Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(=O)OCC)c(-c2cc(C)ccc2C)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
Diethyl bromoterephthalate (45.2 g, 150 mmol), K2CO3 (41.5 g, 300 mmol), 140 ml of toluene and 140 ml of H2O were placed in the reaction vessel and flushed with argon for 30 minutes. 2,5-Dimethylbenzeneboronic acid (24.8 g, 165 mmol) (cf. B3) and Pd(PPh3)4 (0.7 g, 0.6 mmol) were subsequently added under protective gas. The brownish mixture, which was turbid as a result of phase separation, was stirred vigorously under a blanket of protective gas at an internal temperature of 85° C. The reaction was complete after 24 hours (according to TLC). After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The product was obtained as a yellow oil in satisfactory purity (greater than 97%). Yield: 48.7 g (99%).
Reaction SMILES: [CH2:1]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1.[ClH:15]>C(O)(=O)C.[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[ClH:15].[CH2:1]1[CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)cc1n2CCCNC1
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CC1CNCCCN21

Procedure:
A solution of 18.4 g of 2,3,4,5,-tetrahydro-1H-1,4-diazepino[1,2-a]indole (m.p. 75°-77°) in 200 ml of acetic acid and 45 ml of 2N hydrochloric acid is hydrogenated, at 60° and normal pressure, with 13 g of 5% of palladium/barium sulphate. The mixture is cooled, filtered and evaporated to give 2,3,4,5,11,11a-hexahydro-1H-1,4-diazepino[1,2-a]indole. Hydrochloride, m.p. 234° (from ethanol).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][C@@H:8]([O:10][CH2:11][CH2:12][CH3:13])[CH3:9])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:17])=O>>[CH3:1][C@H:2]([CH2:6][CH2:7][C@@H:8]([O:10][CH2:11][CH2:12][CH3:13])[CH3:9])[C:3]([Cl:17])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCO[C@@H](C)CC[C@H](C)C(=O)O
Product: CCCO[C@@H](C)CC[C@@H](C)C(=O)Cl

Procedure:
The (2S,5S)-2-methyl-5-propoxyhexanoic acid prepared above was reacted with oxalyl chloride to obtain (2R,5S)-2-methyl-5-propoxyhexanoic acid chloride. The title compound was prepared in the same manner as in Example 9 from the acid chloride obtained above and the corresponding core-compound, 4-octyloxyphenyl 4'-hydroxy-4-biphenylcarboxylate.
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.FC(F)(C(F)(F)F)C(F)(F)C1C=CC(Br)=CC=1.[C:35]1([CH3:46])[CH:40]=[CH:39][C:38]([C:41]2[N:45]=[CH:44][NH:43][N:42]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=CC=2O)C=CC=1.[NH4+].[OH-]>CN(C=O)C.O.[Cu]I>[F:11][C:3]([F:12])([C:4]1[CH:9]=[CH:8][C:7]([N:43]2[CH:44]=[N:45][C:41]([C:38]3[CH:39]=[CH:40][C:35]([CH3:46])=[CH:36][CH:37]=3)=[N:42]2)=[CH:6][CH:5]=1)[C:2]([F:17])([F:1])[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(F)(F)C(F)(F)c1ccc(I)cc1
Reactant: Cc1ccc(-c2nc[nH]n2)cc1
Agent: [Cu]I
Agent: FC(F)(F)C(F)(F)C(F)(F)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncn(-c3ccc(C(F)(F)C(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 125 °C
Yield: 39 %

Procedure:
Heptafluoropropyl-1-iodopropane (3.14 g, 10.6 mmol), 1-iodo-4-bromobenzene (2.0 g, 7.07 mmol), and copper (powder: 1.123 g, 17.7 mmol) were combined in 16 mL of DMSO in a 20 mL microwave tube, and the solution was stirred and heated at 175° C. for 90 min. The cooled solution was then extracted with 2×30 mL of hexanes, and the combined organic layer was washed with water, dried and concentrated to give 2.0 grams of a yellow oil. This crude material, which consisted of a mixture of 4-heptafluoropropyl-iodobenzene and 4-heptafluoropropyl-bromobenzene, was combined with 3-(p-tolyl)-1H-1,2,4-triazole (1.0 g, 6.28 mmol), cesium carbonate (6.14 g, 18.9 mmol), CuI (0.12 g, 0.63 mmol), and quinolin-8-ol (0.091 g, 0.63 mmol) in 16 mL of 90:10 DMF-water, and the solution was heated to 125° C. for 8 hrs. The cooled solution was then poured onto 60 mL of a 2N aqueous NH4OH solution, and the resulting precipitate was filtered and air-dried. This material was heated in 50 mL of MeOH, filtered, and the filtrate diluted with 30 mL of water. The resulting solid was filtered and air-dried to give 1-(4-(perfluoropropyl)phenyl)-3-(p-tolyl)-1H-1,2,4-triazole as a white solid (1.03 g, 39%): mp 140-143° C.; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.10 (d, J=8.1 Hz, 2H), 7.94 (d, J=8.9 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H), 7.30 (dt, J=8.0, 0.7 Hz, 2H), 2.43 (s, 3H); ESIMS m/z 405 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.NS(O)(=O)=O.[C:24]([O:30][CH3:31])(=[O:29])[CH2:25][C:26]([CH3:28])=O>CCOC(C)=O>[CH3:28][C:26]1[C:25]([C:24]([O:30][CH3:31])=[O:29])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:1]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: NS(=O)(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 2-amino-5-nitrobenzophenone (1 g, 4.1 mmol), H2NSO3H (0.04 g, 041 mmol) and methyl acetoacetate (1.11 ml, 10.3 mmol) was stirred overnight at 120° C. under N2, than cooled to room temperature, diluted to 100 ml with EtOAc and washed with H2O. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from EtOH to give pure product as a creamy solid (1.05 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=2.5 Hz, 1H), 8.48 (dd, J=2.5, 9.2 Hz, 1H), 7.53(m, 3H), 7.34(m, 2H), 3.59(s, 3H), 2.8(s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CC(C)(C)C(Cl)=O.Cl.[CH3:36][NH:37][O:38][CH3:39]>C(Cl)Cl>[CH3:36][N:37]([O:38][CH3:39])[C:16](=[O:18])[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionic acid (2.6 grams, 10 mmol, from Step A) and DIEA (4.4 mL, 25 mmol) in 50 mL CH2Cl2 was cooled to 0° C. Trimethylacetyl chloride (1.4 mL, 11 mmol) was added and the mixture was stirred for 1 h. Solid N,O-dimethylhydroxylamine hydrochloride (1.4 grams, 15 mmol) was added and the mixture was warmed to rt and stirred for 16 h. The solvent was removed and the product was purified by flash chromatography (125 grams silica, 2/1 hexane/EtOAc eluant) to give 1.5 grams (50%) of the title compound. 1H NMR (300 MHz, CDCl3). δ1.05-1.18 (m, 2H), 1.45 (s, 9H), 1.53-1.75 (m, 4H), 2.4-2.5 (t, 2H), 2.6-2.77 (m, 2H), 3.18 (s, 3H), 3.63 (s, 3H), 4.0-4.15 (m, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][CH2:10][NH2:11])[N:5]=1.[OH-].[Na+].[C:14](=S)=[S:15].ClC(OCC)=O>O.C(O)C.C(O)(=O)C>[CH3:3][C:4]1[N:5]=[C:6]2[N:7]([C:14](=[S:15])[NH:11][CH2:10][CH2:9]2)[N:8]=1
Reactant: Cc1nc(CCN)n[nH]1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1nc2n(n1)C(=S)NCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.99 g (10 mmol) of 2-(5-methyl-1,2,4-triazol-3-yl)ethanamine dihydrochloride in a mixture of 13 mL of water and 7 mL (35 mmol) of 5N sodium hydroxide aqueous solution was stirred under nitrogen at room temperature as a solution of 5.4 mL of carbon disulfide in 30 mL of dry ethanol was added dropwise over about 30 minutes. After 5 h, the excess carbon disulfide was removed by rotary evaporation. The resulting solution was stirred under nitrogen at room temperature as 1.08 mL (1.23 g, 11 mmol) of ethyl chloroformate was added dropwise over about 10 minutes. Stirring at room temperature was continued overnight. The solution was partially concentrated to remove the ethanol, resulting in precipitation. The pH was made slightly acidic by addition of acetic acid. Then the solid was collected on a filter, washed with a small volume of water, and dried to give the title compound as a solid. LC-MS 169 (M+1).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:14][C:8]4[CH:7]=[C:6]5[C:11](=[CH:10][CH:9]=4)[NH:12][C:13]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]5=4)=[O:28])[CH2:25][CH2:26]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: Nc1ccc2[nH]c3c(c2c1)CCCC3
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2[nH]c3c(c2c1)CCCC3)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
2,3,4,9-Tetrahydro-1H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol) were dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL, 1.32 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (183 mg, 0.482 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 70° C. The solvent was evaporated and the crude product was then purified on 40 g of silica gel utilizing a gradient of 5-50% ethyl acetate in hexanes to yield 1-(benzo[d][1,3]-dioxol-5-yl)-N-(2,3,4,9-tetrahydro-1H-carbazol-6-yl)cyclopropanecarboxamide as a beige powder (0.115 g, 70%) after drying. ESI-MS m/z calc. 374.2, found 375.3 (M+1)+. Retention time of 3.43 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.39 (s, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.10-6.89 (m, 5H), 6.03 (s, 2H), 2.68-2.65 (m, 2H), 2.56-2.54 (m, 2H), 1.82-1.77 (m, 4H), 1.41-1.34 (m, 2H), 1.04-0.97 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:27][CH:26]=4)[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]5[CH2:35][CH2:36][CH2:37][CH2:38]5)=[CH:27][CH:26]=4)[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 2 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzyl)-carbamic acid tert-butyl ester (1.78 g, 3.37 mmol) was dissolved in dichloromethane (20 ml). Trifluoroacetic acid (20 ml) was added and the reaction was stirred for 2 hours. Neutralisation was performed by adding saturated aqueous sodium hydrogencarbonate. The aqueous phase was extracted twice with dichloromethane, and the combined organics washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired compound. Yield: 460 mg, 32%. 50 mg was purified by preparatory HPLC.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2.[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18])[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]c1=O
Temperature: 0 °C
Yield: 50.6 %

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). 6-Trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (200 mg, 0.869 mmol) was dissolved in 8 mL of concentrated H2SO4 and the yellow-green solution was cooled to 0° C. with stirring. To this was added in small portions KNO3 (87.8 mg, 1.10 mmol). The reaction was allowed to stir 1 h at 0° C. and then was allowed to come to room temperature and stir overnight. The brown-orange reaction mixture was then poured into 10 mL ice H2O. The product was isolated by vacuum filtration as pale yellow crystals which were rinsed with a small amount of cold H2O and air dried. The crystals were further dried under vacuum (0.1 torr, 25° C.) to yield 121.1 mg (50.6% yield). 1H NMR (d6 -DMSO) δ 7.53 (s, 1H, ArH), 7.80 (s, 1H, ArH), 12.4 (s, 2H, NH). EIMS m/z 275 (81, M+), 217 (36), 201 (100, bp), EIHRMS calc. for C9H4N3O4F3 275.0153, found 275.0170.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[C:27]([Mg]Br)([CH3:29])=[CH2:28]>C(OCC)C>[C:27]([CH:6]1[N:7]2[CH2:20][CH2:19][C:18]3[C:13]([C:8]2=[CH:9][C:10]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[C:5]1=2)=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=3)([CH3:29])=[CH2:28]
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Product: C=C(C)C1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added isopropenylmagnesium bromide solution (0.5 M in tetrahydrofuran, 52 mL, 26 mmol) dropwise. After stirring at 0° C. for 2 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-isopropenyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (500 mg, 98%). LC/MS m/e calcd for C23H23NO4 (M+H)+: 378.44, observed: 378.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.72-2.83 (m, 2 H) 3.00-3.09 (m, 1 H) 3.12-3.20 (m, 1 H) 3.71 (s, 3 H) 3.77 (s, 3 H) 4.61 (s, 1 H) 4.92 (d, J=1.52 Hz, 1 H) 5.19 (s, 1 H) 5.80 (s, 1 H) 6.00 (d, J=2.27 Hz, 2 H) 6.69 (d, J=8.59 Hz, 1 H) 6.77 (s, 1 H) 6.85 (d, J=8.34 Hz, 1 H) 7.23 (s, 1 H).
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][CH2:10][C:11]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1>CCOCC.CO.C(OC(C)C)(C)C.CCOCC>[OH:8][CH2:9][CH2:10][C:11]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1
Reactant: Clc1ccc(C2(CCOC3CCCCO3)CCCNC2)cc1Cl
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: CCOCC
Product: OCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
A saturated solution of hydrogen chloride in ether is added to a solution of 55 g of 3-(2-tetrahydropyranyloxyethyl)-3-(3,4-dichlorophenyl)piperidine in 200 ml of methanol until the pH is 1. The mixture is stirred for half an hour at room temperature and concentrated to dryness, the residue is taken up in water, rendered alkaline with a solution of NaOH and extracted with CH2Cl2 and the extract is washed with a saturated solution of NaCl, dried over Na2SO4 and evaporated to dryness to give an oil. This oil is taken up in 200 ml of an isopropyl ether/ether mixture (50/50 v/v). After stirring and filtration, the product is washed with ethyl ether and dried under vacuum over P2O5 to give 45 g of the expected product. M.p.=122° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[F:26][CH:27]([F:37])[CH2:28][N:29]([CH3:36])[C@@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:37][CH:27]([F:26])[CH2:28][N:29]([CH3:36])[C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1
Reactant: CN(CC(F)F)[C@@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@@H](N(C)CC(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N-(2,2-difluoroethyl)-N-methylpiperidin-3-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.58 (m, 1 H) 1.61-1.94 (m, 2 H) 1.97-2.07 (m, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.54-2.87 (m, 3 H) 3.11 (br. s., 3 H) 3.40-3.97 (m, 2 H) 4.20-4.76 (m, 1 H) 6.03-6.58 (m, 1 H) 7.64 (br. s., 1 H) 7.68-7.80 (m, 1 H) 7.94-8.62 (m, 4 H). ESI-MS m/z [M+H]+ 499.3.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.CN(C)CCN=C=NCC.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:9])=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: CSc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(methylthio)benzoic acid (6.76 g, 40.2 mmol) and N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (9.24 g, 48.2 mmol) in THF (100 mL) was added morpholine (4.2 mL, 48.2 mmol). After stirring for 2 hours, the reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and 2M hydrochloric acid (150 mL). The organic phase was separated, washed with 1M aqueous sodium carbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound LC retention time 3.52 mins MS m/z 238 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH2:18][Cl:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].C(OC(C)C)(C)C.CCCCCC>ClCCl.C1(OC)C=CC=CC=1>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][Cl:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (3 g) in dichloromethane (6 ml) and anisole (3 ml) was added dropwise trifluoroacetic acid (6 ml) at 0° C. The mixture was stirred at 0° C. for two hours. The mixture was poured into a chilled mixture of diisopropyl ether and n-hexane (1:1, V/V). The precipitates were collected by filtration and dried under reduced pressure to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (2.50 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:14].O1CCCC1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>CCCCCC>[CH2:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:30])[OH:26])=[C:3]([CH3:14])[CH:4]=1)([OH:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(B(O)O)c(C)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-methylphenyl)pentan-3-ol (19.4 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 23.3 cm3 (58 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the mixture for approximately 2 h with stirring at −70° C. and then add dropwise 13.5 cm3 of triisopropyl borate (58 mmol), over 20 minutes. Leave the mixture with stirring for 3 h, allowing the temperature to increase to −10° C. Hydrolyse the mixture with saturated NH4Cl solution and extract two times with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and dry them over sodium sulfate. Evaporate the solvents under vacuum. This gives 5 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=9/1) to give 4-(1-ethyl-1-hydroxypropyl)-2-methylphenylboronic acid in the form of a highly viscous oil. (Yield=71%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>CCOCC>[C:13]1([C:19]2[CH:20]=[CH:21][C:22]([C:23](=[O:24])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:26][CH:27]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: Brc1ccccn1
Reactant: O=C(O)c1ccc(C2=CCCCC2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccc(C2=CCCCC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
40 g of 2-bromopyridine in 50 ml of absolute ether are added dropwise slowly at -60° C with stirring and in a nitrogen atmosphere to 175 ml of a 1.5 N solution of butyl-lithium in ether, followed, 15 minutes after the completion of the addition, by a solution of 15 g of p-(1-cyclohexenyl)-benzoic acid in 250 ml of absolute ether. The cooling bath is then removed, the reaction mixture is allowed to warm up to room temperature and it is stirred for 2 hours at room temperature. Working up is carried out by pouring the reacton solution onto a mixture of ice and ammonium chloride and partitioning it between ether and water. The ether phase is separated off and washed successively with water, 0.1 N sodium hydroxide solution and water, dried over sodium sulphate and evaporated under reduced pessure. Distillation under reduced pressure of the evaporation residue yields, in the fraction boiling at 200° C (0.9 mm Hg), crude 2-{[p-(1-cyclohexenyl)-phenyl]-oxomethyl}-pyridine of the formula ##STR3## of melting point 58°-60° C.