cf. C.A. 49, 9667i. Lysergic acid (I) has been synthesized in a 15-stage sequence beginning with 3b-carboxyethylindole. 3-Indolepropionic acid (Ia) (94.6 g.) in 600 cc. H2O containing 20 g. NaOH hydrogenated 20-30 hrs. at room temperature and 3000-4000 lb. pressure over about 100 g. Raney Ni and filtered, the filtrate treated with 85 cc. concentrated HCl, cooled, filtered, treated below 40° by the Schotten-Baumann procedure with 210 cc. 12N NaOH and 180 cc. BzCl, cooled, acidified with 300 cc. concentrated HCl, and filtered, the filter residue washed with H2O and extracted with four 1-1. portions hot H2O, and the residual hot sirupy product crystallized from a few vols. MeOH yielded 103 g. 1-benzoyl-3-(b-carboxyethyl) 2,3-dihydroindole (II), m. 151-3°. II (118 g.) and 200 cc. pure SOCl2 allowed to stand 0.5 hr. and warmed gently 15-20 minimum on the steam bath, the excess SOCl2 evaporated below 30° in vacuo, the residue in 200 cc. dry CS2 added with stirring to 240 g. AlCl3 in 1750 cc. CS2, the mixture refluxed with stirring 1 hr., and treated with stirring and cooling with 500 g. ice, 250 cc. concentrated HCl, and 500 cc. H2O, the CS2 removed in vacuo, the residue extracted with 2 l. C6H6, the extract washed with 500 cc. 2N NaOH in 3 portions and then H2O, dried, and evaporated in vacuo, and the residue diluted slowly with several vols. of Et2O yielded 58.3 g. 1-benzoyl-5-oxo-1,2,2a,3,4,5-hexahydrobenz[cd]indole (III), m. 146-7° (from C6H6-Et2O). III (1.5 g.), 1.5 g. H2NCONHNH2.HCl (IV), and 2.25 g. NaOAc in 25 cc. EtOH and 10 cc. H2O refluxed 1.25 hrs. and cooled gave 1.7 g. semicarbazone of III, m. 260-2° (decomposition) (from aqueous AcOH). If C6H6 was used instead of CS2 in the cyclization of II 52% 1-benzoyl-3-(2-benzoylethyl)-2,3-dihydroindole (V), m. 101-2° (from EtOH), was obtained. CH2N2 [from 55 g. H2NCON(NO)Me (VI) and 150 cc. 40% KOH in 500 cc. Et2O] in KOH treated with shaking and cooling with 10 cc. MeOH and 60 g. II in portions, the solution concentrated below 25° in vacuo, the residue dissolved in 400 cc. Et2O, and the solution washed with dilute HCl and 5% aqueous NaHCO3 and worked up yielded 62.5 g. 2-(MeO2CCH2CH2) analog (VII) of II, which did not crystallize. VII mixed with 300 cc. dry Et2O, 36 g. (CO2Me)2, and 12.5 g. NaOMe, refluxed 22 hrs. with stirring, and treated with stirring with ice water, the aqueous layer acidified with 7 cc. concentrated H2SO4 and extracted with 300 cc. Et2O, and the extract worked up gave 44.2 g. 3-(b-methoxalyl-b-carbomethoxyethyl) analog (VIII) of V, sirup, and 32 g. unchanged VII. VIII in 265 cc. 77% H2SO4 heated 20 minimum on the steam bath and poured onto excess ice yielded 18.4 g. 1-benzoyl-a-oxo-3-indolinebutyric acid, crystals, m. 160-1° (decomposition) (from C6H6 dioxane); it gave in dioxane treated with CH2N2 in Et2O the Me ester, m. 146.5-7.5° (from C6H6-Et2O). III (30 g.), 300 cc. concentrated HCl, and 225 cc. glacial AcOH refluxed 16 hrs. and evaporated to dryness in vacuo, the residue in H2O treated with C and filtered, the filtrate basified with excess NH4OH, and the precipitate recrystd. from 60 cc. MeOH gave 13.6 g. 5-oxo-1,2,2a,3,4,5-hexahydrobenz[cd]indole (IX), golden yellow plates, m. 126-7° (from MeOH); HCl salt, m. 195-200°; HBr salt, m. 212-15° (decomposition). IX (1 g.) in 12.5 cc. pyridine and 12.5 cc. Ac2O allowed to stand 0.5 hr., heated 15 minimum on the steam bath, treated with MeOH, concentrated in vacuo to a small volume, and diluted with H2O gave 0.9 g. 1-Ac derivative (X) of IX, yellow prisms, m. 177.5-8.5° (from EtOH). IX (1 g.) and 5 cc. each of pyridine and (PrCO)2O gave similarly 90% 1-PrCO derivative of IX, m. 137.5-8.5° (from EtOH). Ia (71.0 g.), 15.0 g. NaOH, and about 71 g. Raney Ni made up to 450 cc. with H2O, the mixture hydrogenated about 20 hrs. at room temperature and 4300 lb. pressure and filtered, the filtrate acidified with 65 cc. concentrated HCl and filtered to remove 12.9 g. unchanged Ia, the filtrate containing 58.6 g. 3-(2-carboxyethyl)-2,3-dihydroindole (XI) treated with stirring with 92 g. NaOH in 250 cc. H2O and simultaneously with 94 g. Ac2O, the mixture acidified with 100 cc. concentrated HCl and refrigerated overnight, and the precipitate recrystd. from 700 cc. MeOH yielded 45.3 g. 1-Ac derivative (XII) of XI, m. 157-8°. XII (23.3 g.) treated with 50 cc. SOCl2, the excess SOCl2 removed in vacuo, the residue dissolved in 75 cc. PhNO2, the solution added to 60 g. AlCl3 in 300 cc. dry PhNO2 below 20°, the mixture stirred about 4 hrs. at 25°, cooled with Dry Ice-CHCl3, decomposed with crushed ice, 200 cc. H2O, and 100 cc. concentrated HCl, the heavy precipitate filtered off, the PhNO2 layer washed with 2N NaOH and H2O, and the PhNO2 steam distilled left 3.3 g. X, m. 175-7° (from EtOH). IX (2.0 g.) in 30 cc. p-cymene refluxed 1 hr. with 3 g. 5% Pd-C, the solvent removed in vacuo, the residue dissolved in 200 cc. C6H6 and filtered, and the filtrate worked up yielded 0.3 g. 5-oxo-1,3,4,5-tetrahydrobenz[cd] indole (XIII), m. 159.5-60.5° (from C6H6). III (20 g.) and 20 g. 5% Pd-C in 350 cc. xylene refluxed 16 hrs. gave 8.45 g. 1-benzoyl-5-hydroxy-1,2-dihydrobenz[cd]indole (XIV), m. 231-5° (decomposition) (from CHCl3-MeOH). XIV (6.2 g.) in 600 cc. Ac2O and 60 cc. pyridine heated 1 hr. on the steam bath and the solvents distilled in vacuo left 4.25 g. 5-AcO analog (XV) of XIV, m. 168-9° (from EtOAc). III (2.0 g.) and 3.0 g. 5% Pd-C in 30 cc. p-cymene refluxed 1 hr., the solvent distilled in vacuo, the residue extracted with hot MeOH and CHCl3, the extract evaporated, the residue dissolved in CHCl3, and the product filtered off gave 0.25 g. 1-Bz analog (XVI) of XIV, m. 239-47° (decomposition) (from AcOH-MeOH). XIV (1 g.) in 10 cc. Ac2O and 10 cc. pyridine heated 0.5 hr. on the steam bath gave 1-acetyl-5-acetoxy-1,2-dihydrobenz[cd]indole, m. 156-61° (from Me2CO). III (304.7 g.) in 2200 cc. glacial AcOH heated to 40°, while being illuminated with a 250-watt bulb treated with 352 g. pyridine-HBr perbromide (XVII) during 5 minimum with shaking, the mixture warmed 0.5 hr. at 55-60°, treated with C and concentrated to a small volume in vacuo, the residue dissolved in 2200 cc. CHCl3, washed, dried, and evaporated, and the residue recrystd. from 2200 cc. 1:1 AcOH-Et2O yielded 270 g. 4-Br derivative (XVIII) of III, m. 180.5-1.5°; 2nd crop, 31 g. XVIII (19.0 g.) in 300 cc. liquid MeNH2 kept 2 days at 25° in an autoclave, the MeNH2 evaporated, and the residue crystallized from about 10 cc. EtOH yielded 9.5 g. 1-benzoyl-4,5-di(methylamino)-1,2-dihydrobenz[cd]indole, m. 205-9° (decomposition) (from PhMe). Chloroacetone ethylene ketal (3718 g.) and 7150 g. liquid MeNH2 heated 48 hrs. at 155-70°, the MeNH2 vented, the residue mixed with several vols. Et2O, treated slowly with agitation with 1400 g. KOH in 650 cc. H2O and then with excess solid KOH, the Et2O solution decanted and distilled, and the crude product (3210 g.) dissolved in 20 l. dry Et2O and precipitated with HCl gave methylaminoacetone ethylene ketal (XIX) HCl salt, m. 165-7°. The XIX.HCl in Et2O treated with KOH yielded 2165 g. XIX, b. 160-2°. Bromoacetone ethylene ketal (1450 g.) and 2750 cc. liquid MeNH2 heated 24 hrs. at 162-73° gave similarly 843 g. XIX. K (0.9 g.) dissolved with stirring and warming in 6.5 cc. absolute EtOH and 100 cc. PhMe, and the solution warmed with 5.55 g. III in 75 cc. dry PhMe, the solution cooled, treated with 5 cc. BuONO, stirred 4 hrs., and allowed to stand 3 days deposited 6.8 g. 4-isonitroso derivative of III, m. 167-9° (decomposition) (from absolute EtOH). III (41.7 g.), 17.4 g. NH2OH.HCl, 12.6 g. K2CO3, 750 cc. MeOH, and 20 cc. H2O heated 1 hr. with stirring, cooled, and refrigerated a few days gave 41.6 g. oximie (XX) of III, m. 210-11°. XX (87 g.) and 1000 cc. dry pyridine treated with stirring and cooling with 228 g. p-MeC6H4SO2Cl in 500 cc. dry pyridine at 1-2°, the mixture stirred 2 hrs. at 0°, refrigerated overnight, and poured onto ice, and the precipitate washed and recrystd. from EtOH yielded 100.7 g. 1-benzoyl-5-isonitroso-1,2,2a,3,4,5-hexahydrobenz[cd]indole tosylate, m. 152-5°. K (0.86 g.) in 50 cc. absolute EtOH treated at 10° with 8.8 g. XXI in 200 cc. absolute EtOH, the mixture stirred 8 hrs. with cooling and refrigerated 3 days, unchanged XXI (3.69 g.) filtered off, the filtrate poured into 600 cc. dry Et2O, the solution extracted with 225 cc. 6N HCl, the acid extract concentrated to dryness in vacuo, and the residue crystallized from 250 cc. hot absolute EtOH gave 2.30 g. 4-NH2 derivative (XXII) HCl salt of III, m. 248-50°. NaOMe (6.0 g.) and 15 cc. HCO2Et in 150 cc. dry C6H6 treated with stirring and cooling with 27.7 g. III, the mixture stirred 15 minimum in the cold and 2 hrs. at 25°, the Na enolate (XXIII) of the 4-HCO derivative (XXIV) of III, (28.0 g.) filtered off, a sample dissolved in H2O and acidified with HCl, the aqueous solution decanted, and the gummy residue crystallized from HCONMe2-MeOH gave XXIV, m. 142-5° (decomposition). Crude XXIII (20 g.) in 270 cc. CF3CO2H treated with stirring with 4.6 g. NaN3 and then during 12 minimum dropwise with 18 cc. concentrated H2SO4 at 45°, the mixture kept 15 minimum at 45° concentrated below 30° in vacuo to 75-100 cc., and diluted with 200 cc. CHCl3 and 250 cc. ice water, and the organic layer washed with H2O, extracted with cold dilute aqueous NaOH, and worked up gave 2.23 g. 4-OHCNH derivative (XXV) of III (from MeOH); the aqueous NaOH extract acidified with HCl and extracted with 150 cc. CHCl3 yielded 5.83 g. 4-CN derivative of III, m. 190-1° (from HCONMe2-MeOH). NaOMe (15 g.) added with stirring and cooling to 30 g. (CO2Me)2 in 800 cc. cold C6H6, the mixture treated dropwise during 10 minimum with stirring and cooling with 55.5 g. III in 350 cc. PhMe, the mixture stirred 2 hrs. with cooling and treated with cooling with 400 cc. ice water, the aqueous solution acidified with 30 cc. concentrated HCl, and the product isolated with CHCl3 yielded 52.3 g. 4-MeO2CCO derivative (XXVI) of III, m. 202-4° (decomposition) (from AcOH-MeOH). XXVI (3.63 g.) in 15 cc. concentrated H2SO4 treated with stirring with 1.0 g. NaN3, the mixture kept 15 minimum at 40° and poured onto ice, and the amorphous precipitate crystallized from EtOH yielded 0.69 g. 4-Bz derivative (XXVII) of Me 4,5,5a,6-tetrahydroindolo[4,3-fg]benzoxazole-8-carboxylate (XXVIII), m. 237-8° (decomposition) (from HCONMe2-MeOH). XXVII (1 g.) in 50 cc. MeOH saturated with cooling with 12 g. HCl and kept 4 days at 25°, 0.34 g. unchanged XXVII filtered off, and the filtrate worked up gave 0.26 g. XXVIII.HCl, m. 226-7° (decomposition) (from MeOH). XXVII (0.5 g.) in 5.5 cc. hot HCONMe2 treated with 7 cc. pure N2H4 and diluted with an equal volume MeOH gave 0.43 g. 4-benzoyl-4,5,5a,6-tetrahydroindolo[4,3-fg]benzoxazole-8-carboxylic acid hydrazide, m. 270° (decomposition), insol. in the usual solvents. XXVII (7.6 g.) in 400 cc. MeOH saturated with dry HCl, refluxed 4.5 hrs. while being bubbled continuously with a stream of dry HCl, decolorized with C, and evaporated in vacuo yielded 3.4 g. di-HCl salt of 4-NH2 derivative (XXIX.2HCl) of IX, m. above 300°. XXII.HCl (1.11 g.) in 50 cc. concentrated HCl refluxed overnight, treated with C, and evaporated in vacuo yielded 0.6 g. XXIX.2HCl. XXV hydrolyzed with HCI gave similarly XXIX.2HCl, m. indistinctly 280-300°. III (13.8 g.) in 100 cc. Ac2O treated 20 minimum with stirring and cooling with BF3, kept 1.5 hrs. at 25°, and evaporated in vacuo, and the residue dissolved in CHCl3, washed, dried, and evaporated gave 6.0 g. 4-Ac derivative of III, m. 172-5° (from C6H6). III (100 g.) heated about 26 hrs. with 500 cc. CH2:CMeOAc (XXX) and 2 g. pMeC6H4SO3H at such a rate that 250 cc. distillate was removed while replacing the XXX periodically and the mixture decolorized with C and cooled deposited 74 g. 1,2,2a,3-tetrahydro analog (XXXI) of XV, m. 145-6° (from EtOAc). XXXI (63.9 g.) in 250 cc. CHCl3 treated dropwise with stirring and cooling with 10.5 cc. Br and 50 cc. CHCl3 during 10-15 minimum, the solution warmed to about 55°, treated with 50 cc. MeOH in portions during 5 minimum, cooled, and evaporated, and the residue recrystd. from 1:1 AcOH-Et2O yielded 64 g. XVIII, m. 178-80°. III (5.0 g.), 50 cc. HC(OEt)3, 45 cc. absolute EtOH, and 2 drops concentrated H2SO4 refluxed 4 hrs., the volatile material removed in vacuo, and the residual oil triturated with EtOAc-petr. ether and refrigerated overnight yielded 3.0 g. 5-EtO analog (XXXII) of III, m. 97.5-102° (from EtOAc-petr. ether). XXXII (10 g.) in 250 cc. dry C6H6 kept 3 days at room temperature with 7.3 g. o-HO2CC6H4CO2OH in 135 cc. dry Et2O, and the supernatant solution decanted and worked up yielded 8 g. 4. OH analog (XXXIII) of XVIII, m. 205-6° (from EtOAc) XXXII (1.6 g.) in 15 cc. CHCl3 treated with 0.86 g. BzO2H in 22 cc. cold CHCl3, the mixture refrigerated overnight, and the product triturated with 1:1 C6H6-petr. ether gave XXXIII, m. 205-7° (from EtOAc). III (25 g.) in 200 cc. hot absolute EtOH treated dropwise with stirring and refluxing with 2.5 g. NaBH4 in 120 cc. absolute EtOH, the mixture refluxed 1 hr., treated with 50 cc. 10% aqueous NaOH, cooled, and poured into 250 cc. 6N HCl, the EtOH distilled off in vacuo, and the residue extracted with three 200-cc. portions 1:1 Et2O-C6H6 yielded 20 g. 1,2,2a,3,4,5-hexahydro analog (XXXIV) of XIV, m. 182-3° (from EtOAc-petr. ether). XXXIV (2.79 g.) in 100 cc. AcOH treated with shaking with 0.73 g. CrO3 in 7 cc. H2O and 9 cc. AcOH, kept 2 days at 25°, warmed 4 hrs. on the steam bath, and evaporated in vacuo, and the residue worked up with CHCl3 yielded 1.3 g. III, m. 145-6° (from C6H6-Et2O). XXXIV (39.5 g.) in 400 cc. C6H6 treated slowly with cooling and swirling with 25 cc. PBr3, kept overnight at room temperature, refluxed 4 hrs., cooled, and poured onto ice, the aqueous layer extracted with Et2O-C6H6, and the combined organic solns. worked up gave 36 g. 5-Br analog (XXXV) of III; the XXXV and 150 cc. 2,6-lutidine refluxed 4 hrs., cooled, poured into 400 cc. ice cold 6N HCl, and extracted with 1:1 Et2O-C6H6 yielded 15.2 g. 1-benzoyl-1,2,2a,3-tetrahydrobenz[cd]indole (XXXVI), m. 95.5-6.5°. X (3.0 g.) in 50 cc. hot absolute EtOH refluxed 10 minimum with 4 cc. 4% absolute alc. NaBH4, treated with an addnl. 4 cc. NaBH4 solution, refluxed 0.5 hr., diluted with 25 cc. H2O, heated 10 minimum, cooled, acidified with 2 cc. concentrated HCl, and diluted with several vols. H2O, and the product isolated with 75 cc. CHCl3 yielded 2.7 g. 1,2,2a,3,4,5-hexahydro analog of XVI, m. 150-1° (from C6H6). XXXVI (24 g.) added in portions with swirling and cooling to 20% excess BzO2H in CHCl3, kept 44 hrs. at 0°, and worked up gave 20.6 g. 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole (XXXVII), m. 104-5° (from C6H6-petr. ether). XXXVI (8.2 g.) in 150 cc. EtOH hydrogenated over 4.1 g. 5% Pd-C yielded 6.1 g. 1,2,2a,3,4,5-hexahydro analog (XXXVIII) of XXXVI, m. 107-8° (from C6H6-petr. ether). XXXVI (2.61 g.) and 4.0 cc. 50% aqueous NaOH in 25 cc. EtOH refluxed 2 hrs., about 1/2 of the EtOH distilled off, the residue diluted with several vols. H2O and extracted with Et2O, the extract washed with H2O and extracted with dilute HCl, the acidic extract neutralized with NaHCO3 and extracted with 100 cc. Et2O, the extract dried and concentrated to about 25 cc., and the residue treated with 25 cc. MeOH and 4.0 cc. Ac2O and kept 16 hrs. at 25° yielded 1.55 g. 1-Ac analog of XXXVI, m. 120.5-1.5° (from C6H6-petr. ether). XXXVIII (2.63 g.) in 25 cc. EtOH and 5 cc. 50% aqueous NaOH refluxed 2.25 hrs., the solution concentrated to about 10 cc. and diluted with 100 cc. Et2O and 25 cc. H2O, the Et2O layer extracted with dilute HCl, the acidic extract neutralized with NaHCO3 and extracted with Et2O, the extract concentrated to 25 cc. and treated with 25 cc. MeOH and 5 cc. Ac2O, and the mixture kept 18 hrs. at 25° deposited 1.54 g. 1-acetyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole, m. 104-5° (from Et2O-petr. ether). XVIII (3.6 g.) in 25 cc. warm dioxane stirred 1.5 hrs. with 0.28 g. NaBH4 in 6.7 cc. absolute EtOH, diluted with 20 cc. H2O, and cooled yielded 2.12 g. 1-benzoyl-4-bromo-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole (XXXIX) monomethanolate, m. 80° (decomposition) (from MeOH). Br (40 cc.) added dropwise with stirring and cooling to 40 g. Mg in 4 l. absolute Et2O, the mixture warmed until colorless, the solution decanted into 5 l. dry Et2O, the mixture treated with stirring with 20 g. XXXVII in 1 l. dry C6H6, stirred 1.5 hrs., and kept 18 hrs. at 25°, the solvent evaporated in vacuo, the residue refluxed 4 hrs. with stirring with 3 l. dry PhMe, cooled, and washed with ice water, and the organic layer worked up yielded 15.1 g. 4-oxo isomer (XL) of III, m. 149.5-51.5° (from C6H6-Et2O); semicarbazone, colorless prisms, m. 225-6° (from aqueous AcOH). XXXVII (20 g.) heated 16 hrs. in an autoclave with 200 cc. liquid MeNH2 yielded 25 g. 4-methylamino-5-hydroxy derivative (XLI) of XXXVIII, m. 93-5° (from C6H6), crystallizing with 1 mole of C6H6. XLI (0.02 mole) in 12 cc. MeOH and 60 cc. Et2O kept 1 hr. at room temperature with 3 cc. Ac2O and cooled yielded 6.0 g. 4-acetylmethylamino analog (XLII) of XLI, m. 158-60°. XLI (1.54 g.), 0.5 g. NaOH, 10 cc. EtOH, and 5 cc. H2O refluxed 8 hrs., cooled, and extracted with C6H6 yielded 0.5 g. 4-methylamino-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole, m. 185.5-6.5° (decomposition) (from C6H6). XXXVI (0.01 mole) heated 19 hrs. on the steam bath with 5.0 g. XIX, the excess XIX removed in vacuo, the residue dissolved in a few cc. of C6H6, the solution diluted with petr. ether, the precipitated gum dissolved in 10 cc. Me2CO, and the solution treated with dry HCl yielded 81% 4-(N-methyl-N-acetonylamino) analog (XLIII) HCl salt of XLII, m. 156-8° (decomposition) (washed with Me2CO), crystallizing with 1 mole of Me2CO. XXXVI (155.5 g.) and 310 cc. XIX heated 17 hrs. on the steam bath and worked up in the usual manner gave 98.5 g. XLIII, m. 126-9° (from 200 cc. Me2CO); the filtrate treated with dry HCl and crystallized from EtOHMe2CO yielded 88 g. XLIII.HCl, m. 159-60° (decomposition). XLIII in EtOH treated with H2SO4 and recrystd. from aqueous EtOH gave XLIII.H2SO4.EtOH, m. 184-5° (decomposition). XLIII.HCl (15.0 g.) in 250 cc. EtOH and 75 cc. aqueous solution containing 30 g. NaOH kept 16 hrs. at 25°, concentrated in vacuo, diluted with H2O, and extracted with C6H6, the extract dried and treated with dry HCl, and the gummy precipitate recrystd. from EtOH-Me2CO yielded 5.2 g. 5-hydroxy-4-(N-methyl-Nacetonylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole ethylene ketal (XLIV) di-HCl salt, crystallizing with 1 mole Me2CO, m. 166-7° (decomposition). XLIV.2HCl (1 g.) in 10 cc. MeOH kept 3 days at 25° with 0.5 g. NaOAc, 5 cc. Et2O, and 1 cc. Ac2O and evaporated to dryness, the residue treated with excess aqueous NaHCO3 and extracted with CHCl3, and the extract worked up gave 0.705 g. 1-Ac analog (XLV) of XLIII, m. 152-3° (from Me2CO). XLI(14.8 g.), 2.64 g. BrCH2Ac, and 125 cc. C6H6 refluxed 1 hr., and the supernatant liquid decanted and worked up gave 2.8 g. 4-Bz derivative (XLVI) of 4,5,5a,6,6a,8,9,10a-octahydro-7,9-dimethyl-7H-indolo[3,4-gh] [1,4]-benzoxazin-9-ol (XLVII), m. 158-60° (from aqueous Me2CO). XLIII (0.5 g.) in 20 cc. 90% AcOH heated 4.66 hrs. on the steam bath and evaporated in vacuo yielded 40 mg. XLVI, m. 150-1°. XLVI (1.0 g.) in 40 cc. 6N HCl kept 5 days at room temperature, cooled, and filtered from 0.19 g. BzOH, the filtrate concentrated in vacuo, diluted with H2O, and neutralized with NaHCO3, and the product isolated with CHCl3 yielded 0.13 g. XLVII, m. 120-2° (from EtOH). XLVII (1.0 g.) in 40 cc. MeOH saturated with dry HCl, kept 16 hrs. at 25°, and evaporated in vacuo gave 0.3 g. 9-MeO derivative (XLVIII) di HCl salt of XLVII, m. 199-201° (decomposition). XLIII (1 g.) treated in the same manner with MeOH-HCl yielded 150 mg. XLVIII.2HCl, m. 193° (decomposition). III (16.6 g.), 30 g. activated Zn, 300 cc. dry C6H6, and 15 cc. BrCH2CO2Et (XLIX) refluxed with stirring, treated with a small amount of EtMgI and a crystal of iodine and after 0.5 hr. from the start of the reaction with 15 g. Zn and a crystal of iodine, this repeated twice more at 0.5-hr. intervals, the mixture treated 1 hr. after the last addition with 15 g. Zn and 7.5 cc. XLIX and then after another 1 hr. with 15 g. Zn and a crystal of iodine, refluxed 1 hr. with stirring, kept at room temperature, diluted with 200 cc. C6H6, poured into 300 g. ice and H2O, and acidified with 25 g. concentrated H2SO4 in 50 cc. H2O, the aqueous layer extracted twice with C6H6, and the exts. worked up gave 7.7 g. 5-EtO2CCH2 derivative of XXXIV, m. 142-3° (from EtOAc). III (300 g.), 300 g. activated Zn, 1.0 g. HgCl2, 6 l. dry C6H6, and 90 cc. BrCH2CO2Me (L) refluxed with stirring, treated after 3 hrs. with 90 g. L and 20 g. Zn, after 5 hrs. with 75 g. L and 60 g. Zn, refluxed 6 hrs. with stirring, cooled, allowed to stand overnight, treated with stirring with 1500 cc. 2N HCl, the organic layer washed with 1500 cc. 2N HCl, once with H2O, 3 times with 2N NH4OH, and again with H2O, dried, concentrated in vacuo to about 1200 cc., diluted slowly with petr. ether to incipient cloudiness, and filtered, the crude filter residue dissolved in 2250 cc. 98% HCO2H and 500 cc. Ac2O, heated 1 hr. on the steam bath, poured into 6 l. cold H2O, and extracted with 5 l. C6H6 in 2 portions, and the extract worked up yielded 300.4 g. 5-MeO2CCH2 derivative (LI) of XXXVI, m. 114-26° (from MeOH). LI (190 g.) and 1100 cc. absolute EtOH refluxed and treated with stirring with 250 cc. 3N NaOH during 3 hrs., the mixture heated 1.5 hrs., concentrated to about 600 cc. in vacuo, diluted with 2 l. H2O, washed with CHCl3, acidified with 75 cc. concentrated HCl, and extracted with CHCl3, the extract evaporated in vacuo, the residue boiled 20 minimum with 550 cc. hot EtOAc and several g. C and filtered, and the filtrate refrigerated overnight yielded 157 g. 5-HO2CCH2 analog (LII) of LI, m. 168.5-70° (decomposition) (from EtOAc). LII (50 g.) in 750 cc. dry PhMe treated with 40 cc. (COCl)2 and 1 cc. pyridine, the mixture stirred 2 hrs. at room temperature, filtered, and concentrated to dryness in vacuo, the residual oil dissolved in dry C6H6 and again evaporated to dryness, the residue 1 l. dry C6H6 added dropwise during 2 hrs. with stirring and cooling to CH2N2 (from 75 g. VI) in CH2Cl2, the mixture stirred overnight at room temperature, diluted with 500 cc. CHCl3, treated with cooling and stirring with 300 cc. 48% HBr, and stirred 3 hrs. at room temperature, and the organic layer worked up yielded 48 g. 5-BrCH2COCH2 derivative (LIII) of XXXVI, m. 128-32° (from C6H6-petr. ether). LIII (20 g.) added in several portions to 20 g. NaBH4 in 960 cc. MeOH and 40 cc. H2O, refluxed 1 hr., poured into H2O, and extracted with CHCl3, the CHCl3 extract worked up, and the residual oil crystallized from EtOH at 0° gave 9.5 g. 5-(2,3-epoxypropyl) derivative (LIV) of XXXVI, m. 115-17° (from aqueous EtOH). LIV (9.5 g.) and 6.1 g. BzO2H in 90 cc. CHCl3 kept at 0° overnight, the mixture worked up, and the oily product triturated with aqueous EtOH yielded 4.7 g. 5-(2,3-epoxypropyl) derivative (LV) of XXXVII, m. 186-7° (from EtOH), crystallizing with 1 mole of EtOH. LV (3.8 g.) and about 100 cc. liquid MeNH2 heated 24 hrs. at 100° in an autoclave, the MeNH2 evaporated, the residual oil in CHCl3 extracted with dilute HCl, the extract washed with CHCl3, basified with aqueous NaOH, and extracted with CHCl3, the extract evaporated, the crude residual product (3.3 g.) in about 100 cc. 6N HCl treated slowly with stirring with 70 cc. 20% aqueous NaNO2, washed with CHCl3, and basified with cold aqueous NaOH, and the product isolated with CHCl3 and triturated with petr. ether yielded 4-benzoyl-9,10a-dihydroxy-7-methyl-4,5,5a,6,6a,7,8,9,10,10a-decahydroindolo[ 4,3-fg]quinoline (LVI), m. 102-10°. LVI (0.205 g.) in 10 cc. EtOAc and 2 drops PhCH2OH warmed overnight with 4.56 g. MeI gave the LVI.MeI, m. 200-2° (decomposition) (from EtOH-EtOAc). LI (3.5 g.), 30 cc. CHCl3, and 2.2 g. o-HO2CC6H4CO2OH in 37 cc. Et2O kept 1 week at room temperature, the supernatant liquid worked up, and the resulting viscous oil triturated with C6H6 gave 2.0 g. 1-benzoyl-5-carbomethoxymethyl-4,5-epoxy-1,2,2a,3,4,5-hexahydro[cd]indole (LVII), m. 181-2° (from C6H6). LVII (1 g.) and about 100 cc. MeNH2 heated 6 hrs. at 100° in an autoclave, the mixture worked up in the usual manner, and the crystalline product triturated with EtOH gave 4-benzoyl-5,5a,6,6a-tetrahydro-7 -methyl-4H-indolo-[6,5,4-cd]indol-8(7H)-one, m. 201-2° (from EtOH). LVII (1.0 g.) and 4 cc. sarcosine Me ester heated 2.5 hrs. at 100°, the ester evaporated in vacuo, and the residual oil crystallized from aqueous EtOH yielded 1-benzoyl-2,2a,3,4-tetrahydro-4-hydroxybenz[cd]indole-D5(1H),a-a cetic acid lactam monohydrate, m. 160-1°. K (179 g.) dissolved under N in 3700 cc. dry Me3COH and 4900 cc. dry C6H6, the solution evaporated to dryness in vacuo, the residual cake broken by stirring with 3700 cc. dry C6H6 and 4900 cc. dry PhMe under N at -5°, the mixture treated as rapidly as possible with 750 g. III and 593 g. ClCH2CO2Et, stirred 15 minimum with cooling to -5°, heated during 40-5 minimum with stirring to 75°, cooled rapidly to room temperature or below, washed, dried, and evaporated, the sirupy residue dissolved in 5900 cc. com. absolute EtOH, the solution treated with 350 cc. 50% aqueous NaOH, warmed rapidly to 70-5°, kept at that temperature a few minimum, cooled rapidly below room temperature by evaporation in vacuo without cooling, kept 16 hrs. at 0°, and filtered, and the cake washed with absolute EtOH yielded 774 g. Na salt (LVIII) of 1-benzoyl-5-carboxymethyl-a,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indo le, m. 230-2° (decomposition) (from MeOH-EtOH-Et2O) (2nd crop, 109 g.). LVIII (35.7 g.) in 150 cc. H2O mixed with 100 g. NaHSO3 in 200 cc. H2O, filtered, kept 2 hrs. at 25°, and cooled gave the NaHSO3 addition product (LIX), m. 128-30°, of the 5-CHO derivative (LX) of XXXVI. The LIX in 350 cc. H2O decomposed with 25 cc. AcOH and 35 cc. concentrated HCl and cooled yielded 17.0 g. LX, amorphous solid, m. 90-100° (decomposition). LVIII (5 g.), 5 g. IV, and 5 g. NaOAc in 250 cc. 50% aqueous EtOH refluxed 1.25 hrs., concentrated in vacuo to 75 cc., diluted with 100 cc. 5% aqueous NaHCO3, and filtered yielded 2.2 g. semicarbazone (LXI) of LX, m. 200-2° (decomposition) (from 200 cc. EtOH). LVIII (17.9 g.), 21.9 g. NH2OH.HCl, and 21.9 g. NaOAc in 270 cc. H2O, and 180 cc. EtOH refluxed 2 hrs., concentrated to about 250 cc., and diluted with 500 cc. cold H2O yielded 8.5 g. oxime of LX, m. 168-70° (from MeOH). LVIII (71.5 g.) and 25 g. NaOAc in 800 cc. Ac2O and 100 cc. AcOH refluxed 1 hr., concentrated in vacuo, treated slowly with excess MeOH, decolorized, evaporated, diluted slowly with stirring with 2 l. H2O, and filtered gave 49.6 g. 5-acetoxymethylene derivative (LXII) of XXXVI, m. 125-30° and 166-8° (from AcOH); the higher melting form could be obtained from EtOH. LXII was also prepared from LX or LXI. X (335 g.), 4400 cc. CHCI3, 1050 cc. pure AcCO2H, and 15 cc. H2O kept 18 hrs. at 25°, diluted with 1 l. CHCl3, washed with three 1500-cc. portions H2O and 1000 cc. 5% aqueous NaHCO3, dried, and evaporated, the crystalline residue digested with a little hot MeOH, and the mixture cooled yielded 234.3 g. 1,2,2a,3-tetrahydro analog (LXIII) of LX, m. 179.5-80.5° (from EtOH). LVIII (500 g.) and 448 g. XVII added with stirring to 10 l. MeCN at 58°, and the mixture illuminated with two 250-watt heat lamps, stirred 12-15 minimum, treated with 468 g. IV and 460 g. NaOAc, and heated 3 hrs. on the steam bath, and evaporated in vacuo yielded 426 g. semicarbazone (LXIV) of LXIII, m. 231-2° (decomposition) (from AcOH-MeOH), also obtained from LXII. LXIII treated with alc. PhNHNH2 gave the phenylhydrazone, m. 210-12° (from C6H6-EtOH). LXIII (140 g.), 250 cc. (CH2OH)2, 480 cc. PhMe, and 0.4 g. p-MeC6H4SO3H refluxed 7.5 hrs., and the mixture worked up with CHCl3 yielded 130 g. 5-(2-dioxolanyl) derivative (LXV) of XXXVI, m. 153-5° (from EtOAc-petr. ether). LXV (0.5 g.) in 20 cc. 90% AcOH heated 0.5 hr. on the steam bath, diluted with H2O to incipient cloudiness, and cooled gave 0.35 g. LXIII, m. 176-9°. LXV (83.5 g.) in 600 cc. CHCl3 containing 0.3 mole BzO2H kept 23 hrs. at 0-5°, washed twice with 5% aqueous NaHCO3, and worked up gave 75.5 g. 5-(2-dioxolanyl) derivative (LXVI) of XXXVII, m. 178-80° (from MeOH). LXVI (15 g.) and 500 cc. liquid MeNH2 heated 14 hrs. at 120°, the MeNH2 evaporated, the dark amorphous residue dissolved in 250 cc. MeOH, and the solution treated with C and mixed with 9.3 g. picric acid in 60 cc. EtOH yielded 13.2 g. picrate (LXVII) of the 5-(2-dioxolanyl) derivative (LXVIII) of XLI, m. 240° (decomposition) (from HCONMe2-MeOH). LXVII (52.0 g.) shaken with 500 cc. 40% aqueous H2N(CH2)2OH and 300 cc. CHCl3, and the aqueous layer extracted with CHCl3, the combined CHCl3 layer and extract washed, dried, and distilled yielded 23.7 g. LXVIII, m. 151-3° (from EtOAc-petr. ether), pKa' 8.6 (66% HCONMe2); LXVIII.HCl.H2O, hygroscopic solid, m. 221° (decomposition) (from EtOH-EtOAc). 4-(Methyl-2-cyanoethylamino) analog (LXIX) of LXVIII (3.0 g.) in 100 cc. 90% AcOH heated 17 hrs. on the steam bath, treated with C, and evaporated in vacuo, the residue in CHCl3 extracted with dilute HCl, the extract neutralized with excess NaHCO3 and extracted with CHCl3, and the CHCl3 extract worked up gave 0.4 g. LXVIII, m. 150-2°. LXVIII (2.0 g.) and 1.2 g. p-MeC6H4SO2Cl in 8 cc. dry pyridine kept 16 hrs. at 25°, poured into H2O, and extracted with CHCl3 gave 1.43 g. 4-(p-MeC6H4SO2NMe) analog (LXX) of LXVIII, m. 204-6° (from HCONMe2-MeOH). LXVIII (1.0 g.) in 20 cc. EtOH refluxed 0.5 hr. with 1 cc. 50% aqueous NaOH, kept 16 hrs. at 25°, and evaporated in vacuo, the residue dissolved in H2O, and the product isolated with CHCl3 yielded 0.35 g. 5-(2-dioxolanyl)-5-hydroxy-4-methylamino-1,2,2a,3,4,5-hexahydrobenz[cd]indol e (LXXI), m. 207-10° (from HCONMe2-MeOH); LXXI.2HCl, m. 250° (decomposition) (from MeOH-Me2CO). LXVIII (1.0 g.) in 50 cc. MeOH containing 1 cc. concentrated H2SO4 refluxed 16 hrs., the MeOH distilled off, the residue mixed with 20 cc. 6N NaOH, and the product isolated with CHCl3, yielded 0.3 g. LXXI, m. 208-11°. LXVIII (6.5 g.) and 50 cc. CH2CHCN warmed briefly to 50° until homogeneous, kept 16 hrs. at 25°, and evaporated in vacuo gave 5.6 g. LXIX, m. 135-8°; LXIX.HCl, m. 184-6° (decomposition) (from EtOH-Et2O). LXIX (0.5 g.) added to 20 cc. MeOH saturated with dry HCl, kept 4 days at 25°, and evaporated to dryness in vacuo, the residue dissolved in CHCl3 and H2O, the aqueous layer neutralized with excess NaHCO3, and the product isolated with CHCl3 yielded 0.1 g. 4-MeO2C(CH2)2NMe analog of LXVIII, m. 138-40° (from EtOAc). LXIX (2.0 g.) in 40 cc. 6N HCl kept 4 days at 25° and filtered, and the filtrate evaporated in vacuo gave 1.3 g. 5-(2-dioxolanyl)-5-hydroxy-4-(methyl-2-cyanoethylamino) -1,2,2a,3,4,5-hexahydrobenz[cd]indole (LXXII) di-HCl salt crystallizing with 1 mole EtOH, m. 173-5° (from aqueous EtOH). The LXXII.2HCl.EtOH in H2O treated with excess NaHCO3 and extracted with CHCl3 gave the free base, m. 130-2° (from C6H6). LXIII (20 g.), 24 g. NH2OH.HCl, and 24 g. NaOAc in 400 cc. EtOH and 300 cc. H2O refluxed 5 hrs. with stirring and cooled overnight yielded 12.5 g. oxime (LXXIII) of LXIII, m. 142-4° (from C6H6-petr. ether). LXXIII (2.86 g.) stirred 10 hrs. at room temperature with 11.3 g. 30% H2O2, 22.6 g. H2O, 150 cc. Me2CO, and 2.7 cc. 10% aqueous Na2CO3, refluxed 2.5 hrs., concentrated in vacuo on the steam bath, and leached with 50 cc. H2O gave 3.12 g. 5-carbamyl derivative (LXXIV) hemihydrate of XXXVII, m. 229.5-30° (decomposition) (from MeOH). LXXIV (24.5 g.) and 650 cc. liquid MeNH2 heated 18 hrs. in an autoclave on the steam bath, the MeNH2 vented, the residue digested with hot MeOH, and the mixture cooled yielded 25.4 g. 5-carbamyl derivative (LXXV) of XLI, crystallizing with 1 mole MeOH, m. 141-3° (decomposition); it gave dried in vacuo and recrystd. from C6H6 LXXV, m. 191-3°. Additional information in printed abstract.