg, 96%). mp 175-178 °C; νmax (solid) 1727, 1608, 1590, 1514, 1454, 1247, 1182, 1030; δH (500 MHz, acetone-d6) 0.85 (2H, ddd, J = 9.0, 6.6, 4.4 Hz, C(2')H or C(3')H), 1.14 (2H, ddd, J = 8.5, 6.8, 4.4 Hz, C(2')H or C(3')H), 2.96 (1H, app tt, J = 8.5, 5.0 Hz, C(1')H), 3.76 (3H, s, O-CH3), 4.88 (2H, s, N-CH2), 6.55 (1H, d, J = 8.0 Hz, C(7)H), 6.74 (1H, dd, J = 7.9, 0.8 Hz, C(5)H), 6.90 (2H, d, J = 8.7 Hz, ArH), 7.38 (3H, m, ArH and C(6)H); δC (125 MHz, acetone-d6) 11.4, 43.6, 55.6, 108.4, 115.0, 116.7, 118.4, 128.6, 129.8, 138.7, 149.0, 151.8, 159.0, 160.4, 185.0; LRMS m/z (ESI+) 308 ([M+H]+); HRMS (ESI+) C19H17NNaO3+ ([M+Na]+) requires 330.1110; found 330.1110.

Reference： [1]Gianella-Borradori, Matteo; Christou, Ivy; Bataille, Carole J.R.; Cross, Rebecca L.; Wynne, Graham M.; Greaves, David R.; Russell, Angela J. [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 1, p. 241 - 263]

54
[ 77771-03-0 ]
[ 1065010-87-8 ]
(3-cyclopropyl-4-fluorophenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; water; at 100℃; for 4h;Microwave irradiation; Inert atmosphere;	Step 1: (3-Cyclopropyl-4-fluorophenyl)methanol A microwave reaction vial was charged with <strong>[77771-03-0](3-bromo-4-fluorophenyl)methanol</strong> (530 mg, 2.6 mmol), potassium cyclopropyltrifluoroborate (0.77 g, 5.2 mmol), Cs2C03 (2.5 g, 7.8 mmol), Iota,Gamma- bis(diphenylphosphino)ferrocenedichloropalladium(II) (95 mg, 0.13 mmol), THF (10.6 mL) and water (1.1 mL). After sealing with cap under an atmosphere of argon, the mixture was heated at 100 C for 4 h. The reaction was diluted with EtOAc and the mixture was filtered through a celite pad. The residual solid was rinsed with EtOAc and water. The two layers were transferred into a separatory funnel and then separated. The water layer was extracted with EtOAc (x2). The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified on silica gel to give (3-cyclopropyl-4- fluorophenyl)methanol (309 mg, 72%) as a light yellow oil. ,

Reference： [1]Patent: WO2015/2994,2015,A2 .Location in patent: Paragraph 00206

55
[ 26156-48-9 ]
[ 1065010-87-8 ]
methyl 2-cyclopropylpyridine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In tetrahydrofuran; water; at 85℃; for 18h;Inert atmosphere;	A solution of <strong>[26156-48-9]methyl 2-bromoisonicotinate</strong> (500 mg, 2.314 mmol), potassium cyclopropyltrifluoroborate (685 mg, 4.63 mmol) and CS2CO3 (2262 mg, 6.94 mmol) in THF (15 mL) and water (1.5 mL) was degassed by evacuating and flushing with N2. PdCl2(dppf) - CH2C12 adduct (189 mg, 0.231 mmol) was added and the reaction was stirred at 85C for 18 hours. The reaction was diluted with EtOAc and filtered through celite. The eluent was concentrated under vacuum. The crude product was purified by column chromatography on silica eluting with petroleum ether/ethyl acetate from 100/0 to 80/20 to yield methyl 2-cyclopropylpyridine-4-carboxylate as a colourless oil (170 mg, 0.959 mmol, 42 % yield). 1H NMR (400 MHz, DCM-d2) delta ppm 0.98 - 1.10 (m, 4 H) 2.05 - 2.20 (m, 1 H) 3.95 (s, 3 H) 7.52-7.65 (m, 1 H) 7.72 (s, 1 H) 8.47 - 8.65 (m, 1 H) MS ES+: 178.

Reference： [1]Patent: WO2015/19103,2015,A1 .Location in patent: Page/Page column 45

56
[ 126689-01-8 ]
[ 1065010-87-8 ]
C₃₄H₂₈ClN₅O [ No CAS ]
C₁₈H₁₉N₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2A solution of Intermediate Cl (360 mg, 0.65 mmol) in dioxane (6.5 mL) was treated with cyclopropyl trifluoroborate, potassium salt (190 mg, 1.29 mmol), 1.5 M Cs2CO3 (aq.) (1.3 mL, 1.94 mmol) and purged with nitrogen for 10 to 15 minutes. To this mixture was added (2?-amino- [1,1 ?-biphenyl] -2-yl)palladium(II) chloride, di((3 S,5S,7S)- adamantan- 1 -yl)(butyl)phosphine complex (1:1) (43 mg, 0.065 mmol) the mixture was sealed in a microwave vial and heated in a 100C oil bath for 1 8h. The reaction was cooled and unsealed and (2?-amino-[l,1?-biphenyl]-2-yl)palladium(II) chloride, di((3 S,5 5,75)-adamantan- 1 -yl)(butyl)phosphine complex (1:1) (43 mg, 0.065 mmol), <strong>[126689-01-8]cyclopropylboronic acid pinacol ester</strong> (217 mg, 1.29 mmol), and 1.5M Cs2CO3 (aq.) (1.3 mL, 1.94 mmol) were added. The reaction was sealed and stirred in a 120C oil bath for 3 hrs. The reaction was cooled to room temperature, unsealed, diluted with EtOAc (75mL), washed with water (2x) and brine (lx). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford a crude residue. The residue was purified by column chromatography on silica gel (ISCO RediSep 40g silica gel column, gradient elution with 0% to 100% EtOAc in hexanes) to give the desired product with significant impurities present. The material was then subjected to reversed-phase column chromatography (Analogix C 18 column, gradient elution with 0% to 100% MeCN in water with 0.1% TFA). The fractions corresponding to product sat in solution for 2 weeks. The solvent was evaporated to afford the Example Cl with significant impuities. The residue was purified again by reversed-phase column chromatography (AnalogixCl 8, gradient elution with 0% to 100% MeCN in water with 0.1% TFA) to giveExample Cl as an off-white solid.

Reference： [1]Patent: WO2015/26683,2015,A1 .Location in patent: Page/Page column 47; 48; 49

57
[ 1065010-87-8 ]
C₂₄H₂₁ClF₅N₃O₂ [ No CAS ]
C₂₇H₂₆F₅N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With di-(1-adamantyl)-n-butylphosphine; palladium diacetate; caesium carbonate In water; toluene at 100℃; for 16h; Inert atmosphere;	113.1 Step 1 : A mixture of the intermediate from step 1 of the synthesis of example 112 (300 mg, 583 pmol), potassium cyclopropyltrifluoroborate (129 mg, 875 pmol) and Cs2C03 (947 mg, 2.92 mmol) in toluene (16 mL) and water (4 mL) was degassed through purging with Ar for 30 min. Pd(OAc)2 (13 mg, 58 pmol) and di-(1-adamantyl)-n-butylphosphine (41 mg, 116 pmol) were added to the RM and heated at 100°C for 16 h. The RM was diluted with EtOAc and washed with water and brine. The organic layer was dried and concentrated under reduced pressure to give the crude product which was purified by CC (Si02, EtOAc/Hex) to yield the desired product (270 mg, 89%). LC-MS (Method 3): m/z [M+Hf = 520.2 (MW calc. = 519.51); R, = 4.46 min.

Reference： [1]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - WO2015/22073, 2015, A1 Location in patent: Page/Page column 98; 99

58
[ 1065010-87-8 ]
ethyl 6-bromo-3-[(tert-butoxycarbonyl)amino]furo[3,2-b]pyridine-2-carboxylate [ No CAS ]
ethyl 3-[(tert-butoxycarbonyl)amino]-6-cyclopropylfuro[3,2-b]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: potassium cyclopropyltrifluoroborate; ethyl 6-bromo-3-[(tert-butoxycarbonyl)amino]furo[3,2-b]pyridine-2-carboxylate With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 110℃; for 24h; Inert atmosphere; Sealed tube; Stage #2: With dmap; di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 20 - 30℃;	133.1 Step 1. Ethyl 3-[(tert-butoxycarbonyl)amino]-6-cyclopropylfuro[3,2-b]pyridine-2-carboxylate Step 1. Ethyl 3-[(tert-butoxycarbonyl)amino]-6-cyclopropylfuro[3,2-b]pyridine-2-carboxylate To a microwave vial was added ethyl 6-bromo-3-[(tert-butoxycarbonyl)amino]furo[3,2-b]pyridine-2-carboxylate (1.05 g, 2.72 mmol), potassium cyclopropyltrifluoroborate (480 mg, 3.3 mmol), Cs2CO3 (2.66 g, 8.18 mmol), Pd(OAc)2 (61.2 mg, 0.272 mmol) and di-1-adamantyl(butyl)phosphine (150 mg, 0.41 mmol). The vialed was seal and evacuated and filled with N2 three times. Toluene (10.0 mL, 93.9 mmol) and water (1.0 mL, 56 mmol) were added. The reaction mixture was heated at 110° C. for 24 h. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (10 mL), and Boc2O (0.40 g) was added followed by DMAP (40 mg). The resulting solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluting with a gradient of 0-30% EtOAc in hexanes) to give the sub-title compound as a yellow foam (0.91 g, 96%). LCMS calc. for C18H23N2O5 (M+H)+: m/z=347.2. Found: 346.9.

Reference： [1]Current Patent Assignee: INCYTE CORP - US2015/57265, 2015, A1 Location in patent: Paragraph 1543; 1544

59
[ 1065010-87-8 ]
C₁₄H₁₉ClN₂O₃S₂ [ No CAS ]
[ 69034-12-4 ]
C₂₂H₂₅F₃N₄O₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%		Example 151 Racemic Mixture A solution of example 44c (100 mg of the corresponding hydrochloride, 0.25 mmol), <strong>[69034-12-4]2-chloro-5-(trifluoromethyl)-pyrimidine</strong> (55 mg, 0.30 mmol) and N,N-diisopropylethylamine (129 mul, 0.75 mmol) dissolved in 1 ml of anhydrous DMSO is heated in a microwave reactor during 30 minutes at 150 C. The crude is purified by preparative HPLC-MS and the obtained impure intermediate is suspended in 0.9 ml of anhydrous toluene; potassium cyclopropyltrifluoroborate (37 mg, 0.25 mmol), butyldi-1-adamantylphosphine (3 mg, 0.01 mmol), palladium acetate (1 mg, 0.01 mmol), cesium carbonate (245 mg, 0.75 mmol) and 0.1 ml of water are added and the reaction mixture is heated in a microwave reactor during 2 hours at 100 C. The solvent is removed under reduced pressure, the residue is suspended in DMF, filtered and purified by preparative HPLC-MS to obtain the title compound (18.7 mg, 14% yield). [0925] HPLC-MS (Method 16): Rt=4.63 min [0926] MS (ES+): m/z=515 [M+H]+

Reference： [1]Patent: US2015/105397,2015,A1 .Location in patent: Paragraph 0923; 0924; 0925; 0926

60
[ 76-09-5 ]
[ 1065010-87-8 ]
[ 126689-01-8 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 5428 - 5435

61
[ 1065010-87-8 ]
[ 147269-67-8 ]
benzyl (1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27.0%	With [2,2]bipyridinyl; copper diacetate; sodium carbonate; In 1,2-dichloro-ethane; at 70℃; for 15h;	A mixture of benzyl (2-oxo- 1 ,2-dihydropyridin-3 -yl)carbamate (0.800 g, 3.28mmol), potassium cyclopropyltrifluoroborate (0.969 g, 6.55 mmol), copper (II) acetate(0.625 g, 3.44 mmol), 2,2?-dipyridyl (0.53 7 g, 3.44 mmol), and sodium carbonate (0.764 g, 7.21 mmol) in 1,2-dichloroethane (20 mL) was heated at 70 C under air for 15 h. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite. The filtrate was further diluted with ethyl acetate (100 mL), washed with water (40 mL), 0.5 NHC1 solution (40 ml), water (40 mL), and brine (40 mL). The organic solution was dried over anhydrous Mg504. The desired product, benzyl (1-cyclopropyl-2-oxo-1,2- dihydropyridin-3-yl)carbamate (0.25 1 g, 0.883 mmol, 27.0 % yield), was isolated as a white solid by ISCO (80 g silica gel, solid loading, 20-50% ethyl acetate/hexane.

Reference： [1]Patent: WO2015/89143,2015,A1 .Location in patent: Page/Page column 84
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 383 - 388

62
[ 1065010-87-8 ]
benzyl (1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino )cyclohexylcarbamate [ No CAS ]
benzyl (1S,3R)-3-(5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino )cyclohexylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 140℃; for 2h; Microwave irradiation; Inert atmosphere;	10 Benzyl ( 1S,3R )-3-( 5-cyclopropyl-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2- ylamino )cyclohexylcarbamate Benzyl ( 1S,3R )-3-( 5-cyclopropyl-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2- ylamino )cyclohexylcarbamateA degassed solution of benzyl (lS,3R)-3-(5-chloro-4-(l-(phenylsulfonyl)-lH- indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate (prepared similarly to Example 1) (500 mg, 0.812 mmol), CS2CO3(794 mg, 2.435 mmol) and potassium cyclopropyltrifluoroborate (360 mg, 2.435 mmol) in 2: 1 tol/H20 (15 mL) was treated with a premixed solution of Pd(OAc)2(9 mg, 0.04 mmol) and butyldi-l-adamantylphosphine (29 mg, 0.08 mmol) in degassed tol (2 mL) and heated at 140°C (microwave) for 2h. The cooled misture was diluted with EtOAc (50 mL) and saturated NaHC03(20 mL). The layers were separated and the aqueous layer was extracted with EtOAc ( 2 x 20 mL). The combined organic layers were dried over Na2S04, filtered and evaporated to dryness. The residue was purified by Si02chromatography (Hex/EtOAc 0 to 60% gradient) and afforded the title compound (324 mg, 0.521 mmol, 64%) as a pale yellow solid. (lR,3S)-N1-(5-cyclopropyl-4-(l-(phenylsulfonyl)-lH ndol-3-yl)pyrimidin-2-yl)cyclohexa 1,3-diamine
64%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 140℃; for 2h;	Benz vi (1S,3R)-3-(5-cyciopropyi-4-(1-(phenyisuifonyi)-1H-indoi-3-yi)pyrimidin-2- yiamino)cyciohexyicarbamate A degassed solution of benzyl (lS,3R)-3-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3- yl)pyrimidin-2-ylamino)cyclohexylcarbamate (500 mg, 0.812 mmol), CS2CO3 (794 mg, 2.435 mmol) and potassium cyclopropyltrifluoroborate (360 mg, 2.435 mmol) in 1.4/1 tol/H20 (12 mL) was treated with a premixed solution of Pd(OAc)2 (9 mg, 0.04 mmol) and butyldi-1- adamantylphosphine (29 mg, 0.08 mmol) in degassed tol (3 mL) and heated at 140°C (microwave) for 2h. The cooled mixture was diluted with EtOAc (50 mL) and saturated NaHC03 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2S04, filtered and evaporated to dryness. The residue was purified by Si02 chromatography (Hex/EtOAc 0 to 70% gradient) and afforded the title compound (324 mg, 0.521 mmol, 64%) as a yellow solid.
64%	With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 140℃; for 2h; Inert atmosphere; Microwave irradiation;	5 1197 Benzyi (is, 3R)-3-- (5-cyciopropvL4-(iheny1suifony1)-iH-.indo1-3Opyrimidin-2- vlamino)cvclohexylcarbamate [198j A degassed solution of benzyl (1 S,3R)-3-(5-chioro-4-(1 -(phenylsulfonyl}-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate (prepared similarly to Example 3) (500 rng, 0.812mmol), CsCO3 (794 mg, 2.435 mmoi) and potassium cyciopropyitrifluoroborate (360 mg, 2.435mmoi) in 2/i toluene/FLO (15 ml.) was treated with a prernxed solution of Pd(OAc)3 (9 mg,0.04 mmol) and butyidi-i-adamantyiphosphine (29 mg, 0.08 mmoi) in degassed toluene (2 mL)and heated at 140°C (microwave) for 2h. The cooled mixture was diluted with EtOAc (50 mL)and saturated NaHCO3 (20 mL), The layers were separated and the aqueous layer was extracted with FtOAc (2 x 20 mL), The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by Si02 chromatography (Hex/EtOAc 0 to 60% gradient) to afford the title compound (324 rng, 0.521 rnmol, 64%) as a pale yellow solid.

Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE; SYROS PHARMACEUTICALS INC - WO2015/58140, 2015, A1 Location in patent: Paragraph 00355
[2]Current Patent Assignee: SYROS PHARMACEUTICALS INC - WO2015/154039, 2015, A2 Location in patent: Paragraph 561; 562
[3]Current Patent Assignee: SYROS PHARMACEUTICALS INC - WO2016/58544, 2016, A1 Location in patent: Paragraph 197; 198

63
[ 51105-90-9 ]
[ 1065010-87-8 ]
[ 1403333-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	With copper diacetate; In water;	3. Reaction of methyl 1 /-/-pyrazole-3-carboxylate with potassium cyclopropyl(trifluoro)borate and copper(ll) acetate provided methyl 1 -cyclopropyl-1 H- pyrazole-3-carboxylate, which was hydrolyzed with lithium hydroxide to afford the requisite 1 -cyclopropyl-1 /-/-pyrazole-3-carboxylic acid

Reference： [1]Patent: WO2015/155626,2015,A1 .Location in patent: Page/Page column 130

64
[ 1065010-87-8 ]
[ 35578-47-3 ]
1,2-bis(4-cyclopropylphenyl)-ethane-1,2-dione [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 1106 - 1115
[2]European Journal of Organic Chemistry,2017,vol. 2017,p. 3318 - 3327

65
[ 1065010-87-8 ]
[ 915707-65-2 ]
(4-cyclopropyl-1-methyl-1H-pyrazol-3-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); In water; toluene; at 70℃; for 15h;Inert atmosphere;	[0188] (4-Bromo-l-methyl-lH-pyrazol-3-yl)methanol (900 mg, 4.71 mmol), potassium cyclopropyltrifluoroborate (1400 mg, 9.4 mmol), K2C03 (3900 mg, 28 mmol), and 2nd generation XPhos precatalyst (370 mg, 0.47 mmol) were mixed in a microwave reaction vial. The vial was capped, and air was removed by vacuum then back filled with nitrogen (x3).Toluene (16 ml) and water (4 ml) were introduced with a syringe. Air was removed and back filled with nitrogen (x3). Mixture was heated to 70 C for 15 hours. The mixture was diluted with EtOAc, and washed with water and brine. After dried over anhydrous sodium sulfate, the organic layer was concentrated, and the crude was purified by column chromatography on a 50 g prepacked silica gel column, eluting with 0 ~ 100% gradient EtOAc/hexane to give the product as an oil. MS: 153 [M+l]

Reference： [1]Patent: WO2016/81290,2016,A1 .Location in patent: Paragraph 0188

66
[ 34522-69-5 ]
[ 1065010-87-8 ]
7-bromo-5-cyclopropylquinoline [ No CAS ]
5-bromo-7-cyclopropylquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; toluene; at 100℃; for 19h;Inert atmosphere; Sealed tube;	Step 2: A 20 mL vial was charged with mixture of <strong>[34522-69-5]5,7-dibromoquinoline</strong> (300.mg, 1.05 mmol), Pd(dppf)C12CH2CI2 (85.4 mg, 0.105 mmol), C52CO3 (188 mg, 3.14mmol), and potassium cyclopropyltrifluoroborate (186 mg, 1.25 mmol) and sealed with acap containing a septum. A nitrogen atmosphere was established in the vial, andtoluene (6.0 mL) and water (2.0 mL) were added. The reaction mixture was thenheated in a 100C aluminum block for 19 h. After cooling to rt, the reaction mixture was diluted with EtOAc, filtered through Celite, dried over Na2504, and concentrated to a brown oil. Purification by MPLC (29 g Si gel, 0-60% EtOAc/heptane gradient) afforded a ca. 2:1 mixture of Intermediate 4 and 5-bromo-7-cyclopropylquinoline as a light yellowoil (88 mg, 34%). 1H NMR (400 MHz, CDCI3) O 0.76-0.81 (m, 2 H), 1.07-1.14 (m, 2 H),2.29 (tt, 1 H), 7.37-7.39 (m, 1 H), 7.45 (dd, 1 H), 8.14 (d, 1 H), 8.66 (d, 1 H), 8.90 (dd, 1H). LCMS (ESI) m/z: 248.0 [M+H] (56%). LCMS data were acquired from the reaction mixture immediately prior to workup.

Reference： [1]Patent: WO2016/103097,2016,A1 .Location in patent: Page/Page column 43; 60

67
[ 1065010-87-8 ]
[ 1093880-37-5 ]
6-cyclopropyl-2-fluoronicotinaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
501 mg	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; water; caesium carbonate; In tetrahydrofuran; at 63 - 73℃;	To a solution of <strong>[1093880-37-5]6-chloro-2-fluoronicotinaldehyde</strong> (1.21 g) in THF (40ml) were added potassium cyclopropyltrifluoroborate (1.13g), cesium carbonate (7.43g), (1 ,1 '- bis(diphenylphosphino)ferrocene)dichloropalladium (II) dichloromethane adduct (621 mg)and water (4ml). The reaction mixture was stirred at 73C for 2h and at 63C overnight. The mixture was diluted with water and TBME at rt and the layers were separated. The aq. layer was extracted with TBME and the combined org. layers were washed with 1 N aq. HCI (15ml)and sat. aq. NaCI, dried over Na2S04, filtrated off and evaporated in vacuo. The crude was purified by CC (Flash Master, solvent A: heptane, solvent B: EA, gradient in %B: 20, flow rate: 15ml/min) to afford 501 mg of a yellow oil. GC-MS (A) tR = 2.05min; [M+H]+: 165.90.

Reference： [1]Patent: WO2016/177690,2016,A1 .Location in patent: Page/Page column 76-77

68
[ 1065010-87-8 ]
[ 78686-79-0 ]
C₁₀H₉BrClNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
269 mg		The <strong>[78686-79-0]methyl 5-bromo-2-chloronicotinate</strong> (1.2 g, 4.8 mmol) and potassium cyclopropyl trifluoroborate (2.13 g, 14.4 mmol) was dissolved in AcOH (30 mL) and water (30 mL). TFA(0.36 mL, 4.8 mmol) was added. The mixture was stirred at rt for 20 minutes.Mn(OAc)32H20 (11.6 g, 43.2 mmol) was added and the mixture was heated to 70 C underN2 atmosphere. After 48 hours the mixture was cooled to rt and saturated Na2CO3 solutionwas added and then solid was filtered out. The filtrate was extracted with EA (200 mLx3).The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residuewas purified by silica gel chromatography (PE: EA = 100:1 to 50:1) to give the desiredproduct as white solid (269 mg,) and the starting material (696 mg). ESI-MS m/z: 292.0 [M+Hj .
269 mg		The <strong>[78686-79-0]methyl 5-bromo-2-chloronicotinate</strong> (1.2 g, 4.8 mmol) and potassium cyclopropyl trifluoroborate (2.13 g, 14.4 mmol) was dissolved in AcOH (30 mL) and water (30 mL). TFA (0.36 mL, 4.8 mmol) was added. The mixture was stirred at rt for 20 minutes. Mn(OAc)3·2H2O (11.6 g, 43.2 mmol) was added and the mixture was heated to 70C under N2 atmosphere. After 48 hours the mixture was cooled to rt and saturated Na2CO3 solution was added and then solid was filtered out. The filtrate was extracted with EA (200 mL3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE: EA = 100:1 to 50:1) to give the desired product as white solid (269 mg,) and the starting material (696 mg). ESI-MS m/z: 292.0 [M+H]+.

Reference： [1]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 168
[2]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 162

69
[ 939-80-0 ]
[ 1065010-87-8 ]
C₁₀H₈N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With palladium diacetate; caesium carbonate; catacxium A; In 1,4-dioxane; water; at 100℃; for 18h;	Di(1-adamantyl)-N-butylphosphine (157.00 mg, 0.44 mmol) and Pd(OAc)2 (98.00 mg,0.44 mmol) were added to a degassed N2 solution of <strong>[939-80-0]4-chloro-3-nitrobenzonitrile</strong>(800.00 mg, 4.38 mmol), potassiumcyclopropyltrifluoroborate (972.00 mg, 6.57 mmol)and CsCO3 (2.85 g, 8.76 mmol) in a mixture of 1,4-dioxane (18 mL) and distilled water(4 mL). The reaction mixture was stirred and heated at 100 C for 18 h. Then, it wascooled to rt, diluted with DCM and poured onto water. The organic layer was decanted,dried over MgSO4, filtered over celite and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase:DCM/MeOH, gradient from 100:0 to 98:2). The pure fractions were collected and evaporated to dryness to give 546 mg of intermediate 244 (66% yield).

Reference： [1]Patent: WO2017/125530,2017,A1 .Location in patent: Page/Page column 278

70
[ 32896-02-9 ]
[ 1065010-87-8 ]
C₈H₇BrOS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In water; toluene at 100℃; for 20h; Inert atmosphere; Sealed tube;	1 Synthesis of intermediate 2 (compound 2) ((1) 100 mL round bottom flask was added 3,4-dibromothiophene-2-carbaldehyde (5.00 g, 19 mmol)Potassium cyclopropyl borate (2.88 g, 19 mmol),Potassium carbonate (7.88 g, 57 mmol),Pd (dppf) Cl2CH2Cl2 (310 mg, 0.38 mmol)Toluene 30mL and distilled water 10mL,Argon protection,Ultrasonic removal of air in the solvent.Sealed and heated to 100 ° C for 20 h.The reaction was quenched with water, extracted with ethyl acetate (80 mL x 3),The organic phase was combined, washed with saturated brine (100 mL x 3)Dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated,The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80: 1) to give a pale yellow liquid1.70 g, yield 40%.

Reference： [1]Current Patent Assignee: GUANGZHOU MEDICAL UNIVERSITY; CHINESE ACADEMY OF SCIENCES; GUANGZHOU MEDICAL UNIV NEW DRUG CREATION - CN107011320, 2017, A Location in patent: Paragraph 0048; 0049; 0050

71
[ 21427-62-3 ]
[ 1065010-87-8 ]
C₈H₇ClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With palladium diacetate; caesium carbonate; catacxium A; In 1,4-dioxane; water; at 100℃; for 18h;Inert atmosphere;	Di-(1-adamantyl)-N-butylphosphine (143.00 mg, 0.40 mmol) and Pd(OAc)2 (89.00 mg,0.40 mmol) were added to a degassed (N2) solution of <strong>[21427-62-3]2,5-dichloro-3-nitropyridine</strong>(770.00 mg, 4.00 mmol), potassium cyclopropyltrifluoroborate (767.00 mg, 5.19mmol) and Cs2CO3 (2.60 g, 7.98 mmol) in a mixture of 1,4-dioxane (18 mL) anddistilled water (4 mL). The reaction mixture was then heated at 100 C for 18 h, cooled to rt, poured onto water and extracted with DCM. The organic layer was decanted, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 24 g, mobile phase:heptane/DCM, gradient from 70:30 to 20:80). The pure fractions were collected andevaporated to dryness to give 190 mg of intermediate 146 (24% yield).

Reference： [1]Patent: WO2017/125534,2017,A1 .Location in patent: Page/Page column 273; 274

72
[ 1065010-87-8 ]
[ 27104-73-0 ]
[ 1443759-12-3 ]

Reference： [1]Chemical Science,2017,vol. 8,p. 3512 - 3522

73
[ 75090-52-7 ]
[ 1065010-87-8 ]
4-chloro-7-cyclopropylquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 60℃; for 19h;Inert atmosphere; Sealed tube;	<strong>[75090-52-7]7-bromo-4-chloroquinoline</strong> (550 mg, 2.27 mmol), potassium (0548) cyclopropyltrifiuoroborate (369 mg, 2.50 mmol), PdCl2(dppf)-CH2Cl2Adduct (185 mg, 0.23 mmol) and potassium phosphate tribasic (1M in water, 6.80 mL, 6.80 mmol) were added to a sealed tube. Dioxane (45.4 mL) was added and the reaction was purged with nitrogen gas for 5 min. The reaction was heated to 60 C for 4h, then cooled to room temperature. Additional potassium, cyclopropyltrifiuoroborate (369 mg, 2.50 mmol) and PdC^dppO-CLLC^Adduct (185 mg, 0.23 mmol) was added. The reaction was sealed and purged with nitrogen gas and heated to 60 C for 15h. The reaction mixture was diluted with water and extracted with (0549) EtOAc (3x). The combined organic layers were dried with magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-50% 3: 1 EtOAc:EtOH in hexane). (0550) The combined fractions were concentrated to give the title compound. MS: 204 (M + 1).

Reference： [1]Patent: WO2018/34917,2018,A1 .Location in patent: Page/Page column 63

74
[ 1065010-87-8 ]
[ 1138-52-9 ]
1,3-di-tert-butyl-5-cyclopropoxybenzene [ No CAS ]