Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]([NH2:29])=[O:28])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].FC(F)(F)C(N1C2CCC1CC(=C1C3C=CC=C(O)C=3OC3C1=CC=CC=3)C2)=[O:35]>>[CH:10]12[NH:5][CH:6]([CH2:12][CH2:11]1)[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]([NH2:29])=[O:28])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2.[C:3]([OH:35])([C:2]([F:31])([F:30])[F:1])=[O:4]
Reactant: NC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(O)cccc31)C2)C(F)(F)F
Product: NC(=O)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2
Product: O=C(O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 5 substituting (+)-9-[8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carboxylic acid amide 36 for 2,2,2-trifluoro-1-[3-(4-hydroxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]oct-8-yl]-ethanone 4a, title compound 37 was obtained as a TFA salt.
Reaction SMILES: [O-2:1].[O-2:2].[O-2:3].[Cr+6:4].[C:5]([OH:9])([CH3:8])([CH3:7])[CH3:6]>>[C:5]([O:9][Cr:4]([O:3][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:2])=[O:1])([CH3:8])([CH3:7])[CH3:6]
Reactant: [Cr+6]
Reactant: CC(C)(C)O
Reactant: [O-2]
Product: CC(C)(C)O[Cr](=O)(=O)OC(C)(C)C

Procedure:
In accordance with the method described in Synth. Commun., 10,905 (1980), bis(tert-butyl)chromate was synthesized by reaction of chromium trioxide with tert-butanol.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:10][C:11]([CH3:13])=[O:12]>>[C:11]([C:13]1[CH:8]=[CH:9][C:4]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:5]=2)=[CH:5][CH:6]=1)(=[O:12])[CH3:10]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(C)=O
Product: CC(=O)c1ccc(-c2cccc(-c3ccccc3)c2)cc1

Procedure:
Nitrobenzene is stripped with steam and the solid residue is dissolved into acetone. After filtration and the acetone evaporation, 400 g of crude product is obtained.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:20]=[CH:19][C:10]2[C@H:11]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][O:13][C:9]=2[CH:8]=1)(=O)=O.[CH3:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=[C:26]([CH3:38])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CN(C)C=O.O>[CH3:38][C:26]1[CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:29]=[C:24]([CH3:23])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:6][C:7]2[CH:20]=[CH:19][C:10]3[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][O:13][C:9]=3[CH:8]=2)[CH:40]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a solution of methyl(S)-2-(6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (4.88 g) and (2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methanol (5.00 g) in N,N-dimethylformamide (15 mL) was added tripotassium phosphate (4.57 g), and the mixture was stirred at 70° C. for 3 hr. The mixture was allowed to cool to room temperature, toluene (60 mL) and water (60 mL) were added, and an extraction operation was performed. The organic layer was washed with water (60 mL) and 10% brine (60 mL), and concentrated. The obtained oil was dissolved in dimethyl sulfoxide (30 mL), and 2N sodium hydroxide (8 mL) was added at room temperature. The mixture was stirred at 70° C. for 1 hr, and allowed to cool to room temperature. Ethyl acetate (60 mL) and water (60 mL) were added, and the mixture was partitioned. The aqueous layer was acidified with 6N hydrochloric acid to pH 1, ethyl acetate (60 mL) was added, and an extraction operation was performed. The organic layer was washed with water (60 mL), and concentrated. The crude product was recrystallized from acetone (30 mL)-water (60 mL), and the obtained solid was dried at 60° C. under reduced pressure to give the title compound (4.91 g) as white crystals. Yield 65%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]([OH:8])[CH3:11])[C:5]([F:10])=[N:4][CH:3]=1
Reactant: O=Cc1cc(Br)cnc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
To a solution of 5-bromo-2-fluoronicotinaldehyde (10 g, 49 mmol) in THF (100 mL) at −78° C. was added dropwise methylmagnesium bromide (3.0 M solution in diethyl ether, 24.5 mL, 73.5 mmol). After the addition, the reaction was warmed to room temperature and stirred for 17 h. The mixture was carefully quenched with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0-10% EtOAc/hexanes) gave 1-(5-bromo-2-fluoropyridin-3-yl)ethanol (10.8 g, 49.1 mmol, 100% yield) as a yellow oil. LC/MS (ESI+) m/z=220 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2(C([O-])=O)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[K+].[F:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C[Si](C)(C)[O-].[Na+]>>[NH2:51][C:8]1([C:4]2[CH:3]=[C:2]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:16]=3[F:15])[N:23]([CH3:26])[C:22](=[O:27])[CH2:21][CH2:20]4)[CH:7]=[N:6][CH:5]=2)[CH2:9][CH2:10]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])C1(c2cncc(Br)c2)CC1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Product: CN1C(=O)CCc2cc(-c3cncc(C4(N)CC4)c3)c(F)cc21

Procedure:
In analogy to the procedures described for the preparation of example 59, potassium 1-(5-bromopyridin-3-yl)cyclopropanecarboxylate (example 59 [B]) has been reacted with 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22) and subsequently with diphenylphosphoryl azide and sodium trimethylsilanolate to give the title compound as a light yellow oil. MS: 312.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.C(Cl)CCl.[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.C1(N)C=CC=CC=1N>CC#N>[NH2:42][C:40]1[CH:41]=[CH:36][CH:37]=[CH:38][C:39]=1[NH:44][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][NH:14][C:12]2[NH:11][N:10]=[C:9]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:13]=2)=[CH:24][CH:23]=1
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(-c2cc(NCc3ccc(C(=O)O)cc3)[nH]n2)cn1
Agent: Nc1ccccc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(-c2cc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)[nH]n2)cn1
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A solution of 385 (640 mg, 1.97 mmol) in MeCN (10 mL) was sequentially treated with Et3N (831 μL, 603 mg, 5.96 mmol), EDC (571 mg, 2.98 mmol), HOBT (334 mg, 2.18 mmol) and 1,2-phenylene diamine (429 mg, 3.97 mmol) and allowed to stir overnight. The reaction mixture was concentrated and partitioned between DCM (15 mL) and saturated NH4Cl (15 mL). The organic phase was collected, dried with Na2SO4, filtered and concentrated. The resultant solid was purified by flash chromatography using the gradient 3-15% MeOH in DCM to afford the title compound (113 mg, 14% yield). 1H NMR (DMSO-d6) δ9.65 (s, 1H), 8.43 (s, 1H), 7.92 (m, 3H), 7.48 (d, J=8.0 Hz, 2H), 7.16 (d, J=7.4 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.81 (t, J=8.2 Hz, 2H), 6.63 (t, J=7.4 Hz, 1H), 5.85 (s, 1H), 4.34 (s, 2H), 3.85 (s, 3H). LRMS: (calc) 414.2; (found) 415.3 (M+H1)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4](=[N:8][S:9][N:10]=2)[N:5]=[CH:6][N:7]=1.N.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Cl>>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][NH:1][C:2]1[C:3]2[C:4](=[N:8][S:9][N:10]=2)[N:5]=[CH:6][N:7]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: Nc1ncnc2nsnc12
Agent: N
Product: Fc1cccc(Cl)c1CNc1ncnc2nsnc12
Temperature: 110 °C
Yield: 25 %

Procedure:
An autoclave was charged with 1.54 g. (0.01 mole) of 7-amino[1,2,5]thiadiazolo[3,4-d]pyrimidine prepared by the process set forth in Example 1, 5.1 g. (0.3 mole) ammonia and 4.48 g. (0.025 mole) 2-chloro-6-fluorobenzyl chloride. The vessel was sealed and the contents heated at 110° C. for 15 hours. After cooling and evaporation of the excess ammonia, the resulting solid was collected by filtration, washed successively with water and hexane to afford a 25% yield of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C:23]3=[O:31])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]4=[O:31])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
A solution of 1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one (1 eq) in dry CH2Cl2 was treated with methanesulfonyl chloride (1.1 eq) and triethylamine at RT for 15 h. Quenching with H2O and extraction into CH2Cl2 followed by concentration and purification by prep HPLC gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Cl.O.C(=O)(O)[O-].[Na+].[F:24][C:25]([F:33])([F:32])[C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[NH:15][C:27]([C:26]([F:31])([F:30])[C:25]([F:33])([F:32])[F:24])=[N:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)C(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (100 mg, 0.40 mmol) in pentafluoropropanoic acid (5 ml) was added hydrogen chloride (conc) (1 ml). The resulting solution was stirred overnight at 100° C. and then poured into water (50 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (sat). The resulting solution was extracted with ethyl acetate (3×30 ml), combined and dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 8% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-chlorophenyl)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (60.8 mg, 40%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][P:17]([O:23][CH2:24][CH:25]=[CH2:26])([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:11][C:7]=1[C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:30])=O.CN(C)C=O>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][P:17]([O:23][CH2:24][CH:25]=[CH2:26])([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:11][C:7]=1[C:8]([Cl:30])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)Cl)c1
Temperature: 0 °C

Procedure:
2-(Acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoic acid (475.5 mg, 1.24 mmol) obtained from Example 1-(11) was dissolved in tetrahydrofuran (5 ml), and the solution was cooled to 0° C., then oxalyl chloride (189.2 mg, 1.49 mmol) and N,N-dimethylformamide (15 μl) were added thereto with stirring. The mixture was warmed to room temperature and then stirred for 40 minutes. The solvent was distilled off under reduced pressure to give the crude 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:12]N1C(=O)N(O)C(=O)N(O)C1=O.[C:24]([OH:27])(=[O:26])[CH3:25].O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:25]([C:24]([OH:27])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)cc1
Product: CC(C)(C)c1ccc(C=O)cc1

Procedure:
A mixture of 0.445 g of 4-t-butyltoluene, 0.016 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (3% by mole relative to 4-t-butyltoluene), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4 H2O was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 2 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-t-butylbenzoic acid and 4-t-butylbenzaldehyde in 97% and 1% yields, respectively, at 100% conversion of 4-t-butyltoluene.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)[CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:22]=2[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:13]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:41]([O:40][C:38]([CH2:37][CH2:36][C:22]1[C:23]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:12]1[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[C:10]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)[CH:11]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
5-{6-[2-(2-Ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid tert-butyl ester (7.0 g) was dissolved in a mixture of TFA and dichloromethane (1:1, 80 mL) and stirred at room temperature for 1 h. The solvents were removed under reduced pressure and the crude material was purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (5.9 g, 90% yield).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(OCC)C>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)[CH2:29][CH2:28]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CC2CCNCC2)cc1OC1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCC(Cc3ccc(OC)c(OC4CCCC4)c3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 20 ml of tetrahydrofuran (THF) containing 1 g of 4-methoxybenzoyl chloride is added dropwise to a solution of 30 ml of THF containing 0.73 g of 4-(3-cyclopentyloxy-4-methoxybenzyl)piperidine, 0.78 ml of triethylamine and 0.2 g of 4-N,N-dimethylaminopyridine, and the mixture is stirred under argon at room temperature. The reaction mixture is stirred at room temperature for 4 hours, diluted with 150 ml of diethyl ether, washed with a saturated aqueous sodium carbonate solution and then with water, and washed with a 1N HCl solution and then washed again with water. The organic phase is dried over magnesium sulphate and concentrated. The residual oil is filtered over silica by the flash chromatography technique using a toluene/ethanol mixture (97:3) as eluant. 4-(3-Cyclopentyloxy-4-methoxybenzyl)-1-(4-methoxybenzoyl)piperidine is obtained in the form of an oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.[S:15](Cl)([Cl:17])=[O:16].Cl>>[Cl:17][S:15]([N:2]([CH3:1])[C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:12])[CH3:13])[CH:6]=1)=[O:16]
Reactant: CNC(=O)Oc1cccc(C(C)C)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CC(C)c1cccc(OC(=O)N(C)S(=O)Cl)c1
Reaction time: 1 h

Procedure:
Four grams 3-isopropylphenyl methylcarbamate were mixed with excess thionyl chloride and heated up to 80° C. until HCl evolution ceased. Excess thionyl chloride was removed by distillation and the residue was subjected to high vacuum (0.1 mm) for 1 hour. NMR of the residue in chloroform-d-TMS gave the following absorptions: δ7.5-6.9 (m, 4H, aromatic protons). δ3.25 (s, 3H, NCH3), δ3.2-2.7 (m, 1H, CH), and δ1.3-1.2 (d, 6H, C(CH3)2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][CH2:13][CH3:14])[O:11][CH2:10]1.B(F)(F)F.C[CH2:20][O:21]CC.[CH2:24](O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:11][CH2:10][CH3:24])([CH2:12][CH2:13][CH3:14])[CH2:20][OH:21]
Reactant: CCOCC
Reactant: CCO
Reactant: CCCC1(c2ccc(Cl)cc2Cl)CO1
Agent: FB(F)F
Product: CCCC(CO)(OCC)c1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
27.6 g (120 mmoles) of 2-(2,4-dichlorophenyl)-1,2-epoxypentane are dissolved in 60 ml of ethanol. A solution of 17.4 g (120 mmoles) of boron trifluoride-etherate in 60 ml of ethanol is added dropwise at 0° C., the internal temperature being kept at 0°-5° C. by cooling with ice water. The mixture is then left at +7° C. to react further slowly. As soon as epoxide can no longer be detected by gas chromatography, the reaction mixture is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The yield of crude product is 32.3 g. Purification by column chromatography (silica gel; 4:1 petroleum ether/ethyl acetate) gives 15.96 g (53% of theory, taking into account that the epoxide employed is 90% pure). Boiling point 90° C./0.07mbar. 100 MHz-1H-NMR (CDCl3): δ=7.0-7.6 ppm (m, aromatic H); 3.7-4.4 ppm (m, --CH2OH); 3.2-36 ppm (q, --OCH2CH3); 1.6-2.2 ppm (m, --CH2 --, OH); 0.7-1.4 ppm (t, --OCH2CH3 and ##STR21##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:26][CH:25]=[CH2:24])[CH3:2]
Reactant: CCOC(=O)CNC(=O)C(C)(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(NC(=O)C(C)(C)C)C(=O)OCC

Procedure:
13.06 g of the above prepared (2,2-dimethyl-propionylamino)-acetic acid ethyl ester (69.75 mmol) was dissolved in 350 ml of abs. THF and cooled down to −78°. 146 ml of 1M lithium hexamethyldisilazide in THF (2.1 eq.) were slowly added via dropping funnel. After keeping the yellow suspension for 30 Min. at −78°, 6.491 ml of allyl bromide (1.1 eq.) was added and stirring continued for 15 Min. at the same temperature and for 40 Min. at 0°. Pouring of the homogeneous reaction mixture onto crashed ice/HCl, twofold extraction with AcOEt, twofold washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2) afforded 10.50 g of the title compound as colorless solid. In addition, 2.70 g of the di-allylated product (2-allyl-2-(2,2-dimethyl-propionylamino)-pent-4-enoic acid ethyl ester) was obtained from the less polar fractions.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>CN(C)C=O>[Br:13][CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)OCC(CCO)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCBr)CO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To an ice-cooled solution of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan (1.92 g, 12 mmol) and carbon tetrabromide (7.96 g, 24 mmol) in dimethylformamide (100 ml), triphenylphosphine (6.30 g, 24 mmol) was added and the solution was left at 4° C. overnight. To this solution methanol (20 ml) was added and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-acetone (12:1) to afford 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan as a clear colourless liquid (0.89 g, 40%); νmax (film) 2940, 1370, 1270, 1260, 1200, and 1070 cm-1 ; δH (CDCl3) 1.42 (6 H, s, C(CH3)2), 1.94 (3 H, m, CHCH2CH2Br), 3.43 (2 H, t, J 7 Hz, CH2Br), and 3.5-4.1 (4 H, m, 2×CH2O); (Found: C, 42.84; H, 6.93%. C8H15BrO2 requires: C, 43.07; H, 6.78%. [M-CH3 ]+ found 207.0024; C7H12BrO2 requires 207.0021).
Reaction SMILES: N1(C(O[C@H:10](/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H]2C[C@H](C)[C@H](C/C=C(\C)/C=C)O[C@@H]2C)=[O:15])[CH3:11])=O)CCOCC1.[CH:31]([C@H:33]1[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][C@:35]2([O:37][CH2:36]2)[C@@H:34]1[OH:43])=[CH2:32].C1(=O)C=CC(=O)C=C1>C(Cl)CCl>[CH:31]([C@H:33]1[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][C@:35]2([O:37][CH2:36]2)[C@@H:34]1[OH:43])=[CH2:32].[C:14]([NH2:16])(=[O:15])[CH:13]=[CH:12][CH2:10][CH3:11]
Reactant: C=C/C(C)=C/C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCOCC2)C[C@@H]1C
Agent: C=C[C@H]1OC(C)(C)C[C@@]2(CO2)[C@@H]1O
Agent: O=C1C=CC(=O)C=C1
Solvent: ClCCCl
Product: CCC=CC(N)=O
Temperature: 42 °C
Yield: 29 %

Procedure:
A solution of (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (18 mg, 0.099 mmol) was prepared in ClCH2CH2Cl (200 μL) at 23° C. under an open atmosphere. To a stirred solution of (S,Z)-5-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-ylamino)-5-oxopent-3-en-2-yl morpholine-4-carboxylate (26 mg, 0.062 mmol) in ClCH2CH2Cl (200 μL) was added the solution of (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (100 μL), benzoquinone (1.4 mg, (0.012 mmol), followed by Grela catalyst (1.5 mg, 2.2 μmol) at 23° C. under an open atmosphere. The reaction mixture was then heated to 42° C. After 3 h at the same temperature, additional Grela catalyst (1.5 mg, 2.2 μmol) and (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (100 μL) were added. After 11 total hours, the reaction was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10→80% EtOAc in hexanes) on silica gel (8 mL) to give (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-Pentenamide (10.4 mg, 29%), and a mixture of (S,Z)-5-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-ylamino)-5-oxopent-3-en-2-ylmorpholine-4-carboxylate and (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (22.1 mg).