Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Cl)=[CH:4][CH:3]=1.CO.Cl.[CH3:15][O:16][NH2:17].[Br-:18].[Li+]>CC(C)=O>[CH3:15][O:16][N:17]=[C:6]([C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:7][Br:18]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CON
Reactant: [Br-]
Agent: Cl
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CO
Product: CON=C(CBr)c1ccc(F)cc1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
A 2.0 L round bottom flask was charged with 4-fluorophenacyl chloride (100 g, 579 mmol), then methanol (1.0 L), then O-methylhydroxylamine HCl (96.8 g, 1.56 mol), and the mixture was heated to 65° C. for 2 hours. The reaction was then concentrated under reduced pressure, then charged with acetone (750 mL), and lithium bromide (252 g, 2.90 mol), and the mixture was heated to 60° C. for 16 hours. The reaction was then concentrated under reduced pressure, suspended in 1.0 L methylene chloride, and washed with 3×200 mL water. All organic extracts were then pooled; dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 2-bromo-1-(4-fluorophenyl)ethanone O-methyloxime (118 g, 83%). 1H NMR (500 MHz, CDCl3) δ 4.10 (s, 3H), 4.35 (s, 2H), 7.11 (t, J=8.8 Hz, 2H), 7.72 (m, 2H). MS (ESI+) 246.0. Step 2. A 2.0 L round bottom flask was charged with 4-(piperidin-4-yl)pyridine (69.0 g, 425 mmol), methylene chloride (500 mL), and then triethylamine (47.0 g, 468 mmol). CbzCl (80.0 g, 468 mmol) was then added dropwise over 30 minutes via an addition funnel. The reaction was allowed to stir at room temperature for 18 hours. The reaction was then poured into 500 mL of an aqueous solution saturated with NaHCO3 and extracted with an additional 300 mL of methylene chloride. The organic fractions were pooled, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (135 g, 104% yield) was dissolved in 200 mL methylene chloride and applied onto a silica plug that was then eluted with 2.0 L heptane, 3.0 L 1:1 EtOAc:heptane, 1.5 L 2:1 EtOAc:heptane, and 3.0 L EtOAc, collecting 750 mL fractions. Fractions containing desired product were pooled and concentrated under reduced pressure to provide benzyl 4-(pyridin-4-yl)piperidine-1-carboxylate (93.5 g, 74%). 1H NMR (500 MHz, CDCl3) δ 1.87 (m, 2H), 2.30 (m, 2H), 2.69 (m, 1H), 2.91 (bs, 2H), 4.37 (bs, 2H), 5.17 (m, 2H), 7.13 (d, J=6.3 Hz, 2H), 7.39 (m, 5H), 8.54 (d, J=6.3 Hz, 2H). MS (ESI+) 297.1. Step 3. A 2.0 L round bottom flask was charged with pyridine, the compound of Step 2 (88.6 g, 299 mmol), acetone (300 mL), and the compound of Step 1 (73.8 g, 30.0 mmol), followed by additional acetone (200 mL). The reaction was allowed to stir at room temperature for 12 hours, after which TLC analysis was performed to determine formation of pyridinyl salt. The reaction was then concentrated under reduced pressure, charged with methanol (500 mL), and then potassium tert-butoxide (44.3 g, 395 mmol) in small portions. The mixture was then heated to 80° C. for 4 hours. The reaction was then allowed to stir at room temperature for 12 hours, and was then concentrated under reduced pressure, and then slurried in 200 mL methylene chloride with <5% methanol, then loaded onto a silica plug that was eluted with 2.0 L heptane, 3.0 L 1:2-EtOAc:heptane, 1.5 L 1:1 EtOAc:heptane, and 2.0 L EtOAc, collecting 750 mL fractions. Fractions containing pure desired product were pooled and concentrated under reduced pressure to yield benzyl 4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (74.6 g, 58%); fractions containing impure desired product were pooled and concentrated under reduced pressure to yield additional desired compound (21 g, 16%). 1H NMR (500 MHz, CDCl3) δ 1.50 (m, 2H), 1.76 (m, 2H), 2.55 (m, 1H), 2.77 (bs, 2H), 4.45 (bs, 2H), 5.04 (s, 2H), 6.48 (d, J=5.3 Hz, 1H), 6.96 (t, J=8.8 Hz, 2H), 7.24 (m, 6H), 7.57 (s, 1H), 7.76 (m, 2H), 7.86 (d, J=7.1 Hz, 1H). MS (ESI+) 430.2. Step 4. Benzyl 4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (Step 3, 74.6 g, 174 mmol) was dissolved in acetic anhydride (1.0 L) in a 2.0 L round bottom flask. Seven drops of sulfuric acid were then added, and the reaction was heated to 125° C. for 20 hours, then 150° C. for 40 hours, and then 170° C. for 24 hours. The reaction was concentrated under reduced pressure, then diluted with 150 mL methylene chloride, and applied onto a silica plug that was eluted with 3.0 L heptane, 6.0 L 1:2 EtOAc:heptane, 3.0 L 1:1 EtOAc:heptane, and 4.0 L EtOAc 750 mL fractions were collected throughout the chromatography process. Fractions containing desired product still contaminated with starting material were pooled and concentrated under reduced pressure to provide benzyl 4-[3-acetyl-2-(4-fluorophenyl)imidazo-[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (45.9 g, 82% pure by HPLC). Additional desired compound crystallized from several of the chromatography fractions, and was filtered and dried (10.8 g, 100% pure by HPLC). Both pure and impure batches were pooled and carried onto the next step. Overall yield of desired compound: 56.7 g total, or 48.4 g pure (59%). 1H NMR (400 MHz, CDCl3) δ 1.67 (m, 2H), 1.92 (m, 2H), 2.17 (s, 3H), 2.81 (m, 1H), 2.93 (bs, 2H), 4.38 (bs, 2H), 5.16 (s, 2H), 6.48 (d, J=7.2 Hz, 1H), 6.96 (t, J=8.8 Hz, 2H), 7.24 (m, 5H), 7.57 (s, 1H), 7.76 (m, 2H), 7.86 (d, J=7.2 Hz, 1H). MS (ESI+) 472.2. Step 5. Benzyl 4-[3-acetyl-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (Step 4, 3.12 g, 6.62 mmol) was dissolved in DMF-DMA (50 mL) and heated to 100° C. for 12 hours. The reaction was concentrated under reduced pressure, then dissolved in a minimum volume of methylene chloride, and injected onto an Isco RediSep 40 g normal phase cartridge, and eluted with a gradient that started with 100% heptane and ended with 100% ethyl acetate. The cartridge was then eluted with 90:9:1 methylene chloride:methanol:concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure to provide benzyl 4-{3-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl}piperidin-1-carboxylate (2.50 g, 72%). MS (ESI+) 527.3. Step 6. Benzyl 4-{3-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(4-fluorophenyl)imidazo-[1,2-a]pyridin-7-yl}piperidin-1-carboxylate (Step 5, 1.32 g, 2.52 mmol) was dissolved in 1-propanol (20 mL) and charged with acetamidine HCl (945 mg, 10.0 mmol) and 25% (w/w) sodium methoxide in methanol (2.29 mL, 10.0 mmol), and heated to 100° C. for 12 hours. The reaction mixture was then concentrated under reduced pressure, suspended in methylene chloride (20 mL), and washed with 3×50 mL saturated aqueous NaHCO3 solution. The organic phase was then dried over Na2SO4, filtered, concentrated under reduced pressure, then dissolved in a minimum volume of methylene chloride and injected onto an Isco RediSep 40 g normal phase cartridge, and eluted with a gradient that started with 100% heptane and ended with 100% ethyl acetate. Fractions containing desired product were pooled and concentrated under reduced pressure to provide benzyl 4-[2-(4-fluorophenyl)-3-(2-methylpyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (1.17 g, 89%). MS (ESI+) 522.4. Step 7. Benzyl 4-[2-(4-fluorophenyl)-3-(2-ethylpyrimidin-4-yl)imidazo[1,2-a]pylidin-7-yl]piperidine-1-carboxylate (Step 6, 1.17 g, 2.24 mmol) was dissolved in acetonitrile (100 mL) and charged with thiophenol (3.36 mmol, 346 μL), then iodotrimethylsilane (22.4 mmol, 3.18 mL). After stirring at room temperature for 30 minutes, the reaction was concentrated under reduced pressure, then dissolved in a minimum volume of methylene chloride and injected onto an Isco RediSep 40 g normal phase cartridge, and eluted with a gradient that started with 100% methylene chloride and ended with 100% 90:9:1 methylene chloride:methanol:concentrated ammonium hydroxide. Fractions containing desired product were pooled, then concentrated under reduced pressure to provide crude 2-(4-fluorophenyl)-3-(2-methylpyrimidin-4-yl)-7-piperidin-4-ylimidazo[1,2-a]pyridine (1.44 g,>100%), which was carried on to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 2.04 (m, 6H), 2.82 (s, 3H), 2.90 (m, 1H), 3.42 (m, 2H), 4.75 (bs, 1H), 6.90 (d, 3=7.4 Hz, 1H), 6.95 (d, J=5.6 Hz, 1H), 7.13 (m, 2H), 7.54 (s, 1H), 7.59 (m, 2H), 8.39 (d, J=5.5 Hz, 1H), 9.61 (d, J=7.4 Hz, 1H). MS (ESI+) 388.3. Step 8. 2-(4-fluorophenyl)-3-(2-methylpyrimidin-4-yl)-7-piperidin-4-ylimidazo[1,2-a]-pyridine (Step 7, 750 mg, 1.93 mmol) was dissolved in methanol (50 mL), and charged with acetic acid (750 μL), formaldeyhyde (37% w/w in water, 7.74 mmol, 576 μL), and NaBH3CN (9.68 mmol of a 1.0M solution in THF, 9.68 mL). After stirring for 45 minutes at room temperature, the reaction was concentrated under reduced pressure, dissolved in methanol (12 mL), and purified via 24×0.5 mL injections on a reverse phase HPLC column using a gradient that started with 50% methanol: 50% 0.1% Et3N in water and ended with 100% methanol. Fractions containing desired product were pooled and concentrated under reduced pressure to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 1.92 (m, 4H), 2.12 (m, 2H), 2.35 (s, 3H), 2.59 (m, 1H), 2.81 (s, 3H), 3.05 (m, 2H), 6.88 (dd, J=7.3, 1.8 Hz, 1H), 6.94 (d, J=5.5 Hz, 1H), 7.12 (m, 2H), 7.51 (s, 1H), 7.60 (m, 2H), 8.38 (d, J=5.6 Hz, 1H), 9.59 (dd, J=7.3, 0.77 Hz, 1H). MS (ESI+) 402.3.