Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[C:7]12([CH2:17][CH2:18]O)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>>[Br:6][CH2:18][CH2:17][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: Br
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Product: BrCCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
In a 1 l-roundbottom flask equipped with a reflux condenser 164 g concentrated sulphuric acid and 200 g hydrobromic acid (48% in water) were added subsequently under cooling with an ice bath to 126.20 g (0.70 mole) 2-(1-adamantyl)ethanol. The mixture was refluxed for 6 h and after cooling to room temperature, it was poured onto 400 g of ice. The aqueous phase was extracted with 400 ml pentane. The organic layer was washed with a 2 M NaOH-solution and with water, dried over magnesium sulphate, and the solvent was removed in vacuo. The product was distilled in vacuo to yield 153.2 g (90%) of (1-(2-Bromo-ethyl)-adamantane as a colourless oil. 1H-NMR (400 MHz, CDCl3): δ=3.29 (t, 2H, CH2Br), 1.71 (t, 2H, CCH2CH2Br), 1.56-1.17 (m, 15H, aliphatic) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:8])[C:3]=1[N+:16]([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>O1CCCC1.Cl>[NH2:16][C:3]1[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(=O)c2ccccc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(C(=O)c2ccccc2F)c1N
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of (5-methyl-4-nitroisoxazol-3-yl)-2-fluorophenylmethanone of Example VIa (6.2 g, 25 mmoles) in tetrahydrofuran (THF) (25 ml) was added to a mixture of SnCl2 2H2O (22.4 g, 100 mmoles) in concentrated hydrochloric acid (40 ml) and THF (20 ml) with ice-bath cooling over 1 hour. After warming to room temperature, the reaction mixture was poured into cold 10% sodium hydroxide (500 ml) with stirring and extracted with ethyl acetate. The extracts were washed with dilute sodium chloride and dried (sodium sulfate). Concentration gave an oil which was flash chromatographed (20% ethyl acetate:hexane) to yield 2.4 g (44%) of an oil that solidified.
Reaction SMILES: N[C@H](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)CC(=O)O.N[C@@H](C(O)=O)CC(=O)O.N[C@@H](C(O)=O)CCCCN.[NH2:39][C@@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][C:43](=[O:45])[OH:44]>>[NH2:39][C@H:40]([C:46]([OH:48])=[O:47])[CH2:41][CH2:42][C:43](=[O:44])[OH:45]
Reactant: N[C@H](CCC(=O)O)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NCCCC[C@@H](N)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
A10, Gln; Asp; Pro; a bond; D-Asp, D-Lys, D-Glu or -Asp-Glu; and
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[B:16](OCCCC)([O:22]CCCC)[O:17]CCCC.P(=O)(O)(O)O>CCOCC>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([B:16]([OH:22])[OH:17])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: O=P(O)(O)O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: OB(O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-bromoindole (200 mg, 1.02 mmol) in anhydrous ether (4 mL), at −78° C., is treated dropwise with tert-butyllithium (1.7 M solution in pentane, 2 mL, 3.4 mmol). After stirring for 30 minutes the mixture is treated dropwise with tributyl borate (0.822 mL, 3.06 mmol) and allowed to warm up to room temperature. After stirring overnight the reaction mixture is diluted with ether, and this mixture is added in portions to phosphoric acid (15 mL, 1M), stirred for 30 minutes and extracted three times with ether (20 mL). The combined extracts are extracted three times with sodium hydroxide solution (20 mL, 1N). The combined sodium hydroxide extracts are acidified with phosphoric acid (1 M) to pH=2, extracted with ether. The combined ether extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 1H-indol-6-yl-boronic acid [Intermediate (77)] as a solid, which is used for the next step without further purification.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[B:18](OCCCC)([O:24]CCCC)[O:19]CCCC>C1COCC1>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([B:18]([OH:24])[OH:19])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a suspension of potassium hydride (35% oil dispersion, 0.84 g, 7.33 mmol) in THF (10 mL) at 0° C. was added a solution 6-bromoindole (1.43 g, 7.20 mmol) in THF (6 mL). The reaction mixture was stirred for 15 min at 0° C., then cooled to -78° C. and t-butyllithium solution (1.7M in pentance, 14.6 mmol) was added quickly dropwise. After stirring for 20 min. at -78° C., a solution of tri-n-butyl borate (3.94 mL, 14.6 mmol) in THF (4 mL) was added quickly. The reaction mixture was stirred for 1 hour at -78° C. and 2hours at 0° C. The reaction was quenched by addition of 1N aqueous HCl (15 mL) and stirring for 30 min at 0° C. The reaction mixture was partitioned between H2O and ether. The aqueous phase was extracted 3 times with ether. The combined ethereal extracts where washed 3 times with cold 1N aqueous NaOH, and then discarded. The basic aqueous extracts where acidified with 1N aqueous HCl and extracted 3 times with ether. The combined organic layers where dried over Na2SO4, filtered, and concentrated in vacuo to give 6-indolylboronic acid (0.86 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([OH:41])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C@@H:12]([S:32][CH2:33][C:34]1([CH2:37][C:38]([OH:40])=[O:39])[CH2:36][CH2:35]1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[N:30]=2)[CH:18]=1)[CH3:3].[OH-].[Na+:43].CCCCCCC>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C>[CH3:3][C:2]([OH:41])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C@@H:12]([S:32][CH2:33][C:34]1([CH2:37][C:38]([O-:40])=[O:39])[CH2:35][CH2:36]1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[N:30]=2)[CH:18]=1)[CH3:1].[Na+:43]
Reactant: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)[O-])CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
2.6 g of Montelukast acid were dissolved in 26 ml of toluene and 8.9 ml of 0.5M NaOH solution in methanol were added slowly at room temperature. The mixture was stirred for 1 hour and the solvent was removed under vacuum to obtain a residue. Then, heptane (24 ml) was added over 30 minutes to a well stirred solution of the residue in 4 ml of ethyl acetate at room temperature. Two hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 5 ml of heptane. The wet product was dried under vacuum at 70-80° C. for 2 days to yield 2.7 g of Montelukast sodium. Yield: 100%.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.O.[OH-].[Na+].OO>C1COCC1.C1CCCCC1.CCO>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
This synthesis is depicted in FIG. 1. To a 1M solution of lithium tris (1,2 dimethylpropyl) hydridoborate (c, commercially available from Aldrich, 2.5 ml, 2.5 mmol) at -55°, under N2, was added a solution of ketone 1 (500 mg, 1.84 mmol) in THF (7 ml) and the mixture was allowed to warm up to RT. After 3 h, the mixture was cooled to -55° and hydrolyzed by addition of water (1 ml), followed by EtOH (3 ml). The boranes were oxidized by adding to the mixture at -55° 10% aq. NaOH-solution (5 ml), followed by 30% aq. H2O2 -solution (3 ml), and stirring for 3 h at RT. Cyclohexane (100 ml) was added and the organic phase washed successively with water, sat. aq. NaHSO3 -solution and sat. aq. NaCl-solution; after drying (Na2SO4) and evaporation of the solvent, the residue was chromatographed on silica gel (60 g) with toluene/ethyl acetate 2:1. The axial alcohol 2 was eluted first (443 mg, 89%) and the second fraction contained the equatorial alcohol 3 (24 mg, 4.8%). An analytical sample of 2 was recrystallized from PE at 0°. M.p. 142°-144°, [a]D =+15° (C=1.33) ([2]: m.p. 143.5°-144°, [a]D16 =+13.9° (c=0.94)). - IR. (CDCl3): 3625m, 3450w, 1590w. - 1H-NMR. (360 Mhz): 0.77 (s, 3 H); 0.82 (s, 3 H); 4.03 (m, w1/2 ≈8, 1 H); 5.70 (m, 1 H); 5.83 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH:1][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2ccc(O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
100 g (0.55 mol) of 8-aminonaphth-2-ol are poured into 125 ml (135.25 g or 1.325 mol) of acetic anhydride cooled in an ice bath, and the mixture is stirred under cold conditions for 1 h. The mixture obtained is poured into 375 ml of ice-water and stirred for several hours. The violet solid is collected by filtration, washed three times with 30 ml of diethyl ether and dried under reduced pressure. 108.8 g of a product melting point: 193°-195° C. are obtained which is used as it is in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:7][C:8]=1[O:9][CH3:10].S([O-])([O-])(=O)=[O:29].[NH4+].[NH4+].C1(S(OC)(=O)=O)C2C(=CC=CC=2)C=CC=1.[Na].C=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:12][C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[CH:7][C:8]=1[O:9][CH3:10].[OH2:29]
Reactant: O=S(=O)([O-])[O-]
Agent: C=O
Agent: COS(=O)(=O)c1cccc2ccccc12
Agent: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Product: O

Procedure:
2% benziothiazolinone, 83% dimethomorph, 1% ammonium sulfate, 2% alginate, 1% sodium methyl naphthalene sulfonate-formaldehyde condensate, 1% organosilicone, complemented to 100% with bentonite.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([Mg]Cl)([CH3:12])([CH3:11])[CH3:10].C(OCC)C>C1COCC1.[Cl-].[Na+].O.[Cu](I)I>[C:9]([C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Mg]Cl
Reactant: Clc1cccnc1Cl
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ncccc1Cl
Temperature: 0 °C

Procedure:
2,3-Dichloropyridine (1.0 g, 6.8 mmol) and copper iodide (0.065 g, 0.341 mmol) were dissolved in THF (6 mL). The mixture was degassed three times then cooled to 0° C. with an ice bath. Then tert-butyl(chloro)magnesium in diethylether (5.10 mL, 10.2 mmol) was added dropwise to the reaction mixture under a nitrogen atmosphere keeping the temperature at 0° C. with an ice bath. When the addition was complete, it was left to warm up to room temperature for 16 hours. Brine was slowly added to the reaction mixture (20 mL) and the product extracted with TBME (20 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 5% EtOAc in heptane to yield the title compound as a yellow oil (0.108 g, 0.6392 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[I-].[O:9]1[CH2:23][CH:10]1[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>C[Si](C)(C)N[Si](C)(C)C.Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:23][CH:10]([OH:9])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(=[O:7])[OH:6]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: NCCCP(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [I-]
Product: NCCCP(=O)(O)CC(O)CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert atmosphere for 24 hours after which a clear solution results. The excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slight positive pressure of inert gas to afford a colourless oil. The oil is cooled to circa 66° and treated with 0.64 g of anhydrouszinc iodide and 4.62 g of N-(2,3-epoxypropyl)phthalimide. An exothermic reaction occurs. The reaction mixture is refluxed for 6 hours after which time thin layer chromatography indicates the reaction to be complete. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo at 40°. The residue is dissolved in water and stirred at roomtemperature for 1 hour and the water removed in vacuo to give an oily solid. This is dissolved in 25 ml of 2.0M aqueous hydrochloric acid and washed with dichloromethane and ether. Removal of the water at 40° in vacuo affords a brown solid which is purified by ion-exchange chromatography on DOWEX® 50 W ×8 (14-40 mesh) to give 3-aminopropyl(2-hydroxy-3-phthalimido-propyl) phosphinic acid, m.p. 268°-71°, as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)[CH3:8].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:14]2[CH:15]=[CH:16][C:11]([C:10]([O:9][CH2:7][CH3:8])=[O:18])=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A suspension of piperazine (129.2 g, 1.5 mol), ethyl-4-fluorobenzoate (84 g, 0.5 mol), and potassium carbonate (103.65 g, 0.75 mol) in DMSO (200 mL) was stirred at 120° C. under N2 for six hours. The reaction mixture was then cooled to room temperature, poured into water (800 mL), and stirred for 30 minutes. The desired product was collected by filtration and carried to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15]CC)=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2cc(C(=O)O)cnc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C (399 mg, mmol) in THF (6 mL) was added methanol (1 mL) followed by NaOH (5N, 1.5 mL). After stirring at room temperature for 18 hours the reaction was concentrated in vacuo. The residue was acidified with 1N HCl (10 mL). The solution was concentrated in vacuo and azeotroped with toluene (4×). This material was used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][NH:11]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[H-].[Na+].CC([O:34][C@H:35]1[CH:39]=[CH:38][C@@H:37](O)[CH2:36]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:38]2[CH2:39][C@H:35]([OH:34])[CH:36]=[CH:37]2)=[C:7]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-(2,2-Diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Intermediate DA) (10.8 g 28.9 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated tetrahydrofuran (200 mL) and dry dimethyl sulfoxide (5 mL) are added and the suspension is cooled on an ice-bath. Sodium hydride 95% (0.69 g, 28.9 mmol) is then slowly added and the solution is stirred at room temperature for 30 minutes. (1S,4R)-cis 4-Acetoxy-2-cyclopenten-1-ol (3.9 g, 27.5 mmol), triphenylphosphine (1.08 g, 4.13 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (1.27 g, 1.38 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated tetrahydrofuran (20 mL) is added and stirred at room temperature for 30 minutes. This solution is added to the anion solution via syringe and is then stirred at 50° C. for 6 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, 0% to 10% MeOH in DCM). 1H NMR (MeOD, 400 MHz); 8.15 (s, 1H), 7.40-7.15 (m, 10H), 6.30 (m, 1H), 5.95 (m, 1H), 5.60 (m, 1H), 5.50 (m, 1H), 4.85 (m, 1H), 4.55 (m, 1H), 4.30 (m 2H), 4.00 (s, 2H), 2.65 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C

Procedure:
The title compound from Step A above (8.8 g, 40.87 mmoles) and triethylamine (8.55 mL, 61.31 mmoles) were dissolved in CH2Cl2 (100 mL) and the mixture was stirred under nitrogen at 0° C. Methanesulfonylchloride (3.8 mL mL, 49.05 mmoles) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (12.8 g) FABMS (M+1)=294.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Yield: 92.1 %

Procedure:
A solution of 2-hydroxybenzaldehyde (500 mg, 0.44 ml, 4.09 mmol), imidazole (685 mg) and tert-butyldimethylsilyl chloride (680 mg) in DMF is stirred for 24 hours at room temperature. After hydrolysis and customary extraction, chromatography gives 28 (890 mg, 93%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]1[CH:22]=[C:21]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:20]=[CH:19][C:17]=1[NH2:18].C(N(C(C)C)C(C)C)C>ClCCl>[CH3:14][O:15][C:16]1[CH:22]=[C:21]([B:23]2[O:24][C:25]([CH3:30])([CH3:31])[C:26]([CH3:29])([CH3:28])[O:27]2)[CH:20]=[CH:19][C:17]=1[NH:18][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
To a solution containing 1-methyl-1H-2-indolecarbonyl chloride (5.44 g, 0.0281 mol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.00 g, 0.0281 mol) in anhydrous dichloromethane (150 mL), N-ethyl-N,N-diisopropylamine (4.9 mL, 0.0309 mol) was added dropwise at 0° C. and the resulting solution was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (150 mL) and ethyl acetate (150 mL), The organic phase was washed with brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:6)) as mobile phase to yield N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (8.0 g, 0.0197 mol) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[K+]>CO.O>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][CH:7]=[C:6]2[CH2:5][OH:4])=[CH:11][CH:12]=1
Reactant: COc1ccc2cccc(COC(C)=O)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cccc(CO)c2c1
Reaction time: 3 h

Procedure:
34.5 g (0.15 mol) of the compound obtained in Step A are dissolved in 300 ml of methanol. 35 g (4 eq) of potassium hydroxide dissolved in 35 ml of water are added with vigorous stirring. After 3 hours at room temperature, the reaction mixture is hydrolysed over a mixture of ice/concentrated hydrochloric acid. The creamy white precipitate which forms is filtered off, washed several times with ice-cold water and dried over P2O5 using a dessicator. The title alcohol is recrystallised from a mixture of CH2Cl2/cyclohexane to yield white needles.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:23](O)(=O)[CH2:24]CCCCCCCCCCCCCCCC.[OH-].[Na+:44].[N+]([O-])(O)=O>C(O)(=O)CCCCCCCCCCCCCCCCCCCCC.O>[C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][CH3:24].[Na+:44]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 55 °C

Procedure:
In an amount of 32.4 g of behenic acid, 9.9 g of arachidic acid and 5.6 g of stearic acid were dissolved in 945 mL of pure water at 90° C. Then, the solution was added with 98 mL of 1.5 mol/L sodium hydroxide aqueous solution with stirring at high speed. Subsequently, the solution was added with 0.93 mL of concentrated nitric acid, cooled to 55° C. and stirred for 30 minutes to obtain a sodium behenate solution.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](=O)([O-])[O-].[K+].[K+]>[Cl-].C[N+](C)(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3[CH:1]=[CH:2][C:3]([O:4][CH3:22])=[C:5]4[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]2[C@:7]5([C:6]=34)[CH2:21][CH2:20]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C([O-])[O-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 97.6 %

Procedure:
Morphine of 82.5% purity, 235 parts (1 mole parts), potassium carbonate 276 parts (2 moles part) and trimethylphenyl-ammonium chloride 188 parts (1.1 moles part) are heated under stirring in toluene at 45°-110° C. for 4-8 hrs. to yield 292 parts of codeine (97.6% yield) after workup as in Example 1.