Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].[CH:37](=O)[CH:38]([CH3:40])[CH3:39].[BH4-].[Na+]>CO>[Cl:18][C:13]1[C:12]([OH:19])=[C:11]([S:8]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[C:3]([CH2:2][NH:1][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[C:15]([Cl:17])[CH:14]=1
Reactant: NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: CC(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
N-(3-(Aminomethyl)benzyl)-3,5-dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxybenzenesulfonamide (1.0 g, 1.8 mmol, 1.0 eq) was dissolved in dry methanol. The solution was stirred for 10 minutes and treated with isobutyraldehyde (145 mg, 2 mmol, 1.1 eq). The resulting mixture was stirred for 10 minutes at ambient temperature, refluxed for 3 h, cooled to 0° C. and treated with NaBH4 (210 mg, 5.5 mmol, 3 eq). The mixture was stirred for 30 min at 0° C., quenched by the addition of 10% aq. NaHCO3 solution and stirred for 1 h at ambient temperature. The solvent was evaporated under reduced pressure and ethyl acetate was added. The organic layer was washed with water and dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (240-280) column chromatography using 10-20% ethyl acetate/hexane as the eluent to afford the desired product (1 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 0.92-0.94 (s, 6H), 2.0 (t, 1H), 2.67-2.69 (d, 2H), 4.0 (s, 2H), 4.43-4.44 (s, 4H), 7.15-7.16 (d, 2H), 7.22-7.30 (m, 6H), 7.35 (s, 1H), 7.48-7.53 (d, 2H), 7.63-7.64 (d, 1H), 7.65-7.67 (t, 2H). MS (ESI): 602.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:19]=[N:18][C:13]4[O:14][CH2:15][CH2:16][NH:17][C:12]=4[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(N(CC)CC)C.O>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([C:24]([N:17]2[CH2:16][CH2:15][O:14][C:13]3[N:18]=[CH:19][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)=[CH:11][C:12]2=3)=[O:25])[CH:27]=[C:28]([Br:32])[C:29]=1[O:30][CH3:31]
Reactant: c1cc(-c2cnc3c(c2)NCCO3)c2cc[nH]c2c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc5[nH]ccc45)cc32)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 10 ml flask, 7-(1H-indol-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (130 mg, 0.52 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (204 mg, 0.62 mmol) were dissolved in dichloromethane. Triethylamine (0.36 ml, 2.59 mmol) was added thereto and then stirred at room temperature for 3 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(1H-indol-4-yl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (129 mg, 64% in two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18]([OH:25])=[C:19]([C:22](=O)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]>CO>[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18](=[O:25])[C:19](=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)c([N+](=O)[O-])c2)C(=O)OC1=O

Procedure:
Following the procedure of Example 1, 3 g. (0.0195 mol) of 4-amino-2-nitrophenol is added to a refluxing solution of 4.1 g. (0.0195 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol and the mixture is refluxed for about two hours. Filtration of the reaction mixture yields 5-acetyl-4-hydroxy-3-[1-(3-nitro-4-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 236°-237° C. (dec.).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[CH:15]=1)=O.Br[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:15]1[N:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[NH2:5]
Reactant: Brc1nc2ccccc2s1
Reactant: O=C(Nc1cn2cc(F)ccc2n1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1nc2ccc(F)cn2c1-c1nc2ccccc2s1
Temperature: 100 °C

Procedure:
2,2,2-Trifluoro-N-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-acetamide (compound c, 6 g, 0.02 mol), 2-bromo-1,3-benzothiazole (6.8 g, 32 mmol), potassium carbonate (7000 mg, 0.05 mol), and triphenylphosphine (1000 mg, 0.005 mol) were diluted with 60 ml of a 2:1 solution of dioxane/ethanol and treated with palladium acetate (500 mg, 0.002 mol). The reaction was heated at 100° C. overnight. The reaction was cooled and resulting solid was filtered and washed with dichloromethane then dried to give 3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-amine as a yellow solid. Rf 0.37, 70% ethyl acetate/hexanes; MS m/z 285 (M+H).
Reaction SMILES: [CH3:1][C:2]12[CH2:13][CH2:12][C:9]([CH3:14])([CH2:10][CH2:11]1)[C:8]1[CH:7]=[CH:6][C:5]([OH:15])=[CH:4][C:3]2=1.[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[C:5]([OH:15])=[CH:4][C:3]2[C:2]3([CH3:1])[CH2:13][CH2:12][C:9]([CH3:14])([C:8]=2[CH:7]=1)[CH2:10][CH2:11]3
Reactant: CC12CCC(C)(CC1)c1cc(O)ccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: CC12CCC(C)(CC1)c1cc(Br)c(O)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,8-dimethyltricyclo[6.2.2.02,7]dodeca-2(7),3,5-trien-4-ol (Compound 2, 1.58 g, 7.81 mmol) in 10 mL of glacial acetic acid was added bromine (0.40 mL, 7.81 mmol). The reaction mixture was stirred at 25° C. for 4 hours then quenched with 10% Na2S2O3 and extracted with Et2O. The combined ether extracts were washed with water and brine, and dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:hexane (2:98) to yield the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:20]([C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:21])=[O:22])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with methyl 3-(chlorosulfonyl)thiophene-2-carboxylate to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 8.58 (s, 1H), 7.43 (dd, J=5.1 & 10.8 Hz, 2H), 7.35 (dd, J=1.8 & 10.2 Hz, 1H), 7.31 (ddd, J=2.1, 4.2 & 9.3 Hz, 1H), 7.04 (m, 2H), 5.88 (dt, J=2.7, 8.7 & 17.4 Hz, 1H), 5.65 (br s, 1H), 3.85 (s, 3H).
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[C:3]=1[CH3:49].C(O[C@@H](C1C(C)=C(C2C=CN=CC=2)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)O[C:73]2[CH:74]=[CH:75][C:76]([F:99])=[CH:77][C:78]=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:45]([O:44][C@@H:39]([C:4]1[C:3]([CH3:49])=[C:2]([C:73]2[CH:78]=[CH:77][C:76]([F:99])=[CH:75][CH:74]=2)[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:34])=[CH:19][C:18]=2[C:25]2[CH:26]=[C:27]3[CH:33]=[CH:23][CH:24]=2)[CH2:8][CH2:7]1)[C:40]([O:42][CH3:43])=[O:41])([CH3:46])([CH3:47])[CH3:48]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(-c2ccncc2)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(-c2ccc(F)cc2)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 66.7 %

Procedure:
Prepared in 66.7% yield from methyl(2S)-2-[(22S)-5-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(pyridin-4-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 752.4.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:13]=[C:12]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=1.[N+:19]([C:22]1[CH:23]=[C:24]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)([O-:21])=[O:20]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[N:37]1([C:24]2[CH:25]=[C:26]([C:8]3[N:13]=[C:12]([C:14]4([OH:18])[CH2:17][CH2:16][CH2:15]4)[CH:11]=[CH:10][CH:9]=3)[CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: OC1(c2cccc(Br)n2)CCC1
Reactant: CC1(C)OB(c2cc(N3CCOCC3)cc([N+](=O)[O-])c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2cccc(C3(O)CCC3)n2)cc(N2CCOCC2)c1
Temperature: 100 °C

Procedure:
Pd(dppf)Cl2-dichloromethane adduct (40.8 mg, 0.05 mmol) and sodium carbonate (2 N, 1.5 mL, 3.0 mmol) were added to 1-(6-bromopyridin-2-yl)cyclobutanol (228 mg, 1.0 mmol) and 4-[3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (0.2 N in DMF, 5.0 mL, 1.0 mmol) and the reaction mixture was purged and flushed with N2(g) (3×). The reaction mixture was heated to 100° C. for 4 hours, then cooled to room temperature, diluted with water, extracted with diethyl ether, washed with brine, dried over sodium sulfate, filtered an concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate:hexanes) to afford 1-{6-[3-(morpholin-4-yl)-5-nitrophenyl]pyridin-2-yl}cyclobutanol. 1H NMR (500 MHz, CDCl3) δ 8.30-8.23 (m, 1H), 7.98-7.95 (m, 1H), 7.93, (t, J=7.2 Hz 1H), 7.79 (t, J=2.2, 1H), 7.74 (d, J=7.8, 1H), 7.66 (d, J=7.8, 1H), 5.36 (s, 1H), 4.03-3.84 (m, 4H), 3.46-3.29 (m, 4H), 2.82-2.47 (m, 4H), 2.27-2.09 (m, 1H), 2.05-1.91 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20](=[O:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>[Zn]>[OH:22][C:20]([CH3:21])([CH:19]=[CH:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(=O)C=CCCCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCCc1ccc(OCc2ccccc2)cc1

Procedure:
Using 0.68 g of 7-(p-benzyloxyphenyl)-3-hepten-2-one, 0.37 ml of ethyl bromoacetate and 0.19 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 25 (a) affording 0.84 g of ethyl 3-hydroxy-3-methyl-8-(p-benzyloxyphenyl)-4-octenoate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:4]([Br:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][C:21]=1[CH3:27])[CH3:15].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[CH2:14]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]3[CH2:12][CH2:11]3)[CH:5]=[C:4]([Br:13])[CH:3]=2)=[CH:22][C:21]=1[CH3:27])[CH3:15]
Reactant: Brc1cc(Br)cc(OCC2CC2)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CC3)c2)cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-5-cyclopropylmethoxy-benzene (5.27 g; 17.23 mmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (3 g; 13.26 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.36 g; 0.40 mmol), and 1,1′-bis-(diphenylphosphineo)ferrocene (0.44 g; 0.80 mmol) was added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (7.45 mL) and NMP (8 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (20:1→7:3). Yield 2.8 g; 47%). HPLC-MS: m/z: 451.0 (M+); Rt: 2.85 min
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][CH2:4][CH2:5][C:6]([OH:10])([C:8]#[CH:9])[CH3:7]>C(OC)(C)(C)C>[C:8]([C:6]1([CH3:7])[CH2:5][CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[O:10]1)#[CH:9]
Reactant: C#CC(C)(O)CCC=C(C)C
Solvent: COC(C)(C)C
Product: C#CC1(C)CCCC(C)(C)O1
Reaction time: 0.5 h

Procedure:
A solution of 13.82 g (0.09 mol) of dehydrolinalool (II, R1, R2 and R3 =methyl) in 200 ml of methyl tert.butyl ether was added to 28.35 g of Zeocat® Z6-05-02 and stirred for 30 min. The reaction mixture was evaporated (40° C., 300 mbar) and the resulting solid was subjected to microwave irradiation (600 W power for 4 s). The product was separated from the solid by dissolving in 300 ml acetone and evaporating the solvent in vacuo. The crude 2-ethinyl-tetrahydro-2,6,6-trimethylpyran was obtained in 13.30 g (96.2%) yield as yellowish liquid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.Cl[C:8]1[S:9][CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])[CH2:2]1
Reactant: O[C@@H]1CCOC1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: Nc1ccsc1O[C@@H]1CCOC1

Procedure:
Is prepared in a similar manner as intermediate IV.1 from (3R)-tetrahydrofuran-3-ol and 2-chloro-3-nitro-thiophene
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[C:20](Cl)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>C1COCC1>[Cl:10][C:11]1[C:20]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc2ccccc2nc1Oc1ccccc1
Reaction time: 72 h

Procedure:
A solution of phenol (564 mg, 6 mmol) in THF (5 ml) was added to a suspension of sodium hydride (60% in mineral oil, 240 mg, 6 mmol) in THF (10 ml). After 10 min 2,3-dichloroquinoxaline (995 mg, 5 mmol) was added. The mixture was stirred for 3 days. The solvent was removed in vacuo, the residue was dissolved in EtOAc, washed with NaOH (1M), dried (Na2SO4) and evaporated in vacuo to give a yellow solid. Recrystallisation from diisopropylether gave the title compound as off-white needles: δH (DMSO d6) 8.01-7.98 (1H, m), 7.77-7.67 (3H, m), 7.53-7.48 (2H, m), 7.37-7.30 (3H, m); m/z (EI+, 70V) 257.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.13 M) was added triethylamine (1.5 equiv.) followed by methanesulfonyl chloride (1.3 equiv.). The reaction was allowed to stir at room temperature for 15 h. The solution was then quenched with saturated NaHCO3, extracted with dichloromethane, dried with sodium sulfate, and concentrated to give the crude product in >95% yield. LCMS (m/z): 428.9/328.9 (MH+), LC Rt=3.81 min.
Reaction SMILES: C([S:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=O)C.C[O-].[Na+].CO.[C:18]1([CH:24]([O:31][C:32]([C:34]2[N:39]3[C:40](=[O:80])[C@@H:41]([NH:42][C:43](=[O:79])/[C:44](/[C:66]4[N:67]=[C:68]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[S:69][CH:70]=4)=[N:45]\[O:46][C:47](C4C=CC=CC=4)([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C@H:38]3[S:37][CH2:36][C:35]=2OS(C)(=O)=O)=[O:33])C2C=CC=CC=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C=O.O1CCCC1.O>[C:18]1([CH:24]([O:31][C:32]([C:34]2[N:39]3[C:40](=[O:80])[C@@H:41]([NH:42][C:43](=[O:79])/[C:44](/[C:66]4[N:67]=[C:68]([NH:71][C:72]([O:74][C:75]([CH3:77])([CH3:76])[CH3:78])=[O:73])[S:69][CH:70]=4)=[N:45]\[O:46][C:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C@H:38]3[S:37][CH2:36][C:35]=2[S:4][CH2:5][S:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[O:33])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)SCSc1ccccn1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(OS(C)(=O)=O)CS[C@H]23)cs1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4ccccn4)CS[C@H]23)cs1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 145.8 %

Procedure:
To a solution of 2-acetylthiomethylthiopyridine (249 mg: 1.25 mMol.) in a mixture of dimethylformamide (4 ml) and tetrahydrofuran (2 ml) cooling at -78° C. is added dropwise 1.26N-sodium methoxide-methanol solution (0.87 ml: 1.10 mMol.), and the mixture is stirred at -78° C. for 15 minutes. To this reaction mixture is added a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (971 mg: 1.00 mMol.) in dimethylformamide (2 ml) and the mixture is stirred at -78° C. for 1 hour. The reaction mixture is mixed with 10% hydrochloric acid to stop the reaction, diluted with water, and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=4:1) and silica gel rechromatography (toluene: ethyl acetate=7:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(pyrid-2-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester as colorless foam (753 mg). Yield: 73%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:7][CH:8]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[O:37]=[C:34]1[CH2:35][CH2:36][N:31]([C:28]2[CH:29]=[CH:30][C:25]([NH:24][S:17]([C:15]3[S:16][C:12]([S:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][N:7]=4)(=[O:11])=[O:10])=[CH:13][CH:14]=3)(=[O:19])=[O:18])=[CH:26][CH:27]=2)[CH2:32][CH2:33]1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)c2ccc(C(F)(F)F)cn2)s1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(S(=O)(=O)c4ccc(C(F)(F)F)cn4)s3)cc2)CC1

Procedure:
The title compound was prepared from 5-(5-trifluoromethyl-pyridin-2-sulfonyl)-thiophene-2-sulphonyl chloride and 1-(4-amino-phenyl)-piperidine-4-one (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=4.5 Hz, 4H), 3.52 (t, J=4.5 Hz, 4H), 6.90-7.10 (m, 4H), 7.90 (d, J=1.2 Hz, 1H), 8.41 (d, J=6.3 Hz, 1H), 8.50 (d, J=1.2 Hz, 1H), 8.62 (dd, J=6.3, 1.5 Hz, 1H), 9.23 (s, 1H), 9.89 (s, 1H); MS (ES) m/z: 545.9 (MH+); HRMS Calcd. for C21H19F3N3O5S3 (MH+): 546.0439. Found: 546.0466. Anal. Calcd. for C21H18F3N3O5S3: C, 46.23; H, 3.33; N, 7.70. Found: C, 46.46; H, 3.39; N, 7.35.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[C:3]1[SH:13].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27](=[O:30])[CH2:28][CH3:29])[CH:24]=2)[CH2:19]1>>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[C:3]1[S:13][CH2:15][CH2:16][CH2:17][N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27](=[O:30])[CH2:28][CH3:29])[CH:24]=2)[CH2:19]1
Reactant: Cn1c(S)nnc1-c1cccnc1
Reactant: CCC(=O)c1ccc2c(c1)CN(CCCCl)C2
Product: CCC(=O)c1ccc2c(c1)CN(CCCSc1nnc(-c3cccnc3)n1C)C2

Procedure:
The title compound was prepared in analogy to method 1.5 from 4-methyl-5-pyridin-3-yl-4H-1,2,4-triazole-3-thiol (1.43 mmol, 0.33 g) and 1-[2-(3-chloropropyl)-2,3-dihydro-1H-isoindol-5-yl]propan-1-one (1.43 mmol, 0.36 g; preparation in analogy to 1.4 from isoindoline as disclosed in WO 0125200). Yield: 0.04 g.