Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([CH:14]([F:16])[F:15])=[CH:12][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:15][CH:14]([F:16])[C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)F)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(F)F)nc1
Yield: 60.3 %

Procedure:
A solution of the compound obtained in Step C (5.9 g) in dichloromethane (80 ml) was treated with trifluoroacetic acid (3.7 ml) at ambient temperature for 12 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate (saturated) and washed several times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) afforded 6-difluoromethyl-pyridin-3-yl-amine (2.1 g): 1H NMR (400 MHz, CDCl3) 3.98 (br s, 2H), 6.56 (t, 1H), 7.03 (dd, 1H), 7.40 (d, 1H), 8.06 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12](C(C(O)=O)C(O)=O)=[O:13].[CH3:21][CH:22]([CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])[CH2:23][CH2:24][O:25][C:26](=[O:41])[CH2:27][C:28]([O:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])=[O:29].CC1CCCC(C)(C)C=1C=CC(Cl)=O.[H-].[Na+]>>[CH3:21][CH:22]([CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])[CH2:23][CH2:24][O:25][C:26](=[O:41])[CH:27]([C:12](=[O:13])[CH:11]=[CH:10][C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])[C:28]([O:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:38])[CH3:39])=[O:29]
Reactant: CC(C)=CCCC(C)CCOC(=O)CC(=O)OCCC(C)CCC=C(C)C
Reactant: CC1=C(C=CC(=O)C(C(=O)O)C(=O)O)C(C)(C)CCC1
Agent: CC1=C(C=CC(=O)Cl)C(C)(C)CCC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCCC(C)CCOC(=O)C(C(=O)C=CC1=C(C)CCCC1(C)C)C(=O)OCCC(C)CCC=C(C)C

Procedure:
According to the procedure of Example 45, 2-[3-(2,6,6-trimethyl-cyclohex-1-enyl)-acryloyl]-malonic acid bis-3,7-dimethyl-oct-6-enyl) ester was prepared from malonic acid bis-(3,7-dimethyl-oct-6-enyl) ester, 3-(2,6,6-trimethyl-cyclohex-1-enyl)acryloyl chloride (Shimasaki et al., Chem. Pharm. Bull., 43 (1995) 1, 100-107) and sodium hydride.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.C([CH2:10][C:11]([O-:13])=[O:12])=C.C1(=O)C=CC(=O)C=C1.B(F)(F)F.[O:26]([CH2:29]C)[CH2:27][CH3:28]>>[CH3:7][O:6][CH:1]([O:4][CH3:5])[CH2:28][CH:27]([O:26][CH3:29])[O:13][C:11](=[O:12])[CH3:10]
Reactant: C=CCC(=O)[O-]
Reactant: COC(OC)OC
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C1C=CC(=O)C=C1
Product: COC(CC(OC)OC(C)=O)OC
Temperature: 30 °C
Reaction time: 2.3 h

Procedure:
A mixture of 56.00 g trimethyl ortho formate, 60.00 g vinylacetate, 0.75 g PdCl2(ACN)2, 0.60 g 1,4-benzoquinone, and 1.00 ml BF3*OEt2 was stirred at 30° C., and low boiling impurities were removed from the reaction mixture through the application of a slight vacuum. A fractionation column was installed to prevent losses of starting materials and/or products. After 2.3 hours, the ratio of 1,1,3,3-tetramethoxypropane to 1-acetoxy-1,3,3-trimethoxypropane, and the isomeric 1,3-diacetoxy-1,3-dimethoxy-propanes was determined by CG-analysis to be 1.0:2.4:1.3 on the basis of the FID-area-percentages. In a comparative experiment, without removal of low boiling impurities, the referring ratio was determined to be 1.0:1.48:0.50. Both reaction mixtures still contained an excess of vinylacetate.
Reaction SMILES: COC1C=C2C(=CC=1)C=C(C1C=CC=CC=1N)C(C)(C)C2.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N1(CCOC2C=C[C:55]([CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[C:64]3[C:73]([CH3:75])([CH3:74])[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:76][CH3:77])[CH:70]=4)[CH:65]=3)=CC=2)CCCCCC1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][N:57]([CH2:56][CH3:55])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[C:64]3[C:73]([CH3:74])([CH3:75])[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[C:69]([O:76][CH3:77])[CH:70]=4)[CH:65]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc2c(c1)CC(C)(C)C(c1ccccc1N)=C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1=Cc2ccc(OC)cc2CC1(C)C

Procedure:
Synthesized from 2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (451 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(6-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-2-yl)phenyl]amine (423 mg). This compound (421 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (355 mg).
Reaction SMILES: C(C1C=CC(CC(OC)=O)=CC=1)C(C)C.C(=O)(OC)OC.C([O-])([O-])=O.[K+].[K+].[CH2:28]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:43])[C:39]([O:41]C)=[O:40])=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30]>>[OH:41][C:39]([CH:38]([C:35]1[CH:34]=[CH:33][C:32]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:37][CH:36]=1)[CH3:43])=[O:40]
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: COC(=O)Cc1ccc(CC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reaction time: 8 h

Procedure:
Following the procedure of example 1, a mixture of 2 g of methyl (4-isobutylphenyl)acetate (EP 347,939), 16 ml of dimethyl carbonate and 2 g of K2CO3, in a 1:20:1.5 molar ratio, is reacted in autoclave at a temperature of 210° C. The reaction is completed within about 8 hours. The product, methyl α-(4-isobutylphenyl)propionate, is hydrolyzed to α-(4-isobutyl)propionic acid (Ibuprofen) as in the examples above. Yield (starting from the not methylated ester): 90%.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2([OH:21])[CH2:19][CH2:18][O:17][CH:16]2[CH3:20])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34]C(N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[OH:21][C:15]1([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:34]=[CH:35][C:30]([N:26]5[CH2:27][CH2:28][CH2:29][N:23]([CH3:22])[CH2:24][CH2:25]5)=[CH:31][CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:19][CH2:18][O:17][CH:16]1[CH3:20]
Reactant: COC(=O)c1sc(C2(O)CCOC2C)cc1N=CN(C)C
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Product: CC1OCCC1(O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(3-hydroxy-2-methyltetrahydrofuran-3-yl)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 440.57 (C23H28N4O3S) was obtained in this way; MS (ESI): 441 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: Clc1cc(-c2ncco2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Yield: 71.9 %

Procedure:
Following general procedure B1, 2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxazole (0.040 g, 0.18 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.039 g, 0.22 mmol) to afford the title compound (0.047 g, 71%) as a white foam. MW=363.41. 1H NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.66 (s, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.22-7.17 (m, 3H), 5.80 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.61 (s, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.22 (quin, J=7.5 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 364 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(=O)oc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr

Procedure:
To a stirred solution of 3.0 g of 4,5-dimethyl-2-oxo-1,3-dioxole in 100 ml of carbon tetrachloride was added 4.63 g of N-bromosuccinimide. The resulting solution was heated under reflux and irradiated for 15 minutes. The reaction mixture was cooled to 0°-5° C., filtered and evaporated to give the title product.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH:21]=[CH2:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (from Example 1, Step 3) in dioxane (0.15 M) was added tri-n-butyl vinyl tin (1.1 eq.) followed by bis(triphenylphosphine)palladium(II) chloride (0.1 eq.). The reaction was stirred under nitrogen at 100° C. for 3 h and then cooled to RT. The mixture was then diluted with EtOAc and washed with brine (3×). The organic phase was then dried over Na2SO4 and evaporated to dryness. The residual material was purified by chromatography on silica gel (PE:EtOAc, 9:1). The product fractions were evaporated and the residual material re-crystallised from DCM with PE. The product was obtained as yellow crystalline material (60%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:11]1([CH2:14][C:15]#[N:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCN1CCNCC1
Reaction time: 14 h

Procedure:
To a solution of 30% TFA/CH2Cl2 (10 mL) is added 4-cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 6.8 mmol) and the reaction is stirred for 14 h. The reaction is concentrated and chromatoghraphed using silica gel (%1 NH4OH/7% MeOH/CH2Cl2) to isolate piperazin-1-yl-acetonitrile as the free base. 1H NMR (300 MHz, CDCl3) δ4.36 (s, 2H), 3.54 (s, 2H), 3.45 (t, 2H), 3.13 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])=O)=O)[CH3:2].C(Cl)Cl.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>N1C=CC=CC=1>[O:11]1[C:9]2=[CH:8][N:7]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH:17]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CCCCCOC(=O)CNC(=O)C(=O)OCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(cn1)OCCCC2

Procedure:
Ethyl-2-((2-(hex-5-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate (0.35 g) and DCM (4 mL) were added to a vessel with stirring followed by the addition of pyridine (0.13 g). Tf2O (0.58 g) was then added to the mixture slowly at ambient temperature. The mixture was stirred at ambient temperature for 4 days after which time the mixture was extracted with 6N HCl (3×10 mL). The combined acid layers were washed with DCM (10 mL) and the pH was adjusted to ˜10 with solid K2CO3. The basic aqueous layer was extracted with DCM (20 mL). The organic layer was concentrated under reduced pressure to provide the title compound (A) and ethyl 2,3,4,5-tetrahydrooxepino[2,3-c]pyridine-7-carboxylate (B) as a 3:1 mixture as based on NMR analysis. 1H NMR (300 MHz, CDCl3) δ ppm 8.38 (s, 0.3H, cmpd B), 8.11 (s, 1H, cmpd A), 7.95 (s, 0.3H, cmpd B), 4.36-4.51 (m, 2.6H, cmpd A/B CH3CH2), 4.17-4.25 (m, 2H, cmpd A OCH2), 4.06-4.13 (m, 0.6H, cmpd B OCH2), 2.85-2.93 (m, 0.6H, cmpd B CH2), 2.71 (t, J=6.53 Hz, 2H, cmpd A CH2), 2.45 (s, 3H, cmpd A CH3), 1.99-2.15 (m, 2.6H, cmpd A/B CH2), 1.54-1.88 (m, 0.6H, cmpd B CH2), 1.44 (t, J=7.12 Hz, 0.9H, cmpd B CH3), 1.44 (t, J=7.12 Hz, 3H, cmpd A CH3); 13C NMR (75 MHz, CDCl3) δ ppm 166.53, 165.01, 162.88, 159.21, 153.21, 143.48, 143.11, 142.72, 139.52, 136.74, 134.94, 130.12, 127.21, 73.82, 65.85, 61.61, 61.21, 33.74, 31.53, 24.97, 22.11, 21.48, 14.56, 14.28; Cmpd A: HRMS (M+Na) m/z, calcd for C12H15NO3Na, 244.0950; found 244.0961; Cmpd B: HRMS (M+H) m/z, calcd for C12H16NO3, 222.1130; found 222.1130.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.C[N:23](C=O)C>N.CCO.CCOC(C)=O.O>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: N#CCCSCc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: CN(C)C=O
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.67 h

Procedure:
The above thiourea (1 g.) in DMF (10 ml.) and 8 M ammonia in EtOH (10 ml.) was treated with mercuric oxide (3 g.). The mixture was stirred for 40 minutes, diluted with EtOAc/water 1:1 v/v (100 ml.) and filtered through diatomaceous earth. The EtOAc extract was dried (MgSO4) and evaporated in vacuo to give 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionitrile as an oil, which was used without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[C:38](=[O:40])[CH3:39])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: COC[C@H](C)NCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Product: COC[C@H](C)N(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A suspension of urea 334 (66 mg, 0.127 mmol) in acetic anhydride (2 ml) was stirred at rt for 2 days. The reaction mixture was quenched by addition of methanol and water, and partitioned with AcOEt. After separation, the organic layer was collected, washed with water, 1N NaOH (×4), water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid was purified by flash column chromatography on silica gel (eluent 2% of ammonium hydroxyde in MeOH/DCM: 05/90 to 10/90) to afford the title compound 335 (46 mg, 0.08 mmol, 64% yield) as an off-white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.70 (s, 1H), 8.58-8.48 (m, 2H), 8.34 and 8.30 (2s, 1H), 8.27 and 8.19 (2d, J=8.3 Hz, 1H), 7.85-7.69 (m, 2H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (bd, J=9.0 Hz, 1H), 6.67-6.54 (m, 2H), 4.74-4.16 (m, 3H), 3.41-3.22 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.59-2.52 (m, 1H), 2.16 and 1.96 (2s, 3H), 1.09 and 1.04 (2d, J=6.9 Hz, 3H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 564.4 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:43])[C:29]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)([CH3:34])[CH2:30][S:31]2)=[CH:26][CH:25]=1>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:28]1([OH:43])[C:27]2[C:32](=[CH:33][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[S:31][CH2:30][C:29]1([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[CH3:34])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCCCCCO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 870.1 %

Procedure:
8-(t-Butyldimethylsilyloxy)-1-octyne (12 g, 49.9 mmol) was dissolved in dry tetrahydrofuran (150 ml) under argon atmosphere and then cooled to −78C. 2.5M n-Butyllithium (18 ml, 44.9 mmol) was added dropwise thereto, and the mixture was warmed to −10° C. and stirred for 1 hour and then cooled to −78° C. 7-Methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (860 mg,2.9 mmol) was added portionwise and then warmed to room temperature and stirred for 1.5 hour. The mixture was quenched by water. The reaction solvent was evaporated off, then the residue was dissolved in ethyl acetate, which was washed with water. The organic solvent was dried over anhydrous magnesium sulfate and removed by evaporation under vacuum. This product was purified by column chromatography on silica gel, eluting with 10% ethyl acetate in n-hexane. After removal of the solvent, 14 g of the title compound was obtained as colorless oil. (yield: 99.3%)
Reaction SMILES: S(=O)=O.[C:4]([O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10](=[CH:11][CH2:12][C@@H:13]3[C@@H:22]2[C@@H:21](O)[CH2:20][C@@:18]2([CH3:19])[C@H:14]3[C@@H:15]3[CH2:29][C@@H:16]3[C:17]2=[O:28])[CH2:9]1)(=[O:6])[CH3:5]>CS(Cl)(=O)=O.CN(C)C=O.CC1C=C(C)N=C(C)C=1.C(OCC)(=O)C>[C:4]([O:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10](=[CH:11][CH2:12][C@@H:13]3[C:22]2=[CH:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[C@@H:15]3[CH2:29][C@@H:16]3[C:17]2=[O:28])[CH2:9]1)(=[O:6])[CH3:5]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2[C@@H](O)C[C@]2(C)C(=O)[C@H]4C[C@H]4[C@@H]32)C1
Agent: CS(=O)(=O)Cl
Agent: O=S=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3C2=CC[C@]2(C)C(=O)[C@H]4C[C@H]4[C@@H]32)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2.6 ml of a solution of 5% by weight sulphur dioxide in methanesulphonic acid chloride are added to a solution of 1.75 g of 3β-acetoxy-11β-hydroxy-15β,16β-methyleneandrost-5-en-17-one in 10.5 ml of dimethylformamide and 3.5 ml of γ-collidine and the whole is stirred for 20 minutes, the internal temperature being allowed to rise to approximately 45°. While stirring, the mixture, including the precipitate that has formed, is poured onto 17.5 ml of ice-water and stirring is continued for a further 10 minutes. The oil that separates out is taken up in ethyl acetate and washed in succession with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution. Evaporation of the solvent yields 3β-acetoxy-15β,16β-methyleneandrosta-5,9(11)-dien-17-one that is uniform according to thin-layer chromatography and is processed further without purification.
Reaction SMILES: C([C:4]1[N:5]=[C:6](F)[N:7]([C:9]([C:22]2[CH:27]=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1)C=C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:41]([O:44][CH2:45][C:46]1[CH2:47][S:48][C@@H:49]2[CH:56]([NH2:57])[C:55](=[O:58])[N:50]2[C:51]=1[C:52]([OH:54])=[O:53])(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([O:44][CH2:45][C:46]1[CH2:47][S:48][C@@H:49]2[CH:56]([NH:57][C:6]3[N:7]([CH2:9][CH:22]=[CH2:27])[CH:8]=[CH:4][N:5]=3)[C:55](=[O:58])[N:50]2[C:51]=1[C:52]([OH:54])=[O:53])(=[O:43])[CH3:42]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: C=CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1ccnc1NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 11.4 %

Procedure:
A mixture of 4-allyl-2-fluoro-1-triphenylmethyl imidazole (1.21 g.) and toluene-p-sulphonic acid monohydrate (0.635 g.) in DMF (8.5 ml.) was stirred at ambient temperature for 1 minute then at 80°. 3-Acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (0.904 g.) was added and the mixture was heated at 80° for 2.5 hours. The solution was evaporated to dryness in vacuo and water and EtOAc added to the residue. The aqueous layer was separated, evaporated to dryness, the residue redissolved in water and purified by preparative HPLC on Whatman "Partisil 10" using water/MeOH/HOAc 70:30:1 v/v/v as eluant to give 3-acetoxymethyl-7-(3-allylimidazol-2-yl)aminoceph-3-em-4-carboxylic acid (0.142 g.) having the following n.m.r. in d6DMSO+CD3COOD: 2.0 (s, 3H); 3.15 (d, 2H); 3.23 (d, 1H); 3.54 (d, 1H); 4.7 (d, 1H); 4.97 (d, 1H); 4.9- 5.2 (m, 3H); 5.48 (d, 1H); 5.8 (m, 1H); 6.3 (s, 1H).
Reaction SMILES: O(C(OC1C=CC=CC=1)Cl)C1C=CC=CC=1.C1(C)C=CC=CC=1.CC(C)=O.O([C:35]1([CH:56]=[CH:55][CH:54]=[CH:53][CH:52]1C)[C:36](=[N:50][OH:51])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1OC1C=CC=CC=1)C1C=CC=CC=1>CCOCC>[C:36](=[N:50][OH:51])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:35]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC1C=CC=CC1(Oc1ccccc1)C(=NO)c1ccccc1Oc1ccccc1
Agent: ClC(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: ON=C(c1ccccc1)c1ccccc1
Yield: 76 %

Procedure:
are reacted in each case with 5 g of diphenoxy chloromethane. By a thin-layer chromatographic process (silica gel plates, 9:1 mixture of toluene and acetone as the eluant), practically uniform, oily crude products are obtained, viz. the following diphenoxy-methyloxime ethers: (a) Compound No. 86 (yield: 77% of theoretical), (b) Compound No. 87 (yield: 92% of theoretical), (c) Compound No. 88 (yield: 86% of theoretical), and d) the o-diphenoxy-methyl-benzophenone-oxime designated as Compound No. 89 (yield: 76% of theoretical) which is obtained by recrystallization of the crude product from ether and has a melting point of 89°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31]C)[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:53]=CC=[CH:50][CH:49]=1>>[NH:22]([C:20](=[O:21])[C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH3:31])[C:23]1[CH:24]=[CH:50][CH:49]=[CH:48][CH:53]=1
Reactant: Nc1ccccc1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: COc1ccc(Cl)cc1CC1CNC(=O)CN(C(=O)N[C@H](C)C(=O)Nc2ccccc2)C1=O

Procedure:
Instead of the starting material of Example 220, that is, the compound 119, the compound 100 was used, while instead of the glycine tert-butyl ester hydrochloride, aniline was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]([OH:20])([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+]>C(O)C.O>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:9]2([OH:20])[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCC(O)(Cc2ccc(C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(CC2(O)CCNCC2)cc1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mixture of 4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-carboxylic acid ethylester (70.5 g, 0.25 mol) and sodium hydroxide (26 g, 0.65 mol) in ethanol (350 ml) and water (50 ml) was refluxed for 2 days. Sodium hydroxide (20 g, 0.50 mol) was added and refluxing commenced for another day before cooling to room temperature and evaporating the solvent. The residue was taken up with CH2Cl2 (700 ml) and water (1 l), the organic phase was separated and the water phase extracted with CH2Cl2. The organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was crystallized from n-hexane to give 4-(4-methyl-benzyl)-piperidin-4-ol (34 g, 66%) as an off-white solid, m.p. 118°-121° C. and MS: m/e=206 (M+).