4-(2-methylsulfonylethyl)piperidine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (2.02 g, 10.9 mmol) and 4-[2-(methylsulfonyl)ethyl]piperidine (2.48 g, 13.0 mmol) in DMSO (75 mL) was added K2CO3 (5.26 g, 38.1 mmol). The mixture was stirred at 100° C. for 2 days. The mixture was diluted with EtOAc, washed with H2O (4×), and rotovapped down. The crude residue was taken up in DCM and dried (MgSO4), filtered, and concentrated. Purification by flash chromatography provided the title compound of Step D (3.26 g, 9.14 mmol, 84%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (q, J=11.0 Hz, 2H), 1.52 (br. s., 1H), 1.60-1.72 (m, 2H), 1.78 (d, J=12.1 Hz, 2H), 2.17 (s, 3H), 2.67 (t, J=11.6 Hz, 2H), 2.95 (s, 3H), 3.07-3.21 (m, 2H), 3.21-3.35 (m, 2H), 3.88 (s, 3H), 6.66 (s, 1H), 7.74 (s, 1H). washed with H2O (4×) dried (MgSO4) filtered concentrated Purification by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (0.19 g, 0.89 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.20 g, 1.1 mmol), and K2CO3 (0.43 g, 3.1 mmol) was added DMSO (12 mL). The reaction was heated to 100° C. for two days. Reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step B (0.22 g, 0.57 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 6.57 (s, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.20 (d, J=11.6 Hz, 2H), 3.00-3.13 (m, 2H), 2.92 (s, 3H), 2.67 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.77-1.97 (m, 4H), 1.36-1.68 (m, 6H), 1.24 (t, 3H). Reaction extracted with DCM and EtOAc sequentially for two iterations The organic was dried (MgSO4) filtered Purification by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, Step C) (0.20 g, 1.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.23 g, 1.2 mmol), and K2CO3 (0.49 g, 3.5 mmol) was added DMSO (10 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (0.25 g, 0.68 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.22 (d, J=11.5 Hz, 2H), 3.00-3.14 (m, 2H), 2.92 (s, 3H), 2.69 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.76-1.97 (m, 4H), 1.35-1.70 (m, 3H), 1.24 (t, 3H). extracted with DCM and EtOAc sequentially for two iterations The organic was dried (MgSO4) filtered Purification by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (2.02 g, 10.9 mmol) and 4-[2-(methylsulfonyl)ethyl]piperidine (2.48 g, 13.0 mmol) in DMSO (75 mL) was added K2CO3 (5.26 g, 38.1 mmol). The mixture was stirred at 100° C. for 2 days. The mixture was diluted with EtOAc, washed with H2O (4×), and rotovapped down. The crude residue was taken up in DCM and dried (MgSO4), filtered, and concentrated. Purification by flash chromatography provided the title compound of Step D (3.26 g, 9.14 mmol, 84%). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (q, J=11.0 Hz, 2H), 1.52 (br. s., 1H), 1.60-1.72 (m, 2H), 1.78 (d, J=12.1 Hz, 2H), 2.17 (s, 3H), 2.67 (t, J=11.6 Hz, 2H), 2.95 (s, 3H), 3.07-3.21 (m, 2H), 3.21-3.35 (m, 2H), 3.88 (s, 3H), 6.66 (s, 1H), 7.74 (s, 1H). washed with H2O (4×) dried (MgSO4) filtered concentrated Purification by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (0.19 g, 0.89 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.20 g, 1.1 mmol), and K2CO3 (0.43 g, 3.1 mmol) was added DMSO (12 mL). The reaction was heated to 100° C. for two days. Reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step B (0.22 g, 0.57 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 6.57 (s, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.20 (d, J=11.6 Hz, 2H), 3.00-3.13 (m, 2H), 2.92 (s, 3H), 2.67 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.77-1.97 (m, 4H), 1.36-1.68 (m, 6H), 1.24 (t, 3H). Reaction extracted with DCM and EtOAc sequentially for two iterations The organic was dried (MgSO4) filtered Purification by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, Step C) (0.20 g, 1.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.23 g, 1.2 mmol), and K2CO3 (0.49 g, 3.5 mmol) was added DMSO (10 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (0.25 g, 0.68 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.22 (d, J=11.5 Hz, 2H), 3.00-3.14 (m, 2H), 2.92 (s, 3H), 2.69 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.76-1.97 (m, 4H), 1.35-1.70 (m, 3H), 1.24 (t, 3H). extracted with DCM and EtOAc sequentially for two iterations The organic was dried (MgSO4) filtered Purification by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, Step C) (0.20 g, 1.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.23 g, 1.2 mmol), and K2CO3 (0.49 g, 3.5 mmol) was added DMSO (10 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (0.25 g, 0.68 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.22 (d, J=11.5 Hz, 2H), 3.00-3.14 (m, 2H), 2.92 (s, 3H), 2.69 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.76-1.97 (m, 4H), 1.35-1.70 (m, 3H), 1.24 (t, 3H). extracted with DCM and EtOAc sequentially for two iterations The organic was dried (MgSO4) filtered Purification by flash chromatography