Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN(C)C=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: OCCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
Sodium hydride (99 mg, 4.14 mmol) was added to a solution of 3-phenyl-1-propanol (564 μL, 4.14 mmol) in N,N-dimethylformamide (15 mL) while cooling in ice, and the mixture was stirred for 30 min while cooling in ice. A solution of 2-fluoro-5-nitropyridine (500 mg, 3.45 mmol) in N,N-dimethylformamide (5 mL) was added thereto. The mixture was warmed to room temperature and stirred for 19 hr. Subsequently, sodium hydride (99 mg, 4.14 mmol) was added thereto and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was heated to 85° C., stirred for 1.5 hr, and further stirred at room temperature for 2 hr. Water was added to the reaction mixture while cooling in ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and dried over anhydrous magnesium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to afford 5-nitro-2-(3-phenylpropoxy)pyridine as a brown solid (440 mg).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 43.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.8 mg) was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:9]([C:8]3[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=3[O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:11])[CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC3CCCC3)CC2)s1
Yield: 71 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 71%). MS (m/e): 556.3 (M+H+, 35%), 573.5 (M+NH4+, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:14])([CH3:13])[C:9](=[O:12])[CH:10]=[CH2:11])[C:4](=[O:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:22]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[O:22]([C:29]1[CH:30]=[C:31]([NH:32][CH2:11][CH2:10][C:9](=[O:12])[C:8]([N:5]2[C:4](=[O:15])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:2]([CH3:1])[O:7][CH2:6]2)([CH3:13])[CH3:14])[CH:33]=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: Nc1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCNc2cccc(Oc3ccccc3)c2)CO1
Temperature: 40 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methylpent-1-en-3-one (50 mg), 3-phenoxyaniline (30 mg) and pyridine (0.2 ml) was heated at 40° C. for 1 hour then stirred overnight at 20° C. and at 40° C. for 4 hours. After evaporation the residue was purified by silica gel column chromatography eluting with isohexane/ethyl acetate to give 5-(3-phenoxyphenyl)amino-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpentan-3-one (Compound 1082, 69 mg), NMR 1.4(s,6H), 1.9(s,3H), 2.8(m,2H), 3.4(m,2H), 5.3(s,2H), 6.3-6.4(m,3H), 6.9-7.4(m,11H).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH:29]([O-])=O.[NH4+]>CO.[Pd]>[CH3:29][C:20]1[O:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:28][CH:27]=1
Reactant: O=C[O-]
Reactant: c1ccc(COc2ccc(OCCc3coc(-c4ccccc4)n3)cc2)cc1
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(O)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
4-[2-(4-Benzyloxyphenoxy)ethyl]-2-phenyloxazole (7.0 g, 18.8 mmol) was dissolved in methanol (150 mL) and treated with palladium on carbon (1.0 g, 10 mol %) and ammonium formate (20.0 g, 0.32 mol). The suspension was heated at reflux for 8 h and then cooled to ambient temperature. The resultant suspension was filtered through Celite with a methanol wash, and the filtrate was concentrated to provide a colorless oil (3.72 g, 70%). 1H NMR (250 MHz, CDCl3) δ 8.84 (s, 1H), 7.81-7.87 (m, 2H), 7.41-7.49 (m, 3H), 6.72 (d, 2H), 6.59 (d, 2H), 4.04 (t, 2H), 2.81 (t, 2H), 2.30 (s, 3H); MS(EI): 282 (M+H), 280 (M−H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Sc1ccccc1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CCOc1cc(Sc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To 5 ml of chloroform were added 0.57 ml of triethylamine and 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine, to which 0.6 ml of a chloroform solution containing 0.33 g of thiophenol was slowly added dropwise, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(thiophenoxy)pyrimidine (the present compound (97)).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl.CC(N(CC)C(C)C)C>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:25])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of N-tert-butyoxycarbonylpiperazine (2a) (1.86 g) in DCM (100 mL) and N,N-di-2-propyl-ethylamine (2 mL) was cooled in ice-water as a solution of 2-naphthalenesulfonylchloride (2.27 g) in DCM (50 mL) was added drop-wise. After addition, the cooling was removed and the reaction stirred overnight. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was sequentially washed with 0.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. After drying, the solvent was evaporated to provide a white solid. The white solid was dissolved in DCM (35 mL) and treated with trifluoroacetic acid (15 mL). After one hour, the solvent was evaporated, the residue suspended in water and the solution made basic with 1 N sodium hydroxide. The mixture was extracted with ethyl acetate. The extracts were washed with water, dried, and the solvent evaporated to give a white solid (2.7 g).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[CH:25]=[CH:26][CH:27]=1.[Cl-].[NH4+]>[OH-].[Na+].C(OCC)C.O1CCCC1>[OH:35][C:34]1([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[C:33]2[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31](=[O:40])[N:30]1[CH2:29][CH2:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=1
Reactant: Brc1ccncc1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(CCN2C(=O)c3ccccc3C2(O)c2ccncc2)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
0.69 g (3.55 mmol) of 4-bromopyridine hydrochloride was initially converted into the free base. To this end, the salt was dissolved in 5 ml of 1 M aqueous sodium hydroxide solution, the solution was extracted three times with diethyl ether and the combined organic phases were dried and evaporated to dryness using a rotary evaporator. The residue was dissolved in 5 ml of absolute diethyl ether and the solution was added dropwise at −70° C. to a mixture of 1.6 M butyllithium solution in n-hexane (3.98 mmol) and 10 ml of absolute diethyl ether. The mixture was stirred at −70° C. for 30 min, and a solution of 0.5 g (1.78 mmol) of N-(2-(3-methoxyphenyl)ethyl)phthalimide in 10 ml of absolute tetrahydrofuran was then added dropwise (color change from yellow to brown). After 1 h, the reaction mixture was allowed to warm to room temperature, admixed with 10 ml of saturated ammonium chloride solution and extracted three times with diethyl ether. The combined organic phases were washed once with saturated sodium chloride solution, dried and evaporated to dryness using a rotary evaporator. Recrystallization of the crystalline residue from diisopropyl ether/ethanol gave a colorless crystalline product. Yield: 0.28 g. M.p.: 190° C.
Reaction SMILES: OC[C@H](N[C:11](=[O:23])[C@@H:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1.S(=O)(=O)(O)[OH:25]>O1CCOCC1>[CH3:22][C@@H:12]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([OH:23])=[O:25]
Reactant: C[C@@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution consisting of (S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide (19mb(i), 3.5 g, 11.24 mmol) in 1,4-dioxane (80 mL) was added aqueous sulfuric acid (36 mL, 3 N solution) and the mixture was stirred overnight at 80° C. The reaction mixture was extracted with ethyl acetate three times and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane-acetic acid (30:70:0.4 v/v/v) afforded the title compound (2.4 g, quantitative yield) as a clear oil; Rf 0.48 (solvent system: 30:70:0.4 v/v/v ethyl acetate-heptane-acetic acid; HPLC retention time 26.0 minutes; Chiralpak IA, 5μ, 4.6×25 mm, ultraviolet detector at 208 nm 0.75 ml/min 99:1:0.5 v/v heptanes-2-propanol-acetic acid; MS (ESI−) m/z 191.1 (M−H)−; 1H-NMR (CDCl3) δ 7.33-7.27 (m, 2H), 7.22-7.16 (m, 3H), 2.67-2.60 (m, 2H), 2.56-2.46 (m, 1H), 1.80-1.60 (m, 3H), 1.59-1.36 (m, 1H), 1.25-1.14 (m, 3H); [α]Tλ=α/cl, [α]21.9D=+0.089/(0.01501 g/1.5 mL)(0.5)=+17.79° (c=1, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:22]([C:11]1[C:12]([CH3:21])=[N:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
A solution containing 80 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanol and 64μof triethylsilane in 2 ml of trifluoroacetic acid was stirred at rt for 15 h. The mixture was concentrated, diluted with 10 ml of saturated sodium hydrogen carbonate solution and extracted twice with 10 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°–60° C. (1:10) for the elution to give 60 mg of 4-benzyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (EI) m/z 424 [M]+.1H NMR (DMSO-d6) 2.26 (s, 3H), 3.88 (s, 2H), 6.77 (d, 2H), 7.13 (m, 3H), 7.20 (m, 2H), 7.32 (t, 1H), 7.35–7.48 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37]Br>C(#N)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:37][CH2:36][O:35][CH3:34])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3cc(C)on3)CC2)C1
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50 mg, 0.13 mmol), cesium carbonate (85 mg, 0.26 mmol) and 2-bromoethyl methyl ether (0.025 ml, 0.26 mmol) in acetonitrile (1.3 ml) was heated at 70° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (17 mg, 29%) as off-white solid. MS m/e: 442 ([M+H]+).
Reaction SMILES: [H-].[Na+].C[C:4](OS(C1C=CC(C)=CC=1)(=O)=O)([CH2:21][CH2:22][CH3:23])[CH2:5][C:6]1[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[OH:20].O.[CH2:36]1COCC1>C(OCC)(=O)C>[CH3:36][C:22]1([CH3:23])[CH2:21][CH2:4][CH2:5][C:6]2[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[O:20]1
Reactant: CCCC(C)(Cc1c(NC(C)=O)ccc(C(=O)OC)c1O)OS(=O)(=O)c1ccc(C)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)c2c1OC(C)(C)CCC2

Procedure:
To a mixture of 2.2 g sodium hydride (60%) and 20 ml THF is added dropwise at 0° C. a solution of 15 g of methyl 3-(2'-methyl-2'-tosyloxypentyl)-4-acetylaminosalicylate in 10 ml THF. This is allowed to come to room temperature over several hours, then chilled and 2 ml H2O added slowly. This is then diluted with ethyl acetate, the salts filtered off, washed with water and brine, dried and concentrated to dryness to obtain methyl 2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate which is used directly in the next step.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[N:13]=[C:12]3[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.O.CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[C:12]3[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2nc(C(=O)O)cn2-c2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.62 g (1.7 mmol) of the compound from Step B in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 337.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]([C:8]([Cl:14])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)Cl)o1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2,4-dimethyl-oxazole-5-carboxylic acid (30 mg) in DCM (2.0 mL), oxalyl chloride (3.0 eq) was added at room temperature. The reaction mixture was stirred for 30 minutes. Solvents were evaporated and dried under vaccuo to afford 2,4-dimethyl-oxazole-5-carbonyl chloride.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl.C(OCC)C>[C:18]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: CC(C)Oc1ccccc1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Oc1ccccc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-isopropoxyphenol (1.53 g, 10 mmol) in CH2Cl2 at 0° C., was added pyridine (1.76 mL, 22 mmol) followed by acetyl chloride (0.79 mL, 1.1 eq). The mixture was stirred at 0° C. for 1.0 h, diluted with diethyl ether, washed with 5% citric acid and brine. The organic extract was dried over Na2SO4, evaporated to give 2-isopropoxyphenyl acetate as an oil.
Reaction SMILES: [C:1]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([OH:21])[C:15]([CH3:23])([CH3:22])[CH2:14]1)=[O:11].OO.C(=O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)(C)C.C(O)(=O)C>[C:1]([O:25][CH:26]1[CH2:27][C:28]([CH3:36])([CH3:35])[N:29]([O:34][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH3:40])[C:30]([CH3:33])([CH3:32])[CH2:31]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:23])[N:16]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:17]([CH3:19])([CH3:20])[CH2:18]1)=[O:11]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CCCCCCCCC=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 40 °C
Reaction time: 10 h

Procedure:
10.0 g Bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate (Prostab 5415, commercial product of Ciba Specialty Chemicals Inc.) are dissolved in 40 ml toluene/tert-butanol (2:1) and 8 g 50% aqueous hydrogen peroxide are added, followed by 18 ml nonanal, 0.1 ml acetic acid and 0.15 g CuCl2. The reaction mixture is stirred for 2 h at 25-25° C. and afterwards for 10 h at 40° C. The mixture is poured into 100 ml 0.1 N NaOH and subsequently extracted with methylene chloride. The organic phase is washed twice with water and then with sat. sodium chloride solution and dried over sodium sulfate. The organic phase is removed in vacuo and the residue subjected to column chromatography on silica gel to afford 5.4 g of product.
Reaction SMILES: [CH3:1]N(C)C=O.[ClH:6].[C:7]1(/[CH:13]=[CH:14]/[C:15]([NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].CI>O>[ClH:6].[C:7]1(/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:1])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)=[O:16])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(/C=C/c1ccccc1)NCCC1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(CCC1CCN(Cc2ccccc2)CC1)C(=O)/C=C/c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a dimethylformamide solution (5 ml) of (E)-3-phenyl-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide.hydrochloride (0.6 g) obtained in Example 1 was gradually added sodium hydride (80 mg) at room temperature and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled on an ice-bath and there was added methyl iodide (0.21 g), followed by stirring at room temperature for one hour. To the resultant mixture was added water and the mixture was subjected to extraction with dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous sodium sulfate, then the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography [developing solvent : ethyl acetate - methanol=10 : 1(V/V)]. Then the solvent of the solution containing the object compound was distilled off. To the residue was added an ethanolic solution (0.5 ml) of 3N hydrogen chloride, followed by distilling off the solvent to obtain an amorphous powder (0.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:10]1([CH2:13]O)[CH2:12][CH2:11]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:13][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: OCC1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,5-Dibromo-phenol (5 g; 19.9 mmol), cyclopropylcarbinol (1.4 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in THF (500 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (9.0 g; 35.7 mmol) dissolved in THF (100 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was partly evaporated, filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane 0:1→1:10). Yield: 5.45 g; 90%.