The synthetic process of (S)-1-Pyridin-3-yl-ethylamine bis hydrochloride contains 4 steps. The synthetic route is as follows:

A. (E)-1-Pyridin-3-yl-ethanone oxime. A 250 mL, three-necked, round-bottomed flask is equipped with a 2 cm -coated magnetic stir bar, a reflux condenser, a pressure-equalizing dropping funnel and a rubber septum through which a thermocouple thermometer probe is inserted. The flask is charged with 3-acetyl pyridine (12.1 g, 100 mmol), EtOH (100 mL) and NH₂OH^.Cl (11.85 g, 170 mmol), and the mixture is heated with a heating mantle to 55 °C. A pre-made solution of Na₂CO₃ (7.46 g, 70 mmol) in water (20 mL) is added dropwise over 10 min via the dropping funnel. At the end of the addition, the temperature has risen to 62 °C. The heterogeneous mixture is stirred at 60 °C for 2.5 h, then filtered through a 60 mL medium-porosity sintered-glass funnel to remove the inorganic salts. The solid is washed with EtOH (2 × 20 mL) and the combined filtrate is transferred to a 500-mL, round-bottomed flask and concentrated by rotary evaporation (50 °C, 20 mmHg) to afford 19 g of solid residue. Then, water (250 mL) is added along with a 2.5-cm Teflon-coated magnetic stir bar and the mixture is warmed to 70 °C using a heating mantle. The heat is turned off, allowing the mixture to slowly cool to ambient temperature over 3 h. The product is isolated by filtration on a 150-mL medium-porosity sintered glass funnel, washed with water (2 × 15 mL), and dried for 15 h under vacuum (60 °C, 20 mmHg) to afford (E)-1-pyridin-3-yl-ethanone oxime (1) (11.3 g, 83%) as a white crystalline solid. A second crop is obtained as follows. The filtrate from the crystallization is extracted with EtOAc (3 × 100 mL). The combined organic extracts are washed with brine (50 mL), filtered through a bed of sulfate, and concentrated by rotary evaporation (40 °C, 20 mm Hg) to 1.9 g. This solid material is transferred to a single-necked 100-mL round-bottomed flask along with water (35 mL) and a 1.5 cm Teflon-coated magnetic stir bar. The mixture is warmed using a heating mantle to 80 °C with stirring to dissolve all the solids. The heating mantle is turned off, allowing the solution to slowly cool to ambient temperature over 1 h. The mixture is held at room temperature an additional hour, then filtered through a 60 mL medium porosity sintered glass funnel, washed with water (2 × 5 mL), and dried for 15 h under vacuum (60 °C, 20 mmHg) to afford (E)-1-pyridin-3-yl-ethanone oxime (1.40 g, 10%) containing 0.6% of the undesired Z-isomer. The first and second crops have similar purity by NMR and can be combined (12.7 g, 93%).

B. (E)-1-Pyridin-3-yl-ethanone O-benzyl-oxime. An oven-dried 500-mL, three-necked, round-bottomed flask is equipped with a 2.5-cm oval Teflon-coated magnetic stirrer, a pressure-equalizing dropping funnel on the middle neck, a rubber septum through which is inserted a thermocouple temperature probe, and a inlet adapter connected to a nitrogen line and gas bubbler. Nitrogen is flowed through the flask while cooling. The flask is charged with anhydrous DMF (175 mL, dried with 3 Å 1.6 mm pelleted sieves) and cooled to -15 °C (internal temperature) using a dry-ice acetone bath at -25 °C. (4.59 g, 60%, 115 mmol, 1.4 equiv) is added to the cold DMF solution. A solution of (E)-1-pyridin-3-yl-ethanone oxime (10.95 g, 80.5 mmol) in anhydrous DMF (80 mL, dried with 3 Å 1.6 mm pelleted sieves is added dropwise via the dropping funnel over 15 min, followed by a rinse of DMF (5 mL). The temperature of the yellow heterogeneous mixture rises to -10 °C during the addition of the oxime. The resulting mixture is stirred for 30 min at -12 to -10 °C, then benzyl bromide (14.45 g, 85 mmol, 1.05 equiv) is added dropwise via syringe over 10 min. After complete addition, the mixture is stirred for 40 min at -12 to -10 °C and checked by TLC for reaction completion. A saturated aqueous NH₄Cl solution (100 mL) is added to quench the reaction. The first 20 mL is added slowly over 10 min with hydrogen evolution, with an exotherm of +5 °C being observed during those 10 min. The remaining 80 mL is added over the next 5 min with an exotherm leading to a temperature of 23 °C. The mixture is transferred to a 2-L separatory funnel. The flask is rinsed with water (100 mL) and EtOAc (200 mL), which are also transferred to the separatory funnel. The layers are separated. The aqueous layer is extracted with EtOAc (2 × 100 mL). The organic layers are combined, washed with water (2 × 100 mL), then with brine (50 mL). The organic layer is filtered through a bed of sodium sulfate (40 g), rinsing the bed with EtOAc (100 mL). The resulting organic filtrate is concentrated by rotary evaporation (40 °C, 20 mmHg) to give a yellow oil (22 g). The material is purified by chromatography on SiO₂. The resulting oil is further vacuum dried at room temperature (20 mmHg) for 15 h to afford (E)-1-pyridin-3-yl-ethanone O-benzyl-oxime (18.02 g, 99%) as a pale yellow oil.

C. (S)-1-Pyridin-3-yl-ethylamine. An oven-dried, 1-L, 3-necked, round-bottomed flask, marked at the 465 mL fill prior to drying, is equipped with a 3-cm oval Teflon-coated magnetic stir bar, two rubber septa on the outer necks, and a 100-mL gas equilibrating addition funnel that is connected by a gas adapter to a nitrogen inlet and gas bubbler. A thermocouple thermometer probe is inserted through one of the septa. Nitrogen is flowed through the system as the flask is cooling. Spiroborate ester 33 (5.80 g, 18 mmol) and anhydrous dioxane (230 mL, dried with 3 Å 1.6 mm pelleted sieves) are added to the flask and the heterogeneous mixture is stirred at ambient temperature. Borane-tetrahydrofuran complex (1.0 M, 235 mL, 235 mmol, 3.9 equiv) is added via cannula to the reaction flask over 5 min, resulting in gentle hydrogen evolution, which cools the reaction mixture by 2 °C. The resulting mixture is stirred for 0.5 h at room temperature, whereby most of the solids dissolve to give a hazy solution. This solution is cooled to 3 °C using an ice-bath, then a solution of (E)-1-pyridin-3-yl-ethanone O-benzyl-oxime (13.54 g, 60 mmol) in anhydrous dioxane (40 mL) is added over 1 h via the addition funnel. The addition funnel is rinsed with dioxane (5 mL). The mixture is stirred for 30 h at 0-5 °C in an ice bath. The cold reaction is carefully quenched by the dropwise addition of methanol (100 mL) over 15 min. The flask is equipped with a reflux condenser and heated under reflux (67-69 °C) for 15 h. Then the solution is concentrated by rotary evaporation (50 °C bath, 20 mmHg) to afford 30 g of crude solid. The residue is purified by chromatography on SiO₂ to provide (S)-1-pyridin-3-yl-ethylamine (4) (8.03 g) as a hazy oil that is approximately 83 wt % pure (91% yield corrected for purity). The enantiomeric excess is 98% by chiral HPLC of the acetyl derivative of (S)-1-pyridin-3-yl-ethylamine.

D. (S)-1-Pyridin-3-yl-ethylamine hydrochloride. An oven-dried 250 mL, 3-necked, round-bottomed flask is equipped with 2 cm Teflon-coated magnetic stirrer, sealed with two rubber septa on each outer neck, through one of which is inserted a thermocouple thermometer probe, and a 100 mL gas-equilibrating addition funnel on the center neck. (S)-1-Pyridin-3-yl-ethylamine 4 (7.49 g, 83% pure, 50.9 mmol) is dissolved in MeOH (25 mL) and the hazy solution is filtered by syringe through a 0.45 micron Teflon syringe filter into the addition funnel. Hydrochloric acid in ether (2.0 M, 60 mL, 120 mmol, 2.4 equiv) is added to the flask via syringe and the solution is stirred vigorously (500 rpm) at ambient temperature. The amine in methanol solution is added dropwise to the HCl solution over 20 min, during which time crystallization occurs and the temperature rises to 30 °C. The dropping funnel is rinsed with MeOH (3 mL). The mixture is stirred at ambient temperature for 2 h, then filtered through a pressure filter, washed with diethyl ether (2 × 10 mL), and dried for 15 h (60 °C, 20 mmHg,) to afford (S)-1-pyridin-3-yl-ethylamine bis-hydrochloride (8.90 g, 89% yield) as an analytically pure white solid. Enantiomeric excess determined by chiral HPLC analysis of the acetyl derivative is 99%.