Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10]([C:12]1([NH2:20])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30](Cl)=[O:31]>C(#N)C>[CH3:8][O:9][C:10]([C:12]1([NH:20][C:30](=[O:31])[CH2:29][C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[CH3:21])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)C1(N)CCN(OC)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(NC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To 5.4 g of potassium carbonate and 2 g of 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride in 10 ml of acetonitrile was added 1.94 g of (2,5-dimethyl-phenyl)-acetyl chloride in 5 ml of acetonitrile at a temperature of 0-5° C. After stirring for 22 hours at room temperature, the reaction mixture was poured on ice water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to yield 2.13 g of 4-[2-(2,5-dimethyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester as a beige crystalline solid, mp: 91-93° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.N>[Ni].CO.ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 24 h

Procedure:
Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (32 g, 89 mmol) and ethanol (150 mL) in a Parr bottle. Add Raney nickel (100 g) and an aqueous concentrated ammonia solution (40 mL). Hydrogenate at 50 psi for 24 h. Filter through a celite pad and rinse the solids with ethanol. Evaporate the filtrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 6% methanol/dichloromethane to give the title compound: Rf=0.34 (silica gel, 6% methanol/dichloromethane); mp; 87-90° C. Elemental Analysis calculated for C14H15Cl2NO3: C 53.18; H 4.78; N 4.43; Found: C 53.34; H 4.71; N 4.51.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.N>[Ni].O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1

Procedure:
Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (6.7 kg, wet cake containing isopropanol, about 3% L.O.D.) and 3C ethanol (52 kg) in a pressure reactor. Add Raney nickel in water (17.5 kg, about 11 kg of active catalyst) and an aqueous concentrated ammonia solution (8.7 kg). Hydrogenate at 200 psi and 35° C. When the reaction is complete, cool, vent the reactor, and purge with nitrogen. Filter through a filter bag, rinse with ethanol, and then filter through a 0.2 micron cartridge filter, and rinse the solids with ethanol. Evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:25]([OH:27])=O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[N:30](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.N.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:30][C:25]([C:12]1([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:27]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Reaction time: 18 h
Yield: 20.6 %

Procedure:
To a solution of 4-{[(benzyloxy)carbonyl]amino}-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.09 g, 5.52 mmol) in N,N-dimethylformamide (10 mL) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.27 g, 6.63 mmol), 1-hydroxybenzotriazole hydrate (0.37 g, 2.76 mmol) and triethylamine (0.92 mL, 6.63 mmol), followed by ammonia (0.5 M in dioxane; 13.3 mL, 6.63 mmol). After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→94% dichloromethane/methanol) to give the title compound (0.43 g). MS 378.2 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[O:15][CH3:16]>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:3][CH2:2][CH2:1][NH2:4])=[C:7]([O:15][CH3:16])[CH:8]=1)([O-:14])=[O:13]
Reactant: NCCN
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Product: COc1cc([N+](=O)[O-])ccc1NCCN

Procedure:
Ethylene diamine is reacted with 2-chloro-5-nitroanisole to form 4-nitro-2-methoxy-N-(β-aminoethyl)aniline which is isolated in the form of its monohydrochloride. This monohydrochloride is reacted with potassium isocyanate to form 4-nitro-2-methoxy-N-(β-ureidoethyl) aniline which is reduced by a sodium hydrosulfite solution to 4-amino-2-methoxy-N-(β-ureidoethyl) aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[N:6][C:7]=1[Cl:8].[CH2:16](Br)[CH:17]=[CH2:18]>[Cl-].C[N+](CCCC)(CCCC)CCCC.C(OC)(C)(C)C.[OH-].[Na+]>[CH2:18]([N:9]([C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: COC(CNc1cnc(Cl)c(Cl)c1)OC
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: C=CCN(CC(OC)OC)c1cnc(Cl)c(Cl)c1

Procedure:
As shown in Scheme 2, the sequential treatment of 2-hydroxy-5-nitropyridine with potassium chlorate under heated conditions provides 3-chloro-2-hydroxy-5-nitropyridine which when further treated with phosphorous oxychloride under heated conditions provides 2,3-dichloro-5-nitropyridine. The nitro containing compound when treated to the reductive conditions of Raney-nickel and 40 PSI of hydrogen provides the amine which when further treated with glyoxal-1,2-dimethyl acetal in the presence of Raney-nickel under heated condition provides (5,6-dichloro-pyridin-3-yl)-(2,2-dimethoxy-ethyl)-amine. The amine when treated with allyl bromide and methyl tributyl ammonium chloride in a mixture of methyl tert-butyl ether and 50% aqueous sodium hydroxide provides allyl-(5,6-dichloro-pyridin-3-yl)-(2,2-dimethoxy-ethyl)amine (Compound 6E).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=2)[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH2:12])=[O:11])=[CH:13][CH:14]=2)[CH2:2]1)=[O:18]
Reactant: CN=C=O
Reactant: NC(=O)c1ccc(OC2CNC2)cc1
Product: CNC(=O)N1CC(Oc2ccc(C(N)=O)cc2)C1

Procedure:
The compound was prepared from 4-(3-azetidinyloxy) benzamide and methylisocyanate as described in Example 7 of U.S. Pat. No. 4,226,861, m.p. 208°-210° C.
Reaction SMILES: [NH:1]([C:6]([NH2:8])=[O:7])[NH:2][C:3](N)=[O:4].[CH2:9](N)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CN1CCCC1=O>[CH2:9]([N:8]1[C:3](=[O:4])[NH:2][NH:1][C:6]1=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(=O)NNC(N)=O
Reactant: CCCCCCN
Solvent: CN1CCCC1=O
Product: CCCCCCn1c(=O)[nH][nH]c1=O

Procedure:
60 g of hydrazodicarboxamide and 56 g of n-hexylamine in 100 ml of N-methylpyrrolidone are stirred at 150° C. for 6 hours, at 175° C. for 20 hours and at 180° C. for 20 hours. The solvent is then distilled off in vacuo and the residue is triturated with 100 ml of 10% strength sodium hyroxide solution. The precipitate is filtered off and the filtrate is neutralised with 10% strength hydrochloric acid. A precipitate thereby separates out, and is filtered off, washed with water and dried in vacuo. 75 g (81% of the theoretical yield) of 4-(n-hexyl)-1,2,4-triazolidine-3,5-dione are obtained as colourless crystals of melting point 144°-145° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[C:5](/[CH3:30])=[CH:6]/[C@H:7]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([CH3:30])[CH2:6][CH:7]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Solvent: CCO
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Next, to a solution of (E)-(R)-4-tert-butoxycarbonylamino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pent-2-enoic acid ethyl ester (2.5 g, 5.63 mmol) in ethanol (20 mL) is added PUC (250 mg) and the mixture is stirred overnight under an atmosphere of hydrogen (H2 balloon). The catalyst is filtered through a Celite pad and, the filtrate is concentrated to give (S)-4-tert-butoxycarbonylamino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][C:2]([CH3:11])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]=1
Reactant: NC(N)=S
Reactant: CC(Br)C(=O)c1ccccc1
Product: Cc1sc(N)nc1-c1ccccc1

Procedure:
Reaction of a α-substituted-α-bromoacetophenone with thiourea or substituted thiourea, at elevated temperatures may give gave an intermediate G1. Suitably, this reaction may be performed under refluxing conditions in the presence of DMF (dimethylformamide). This intermediate (G1) may be reacted with chlorosulfonic acid to yield the sulfonyl chloride B-1. For example 2-bromopropiophenone may be reacted with thiourea to yield 2-amino-5-methyl-4-phenylthiazole, which can be further transformed to 4-(2-amino-5-methylthiazol-4-yl)phenyl sulfonyl chloride.
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)S([O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.O1CCC(C=O)CC1>C(Cl)Cl>[CH3:17][Si:16]([O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])([CH3:19])[CH3:18]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=CC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of DIPEA (6.12 mL, 35.0 mmol) in DCM (80 mL) was added trimethylsilyl trifluoromethanesulfonate (7.79 g, 35.0 mmol) followed by a solution of tetrahydro-2H-pyran-4-carbaldehyde (2 g, 17.52 mmol) in DCM (80 mL) at 0° C. Upon completion of the addition, the reaction mixture was allowed to stir at ambient temperature for 2 hr. The mixture was concentrated in vacuo and the resulting residue was treated with hexane (200 mL). The precipitate was filtered off and the solution was concentrated in vacuo providing crude trimethylsilyl ether, which was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14]C2CCCCO2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][OH:14])[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CO
Product: NCC(CCO)c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a mechanically stirred solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (550 g) in methanol (3300 mL) was added in one portion 6.0N hydrochloric acid (352 mL), resulting in a slight exotherm. After being stirred for 3 hours, the reaction mixture was evaporated, and the residue was diluted with water to 3 L volume. This solution was extracted with ether (2 times 500 mL), basified with sodium hydroxide pellets (100 g), and extracted with ethyl acetate (4 times 500 mL). The combined ethyl acetate extracts were washed (800 mL saturated sodium chloride), dried, and evaporated to give the alcohol as an amber oil (367 g) that solidified under high vacuum; NMR: 7.39 (d, 1, J=8.2), 7.28 (d, 1, J=2.0), 7.04 (dd, 1, J=8.2, 2.0), 3.65 (m, 1), 3.50 (m, 1), 2.90 (m, 2), 2.71 (m, 1), 2.25 (m, 2), 1.86 (m, 2).
Reaction SMILES: [C:1]1([C:7]2[O:16][C:10]3[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O.Cl.N>O>[Cl:19][C:14]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: O
Product: Clc1ncnc2oc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspend 50 g (235.6 mmol) 6-phenylfuro[2,3-d]pyrimidin-4(3H)-one at RT in 375 ml (4023 mmol) phosphoryl chloride and heat the mixture to boiling (evolution of HCl). After 1 h, cool the dark solution to RT and add dropwise to a vigorously stirred mixture of 1.25 litre water and 2.25 litre conc. ammonia solution (25 wt. %) (heating to 55-75° C., pH>9). At the end of addition, cool to RT and extract the mixture three times with 1.6 litre dichloromethane each time. Combine the organic phases, dry, and concentrate by vacuum evaporation. Stir the residue with diethyl ether, filter with suction, and dry at high vacuum. 47.3 g (87% of theor.) of the target compound is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred solution of 2-Bromo-(trifluoromethyl)benzene (18.2 mL, 0.133 moles) in dry THF (150 mL) at -78° was added dropwise over a 25 min period n-butyllithium (60 mL of 2.5M in hexanes, 0.147 moles). The solution was stirred at -78° for 1 hour, and then a solution of triisopropyborate (37 mL) in THF (50 mL) was added dropwise over 30 min at -78°. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight. The solution was then cooled to 0°, and made acidic with 1N aqueous hydrochloric acid. The resulting mixture was extracted twice with ether, and the combined extracts were extracted twice with 1N sodium hydroxide. The combined aqueous extracts were acidified to pH 2 with 1N hydrochloric acid and extracted twice with ether. The combined extracts were dried over magnesium chloride, and concentrated in vacuo to a white solid (20.95 g). Two recrystallizations from water afforded the title compound as a colorless solid (11.35 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Na].C(S)C>CN(C=O)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:11][C:7]1=2
Reactant: COc1ccc2ccsc2c1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1ccc2ccsc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Dissolve 6-methoxy-benzo[b]thiophene (J. Med. Chem. 32:2548, 1989; 26.1 g, 146 mmol) in DMF (500 mL). Add ethanethiol sodium salt (37 g, 440 mmol) and heats to 150° C. with stirring overnight. Add additional ethanethiol sodium salt (112.8 g, 152 mmol) and continue to heat at 150° C. overnight. Concentrate in vacuo to ¼ volume. Partition reaction mixture between ethyl acetate (500 mL) and water (500 mf), separate layers, wash organic layer with water (2×500 mL), brine (500 mL), and dry with magnesium sulfate. Filter and concentrate in vacuo to give 8 g of benzo[b]thiophen-6-ol. Back extract aqueous layers with ethyl acetate (3×1000 mL) wash organics with brine, and dry with magnesium sulfate. Concentrate in vacuo to obtain an additional 15 grams of benzo[b]thiophen-6-ol. Distill off remaining DMF to yield 22.7 g (100%) of benzo[b]thiophen-6-ol.
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.CO.N#N.O.NN>[Pd].O>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: N#N
Agent: NN
Solvent: O
Solvent: CO
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
Compound 4 (0.95 g, 2 mmol) and 10% Pd—C (0.02 mmol) were added to 20 mL of methyl alcohol and the air was replaced with N2. Hydrazine hydrate (4 mmol) was added and on the mixture was stirred at 0° C. for 24 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 0.52 g of white solid in 88% yield. HPLC: 99%.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C@@H:19]([OH:22])[CH:20]=[CH:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.[C:23]([OH:36])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(O)C.C(O)C.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.C(OCC)(=O)C>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C@@H:19]([OH:22])[CH:20]=[CH:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.[C:23]([O-:36])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCC(=O)O
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)[O-]
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Codeine base (4.0002 g; 12.60 mmol) was dissolved in ethanol (100 mL; 99.7-100%) with stirring. Lauric acid (2.7822 g; 13.86 mmol; 10% excess relative to codeine base) was dissolved in the ethanol/codeine solution. The resulting solution was stirred for 5 minutes. The ethanol was removed by rotary-evaporation to give a pale yellow residue. The residue was redispersed in ethyl acetate (10 mL) by heating on a water bath (60° C.). Once all the material had redissolved the solution was placed at 4° C. for 16 hours. A white precipitate formed which was isolated by vacuum filtration. The precipitate was dried further in a vacuum oven for 16 hours at 40° C. to give codeine laurate (2.4757 g; 36.50%). The material was analysed by Differential Scanning Calorimetry in order to determine the melting point. However, thermal analysis from 50 to 200° C. showed no thermal event.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:15]1[CH:16]=[CH:17][C:18]([CH2:21][C@H:22]([NH:61][C:62]([CH2:64][NH:65][C:66]([C@H:68]2[N:72]([C:73]([C@H:75]3[N:79]([C:80]([C@@H:82]([NH2:90])[CH2:83][CH2:84][CH2:85][NH:86][C:87]([NH2:89])=[NH:88])=[O:81])[CH2:78][CH2:77][CH2:76]3)=[O:74])[CH2:71][CH2:70][CH2:69]2)=[O:67])=[O:63])[C:23]([NH:25][C@H:26]([C:29]([N:31]2[C@H:35]([C:36]([NH:38][C@H:39]([C:47]([NH:49][C@H:50]([C:58]([OH:60])=[O:59])[CH2:51][CH2:52][CH2:53][NH:54][C:55]([NH2:57])=[NH:56])=[O:48])[CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:37])[CH2:34][CH2:33][CH2:32]2)=[O:30])[CH2:27][OH:28])=[O:24])=[CH:19][CH:20]=1.N1CCCCC1.C(O)(=O)CCCCCCCCCCCCCCCCC>CO>[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([NH:61][C:62]([CH2:64][NH:65][C:66]([C@H:68]2[N:72]([C:73]([C@H:75]3[N:79]([C:80]([C@@H:82]([NH2:90])[CH2:83][CH2:84][CH2:85][NH:86][C:87]([NH2:89])=[NH:88])=[O:81])[CH2:78][CH2:77][CH2:76]3)=[O:74])[CH2:71][CH2:70][CH2:69]2)=[O:67])=[O:63])[C:23]([NH:25][C@H:26]([C:29]([N:31]2[C@H:35]([C:36]([NH:38][C@H:39]([C:47]([NH:49][C@H:50]([C:58]([OH:60])=[O:59])[CH2:51][CH2:52][CH2:53][NH:54][C:55]([NH2:57])=[NH:56])=[O:48])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:37])[CH2:34][CH2:33][CH2:32]2)=[O:30])[CH2:27][OH:28])=[O:24])=[CH:17][CH:16]=1.[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(=O)O
Solvent: CO
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)[O-]

Procedure:
Lauric acid (2 g, 10 mmol) was dissolved in 80 mL of methanol in a round bottom flask; 160 mg (0.13 mmol) of bradykinin was dissolved in 10 mL methanol, and 112 mg (1.36 mmol) of piperidine was. The peptide solution was then added to the stearic acid solution and stirred for three to four hours. The solvent was evaporated by rotary evaporation; 150 mL of ether/chloroform (6:4) was added to the residue, and stirred for one hour. The mixture was filtered through a 5 μm teflon filter (Millipore Type Ls), and the solid product (85 mg) collected and dried in a vacuum dessicator. The NMR (methanol d-4) confirmed the presence of laurate at 1.3-1.4 ppm.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][C@H:13]1[CH2:18][C@@H:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C@H:16]([CH3:24])[CH2:15][CH2:14]1.C(OCC)C.[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl>[CH3:24][C@@H:16]1[CH2:15][CH2:14][C:13](=[O:12])[CH2:18][C@H:17]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CC[C@H]1C
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(=O)CC[C@H]1C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of pyridinium chlorochromate (36.0 g, 167 mmol) in methylene chloride (200 mL) was added 10 (17.27 g, 92.8 mmol), whereupon the mixture became a dark homogenous solution. The reaction was stirred overnight. Diethyl ether (3×300 mL) was added and the product was passed through a short column of florisil to remove the chromium salts. Removal of the solvent in vacuo gave an oil (15.9 g, 93% yield). This was carried onto the next step without further purification. Rf 0.61 (ethyl acetate/hexane 3:7); 1H NMR (300 MHz, CDCl3) δ 4.18 (dq, J=1.1, 7.2, 2H), 2.35-2.63 (m, 5H), 2.01-2.19 (m, 2H), 1.42-1.53 (m, 1H), 1.28 (t, J=7.2, 3H), 1.03 (d, J=6.4, 3H); 13C NMR (75 MHz, CDCl3) δ 208.9, 173.5, 60.6, 50.5, 42.7, 40.3, 33.4, 33.2, 19.0, 14.1; MS (EI) m/z 184 (M+, 23), 169 ([M-CH3]+, 3), 155 ([M-CH2CH3]+, 8), 139 ([M-OCH2CH3]+, 8), 128 (35), 111 (100), 99 (46). 55 (50); [α]D−46.9° (c=1.00, CH2Cl2). Analysis calc'd for C10H16O3: C, 65.19; H, 8.75. Found: C, 65.06; H, 8.73.