Target Compound and Intermediate Synthesis

Pd(PPh₃)₄ (6.290 g, 5.443 mmol) was added in one portion to a mixture of 5-bromo-2,4-di-tert-butoxypyrimidine (34) (33.00 g, 108.8 mmol), Na₂CO₃ (23.07 g, 217.7 mmol) and (3,5-difluorophenyl)boronic acid (18.10 g, 114.6 mmol) in 1,4-dioxane (500 mL) and water (80 mL) under nitrogen at rt. The resulting suspension was stirred at 90 °C for 2 h. The reaction mixture was quenched with saturated brine (100 mL) and then extracted with EtOAc (3 × 500 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford a pale yellow solid. The crude product was purified by flash silica chromatography, elution gradient 0–10% MeOH in CH₂Cl₂. Fractions containing the desired compound were evaporated to dryness. To this solid was added HCl in 1,4-dioxane (4 M, 500 mL, 2000 mmol) and the solution was stirred overnight at rt. The solvent was removed under reduced pressure and the crude product was purified by crystallization from EtOAc/dioxane to afford 5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (20.60 g, 84% over two steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.38 (br s, 2H), 7.88 (d, J = 6.1 Hz, 1H), 7.44–7.35 (m, 2H), 7.18–7.10 (m, 1H); MS (ESI) m/z calculated for [C₁₀H₅F₂N₂O₂]⁻ [M – H]⁻= 223.0325, found = 223.1.

To a solution of 5-bromopyrimidine-2,4(1H,3H)-dione (35) (20.00 g, 104.7 mmol) and KOH (11.75 g, 209.4 mmol) in DMF (200 mL) and water (25 mL) under nitrogen at 60 °C, was added (1-bromoethyl)benzene (23.26 g, 125.7 mmol) in one portion. The resulting solution was stirred overnight at 60 °C. The reaction was concentrated under reduced pressure and subsequently quenched with saturated NH₄Cl (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford a white solid. The crude product was purified by crystallization from EtOAc/petroleum ether to afford 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (21.45 g, 69%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.10 (s, 1H), 7.47–7.26 (m, 5H), 5.74 (q, J = 7.2 Hz, 1H), 1.71 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₂H₁₂BrN₂O₂]⁺ [M + H]⁺ = 295.0077, found = 294.9.

(1-Bromoethyl)benzene (198 mg, 1.07 mmol) was added to a solution of 5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (33) (400 mg, 1.78 mmol) and KOH (250 mg, 4.46 mmol) in DMF (15 mL) and water (4.5 mL) under nitrogen at rt. The resulting solution was stirred at 60 °C for 18 h. The reaction mixture was filtered through filter paper and the solvent of the filtrate was removed under reduced pressure. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 5 μm, 19 × 250 mm) using decreasingly polar mixtures of water (10 mmol/L NH₄HCO₃) and MeCN (elution gradient 46–47%). Fractions containing the desired compound were evaporated to dryness to afford 5-(3,5-difluorophenyl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (400 mg, 68%) as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (s, 1H), 7.51–7.40 (m, 4H), 7.36 (ddd, J = 9.3, 3.9, 1.8 Hz, 1H), 7.18–7.08 (m, 2H), 6.89 (tt, J = 9.1, 2.3 Hz, 1H), 5.96 (q, J = 7.2 Hz, 1H), 1.82 (d, J = 7.2 Hz, 3H); ¹⁹F NMR (376 MHz, Methanol-d₄) δ −112.22; MS (ESI) m/z calculated for [C₁₈H₁₅F₂N₂O₂]⁺ [M + H]⁺ = 329.1096, found = 329.2.

The enantiomeric mixture above (2) was purified by preparative chiral-HPLC (Phenomenex Lux cellulose-4 Axia packed, 5 μm, 21.2 × 250 mm), isocratic 40% MeOH in scCO₂. Fractions containing the desired products were evaporated to dryness to afford enantiopure (S)-5-(3,5-difluorophenyl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (RT: 5.82 min, 100 mg, 25%) and enantiopure (R)-5-(3,5-difluorophenyl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (RT: 7.29 min, 97 mg, 24%) as white solids. Data for 3: NMR and MS (ESI) results are identical to 2; ee = 97%. Data for (S)-5-(3,5-difluorophenyl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione: ee = 98%.

To solution of 5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (33) (150 mg, 0.669 mmol) and KOH (56.3 mg, 1.00 mmol) in DMF (10 mL) and water (2 mL) under nitrogen at rt, was added (bromomethyl)benzene (114 mg, 0.667 mmol) in one portion. The resulting solution was stirred at 60 °C for 10 h. The reaction mixture was subsequently neutralized with 2 M HCl, the solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 5 μm, 19 × 150 mm) using decreasingly polar mixtures of water (10 mmol/L NH₄HCO₃) and MeCN (elution gradient 43–44%). Fractions containing the desired compound were evaporated to dryness to afford 1-benzyl-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (98.0 mg, 47%) as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.00 (s, 1H), 7.42–7.29 (m, 5H), 7.26–7.19 (m, 2H), 6.88 (tt, J = 9.1, 2.3 Hz, 1H), 5.02 (s, 2H); ¹⁹F NMR (376 MHz, Methanol-d₄) −112.28; MS (ESI) m/z calculated for [C₁₇H₁₃F₂N₂O₂]⁺ [M + H]⁺ = 315.0940, found = 314.9.

To a solution of 5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (33) (150 mg, 0.669 mmol), KI (111 mg, 0.669 mmol) and 1-chloro-2-(1-chloroethyl)benzene (117 mg, 0.668 mmol) in DMF (4 mL) and water (1 mL) under nitrogen at rt, was added KOH (75.0 mg, 1.34 mmol). The resulting solution was stirred at 60 °C overnight. Subsequently, the reaction was concentrated and purified by flash silica chromatography, elution gradient 0–20% MeOH in CH₂Cl₂. Fractions containing the desired compound were evaporated to dryness to afford 1-(1-(2-chlorophenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (89.0 mg, 37%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.69 (s, 1H), 7.84 (s, 1H), 7.60 (dd, J = 7.5, 1.4 Hz, 1H), 7.49 (dd, J = 7.5, 1.8 Hz, 1H), 7.48–7.28 (m, 4H), 7.15 (tt, J = 9.3, 2.2 Hz, 1H), 5.91 (q, J = 7.0 Hz, 1H), 1.76 (d, J = 7.1 Hz, 3H); MS (ESI) m/z calculated for [C₁₈H₁₄ClF₂N₂O₂]⁺ [M + H]⁺ = 363.0706, found = 363.2.

1-(1-Bromoethyl)-4-fluorobenzene (181 mg, 0.891 mmol) was added in one portion to a solution of 5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (33) (200 mg, 0.892 mmol), KI (29.6 mg, 0.178 mmol) and K₂CO₃ (370 mg, 2.68 mmol) in DMSO (10 mL) under nitrogen at rt. The resulting suspension was stirred at 50 °C for 12 h. The reaction mixture was subsequently filtered through filter paper. The filtrate was purified by preparative HPLC (Xselect CSH OBD column, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.05% TFA) and MeCN (elution gradient 43–54%). Fractions containing the desired compound were evaporated to dryness to afford 5-(3,5-difluorophenyl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (127 mg, 41%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.01 (s, 1H), 7.52–7.43 (m, 2H), 7.42–7.31 (m, 2H), 7.26–7.11 (m, 3H), 5.75 (q, J = 7.1 Hz, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₈H₁₄F₃N₂O₂]⁺ [M + H]⁺ = 347.1002, found = 347.2.

To a solution of 5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (33) (150 mg, 0.669 mmol) and 1-(1-bromoethyl)-3-chlorobenzene (147 mg, 0.670 mmol) in DMF (4 mL) and water (1 mL) under nitrogen at rt, was added KOH (75.0 mg, 1.34 mmol). The resulting solution was stirred at 60 °C overnight. The reaction was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution gradient 40–70%). Fractions containing the desired compound were evaporated to dryness to afford 1-(1-(3-chlorophenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (144 mg, 59%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.68 (s, 1H), 8.08 (s, 1H), 7.52 (s, 1H), 7.48–7.32 (m, 5H), 7.16 (tt, J = 9.3, 2.4 Hz, 1H), 5.74 (q, J = 7.2 Hz, 1H), 1.79 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₈H₁₄ClF₂N₂O₂]⁺ [M + H]⁺ = 363.0706, found = 363.2.

KI (592 mg, 3.57 mmol) was added in one portion to a solution of 5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (33) (800 mg, 3.57 mmol), 1-bromo-3-(1-chloroethyl)benzene (862 mg, 3.93 mmol) and K₂CO₃ (1.48 g, 10.7 mmol) in DMSO (10 mL) under nitrogen at rt. The resulting suspension was stirred at 50 °C overnight. The suspension was then filtered and the filtrate was directly purified by C18-flash chromatography, elution gradient 0–60% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford impure 1-(1-(3-bromophenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (750 mg, 42% pure by LC-MS) as a gray solid. This material was used in the subsequent reactions without further purification. MS (ESI) m/z calculated for [C₁₈H₁₃F₂N₂O₂]⁺ [M + H]⁺ = 407.0202 and 409.0181, found = 408.8.

Pd(PPh₃)₄ (25.5 mg, 0.0221 mmol) was added in one portion to a mixture of 1-(1-(3-bromophenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (180 mg, 0.442 mmol; material assumed pure for the purposes of reagent equivalent calculation), Na₂CO₃ (117 mg, 1.10 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (129 mg, 0.665 mmol) in 1,4-dioxane (12 mL) and water (3 mL) under nitrogen at rt. The resulting solution was stirred at 110 °C for 5 h. The reaction was then concentrated under reduced pressure and purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution at 35% isocratic). Fractions containing the desired compound were evaporated to dryness to afford 1-(1-(3-(1H-pyrazol-3-yl)phenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (70.0 mg, 40%) as a white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 7.86 (br s, 1H), 7.79–7.70 (m, 2H), 7.67 (br s, 1H), 7.52–7.37 (m, 2H), 7.21–7.07 (m, 2H), 6.86 (tt, J = 9.2, 2.4 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 5.98 (q, J = 7.1 Hz, 1H), 1.85 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₁H₁₇F₂N₄O₂]⁺ [M + H]⁺ = 395.1314, found = 395.2.

Pd(PPh₃)₄ (25.5 mg, 0.0221 mmol) was added in one portion to a mixture of 1-(1-(3-bromophenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (180 mg, 0.442 mmol; material assumed pure for the purposes of reagent equivalent calculation), Na₂CO₃ (141 mg, 1.33 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103 mg, 0.531 mmol) in 1,4-dioxane (8 mL) and water (2 mL) under nitrogen at rt. The resulting suspension was stirred at 110 °C for 5 h. The mixture was diluted with EtOAc (10 mL) and washed sequentially with water (10 mL) and saturated brine (2 × 10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD, 5 μm, 19 × 150 mm) using decreasingly polar mixtures of water (10 mmol/L NH₄HCO₃ + 0.1% NH₃·H₂O) and MeOH (elution at 58% isocratic). Fractions containing the desired compound were evaporated to dryness to afford 1-(1-(3-(1H-pyrazol-4-yl)phenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (60.0 mg, 34%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 2H), 7.96 (s, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.53 (dt, J = 7.8, 1.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.35–7.26 (m, 2H), 7.22–7.16 (m, 1H), 7.11 (tt, J = 9.4, 2.4 Hz, 1H), 5.76 (q, J = 7.1 Hz, 1H), 1.79 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₁H₁₇F₂N₄O₂]⁺ [M + H]⁺ = 395.1314, found = 395.1.

Pd(PPh₃)₄ (56.8 mg, 0.0492 mmol) was added in one portion to a mixture of 4-(tributylstannyl)-1-trityl-1H-imidazole (294 mg, 0.490 mmol) and 1-(1-(3-bromophenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (200 mg, 0.491 mmol; material assumed pure for the purposes of reagent equivalent calculation) in 1,4-dioxane (20 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 5 h. The crude product was purified by C18-flash chromatography, elution gradient 30–40% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford impure 5-(3,5-difluorophenyl)-1-(1-(3-(1-trityl-1H-imidazol-4-yl)phenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (200 mg) as a white solid. The impure material was used in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₄₀H₃₁F₂N₄O₂]⁺ [M + H]⁺ = 637.2410, found = 637.3 (weak detection of desired peak, ESI was dominated by the trityl cation (m/z = 243.2)).

TFA (3.00 mL, 39.2 mmol) was added in one portion to a solution of the above impure 5-(3,5-difluorophenyl)-1-(1-(3-(1-trityl-1H-imidazol-5-yl)phenyl)ethyl)pyrimidine-2,4(1H,3H)-dione in CH₂Cl₂ (6 mL) under nitrogen at rt. The resulting solution was stirred at rt for 3 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge Prep C18 OBD column, 5 μm, 30 × 100 mm) using decreasingly polar mixtures of water (containing 0.5% FA) and MeCN. Fractions containing the desired compound were evaporated to dryness to afford 1-(1-(3-(1H-imidazol-5-yl)phenyl)ethyl)-5-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione (60.0 mg, 31% over two-steps) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 11.70 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.78–7.59 (m, 3H), 7.48–7.31 (m, 3H), 7.23 (d, J = 7.4 Hz, 1H), 7.16 (tt, J = 9.1, 2.1, 1H), 5.82 (q, J = 6.6 Hz, 1H), 1.82 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₁H₁₇F₂N₄O₂]⁺ [M + H]⁺ = 395.1314, found = 395.2.

Pd(PPh₃)₄ (78.0 mg, 0.0675 mmol) was added in one portion to a mixture of 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (200 mg, 0.678 mmol), Na₂CO₃ (144 mg, 1.36 mmol) and phenylboronic acid (83.0 mg, 0.681 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) under nitrogen at rt. The resulting solution was stirred at 100 °C for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution gradient 40–50%). Fractions containing the desired compound were evaporated to dryness to afford 5-phenyl-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (82.9 mg, 42%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.56 (s, 1H), 7.74 (s, 1H), 7.53–7.23 (m, 10H), 5.82 (q, J = 7.1 Hz, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₈H₁₇N₂O₂]⁺ [M + H]⁺ = 293.1285, found = 292.9.

Pd(PPh₃)₄ (58.7 mg, 0.0508 mmol) was added in one portion to a mixture of 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.508 mmol) and 2-(tributylstannyl)pyridine (187 mg, 0.508 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) under nitrogen at rt. The resulting solution was stirred at 100 °C for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge Prep OBD C18, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (10 mmol/L NH₄HCO₃ + 0.1% NH₃.H₂O) and MeCN (elution gradient 28–48%). Fractions containing the desired compound were evaporated to dryness to afford 1-(1-phenylethyl)-5-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-dione (66.0 mg, 44%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.49 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.35 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.77 (td, J = 7.8, 1.9 Hz, 1H), 7.46–7.28 (m, 5H), 7.24 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 5.88 (q, J = 7.1 Hz, 1H), 1.73 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₇H₁₆N₃O₂]⁺ [M + H]⁺ = 294.1237, found = 294.1.

Pd(PPh₃)₄ (58.7 mg, 0.0508 mmol) was added in one portion to a mixture of 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.508 mmol) and 2-(tributylstannyl)pyrimidine (188 mg, 0.509 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) under nitrogen at rt. The resulting solution was stirred at 100 °C for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution gradient 25–39%). Fractions containing the desired compound were evaporated to dryness to afford 1′-(1-phenylethyl)-[2,5′-bipyrimidine]-2′,4′(1′H,3′H)-dione (30.0 mg, 20%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.81 (d, J = 4.9 Hz, 2H), 8.21 (s, 1H), 7.48–7.27 (m, 6H), 5.86 (q, J = 7.1 Hz, 1H), 1.74 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₆H₁₅N₄O₂]⁺ [M + H]⁺ = 295.3215, found = 295.2.

Pd(PPh₃)₄ (39.2 mg, 0.0339 mmol) was added to a mixture of 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (100 mg, 0.339 mmol), Na₂CO₃ (71.8 mg, 0.677 mmol) and (1H-indol-5-yl)boronic acid (82.0 mg, 0.509 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) under nitrogen at rt. The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine (2 × 50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD, 5 μm, 19 × 150 mm) using decreasingly polar mixtures of water (10 mmol/L NH₄HCO₃) and MeOH (elution at 50% isocratic). Fractions containing the desired compound were evaporated to dryness to afford 5-(1H-indol-5-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (20.0 mg, 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.46 (s, 1H), 11.08 (s, 1H), 7.62 (d, J = 11.3 Hz, 2H), 7.49–7.26 (m, 7H), 7.16 (dd, J = 8.5, 1.7 Hz, 1H), 6.53–6.32 (m, 1H), 5.83 (q, J = 7.2 Hz, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₀H₁₈N₃O₂]⁺ [M + H]⁺ = 332.1394, found = 332.1.

Pd(PPh₃)₄ (29.4 mg, 0.0254 mmol) was added in one portion to a mixture of 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.508 mmol), Na₂CO₃ (135 mg, 1.27 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (149 mg, 0.610 mmol) in 1,4-dioxane (12 mL) and water (3 mL) under nitrogen at rt. The resulting solution was stirred at 100 °C for 5 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (Xselect CSH OBD Column, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution gradient 30–40%). Fractions containing the desired compound were evaporated to dryness to afford 5-(1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (120 mg, 71%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, 1H), 11.60 (s, 1H), 8.07 (d, J = 1.3 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.46–7.35 (m, 4H), 7.34–7.27 (m, 1H), 7.18–7.07 (m, 2H), 5.81 (q, J = 7.2 Hz, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₇N₄O₂]⁺ [M + H]⁺ = 333.1346, found = 333.0.

Pd(PPh₃)₄ (193 mg, 0.167 mmol) was added to a mixture of 4-(tributylstannyl)-1-trityl-1H-imidazole (1.00 g, 1.67 mmol) and 1-(3-bromophenyl)ethan-1-ol (335 mg, 1.67 mmol) in 1,4-dioxane (10 mL) under nitrogen at rt. The resulting solution was stirred at 100 °C for 4 h. The reaction was then concentrated under reduced pressure and purified by flash silica chromatography, elution gradient 0–50% EtOAc in petroleum ether. Fractions containing the desired compound were evaporated to dryness to afford 1-(3-(1-trityl-1H-imidazol-4-yl)phenyl)ethan-1-ol (500 mg, 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (t, J = 1.7 Hz, 1H), 7.58 (dt, J = 7.8, 1.5 Hz, 1H), 7.47–7.38 (m, 12H), 7.25 (t, J = 7.7 Hz, 1H), 7.21–7.16 (m, 6H), 5.12 (d, J = 4.3 Hz, 1H), 4.76–4.60 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H); MS (ESI) m/z calculated for [C₃₀H₂₆N₂NaO]⁺ [M + Na]⁺ = 453.1937, found = 453.2.

N-Bromosuccinimide (165 mg, 0.927 mmol) was added portion wise to a mixture of PPh₃ (244 mg, 0.930 mmol) and 1-(3-(1-trityl-1H-imidazol-4-yl)phenyl)ethan-1-ol (400 mg, 0.929 mmol) in THF (10 mL) under nitrogen at 0 °C. The resulting mixture was stirred at rt for 1 h. The reaction was then concentrated under reduced pressure to afford the crude 4-(3-(1-bromoethyl)phenyl)-1-trityl-1H-imidazole (500 mg). The crude product was used in the subsequent reaction without further purification. MS (ESI) no product mass signal detected. ESI detection was dominated by the trityl cation (m/z = 243.2).

K₂CO₃ (280 mg, 2.03 mmol) was added to a mixture of 4-(3-(1-bromoethyl)phenyl)-1-trityl-1H-imidazole (500 mg, 1.01 mmol; material assumed pure for the purposes of reagent equivalent calculation), KI (168 mg, 1.01 mmol) and 5-bromopyrimidine-2,4(1H,3H)-dione (35) (194 mg, 1.01 mmol) in DMSO (10 mL) at rt. The resulting mixture was stirred at 100 °C for 12 h. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (petroleum ether: EtOAc = 1:1), to afford 5-bromo-1-(1-(3-(1-trityl-1H-imidazol-4-yl)phenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (200 mg, 36% over two steps) as a white solid. MS (ESI) m/z calculated for [C₃₄H₂₇BrN₄NaO₂]⁺ [M + Na]⁺ = 625.1210, 627.1190, found = 627.1 (weak detection of desired peak, ESI was dominated by the trityl cation (m/z = 243.2)).

Pd(PPh₃)₄ (38.3 mg, 0.0331 mmol) was added in one portion to a mixture of 5-bromo-1-(1-(3-(1-trityl-1H-imidazol-4-yl)phenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (200 mg, 0.331 mmol), Na₂CO₃ (52.7 mg, 0.497 mmol) and (1H-indazol-7-yl)boronic acid (81.0 mg, 0.500 mmol) in 1,4-dioxane (2 mL) and water (1 mL) under nitrogen at rt. The resulting mixture was stirred at 100 °C for 4 h. The reaction mixture was then diluted with EtOAc (25 mL) and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford the crude product which was used in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₄₁H₃₃N₆O₂]⁺ [M + H]⁺ = 641.2660, found = 641.6 (weak detection of desired peak, ESI was dominated by the trityl cation (m/z = 243.2)).

The above crude product was added to TFA (2 mL). The resulting mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (10 mmol/L NH₄HCO₃) and MeCN (elution gradient 25–28%). Fractions containing the desired compound were evaporated to dryness to afford 1-(1-(3-(1H-imidazol-5-yl)phenyl)ethyl)-5-(1H-indazol-7-yl)pyrimidine-2,4(1H,3H)-dione (13.0 mg, 10% over two steps) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (br s, 1H), 8.07 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.76–7.64 (m, 3H), 7.59 (s, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 6.9 Hz, 1H), 7.13–7.06 (m, 1H), 6.06 (br s, 1H), 5.83 (q, J = 7.0 Hz, 1H), 1.78 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₂H₁₉N₆O₂]⁺ [M + H]⁺ = 399.1564, found = 399.0.

AcOH (3.05 g, 50.8 mmol) was added in one portion to a mixture of 7-bromo-1H-indazole (1.00 g, 5.08 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (3.60 g, 10.2 mmol) in MeCN (30 mL) under nitrogen at rt. The resulting solution was stirred at 85 °C for 2 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated Na₂CO₃ (150 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0–30% EtOAc in petroleum ether. Fractions containing the desired compound were evaporated to dryness to afford 7-bromo-3-fluoro-1H-indazole (600 mg, 55%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.05 (s, 1H), 7.80–7.67 (m, 2H), 7.18–7.06 (m, 1H); MS (ESI) m/z calculated for [C₇H₅BrFN₂]⁺ [M + H]⁺ = 214.9615, found = 215.1.

Pd(dppf)Cl₂·CH₂Cl₂ (106 mg, 0.130 mmol) was added in one portion to a mixture of 7-bromo-3-fluoro-1H-indazole (350 mg, 1.63 mmol), KOAc (240 mg, 2.44 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (455 mg, 1.79 mmol) in 1,4-dioxane (20 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 12 h to give a black suspension. To this suspension was added Pd(PPh₃)₄ (94.0 mg, 0.0813 mmol), Na₂CO₃ (518 mg, 4.88 mmol), 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (480 mg, 1.63 mmol) and water (5 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 3 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5 μm, 19 × 150 mm) using decreasingly polar mixtures of water (containing 0.05% FA) and MeCN (elution gradient 38–48%). Fractions containing the desired compound were evaporated to dryness to afford 5-(3-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (150 mg, 26% over two steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.28 (s, 1H), 11.64 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.45–7.35 (m, 4H), 7.34–7.22 (m, 2H), 7.22–7.11 (m, 1H), 5.79 (q, J = 7.1 Hz, 1H), 1.75 (d, J = 7.2 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −136.61; MS (ESI) m/z calculated for [C₁₉H₁₆FN₄O₂]⁺ [M + H]⁺ = 351.1252, found = 350.9.

Pd(dppf)Cl₂·CH₂Cl₂ (77.0 mg, 0.0943 mmol) was added in one portion to a mixture of 7-bromo-3-methyl-1H-indazole (250 mg, 1.18 mmol), KOAc (174 mg, 1.77 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (331 mg, 1.30 mmol) in 1,4-dioxane (2 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 12 h to give a black suspension. To this suspension was added Pd(PPh₃)₄ (68.4 mg, 0.0592 mmol), Na₂CO₃ (377 mg, 3.56 mmol), 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (350 mg, 1.19 mmol) and water (0.5 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 3 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 10 mmol/L NH₄HCO₃ + 0.1% NH₃.H₂O) and MeCN (elution at 34% isocratic). Fractions containing the desired compound were evaporated to dryness to afford 5-(3-methyl-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (133 mg, 33% over two-steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.32 (s, 1H), 9.96 (br s, 1H), 7.76 (br s, 1H), 7.65 (dd, J = 8.0, 0.9 Hz, 1H), 7.45–7.22 (m, 5H), 7.14–6.99 (m, 2H), 5.78 (q, J = 7.2 Hz, 1H), 2.47 (s, 3H), 1.74 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₀H₁₉N₄O₂]⁺ [M + H]⁺ = 347.1503, found = 347.2.

NaH (60% dispersion in mineral oil, 306 mg, 7.65 mmol) was added portionwise to a solution of methyl 7-bromo-1H-indazole-3-carboxylate (1.50 g, 5.88 mmol) in THF (100 mL) under nitrogen at 0 °C, over a period of 5 min. The resulting solution was stirred for 30 min at 0 °C and subsequently (2-(chloromethoxy)ethyl)trimethylsilane (1.08 g, 6.48 mmol) was added dropwise. The reaction was allowed to reach rt and stirred for 1 h. The reaction mixture was quenched with saturated NH₄Cl (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford crude methyl 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxylate (2.20 g, 97%) as a pale yellow oil. The crude product was used in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₁₅H₂₂BrN₂O₃Si]⁺ [M + H]⁺ = 385.0578 and 387.0558, found = 387.1.

A solution of methyl 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxylate (2.20 g, 5.71 mmol) and ammonia in MeOH (8 M, 36.0 mL, 288 mmol) in a 100 mL sealed tube was stirred at 100 °C for 12 h. The solvent was removed under reduced pressure to afford the crude 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (2.10 g, 99%) as a pale yellow solid. The crude product was used in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₁₄H₂₀BrN₃NaO₂Si]⁺ [M + Na]⁺ = 392.0400 and 394.0380, found = 392.2.

Pd(dppf)Cl₂·CH₂Cl₂ (212 mg, 0.260 mmol) was added in one portion to a mixture of 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (1.20 g, 3.24 mmol), KOAc (477 mg, 4.86 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (905 mg, 3.56 mmol) in 1,4-dioxane (30 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 12 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 0–50% EtOAc in petroleum ether. Fractions containing the desired compound were evaporated to dryness to afford 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (660 mg, 49%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (dd, J = 8.1, 1.3 Hz, 1H), 7.82–7.72 (m, 2H), 7.47 (s, 1H), 7.31 (dd, J = 8.2, 6.9 Hz, 1H), 6.09 (s, 2H), 3.27 (t, J = 8.0 Hz, 2H), 1.36 (s, 12H), 0.70 (t, J = 8.0 Hz, 2H), −0.18 (s, 9H); MS (ESI) m/z calculated for [C₂₀H₃₂BN₃NaO₄Si]⁺ [M + Na]⁺ = 440.2147, found = 440.4.

Pd(PPh₃)₄ (120 mg, 0.104 mmol) was added in one portion to a mixture of 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (382 mg, 1.29 mmol), Na₂CO₃ (343 mg, 3.24 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (648 mg, 1.55 mmol) in 1,4-dioxane (20 mL) and water (5 mL) under nitrogen at rt. The resulting solution was stirred at 100 °C for 5 h. The solvent was removed under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 30–40% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 7-(2,4-dioxo-1-(1-phenylethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (250 mg, 38%) as a white solid. MS (ESI) m/z calculated for [C₂₆H₃₁N₅NaO₄Si]⁺ [M + Na]⁺ = 528.2038, found = 528.4.

2,2,2-Trifluoroacetic anhydride (110 μL, 0.791 mmol) was added dropwise to a solution of 7-(2,4-dioxo-1-(1-phenylethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (200 mg, 0.396 mmol) and pyridine (160 μL, 1.98 mmol) in CH₂Cl₂ (5 mL) under nitrogen at 0 °C, over a period of 5 min. The resulting solution was stirred at rt for 1 h. The solvent was removed under reduced pressure to afford the crude 7-(2,4-dioxo-1-(1-phenylethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile (200 mg) as a pale yellow gum. The crude product was used in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₂₆H₂₉N₅NaO₃Si]⁺ [M + H]⁺ = 510.1932, found = 510.0.

The above crude 7-(2,4-dioxo-1-(1-phenylethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile was diluted in CH₂Cl₂ (6 mL) and to this solution was added dropwise 2,2,2-trifluoroacetic acid (2.00 mL, 26.1 mmol) under nitrogen at rt. The resulting solution was stirred at rt for 4 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution gradient 38–48%). Fractions containing the desired compound were evaporated to dryness to afford 7-(2,4-dioxo-1-(1-phenylethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-indazole-3-carbonitrile (50.0 mg, 35% over two steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 14.06 (s, 1H), 11.71 (s, 1H), 7.97 (s, 1H), 7.86 (dd, J = 7.6, 1.4 Hz, 1H), 7.46–7.24 (m, 7H), 5.80 (q, J = 7.3 Hz, 1H), 1.76 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₀H₁₆N₅O₂]⁺ [M + H]⁺ = 358.1299, found = 358.3.

Pd(dppf)Cl₂·CH₂Cl₂ (47.5 mg, 0.0582 mmol) was added in one portion to a mixture of 7-bromo-6-fluoro-1H-indazole (250 mg, 1.16 mmol), KOAc (285 mg, 2.91 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (886 mg, 3.49 mmol) in 1,4-dioxane (20 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 18 h to give a black suspension. The crude product was used as a suspension in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₁₃H₁₇BFN₂O₂]⁺ [M + H]⁺ = 263.1362, found = 263.1.

Water (5 mL), 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (282 mg, 0.955 mmol), Na₂CO₃ (303 mg, 2.86 mmol) and Pd(PPh₃)₄ (55.1 mg, 0.0477 mmol) were added sequentially to the above suspension under nitrogen at rt. The resulting suspension was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm), using decreasingly polar mixtures of water (containing 0.1% FA) and MeOH (elution gradient 50–51%). Fractions containing the desired compound were evaporated to dryness to afford 5-(6-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (25.0 mg, 6% over two steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.98 (s, 1H), 11.66 (s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.77 (dd, J = 8.8, 4.9 Hz, 1H), 7.49–7.28 (m, 5H), 7.00 (t, J = 9.3 Hz, 1H), 5.81 (q, J = 7.1 Hz, 1H), 1.73 (d, J = 7.2 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −119.94; MS (ESI) m/z calculated for [C₁₉H₁₆FN₄O₂]⁺ [M + H]⁺ = 351.1252, found = 351.2.

Pd(dppf)Cl₂ (197 mg, 0.241 mmol) was added in one portion to a mixture of KOAc (445 mg, 4.53 mmol), 7-bromo-5-fluoro-1H-indazole (37) (650 mg, 3.02 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (844 mg, 3.33 mmol) in 1,4-dioxane (20 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 12 h to give a black suspension. The crude product was used as a suspension in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₁₃H₁₇BFN₂O₂]⁺ [M + H]⁺ = 263.1362, found = 263.0.

Water (5 mL), 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (803 mg, 2.72 mmol), Na₂CO₃ (961 mg, 9.07 mmol) and Pd(PPh₃)₄ (175 mg, 0.151 mmol) were added sequentially to the above suspension under nitrogen at rt. The resulting suspension was stirred at 100 °C for 3 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by C18-flash chromatography, elution gradient 30–60% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-(5-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (540 mg, 51% over two steps) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.93 (s, 1H), 11.59 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.56–7.48 (m, 1H), 7.47–7.33 (m, 4H), 7.35–7.25 (m, 1H), 7.15 (s, 1H), 5.78 (q, J = 7.2 Hz, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₆FN₄O₂]⁺ [M + H]⁺ = 351.1252, found = 351.0.

N-Bromosuccinimide (274 mg, 1.54 mmol) was added to a mixture of 5-(5-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (21) (540 mg, 1.54 mmol) and NaOH (123 mg, 3.08 mmol) in DMF (6 mL) under nitrogen at rt. The resulting solution was stirred at rt for 30 min to give a black suspension. The crude suspension was purified by C18-flash chromatography, elution gradient 30–70% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-(3-bromo-5-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (400 mg, 61%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.28 (br s, 1H), 11.71 (br s, 1H), 8.05 (s, 1H), 7.48–7.24 (m, 7H), 5.78 (q, J = 7.1 Hz, 1H), 1.76 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₅BrFN₄O₂]⁺ [M + H]⁺ = 429.0357 and 431.0337, found = 430.9.

Pd(PPh₃)₄ (808 mg, 0.699 mmol), 5-(3-bromo-5-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (300 mg, 0.699 mmol) and dicyanozinc (164 mg, 1.40 mmol) were suspended in DMA (6 mL) under nitrogen at rt and sealed into a microwave tube. The reaction was heated to 160 °C for 30 min in a microwave reactor and subsequently cooled to rt. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution gradient 40–60%). Fractions containing the desired compound were evaporated to dryness to afford to afford 7-(2,4-dioxo-1-(1-phenylethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-5-fluoro-1H-indazole-3-carbonitrile (50.0 mg, 19%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 14.16 (s, 1H), 11.74 (s, 1H), 8.07 (s, 1H), 7.71 (dd, J = 8.4, 2.3 Hz, 1H), 7.45–7.22 (m, 6H), 5.77 (q, J = 7.2 Hz, 1H), 1.75 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₀H₁₅FN₅O₂]⁺ [M + H]⁺ = 376.1204, found = 376.3.

Diethyl azodicarboxylate (1.29 mL, 8.15 mmol) was added dropwise to a mixture of 5-bromopyrimidine-2,4(1H,3H)-dione (35) (1.20 g, 6.28 mmol), 1-(pyridin-2-yl)ethan-1-ol (696 mg, 5.65 mmol) and PPh₃ (2.14 g, 8.16 mmol) in THF (50 mL) under nitrogen at rt, over a period of 1 min. The resulting solution was stirred at rt for 2 h. The mixture was filtered through a Celite pad. The solvent of the filtrate was removed under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 0–60% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-bromo-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (1.10 g, 59%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.79 (s, 1H), 8.54 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.18 (s, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.41 (dd, J = 7.9, 1.3 Hz, 1H), 7.31 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 5.72 (q, J = 7.2 Hz, 1H), 1.69 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₁H₁₁BrN₃O₂]⁺ [M + H]⁺ = 296.0030 and 298.0009, found = 296.0.

Pd(dppf)Cl₂·CH₂Cl₂ (152 mg, 0.186 mmol) was added in one portion to 7-bromo-5-fluoro-1H-indazole (37) (500 mg, 2.33 mmol), KOAc (571 mg, 5.81 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (709 mg, 2.79 mmol) in 1,4-dioxane (20 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 12 h. The crude product was used as a suspension in the subsequent reaction without further purification. MS (ESI) m/z calculated for [C₁₃H₁₇BFN₂O₂]⁺ [M + H]⁺ = 263.1362, found = 263.2.

Water (5 mL), 5-bromo-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (600 mg, 2.03 mmol), Na₂CO₃ (644 mg, 6.08 mmol) and Pd(PPh₃)₄ (117 mg, 0.101 mmol) were added sequentially to the above suspension under nitrogen at rt. The resulting suspension was stirred at 100 °C for 5 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by C18-flash chromatography, elution gradient 0–50% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-(5-fluoro-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (330 mg, 40% over two steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.90 (s, 1H), 11.65 (s, 1H), 8.55 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 1.3 Hz, 1H), 8.03 (s, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.53 (dd, J = 8.9, 2.2 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 6.8, 4.9 Hz, 1H), 7.17 (dd, J = 9.8, 2.3 Hz, 1H), 5.82 (q, J = 7.1 Hz, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₈H₁₅FN₅O₂]⁺ [M + H]⁺ = 352.1204, found = 352.2.

N-Bromosuccinimide (152 mg, 0.854 mmol) was added in one portion to a mixture of 5-(5-fluoro-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (300 mg, 0.854 mmol) and NaOH (68.3 mg, 1.71 mmol) in DMF (5 mL) under nitrogen at rt. The resulting solution was stirred at rt for 1 h. The crude product was purified directly by C18-flash chromatography, elution gradient 0–40% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-(3-bromo-5-fluoro-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (250 mg, 68%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.65 (br s, 1H), 8.54 (d, J = 4.1 Hz, 1H), 8.37 (br s, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.49–7.23 (m, 4H), 5.82 (q, J = 7.1 Hz, 1H), 1.78 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₈H₁₄BrFN₅O₂]⁺ [M + H]⁺ = 430.0310 and 432.0289, found = 430.2.

Pd(PPh₃)₄ (33.6 mg, 0.0291 mmol), 5-(3-bromo-5-fluoro-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (250 mg, 0.581 mmol) and dicyanozinc (341 mg, 2.90 mmol) were suspended in DMA (10 mL) under nitrogen at rt and sealed into a microwave tube. The reaction was heated to 180 °C for 2 h in a microwave reactor and subsequently cooled to rt. The solvent was removed under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 0–100% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 7-(2,4-dioxo-1-(1-(pyridin-2-yl)ethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-5-fluoro-1H-indazole-3-carboxamide (130 mg, 57%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.33 (s, 1H), 11.70 (s, 1H), 8.60–8.51 (m, 1H), 8.08 (s, 1H), 7.88–7.70 (m, 3H), 7.46 (d, J = 7.9 Hz, 1H), 7.38 (br s, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.23 (dd, J = 9.7, 2.3 Hz, 1H), 5.83 (q, J = 7.1 Hz, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₆FN₆O₃]⁺ [M + H]⁺ = 395.1262, found = 395.3.

NEt₃ (138 μL, 0.990 mmol) was added to a solution of 7-(2,4-dioxo-1-(1-(pyridin-2-yl)ethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-5-fluoro-1H-indazole-3-carboxamide (130 mg, 0.330 mmol) and 2,2,2-trifluoroacetic anhydride (138 μL, 0.993 mmol) in THF (8 mL) under nitrogen at rt. The resulting suspension was stirred at rt for 2 h. The reaction was concentrated under reduced pressure and purified by C18-flash chromatography, elution gradient 0–100% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford a white solid as the crude product. The crude product was repurified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.05% TFA) and MeCN (elution gradient 30–60%). Fractions containing the desired compound were evaporated to dryness to afford 7-(2,4-dioxo-1-(1-(pyridin-2-yl)ethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-5-fluoro-1H-indazole-3-carbonitrile (20.0 mg, 16%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 14.20 (s, 1H), 11.76 (s, 1H), 8.59–8.50 (m, 1H), 8.14 (s, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.51–7.27 (m, 3H), 5.89–5.75 (m, 1H), 1.77 (d, J = 7.4 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₄FN₆O₂]⁺ [M + H]⁺ = 377.1157, found = 377.2.

K₂CO₃ (4.08 g, 29.5 mmol) was added to a solution of 5-bromopyrimidine-2,4(1H,3H)-dione (35) (3.39 g, 17.8 mmol) and 1-(1-bromoethyl)-4-fluorobenzene (2.00 g, 9.85 mmol) in DMSO (18 mL) under nitrogen at rt. The resulting suspension was stirred at 60 °C for 3 h. The reaction was concentrated under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 0–100% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-bromo-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (2.50 g, 81%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (s, 1H), 7.33 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 5.77 (q, J = 7.2 Hz, 1H), 1.56 (d, J = 7.3 Hz, 3H); MS (ESI) m/z calculated for [C₁₂H₁₁BrFN₂O₂]⁺ [M + H]⁺ = 312.9982, found = 313.1.

Pd(dppf)Cl₂ (408 mg, 0.558 mmol) was added in one portion to a mixture of KOAc (1.64 g, 16.7 mmol), 7-bromo-5-fluoro-1H-indazole (37) (1.20 g, 5.58 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.42 g, 5.59 mmol) in 1,4-dioxane (30 mL) under nitrogen at rt. The resulting mixture was stirred at 100 °C for 12 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 40–50% EtOAc in petroleum ether. Fractions containing the desired compound were evaporated to dryness to afford 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.50 g, 53% pure by LC-MS) as a brown solid. The impure material was used in the next step without further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 12.68 (s, 1H), 8.09 (s, 1H), 7.69 (dd, J = 9.0, 2.6 Hz, 1H), 7.39 (dd, J = 9.1, 2.5 Hz, 1H), 1.34 (s, 12H); MS (ESI) m/z calculated for [C₁₃H₁₇BFN₂O₂]⁺ [M + H]⁺ = 263.1362, found = 263.2.

Pd(PPh₃)₄ (661 mg, 0.572 mmol) was added in one portion to a mixture of 5-bromo-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (36) (1.79 g, 5.72 mmol), 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (38) (1.50 g, 5.72 mmol; material assumed pure for the purposes of reagent equivalent calculation) and Na₂CO₃ (1.82 g, 17.2 mmol) in 1,4-dioxane (20 mL) and water (20 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 12 h. The reaction was concentrated under reduced pressure and purified by C18-flash chromatography, elution gradient 50–60% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-(5-fluoro-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (700 mg, 34% over two steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.61 (br s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.45–7.27 (m, 3H), 7.13 (t, J = 8.9 Hz, 3H), 5.87 (q, J = 7.1 Hz, 1H), 1.67 (d, J = 7.3 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₅F₂N₄O₂]⁺ [M + H]⁺ = 369.1158, found = 369.2.

300 mg of an enantiomeric mixture of 5-(5-fluoro-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione, were purified by preparative chiral-HPLC (CHIRALPAK IG, 5 μm, 20 × 250 mm), isocratic 50% EtOH in hexane (containing 8 mmol/L NH₃.MeOH). Fractions containing the desired products were evaporated to dryness to afford enantiopure (S)-5-(5-fluoro-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (Rt: 8.65, 30.0 mg, 10%) (27) and (R)-5-(5-fluoro-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (Rt: 11.82, 50.0 mg, 17%) as white solids. Data for 27: NMR and MS (ESI) results are equivalent to 26; purity 93–94%; ee >99%. Data for (R)-5-(5-fluoro-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione: ee = 98%.

N-Iodosuccinimide (366 mg, 1.63 mmol) was added to a solution of 5-(5-fluoro-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (26) (400 mg, 1.09 mmol) and NaOH (87.0 mg, 2.17 mmol) in DMF (20 mL) at rt to give a brown solution. The resulting mixture was stirred at rt for 5 h. The crude product was purified directly by C18-flash chromatography, elution gradient 40–50% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-(5-fluoro-3-iodo-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (450 mg, 84%) as a white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 7.86 (s, 1H), 7.54–7.41 (m, 3H), 7.22 (dd, J = 9.6, 2.3 Hz, 1H), 7.17–7.04 (m, 2H), 5.93 (q, J = 7.2 Hz, 1H), 1.81 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₄F₂IN₄O₂]⁺ [M + H]⁺ = 495.0124, found = 495.1.

Pd(PPh₃)₄ (105 mg, 0.0909 mmol) was added to a mixture of 5-(5-fluoro-3-iodo-1H-indazol-7-yl)-1-(1-(4-fluorophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione (450 mg, 0.910 mmol) and dicyanozinc (321 mg, 2.73 mmol) in DMA (20 mL) at rt to give a brown solution. The solution was stirred at 100 °C for 12 h. The reaction was filtered and directly purified by C18-flash chromatography, elution gradient 5–95% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford the 5-fluoro-7-(1-(1-(4-fluorophenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-indazole-3-carbonitrile (106 mg, 30%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 14.19 (s, 1H), 11.76 (s, 1H), 8.11 (s, 1H), 7.73 (dd, J = 8.3, 2.1 Hz, 1H), 7.47 (dd, J = 8.6, 5.5 Hz, 2H), 7.39 (dd, J = 9.7, 2.0 Hz, 1H), 7.20 (t, J = 8.8 Hz, 2H), 5.76 (q, J = 6.9 Hz, 1H), 1.76 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₀H₁₄F₂N₅O₂]⁺ [M + H]⁺ = 394.1110, found = 394.3.

The enantiomeric mixture above (24) was purified by preparative chiral-HPLC (CHIRALPAK IG-03, 5 μm, 20 × 250 mm), isocratic 40% EtOH in hexane (8 mmol/L NH₃.MeOH). Fractions containing the desired products were evaporated to dryness to afford enantiopure (S)-5-fluoro-7-(1-(1-(4-fluorophenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-indazole-3-carbonitrile (Rt: 8.05 min, 30.0 mg, 28%) (25) and enantiopure (R)-5-fluoro-7-(1-(1-(4-fluorophenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-indazole-3-carbonitrile (Rt: 10.08 min, 30.0 mg, 28%) as white solids. Data for 25: ¹H NMR (300 MHz, Methanol-d₄) δ 7.87 (s, 1H), 7.55–7.40 (m, 3H), 7.23 (dd, J = 9.6, 2.3 Hz, 1H), 7.17–7.04 (m, 2H), 5.93 (q, J = 7.2 Hz, 1H), 1.81 (d, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, Methanol-d₄) δ 163.83 (d, J_CF = 256.6 Hz), 163.80, 160.6 (d, J_CF = 253.2 Hz), 152.4, 143.3, 137.6, 137.1, 130.3 (d, J_CF = 8.3 Hz), 126.0 (d, J_CF = 11.4 Hz), 121.4 (d, J_CF = 9.8 Hz), 118.8 (d, J_CF = 28.4 Hz), 116.6 (d, J_CF = 21.8 Hz), 114.4, 112.06, 112.04, 103.7 (d, J_CF = 25.1 Hz), 55.7, 18.9; ¹⁹F NMR (282 MHz, Methanol-d₄) δ −115.97, −120.35; MS (ESI) m/z calculated for [C₂₀H₁₄F₂N₅O₂]⁺ [M + H]⁺ = 394.1110, found = 394.2; ee = 99%. Data for (R)-5-fluoro-7-(1-(1-(4-fluorophenyl)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-indazole-3-carbonitrile: ee = 97%

N-Bromosuccinimide (517 mg, 2.91 mmol) was added portionwise to a mixture of 5-(1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (15) (920 mg, 2.77 mmol) and NaOH (221 mg, 5.54 mmol) in DMF (10 mL) under nitrogen at 0 °C. The resulting suspension was stirred at rt for 1 h. The reaction was concentrated under reduced pressure and the crude product purified by C18-flash chromatography, elution gradient 0–40% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 5-(3-bromo-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (950 mg, 83%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.36 (br s, 1H), 8.08 (s, 1H), 7.51 (dd, J = 8.1, 0.9 Hz, 1H), 7.47–7.26 (m, 6H), 7.17 (dd, J = 8.0, 7.2 Hz, 1H), 5.82 (q, J = 7.1 Hz, 1H), 1.76 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₉H₁₆BrN₄O₂]⁺ [M + H]⁺ = 411.0452 and 413.0431, found = 413.1.

Pd(PPh₃)₂Cl₂ (42.7 mg, 0.0608 mmol) and CuI (11.6 mg, 0.0609 mmol) was added in one portion to a mixture of 5-(3-bromo-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (250 mg, 0.608 mmol), NEt₃ (615 mg, 6.08 mmol) and ethynyltrimethylsilane (299 mg, 3.04 mmol) in DMF (5 mL) under nitrogen at rt. The resulting suspension was stirred at 100 °C for 12 h. The reaction was concentrated under reduced pressure and the crude product purified by C18-flash chromatography, elution gradient 0–40% MeCN in water. Fractions containing the desired compound were evaporated to dryness to afford 1-(1-phenylethyl)-5-(3-((trimethylsilyl)ethynyl)-1H-indazol-7-yl)pyrimidine-2,4(1H,3H)-dione (130 mg, 50%) as a pale yellow solid. MS (ESI) m/z calculated for [C₂₄H₂₅N₄O₂Si]⁺ [M + H]⁺ = 429.1741, found = 429.2.

K₂CO₃ (74.2 mg, 0.537 mmol) was added in one portion to a solution of 1-(1-phenylethyl)-5-(3-((trimethylsilyl)ethynyl)-1H-indazol-7-yl)pyrimidine-2,4(1H,3H)-dione (115 mg, 0.268 mmol) in MeOH (5 mL) under nitrogen at rt. The resulting suspension was stirred at rt for 1 h. The reaction was concentrated under reduced pressure and the crude product purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 150 mm) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN (elution gradient 38–48%). Fractions containing the desired compound were evaporated to dryness to afford 5-(3-ethynyl-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (39.4 mg, 41%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.14 (s, 1H), 11.62 (s, 1H), 7.88 (s, 1H), 7.73–7.64 (m, 1H), 7.47–7.26 (m, 5H), 7.26–7.16 (m, 2H), 5.80 (q, J = 7.1 Hz, 1H), 4.49 (s, 1H), 1.76 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₁H₁₇N₄O₂]⁺ [M + H]⁺ = 357.1346, found = 357.2.

Silver sulfate (5.80 g, 18.6 mmol) was added to a mixture of I₂ (4.72 g, 18.6 mmol) and 7-bromo-5-fluoro-1H-indazole (37) (4.00 g, 18.6 mmol) in EtOH (500 mL) under air at rt. The resulting solution was stirred at rt for 17 h. The reaction mixture was filtered through glass fiber paper and the filtrate was concentrated under reduced pressure to afford 7-bromo-5-fluoro-3-iodo-1H-indazole (6.00 g, 95%) as a pale yellow solid. The crude product was used in the subsequent reaction without further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (br s, 1H), 7.71 (dd, J = 8.7, 2.2 Hz, 1H), 7.24 (dd, J = 8.4, 2.2 Hz, 1H); MS (ESI) m/z calculated for [C₇H₄BrFN₂]⁺ [M + H]⁺ = 340.8582 and 342.8561, found = 342.9.

Ethynyltrimethylsilane (1.73 g, 17.6 mmol) was added to a degassed suspension of 7-bromo-5-fluoro-3-iodo-1H-indazole (39) (6.00 g, 17.6 mmol), CuI (335 mg, 1.76 mmol) and Pd(PPh₃)₄ (2.03 g, 1.76 mmol) in NEt₃ (50 mL) and MeCN (50 mL) under nitrogen at rt. The reaction was stirred at 80 °C for 17 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 0–20% EtOAc in petroleum ether. Fractions containing the desired compound were evaporated to dryness to afford 7-bromo-5-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazole (2.40 g, 44%) as a pale yellow solid. ¹H NMR (500 MHz, Chloroform-d) δ 10.12 (s, 1H), 7.43–7.41 (m, 2H), 0.31 (s, 9H); MS (ESI) m/z calculated for [C₁₂H₁₃BrFN₂Si]⁺ [M + H]⁺ = 311.0010 and 312.9990, found = 311.0.

Pd(dppf)Cl₂·CH₂Cl₂ (630 mg, 0.771 mmol) was added to a suspension of 7-bromo-5-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazole (40) (2.40 g, 7.71 mmol), KOAc (2.27 g, 23.1 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.94 g, 11.6 mmol) in 1,4-dioxane (100 mL) under nitrogen at rt. The resulting suspension was stirred at 80 °C for 17 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 0–5% EtOAc in petroleum ether. Fractions containing the desired compound were evaporated to dryness to afford 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole (2.10 g, 76%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.08 (s, 1H, s), 7.55 (dd, J = 8.4, 2.5 Hz, 1H), 7.46 (dd, J = 9.0, 2.6 Hz, 1H), 1.35 (s, 12H), 0.28 (s, 9H); MS (ESI) m/z calculated for [C₁₈H₂₅BFN₂O₂Si]⁺ [M + H]⁺ = 359.1757, found = 359.2.

XPhos Pd G2 (42.3 mg, 0.0538 mmol) was added to a solution of 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole (41) (269 mg, 0.751 mmol), 5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (148 mg, 0.501 mmol) and K₂CO₃ (173 mg, 1.25 mmol) in 1,4-dioxane (2.0 mL) and water (0.5 mL) under nitrogen at rt. The reaction was degassed and then stirred at 80 °C for 3 h. After cooling, the reaction was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc. The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0–100% EtOAc in heptane. Fractions containing the desired compound were evaporated to dryness.

The above residue was dissolved in MeOH (2.5 mL) before the addition of K₂CO₃ (500 mg, 3.62 mmol) to the reaction mixture. The reaction was stirred at rt for 1 h and upon completion, the reaction was filtered and the solids washed with CH₂Cl₂. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 100 mm) using decreasingly polar mixtures of water (containing 1% NH₃) and MeCN. Fractions containing the desired compound were evaporated to dryness to afford 5-(3-ethynyl-5-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (46.0 mg, 25% over two steps) as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ 13.29 (br s, 1H), 11.66 (br s, 1H), 8.07 (s, 1H), 7.44–7.40 (m, 3H), 7.39–7.34 (m, 2H), 7.33–7.22 (m, 2H), 5.78 (q, J = 7.4 Hz, 1H), 4.52 (s, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₁H₁₆FN₄O₂]⁺ [M + H]⁺ = 375.3829, found = 375.4.

Diisopropyl azodicarboxylate (2.39 mL, 12.3 mmol) was added dropwise to a mixture of PPh₃ (3.22 g, 12.3 mmol), (R)-1-phenylethan-1-ol (1.00 g, 8.19 mmol) and 5-bromopyrimidine-2,4(1H,3H)-dione (35) (1.56 g, 8.17 mmol) in THF (40 mL) under nitrogen at rt. The resulting solution was stirred at rt for 17 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 0–40% EtOAc in petroleum ether. Fractions containing the desired compound were evaporated to dryness to afford an impure mixture which was repurified by C18-flash chromatography, elution gradient 0–60% MeCN in water (containing 0.1% FA). Fractions containing the desired compound were evaporated to dryness to afford (S)-5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (500 mg, 21%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.08 (s, 1H), 7.42–7.26 (m, 5H), 5.71 (q, J = 7.2 Hz, 1H), 1.68 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₂H₁₂BrN₂O₂]⁺ [M + H]⁺ = 295.0077 and 292.0057, found = 294.9; ee = 91%.

Pd(dppf)Cl₂ (199 mg, 0.305 mmol) was added to a suspension of K₃PO₄ (432 mg, 2.04 mmol), (S)-5-bromo-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (42) (300 mg, 1.02 mmol) and 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole (41) (364 mg, 1.02 mmol) in toluene (24 mL) and water (0.40 mL) under nitrogen at rt. The resulting suspension was stirred at 80 °C for 17 h. The solvent was removed under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 0–60% MeCN in water (containing 0.1% FA). Fractions containing the desired compound were evaporated to dryness to afford (S)-5-(5-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (120 mg, 26%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 11.70 (s, 1H), 8.06 (s, 1H), 7.43–7.36 (m, 5H), 7.31–7.23 (m, 2H), 5.78 (q, J = 7.1 Hz, 1H), 1.77 (d, J = 7.3 Hz, 3H), 0.30 (s, 9H); MS (ESI) m/z calculated for [C₂₄H₂₄FN₄O₂Si]⁺ [M + H]⁺ = 447.1647, found = 447.1.

K₂CO₃ (204 mg, 1.48 mmol) was added to a solution of (S)-5-(5-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (43) (110 mg, 0.246 mmol) in MeOH (10 mL) at rt. The resulting mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 0–50% MeCN in water (containing 0.1% FA). Fractions containing the desired compound were evaporated to dryness and subsequently repurified by preparative chiral-HPLC (CHIRALPAK IG, 5 μm, 20 × 250 mm), isocratic 30% EtOH in hexane (containing 0.5% 2 M NH₃·MeOH). Fractions containing the desired product were evaporated to dryness to afford enantiopure (S)-5-(3-ethynyl-5-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (Rt: 13.70 min, 40.0 mg, 43%) as a pale yellow solid. The impurity (R)-5-(3-ethynyl-5-fluoro-1H-indazol-7-yl)-1-(1-phenylethyl)pyrimidine-2,4(1H,3H)-dione eluted at 18.43 min. ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (s, 1H), 11.71 (s, 1H), 8.05 (s, 1H), 7.48–7.39 (m, 3H), 7.37 (t, J = 7.5 Hz, 2H), 7.34–7.21 (m, 2H), 5.78 (q, J = 7.1 Hz, 1H), 4.55 (s, 1H), 1.77 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 161.6, 157.5 (d, J_CF = 237.9 Hz), 150.6, 141.8, 140.6, 136.4 (d, J_CF = 2.9 Hz), 128.6, 127.7, 126.9, 126.8, 124.2 (d, J_CF = 10.9 Hz), 119.6 (d, J_CF = 9.7 Hz), 116.9 (d, J_CF = 27.9 Hz), 110.1, 102.7 (d, J_CF = 23.6 Hz), 84.6, 75.5, 54.3, 18.6; ¹⁹F NMR (376 MHz, DMSO-d₆) −121.67; MS (ESI) m/z calculated for [C₂₁H₁₆FN₄O₂]⁺ [M + H]⁺ = 375.1252, found = 375.1; HRMS (ESI) m/z calculated for [C₂₁H₁₆FN₄O₂]⁺ [M + H]⁺ = 375.1252, found = 375.1270; ee > 99%.

XPhos Pd G2 (42.3 mg, 0.0538 mmol) was added to a solution of 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole (41) (269 mg, 0.751 mmol), 5-bromo-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (148 mg, 0.500 mmol) and K₂CO₃ (173 mg, 1.25 mmol) in 1,4-dioxane (2.0 mL) and water (0.50 mL) under nitrogen at rt. The reaction was degassed and then stirred at 80 °C for 3 h. After cooling, the reaction was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc. The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0–100% EtOAc in heptane. Fractions containing the desired compound were evaporated to dryness.

The above residue was dissolved in MeOH (2.5 mL) before the addition of K₂CO₃ (500 mg, 3.62 mmol) to the reaction mixture. The reaction was stirred at rt for 1 h and upon completion, the reaction was filtered and the solids washed with CH₂Cl₂. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (Xselect CSH OBD, 5 μm, 30 × 100 mm) using decreasingly polar mixtures of water (containing 1% NH₃) and MeCN. Fractions containing the desired compound were evaporated to dryness to afford 5-(3-ethynyl-5-fluoro-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (24.0 mg, 13% over two steps) as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ 13.21 (br s, 1H), 11.71 (br s, 1H), 8.56–8.52 (m, 1H), 8.23 (br s, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.32 (ddd, J = 7.3, 4.7, 0.7 Hz, 2H), 5.82 (q, J = 7.1 Hz, 1H), 4.51 (s, 1H), 1.77 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₂₀H₁₅FN₅O₂]⁺ [M + H]⁺ = 376.1204, found = 376.4.

Diisopropyl azodicarboxylate (1.58 mL, 8.13 mmol) was added dropwise to a mixture of PPh₃ (2.13 g, 8.12 mmol), (R)-1-(pyridin-2-yl)ethan-1-ol (1.00 g, 8.12 mmol) and 5-bromopyrimidine-2,4(1H,3H)-dione (35) (2.33 g, 12.2 mmol) in THF (20 mL) under nitrogen at 0 °C. The resulting solution was stirred at rt for 20 h. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 0–10% MeOH in CH₂Cl₂. Fractions containing the desired compound were evaporated to dryness to afford an impure mixture which was repurified by C18-flash chromatography, elution gradient 0–20% MeCN in water (containing 0.1% FA). Fractions containing the desired compound were evaporated to dryness to afford (S)-5-bromo-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (1.00 g, 42%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 8.58–8.52 (m, 1H), 8.19 (s, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.37–7.29 (m, 1H), 5.74 (q, J = 7.2 Hz, 1H), 1.70 (d, J = 7.2 Hz, 3H); MS (ESI) m/z calculated for [C₁₁H₁₁BrN₃O₂]⁺ [M + H]⁺ = 296.0029 and 298.0009, found = 298.1; ee = 99% (the Rt of the minor peak was determined as the enantiomer following the synthesis of (R)-5-bromo-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione).

Pd(dppf)Cl₂ (182 mg, 0.279 mmol) was added to a suspension of K₃PO₄ (741 mg, 3.49 mmol), (S)-5-bromo-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (413 mg, 1.39 mmol) and 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole (41) (500 mg, 1.40 mmol) in toluene (20 mL) and water (0.33 mL) under nitrogen at rt. The resulting suspension was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 0–50% MeCN in water (containing 0.1% FA). Fractions containing the desired compound were evaporated to dryness to afford (S)-5-(5-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (83.0 mg, 13%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.33 (s, 1H), 11.70 (s, 1H), 8.59–8.51 (m, 1H), 8.09 (s, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.3, 2.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.27 (d, J = 9.7 Hz, 1H), 5.81 (q, J = 7.2 Hz, 1H), 1.78 (d, J = 7.2 Hz, 3H), 0.30 (s, 9H); MS (ESI) m/z calculated for [C₂₃H₂₃FN₅O₂Si]⁺ [M + H]⁺ = 448.1600, found = 448.2.

Tetrabutylammonium fluoride in THF (1 M, 174 μL, 0.174 mmol) was added to a solution of (S)-5-(5-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (78.0 mg, 0.174 mmol) in CH₂Cl₂ (5 mL). The resulting solution was stirred at rt for 30 min. The solvent was removed under reduced pressure and the crude product was purified by C18-flash chromatography, elution gradient 0–20% MeCN in water (containing 0.1% NH₄HCO₃). Fractions containing the desired compound were evaporated to dryness and subsequently repurified by preparative chiral-HPLC (CHIRALPAK ID, 5 μm, 20 × 250 mm), isocratic 50% iPrOH in hexane (containing 0.5% 2 M NH₃.MeOH). Fractions containing the desired products were evaporated to dryness to afford enantiopure (S)-5-(3-ethynyl-5-fluoro-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione (Rt: 14.9 min, 43.0 mg, 66%) as a white solid. The impurity (R)-5-(3-ethynyl-5-fluoro-1H-indazol-7-yl)-1-(1-(pyridin-2-yl)ethyl)pyrimidine-2,4(1H,3H)-dione eluted at 5.9 min. ¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H), 11.72 (s, 1H), 8.55 (d, J = 4.2 Hz, 1H), 8.14 (br s, 1H), 7.82 (td, J = 1.6, 7.7 Hz, 1H), 7.50–7.40 (m, 2H), 7.36–7.23 (m, 2H), 5.82 (q, J = 7.1 Hz, 1H), 4.55 (s, 1H), 1.77 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 161.6, 158.8, 157.5 (d, J_CF = 237.9 Hz), 150.6, 149.2, 142.7, 137.2, 136.3, 127.0, 124.3 (d, J_CF = 11.0 Hz), 122.9, 121.6, 119.8, 116.6 (d, J_CF = 28.0 Hz), 109.4, 102.7 (d, J_CF = 23.5 Hz), 84.6, 75.5, 55.6, 18.5; ¹⁹F NMR (376 MHz, DMSO-d₆) −121.61; MS (ESI) m/z calculated for [C₂₀H₁₅FN₅O₂]⁺ [M + H]⁺ = 376.1204, found = 376.2; HRMS (ESI) m/z calculated for [C₂₀H₁₅FN₅O₂]⁺ [M + H]⁺ = 376.1204, found = 376.1214; ee > 99% (the Rt of the enantiomer was identified following the analytical chiral separation of the racemate).