To a stirred solution of 17.3 g of 1,3-diethoxy-2-ethylthiobenzene in 175 mL CH₂Cl₂ there was added 11.8 g elemental bromine dissolved in 100 mL CH₂Cl₂. There was an immediate loss of color, and the obvious evolution of HBr gas. After stirring at ambient temperature for 1 h, the dark solution was added to 150 mL H₂O containing 1 g of sodium dithionite. Shaking immediately discharged the residual bromine color, and the organic phase was separated, The aqueous phase was extracted once with 75 mL CH₂Cl₂, the pooled extracts washed first with H₂O, and then with saturated brine. Removal of the solvent under vacuum provided 34.2 g of a pale yellow oil with several globs of H₂O that were mechanically removed. This wet product was distilled at 105–125 °C at 0.35 mm/Hg to yield 4-bromo-1,3-diethoxy-2-ethylthiobenzene as an off-white oil weighing 21.6 g. It could not be crystallized. Anal. (C₁₂H₁₇BrO₂S) C,H.

To a solution of 20.2 g diisopropylamine in 200 mL anhydrous THF that had been cooled to -10 °C under a He atmosphere with an external ice/MeOH bath, there was added 125 mL of a 1.6 M solution of butyllithium in hexane. There was then added, in sequence, 5.1 mL of dry CH₃CN followed by the dropwise addition of 15.3 g 4-bromo-1,3-diethoxy-2-ethylthiobenzene diluted with a little anhydrous THF. There was only a modest color development. Analysis by thin-layer chromatography showed that the reaction components were largely starting bromide and only a little product nitrile. An additional 2.5 mL dry CH₃CN was added, followed immediately by a solution of lithium diisopropylamide prepared separately from 14 mL isopropylamine in 50 mL hexane treated with 60 mL butyllithium solution. There was an immediate darkening of color. After 15 min stirring, the bromo starting material was gone, by TLC analysis. The reaction mixture was then poured into 1 L dilute H₂SO₄. The organic phase was separated and the aqueous fraction extracted with 2×100 mL CH₂Cl₂. These extracts were pooled, washed with H₂O, dried with anhydrous K₂CO₃, and the solvent was removed under vacuum. The residue was distilled at 0.3 mm/Hg yielding two fractions. The first fraction boiled at 124–145 °C and gave an amber liquid weighing 2.4 g. It was largely starting bromo compound with a little nitrile, and was not processed further. The second fraction distilled at 140–190 °C and weighed 6.2 g. Although this was largely product nitrile, it was quite complex by chromatographic analysis. It was redistilled at 0.3 mm/Hg and several fractions taken. The material collected at 145–165 °C weighed 3.2 g and was approximately 80% 3,5-diethoxy-4-ethylthiophenylacetonitrile by TLC assay. This was used in the subsequent reduction. The earlier fraction in this second distillation (130–145 °C) weighed 2.1 g but contained only 50% product nitrile by TLC analysis, and was discarded.

A solution of LAH in anhydrous THF under N₂ (20 mL of a 1.0 M solution) was cooled to 0 °C and vigorously stirred. There was added, dropwise, 0.53 mL 100% H₂SO₄, followed by 3.0 g 3,5-diethoxy-4-ethylthiophenylacetonitrile diluted with a little anhydrous THF. The reaction mixture was stirred at room temperature for 1 h, and then at reflux on the steam bath for an additional 0.5 h. After cooling back to room temperature, there was added IPA to destroy the excess hydride and 10% NaOH to bring the reaction to a basic pH and convert the aluminum oxide to a loose, white, filterable consistency. This was removed by filtration, and washed first with THF followed by IPA. The combined filtrate and washes were stripped of solvent under vacuum, the residue added to 1 L dilute H₂SO₄. This was washed with 2×75 mL CH₂Cl₂, made basic with 25% NaOH, and extracted with 3×100 mL CH₂Cl₂. After combining, the solvent was removed under vacuum providing a residue that was distilled. A fraction boiling at 135–150 °C at 0.3 mm/Hg weighed 1.2 g and was a light yellow oil. This was dissolved in 20 mL of IPA, and neutralized with 17 drops of concentrated HCl which produces white crystals spontaneously. These were dissolved by bringing the IPA suspension to a boil on the steam bath and, with stirring, there was added 40 mL of hot anhydrous Et₂O. There was the immediate formation of crystals which were removed by filtration, washed with an IPA/Et₂O mixture, followed by Et₂O. After air drying there was obtained 1.0 g of 3,5-diethoxy-4-ethylthiophenethylamine hydrochloride (4-T-TRIS) as sparkling white crystals. The mp was 177–178 °C. Anal. (C₁₄H₂₄ClNO₂S) C,H.

(with 200 mg) “There was a passing awareness at the third hour. Otherwise, no effects, either mental or physical.”