Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[N:33](C(OCC)=O)[CH2:34][CH2:35][N:36]=1.C([O-])(O)=O.[Na+]>CCO>[NH:36]1[CH2:35][CH2:34][N:33]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: CCOC(=O)N1CCN=C1SC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCN3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A mixture of N-(4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl)acetamide (150 mg), ethyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate (78.9 mg), ACOH (0.3 ml) and EtOH (3 ml) was refluxed for 7 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The amorphous substance was solidified with ethyl ether to give N-{4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (17.9 mg) as an off-white amorphous solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](Cl)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:20]>>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([I:20])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: I
Reactant: O=c1cc(Cl)nc2sc(SCc3ccccc3)nn12
Product: O=c1cc(I)nc2sc(SCc3ccccc3)nn12
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of 12.2 g of the thus obtained 2-benzylthio-7-chloro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and 124 g of 57% hydroiodic acid was heated to 100°-105° C. and stirred for 4 hours. After cooling, the mixture was filtered and the solid was washed with water and dissolved in chloroform. The organic layer was washed with a sodium hydrogen carbonate aqueous solution, a sodium thiosulfate aqueous solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 13.9 g of 55% pure 2-benzylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 48%.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P([O-])([O-])(O)=O.[Na+].[Na+].[Br:20]Br>O.C(O)(=O)C>[C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:20])=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: BrBr
Reactant: CCCC(=O)Nc1ccccn1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)Nc1ccc(Br)cn1
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To 53.6 g of an aqueous solution containing 0.2 mol of 2-butanamido pyridine (If), a solution containing 71 g (0.5 mol) of disodium hydrogenphosphate dissolved in 490 g of water was added. To this mixture, a solution containing 54.2 g (0.34 mol) of bromine dissolved in 54 g of acetic acid was added with stirring at 10°-17° C. for 5 hours. After having been stirred at room temperature for one hour and then at 60° C. for one hour, the mixture was cooled. The crystal precipitated thereby was filtered. After the crystal was washed with water and dried, 43.7 g (yield: 89.8%) of 2-butanamido-5-bromopyridine (IIf) was obtained as a pale brown crystal.
Reaction SMILES: [Mg].Br[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.N1(N[C:19](=[O:27])[CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])CCCCC1.S(=O)(=O)(O)O>C(OCC)C>[CH2:22]([O:21][C:20]([O:24][CH2:25][CH3:26])([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH:19]=[O:27])[CH3:23]
Reactant: CCOC(OCC)C(=O)NN1CCCCC1
Reactant: BrC1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(C=O)(OCC)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.73 g of magnesium turnings are covered with 90 ml of dry diethylether. To that mixture is then added 6 g of 2-bromoindane in 20 ml of dry diethylether at such a rate that a gentle boiling is maintained. When the magnesium turnings have reacted the solution containing the Grignard reagent is cooled to room temperature. The reaction mixture is then added dropwise, over a period of 3 hours, to a cooled (0°-5° C. solution of diethoxyacetic acid piperidinyl amide (6.4 g) in 20 ml of dry diethylether. After the addition is complete, the reaction mixture is stirred for two hours at about 5° C. The mixture is then poured into a cold 2% sulfuric acid solution (50 ml). The solution is extracted with ether and the combined ether extracts are washed with water and evaporated to dryness to give a residue of crude product, which is used without purification in step (b).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23]I.[H-].[Na+]>CN(C=O)C>[C:1]([N:11]([C@@H:12]([CH3:22])[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH3:23])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc([N+](=O)[O-])cc1)N(C)C(=O)OCc1ccccc1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of (S)-(-)-N-carbobenzyloxy-α-methyl-4-nitrobenzylamine (8.2 gm, 28 mmol) and methyl iodide (2.6 mL, 42 mmol) in DMF (50 mL) was cooled under nitrogen in an ice bath to 5-10° C. and sodium hydride (60% suspension in mineral oil) (1.2 gm, 31 mmol) was added in portions over 15 min while maintaining the temperature at 5-10° C. The reaction was stirred for 1 hr and then slowly quenched into a mixture of ice water, 2N hydrochloric acid (20 mL) and ether and the layers were separated. The ether layer was washed with water and brine and the aqueous layers were consecutively extracted with a second portion of ether. The pooled ether layers were dried over sodium sulfate and evaporated. The residue was purified by flash chromatography using 10-30% ethyl acetate/hexanes to give 6.6 gm (77%) of the title compound. [α]D (EtOH)=-97°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].N[C:12](N)=[O:13].Cl>>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:10][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1)[CH3:9]
Reactant: CCc1ccc(O)c(N)c1
Reactant: NC(N)=O
Agent: Cl
Product: CCc1ccc2oc(=O)[nH]c2c1
Temperature: 180 °C
Yield: 60.5 %

Procedure:
8.2 g (0.06 M) 2-amino-4-ethylphenol and 5.4 g (0.09 M) urea were thoroughly mixed and heated in an oil bath to 180° C. for 2.0 hours. Thereafter the mixture was allowed to cool to 100° C. HCl solution (1.0 normal) was added to the mixture while stirring and the mixture was cooled to room temperature. The cooled mixture was extracted three times with methylene chloride. The combined organic phases were dried and stripped in vacuum. The sample yielded 5.9 g dark solid with a melting point of 75°-77° C. Spectroscopic data: nuclear magnetic resonance (NMR), C-13 NMR, infrared, and mass spectroscopy are consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:11](Br)([CH3:13])[CH3:12]>CS(C)=O>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH:11]([CH3:13])[CH3:12]
Reactant: Cc1ccccc1O
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccccc1OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 54.1 g (0.5 mol) of ortho-cresol in 150 ml of DMSO was added portionwise and with stirring 12 g of 57% sodium hydroxide. This addition was exothermic to 45° C. After 2 hours at ambient temperature, 61.5 g (0.5 mol) of isopropyl bromide in 50 ml of DMSO was added dropwise with stirring. After another 2 hours, the reaction mixture was poured into 1000 ml of ice water and extracted with ether. Distillation of the dried extract gave 53.9 g of product as a colorless liquid; b.p. 94°-96° C. (30 mm).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:3][C:4]=2[CH:10]=1
Reactant: CCOC(=O)[C@@H]1CCCCN1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: CCOC(=O)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1

Procedure:
The title compound was prepared by a similar method to Preparation 42 from 2,6-dichloro-1,3-benzothiazole [see J. Ind. Chem. Soc., (1993), 10, 565-569] and ethyl (2S)-2-piperidinecarboxylate (471 mg) [see J.A.C.S. (1993), 115(22), 9925-9938] to afford ethyl (2S)-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxylate as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:30])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH:19](N4CCCC4)[CH2:18][N:17]([CH3:27])[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:31].Br.C(O)(=[O:39])C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:30])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][C:19](=[O:39])[CH2:18][N:17]([CH3:27])[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:31]
Reactant: CC(=O)O
Reactant: CN1CC(N2CCCC2)CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Agent: Br
Solvent: C1COCCO1
Product: CN1CC(=O)CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-4-pyrrolidin-1-yl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (40 mg, 0.08 mmol) and 33% hydrogen bromide in acetic acid (0.5 mL) in dioxane (1 mL) was stirred at room temperature for 1.5 hour. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][OH:7].[CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH2:9]>C(O)C>[OH:7][CH2:6][CH2:5][S:4][CH2:9][CH2:8][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: OCCS
Reactant: C=Cc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCSCCc1ccncc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (1.62 g., 0.03 mole) was dissolved in 36 ml. of stirring absolute ethanol and the solution cooled in an ice bath. 2-Mercaptoethanol (2.34 g., 0.03 mole) in 6 ml. of absolute ethanol was added over approximately 5 minutes. Finally, 4-vinylpyridine (3.22 g., 0.03 mole) in approximately 20 ml. of absolute ethanol was added over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 23 hours. The reaction mixture was concentrated to a thick oil (7.28 g.). The oil was diluted with a small amount of chloroform (a strong exotherm occurred, leading to refluxing of the chloroform) and chromatographed on silica gel, with large volumes of chloroform and finally chloroform/1% methanol as eluant. Product containing fractions (from the latter eluant) were combined and evaporated to yield the free base of 4-[2-(2-hydroxyethylthio)ethyl]pyridine [2.49 g.; oil; m/e calcd.: 183, found: 183; ir (film): 3.10, 3.45, 3.52, 6.23, 7.07, 9.40, 9.57, 9.98 and 12.44μ; pnmr/CDCl3 /TMS/δ: 8.53 (m, 2H), 7.17 (m, 2H), 3.77 (t, 2H), 3.57 (s, 1H, exchanges with D2O), 2.85 (m, 4H) and 2.73 ppm (t, 2H)].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.[BH4-].[Na+]>CO.[Ni]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:20])[F:21])[CH:14]=[C:13]([F:24])[CH:12]=2)[OH:25])=[CH:6][C:3]=1[CH2:4][NH:5][C:27](=[O:26])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrile (1.30 g, 3.62 mmol), BOC2O (1.68 mL, 7.24 mmol) and Nickel (H) chloride (0.47 g, 3.62 mmol) in MeOH at 0° C. was added sodium borohydride (0.96 g, 25.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 6 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was diluted with EtOAc and the solution was washed with sat. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 2-fluoro-5-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(hydroxy)methyl)benzylcarbamate as a clear, colorless oil (1.43 g, 85% yield). This product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 1H), 7.22 (m, 1H), 7.03 (m, 3H),), 6.87 (d, J=8.84 Hz, 1H), 5.90 (m, 2H), 4.98 (br. s., 1H), 4.31 (d, J=5.05 Hz, 2H).
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C:9]1[C:17]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1c(OC(F)(F)F)cccc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(OC(F)(F)F)cccc1C(=O)O
Yield: 70.5 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-trifluoromethoxy-benzoic acid (0.8 g, 2.5 mmol) in 30% v/v TFA/methylene chloride (50 mL) was stirred at room temperature for 1 h. Concentration of the mixture gave 2-amino-3-trifluoromethoxy-benzoic acid (0.39 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 1H), 7.34 (d, 1H), 6.63 (t, 1H), 6.04 (br, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:18]=CC=[C:14](O)[CH:13]=1)[OH:12].O>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[CH:18][C:11]([OH:12])=[CH:13][CH:14]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Ethyl 4-chloroacetoacetate (14.0 g, 85.0 mmol) was dissolved in conc. sulfuric acid (30 mL) under ice-cooling and resorcinol (8.81 g, 80.0 mmol) was added by small portions, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into iced water. The resulting solid was collected by filtration, washed with water and air dried to give the title compound (14.1 g, 84%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1>>[C:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)CCC1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCC(CCC(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 3-(4-piperidyl)propionate hydrochloride as starting raw materials, to produce ethyl 3-(1-((E)-2-decenoyl)-4-piperidyl)propionate (ethyl ester of Compound 36).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]=2[CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C1CCc2ccccc2O1
Product: O=C(O)C1CCc2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
30 Parts of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid were added slowly, during a 30 minutes-period, to 79 parts of a solution of nitric acid 60% while cooling on an ice bath. The whole was stirred for 10 minutes at room temperature. The reaction mixture was poured onto ice water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and water (80:20 by volume), yielding 17 parts (45%) of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylic acid; mp. 180° C. (intermediate 22).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:6]=2[C:5](=[O:25])[NH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:9]2[N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:6]3[C:5](=[O:25])[NH:4][CH:3]=[CH:2][C:7]=3[N:8]=2)[CH2:29][CH2:28]1
Reactant: OC1CCNCC1
Reactant: CSc1nc(Nc2cccc(C(F)(F)F)c2)c2c(=O)[nH]cc(Br)c2n1
Product: O=c1[nH]ccc2nc(N3CCC(O)CC3)nc(Nc3cccc(C(F)(F)F)c3)c12
Yield: 60 %

Procedure:
The title compound was prepared as described in Example 1g by starting from 8-bromo-2-(methylthio)-4-(3-(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (60 mg, 0.26 mmol) and 4-hydroxypiperidine and continuing until the reaction yielded the title compound (40 mg, 60%)) as grey solid. MS m/z: 484 and 486 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.O>C1C=CC=CC=1>[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[N:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:7][OH:8]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=Cc1ccc(F)cc1F
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1F

Procedure:
A solution of (S)-(+)-leucinol (2.47 g, 21 mmol) and 2,4-difluorobenzaldehyde (3 g, 21 mmol) in benzene (50 mL) was heated to reflux for 4 hours during which time water was collected in a Dean-Stark trap. The solvent was evaporated in vacuum to give (2S)-2-[(2,4-difluorobenzylidene)-amino]-4-methylpentan-1-ol.
Reaction SMILES: C([NH:9][C:10](=[S:25])[NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([Br:24])=[CH:14][N:13]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:24][C:15]1[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:12]([NH:11][C:10]([NH2:9])=[S:25])=[N:13][CH:14]=1
Reactant: CCOC(=O)Cc1cc(NC(=S)NC(=O)c2ccccc2)ncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)Cc1cc(NC(N)=S)ncc1Br
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A flask was charged with ethyl 2-(2-(3-benzoylthioureido)-5-bromopyridin-4-yl)acetate (2.940 g, 6.962 mmol) and ethanol (100 mL), and potassium carbonate (4.811 g, 34.81 mmol) was added. The mixture was heated at 70° C. for 2 hours, then filtered hot. The filter cake was washed with a small amount of ethanol, and the filtrate was concentrated to provide the desired product (2.205 g, 99.54%) as a yellow solid.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15])[NH2:13].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([C:38](O)=[O:39])[S:35][C:34]=2[CH:41]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([C:38]([NH:13][C@@H:12]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:20][CH2:21]3)=[O:15])[CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)=[O:39])[S:35][C:34]=2[CH:41]=1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3cc4ccc(Cl)cc4s3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (53%).
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][OH:30])[CH:23]=[N:24][CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][OH:30])[CH:23]=[N:24][CH:25]=1.[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CO)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OC[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M anhydrous HCl/ether (2.0 mL) was added to a stirred solution of (1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropylmethanol (200 mg, 0.59 mmol) in dry MeOH (2.0 mL) at 0° C. The resulting mixture was stirred at room temperature for 12 h, concentrated, and purified by HPLC to give the title compound as its hydrochloride (106 mg). 1H NMR (CD3OD, 300 MHz) δ 8.36 (s, 1H), 8.28 (s, 1H), 7.70 (s, 1H), 4.98-4.92 (m, 1H), 4.52-4.47 (m, 2H), 4.16-4.02 (m, 2H), 3.76-3.68 (m, 1H), 3.53-3.45 (m, 1H), 3.33-3.29 (m, 2H), 2.10-2.02 (m, 1H), 1.64-1.49 (m, 1H), 1.17 (t, 1H, J=7.2 Hz); MS (ESI) m/z 257 (M+Na+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]#[C:26]Br>CO.C(#N)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3=[N:23][C:26](=[NH:25])[N:24]=[C:19]3[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1N
Reactant: N#CBr
Solvent: CC#N
Solvent: CO
Product: N=C1N=c2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 4-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (202 mg, 0.62 mmol) in MeOH (1.5 mL) was added 130 μL of 5.0 M solution of cyanogen bromide in acetonitrile. The resulting mixture was stirred at r.t. under N2 for 24 h, then evaporated, and the residue was purified by chromatography over silica gel (CHCl3 --MeOH, 4:1) to give 174 mg (80%) of the title compound as a viscous oil. 1H NMR (CDCl3): 1.35-1.46 (m, 2H), 1.50-1.67 (m, 3H), 2.04-2.12 (m, 2H), 2.539 (d, 2H, J=7), 2.773 (t, 2H, J=6), 3.00-3.03 (m, 2H), 3.50 (bs, 1H), 4.035 (t, 2H, J=6), 6.243 (dd, 1H, J=8; 3), 6.317 (d, 1H, J=3), 6.614 (d, 1H, J=8), 7.12-7.30 (m, 5H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[OH:23]O>>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:23])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Reactant: OO
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Yield: 57 %

Procedure:
Oxidation of codeinone (VI) by action of peroxoacids, of combination of organic acids and hydrogen peroxide, or of inorganic oxidizing agents (e.g. Co3+ salts), with a maximum yield of 57% of 14β-hydroxycodeinone, which is hydrogenated to Oxycodone (I) (Coop A., Rice K. C.: Tetrahedron 55, 11429 (1999)).