Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][CH2:25]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:23][O:24][CH2:25][N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COCCl
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COCN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Reaction time: 3 h

Procedure:
N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.007 M) was stirred at room temperature in a two phase system of toluene-50% sodium hydroxide with 100 mg of phase transfer catalyst (tetra-n-butylammonium hydrogen sulfate). Methoxymethyl chloride (1.2 g, 0.015 M) was added dropwise and the mixture was stirred 3 hours. The layers were separated and the toluene layer was washed several times with water (until the water washes were neutral). The toluene solution was dried over anhydrous magnesium sulfate and the toluene removed under vacuum to afford N-methoxymethyl-N'-t-butyl-N,N'-dibenzoylhydrazine as a thick oil.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:36][N:35]=[N:34][N:29]=3)=[CH:20][CH:21]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 96 h

Procedure:
A mixture of 800 mg of 2-butyl-3-(2'-cyano-biphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]-pyridine, 515 mg of trimethyltin azide and 20 ml of toluene is boiled for 96 hours and evaporated. Chromatography of the residue (silica gel; methylene chloride/-methanol 9:1, then 85:15 and 80:20) yields 2-butyl-4,5-dihydro-4-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]- 3H-imidazo[4,5-c]pyridine, m.p.167°. The corresponding K salt is prepared therefrom in conventional manner.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.C([N:28](CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37].O>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:42]4[C:34]([CH3:33])=[C:35]([CH:39]=[CH:40][CH:41]=4)[C:36]([NH2:28])=[O:37])=[CH:18][CH:17]=3)=[O:23])[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(N)=O)cccc1-c1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.131 g of triethylamine and 0.201 g of 2-methylbenzoyl chloride in 13 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is poured into water and the organic layer separated. The organic layer is washed with 1N HCl, H2O, 1N NaHCO3, brine and dried (Na2 SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the solid crystallized from dichloromethane-hexane to give 0.32 g of crystals, m.p. 187°-189° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:14][C:13]=1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1cc(Oc2cncc(Br)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(Oc2cncc(Br)c2)ccc1N
Yield: 93.2 %

Procedure:
The reaction and post-treatment were carried out according to Example (1b) using tert-butyl {5-[(5-bromopyridin-3-yl)oxy]-2-nitrophenyl}methylcarbamate produced in Example (19a) (11.1 g, 26.2 mmol), iron powder (4.38 g, 78.5 mol), ammonium chloride (0.70 g, 13.1 mmol), ethanol (87 mL) and water (40 mL) to obtain the title compound (9.63 g, 94%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][N:16]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:30])C=CC=CC=1>ClCCl>[CH3:22][S:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)=[O:30]
Reactant: CSc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(S(C)=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-methylsulfanyl-pyridine (70 mg, 0.22 mmol) in dichloromethane (2.1 mL) was added 2-benzenesulfonyl-3-phenyl-oxaziridine (58.5 mg, 0.22 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 1:3) afforded the title compound (70 mg, 95%) as a white solid. MS: m/e=329.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid methyl ester (56 mg, 0.17 mmol) in THF (0.6 mL) was added a solution of lithium hydroxide monohydrate (15 mg, 0.34 mmol) in water (0.6 mL) followed by methanol (0.2 mL) and the resulting mixture stirred at room temperature for 2 h. The mixture was then evaporated and acidified with HCl (1 N) and the mixture cooled to 0° C. for 30 min. A solid formed which was filtered off, washed with water and dried to afford the title compound (41 mg, 76%) which was obtained as a white solid. MS: m/e=310.3 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[CH2:33]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:34]#[CH:35]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:35]#[C:34][CH2:33][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:19]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCc3ccc(Cl)cc3)c2)cc1C

Procedure:
(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (300 mg; 0.56 mmol), 4-prop-2-ynyl-morpholine (280.4 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110° C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 300 mg; 92%. HPLC-MS: m/z: 580.7 (M+H)+; Rt: 2.16 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH4+:16].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH2:16])=[O:7])[CH2:3]1
Reactant: [NH4+]
Reactant: CC1(C)CC(C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
Treat a solution of 3,3-dimethylcyclobutylcarboxylic acid (0.500 g, 3.90 mmol) and oxalyl chloride (0.512 mL, 5.85 mmol) in DCM (30 mL) with catalytic DMF (1 drop), stir at RT for 4 h, concentrate to dryness, add additional DCM and concentrate to dryness again. Dissolve the residue in THF (10 mL), add drop-wise to a solution of NH4OH (2 mL, 51.4 mmol) in THF (20 mL), and stir at RT overnight. Extract with EtOAc (2×), wash the combined organics with brine, dry over MgSO4 and concentrate to dryness to afford the title compound (440 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.07 (s, 1H); 6.63 (s, 1H); 2.86 (m, 1H); 1.85 (m, 2H); 1.74 (m, 2H); 1.10 (s, 3H); 1.00 (s, 3H); MS(ESI) m/z: 128.2 (M+H+).
Reaction SMILES: [N+](=C)=[N-].[CH3:4]COCC.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[ClH:17]>O>[Cl:17][CH2:4][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][Cl:9]
Reactant: Cl
Reactant: O=C(Cl)CCCCCl
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: O
Product: O=C(CCl)CCCCCl
Reaction time: 2 h

Procedure:
In 300 ml of ehter solution of diazomethane prepared from 43 g of p-tosyl-N-methyl-N-nitrosoacetamide was added under stirring 30 ml of ether solution of 8 g of 5-chlorovalerylchloride dropwise at -5° to 0° C., and the solution was allowed to stand at the same temperature for 2 hours. Hydrogen chloride gas was passed through the reaction solution at 0° C. and the solution was allowed to stand at the same temperature for 0.5 hours. To the solution was added 100 ml of water and the ether layer was separated. The aqueous layer was further extracted twice each time with 100 ml of ether. The ether layers were combined and the obtained ether solution was dried over anhydrous magnesium sulfate and the solvent was distilled away and the residue was distilled under reduced pressure to provide 8.2 g of 1,6-dichloro-2-hexanone showing a boiling point of 120° to 125° C. (14 mm Hg). ##STR51##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([OH:34])[CH2:17][O:18][C:19]3[C:27]4[CH:26]=[C:25]([C:28]5[O:29][C:30]([CH3:33])=[N:31][N:32]=5)[O:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[ClH:1].[C:35]([O:34][C@@H:16]([CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:13]1)[CH2:17][O:18][C:19]1[C:27]2[CH:26]=[C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1)(=[O:37])[CH3:36]
Reactant: Cc1nnc(-c2cc3c(OC[C@@H](O)CN4CCC(c5ccc(Cl)c(Cl)c5)CC4)cccc3o2)o1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H](COc1cccc2oc(-c3nnc(C)o3)cc12)CN1CCC(c2ccc(Cl)c(Cl)c2)CC1
Product: Cl
Reaction time: 12 h

Procedure:
(S)-1-(4-(3,4-Dichlorophenyl)piperidino)-3-(2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol (1.0 g) was dissolved in pyridine (20 ml) and acetic anhydride (10 ml), and the mixture was left standing at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol). The obtained oil was dissolved in ethanol and a solution of hydrogen chloride in ether was added. The precipitated crystals were collected by filtration and dried to give the title compound (0.58 g) as pale-yellow crystals, melting point 163-166° C. (decomposition).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH:9]=O>CCO.O.[Pd].C(Cl)Cl>[CH3:6][O:7][CH:8]([O:11][CH3:12])[CH2:9][NH:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCCCNCC(OC)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 101 %

Procedure:
To a solution of butan-1-amine (limiting reagent) in EtOH (5 volumes) was added 2,2-dimethoxyacetaldehyde (60%) in water (1 molar equivalent) and the mixture was stirred at room temp for 4 clays. A slurry of 5% palladium on carbon (0.01 molar equivalent) in EtOH (1 volume) was added and the mixture was hydrogenated at 3 bar pressure for 20 hours. The mixture was filtered through a glass fibre filter paper, washed with EtOH (2×3 volumes) and the mother liquor was carefully concentrated to leave a cloudy brown oil. This oil was dissolved in DCM (15 volumes), dried (Na2SO4), filtered and carefully concentrated in vacuo to leave an orange oil. Yield: 101% of theoretical.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13]Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19](NCC)[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>>[Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13][N:5]([CH2:4][CH2:3][C:19]1[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=1)[CH3:8]
Reactant: CCNc1cc(OC)c(OC)c(OC)c1
Reactant: Cn1ncc(Cl)c(NCCCCl)c1=O
Product: COc1cc(CCN(C)CCCNc2c(Cl)cnn(C)c2=O)cc(OC)c1OC
Reaction time: 2.5 h
Yield: 34 %

Procedure:
On starting from 5-chloro-4-(3-chloropropylamino)-2-methyl-3(2H)-pyridazinone and 3,4,5-trimethoxyphenyl ethyl amine and proceeding according to method c) with the difference that melting is carried out at 140° C. for 2.5 hours the desired compound is obtained with a yield of 34%. Rf =0.6.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].IC.[C:12](=O)([O-])[O-].[K+].[K+].[H-].[Na+]>CC#N.O>[CH3:12][O:6][CH2:5][C:4]1[CH:3]=[C:2]([I:1])[CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cccc(I)c1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: COCc1cccc(I)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a solution of 508 μl (4.0 mmol) of 3-iodobenzylalcohol and 1.25 ml (20.0 mmol) of iodomethane in MeCN (20 ml) there were added 829 mg (6.0 mmol) of potassium carbonate. After stirring 3 h at 30° C., 320 mg (8.00 mmol) of NaH were added and stirring was continued a further 3 h at RT. Water was then added to the reaction mixture, which was extracted with chloroform. The organic phase was successively washed with water and a satd aq. NaCl soln and dried over MgSO4. Following filtration and removal of the solvent in vacuo there were obtained 863 mg (3.5 mmol, 87%) of 3-methoxymethyliodobenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Pd].C(O)C.O1CCOCC1>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccc(C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reaction time: 6 h

Procedure:
A mixture of ethyl [2-methyl-4-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethenyl)phenoxy]acetate (intermediate 19, 0.23 g) and 10% palladium on carbon (0.2 g) in ethanol:1,4-dioxan (1:1, 20 ml) was stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite™ and the filtrate evaporated. The residue was purified by Biotage™ chromatography using a mixture of petroleum ether:ethyl acetate (4:1) as eluent to give the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CCN(CC)CC.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CC(F)(F)F)CC3)c2)c2ccc(F)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 277 mg; 0.63 mmol), Et3N (0.40 mL; 2.87 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (147 mg; 0.63 mmol) in toluene (40 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase flash chromatography to afford 275 mg (84%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:17]([Cl:22])(Cl)(Cl)(Cl)[Cl:18].C(O)=[O:24]>C(Cl)(Cl)(Cl)Cl>[Cl:18][P:17]([Cl:22])([NH:13][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:24]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: NC(=O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1cccc(Oc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
A mixture containing 21.3 g (0.1 mole) of 3-phenoxybenzamide, 20.8 g (0.1 mole) of phosphorus pentachloride and 250 ml of Ar carbon tetrachloride was heated at 70° for 30 min. The resulting solution was cooled to 30° and 4.7 g (0.1 mole) of 97% formic acid added dropwise. Stirring was continued for 20 min., the reaction was filtered, washed with AR carbon tetrachloride and air-dried to give 31 g, m.p. 122°-125°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[OH:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]4[CH2:27][CH2:28][C@@H:24]([OH:23])[CH2:25]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: O[C@@H]1CCNC1
Product: O[C@@H]1CCN(CCCCOc2ccc3c(-c4ccc(Cl)cc4)nsc3c2)C1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and (R)-3-Hydroxypyrrolidine were converted to yield (3R)—1-{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-pyrrolidin-3-ol, MS: 403 (MH+, 1Cl).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=1)=[O:6].C(N([CH2:34][CH3:35])CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:16]([O:15][C:13]([C:35]1[CH:34]=[CH:21][C:22]([O:1][C:2]2[CH:3]=[C:4]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=2)=[O:6])=[CH:2][CH:3]=1)=[O:14])[CH3:17]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reactant: CCN(CC)CC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(C(=O)Nc3ccn(C(=O)OC(C)(C)C)n3)c2)cc1
Yield: 39 %

Procedure:
tert-Butyl 3-({3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoyl}amino)-1H-pyrazole-1-carboxylate (391 mg, 1 mmol), ethyl-4-boronic acid benzoate (388 mg, 2.0 equiv), copper (II) acetate (363 mg, 2.0 equiv) and triethylamine (0.7 mL; 5.0 equiv) were suspended in dry DCM over freshly activated powdered 4A molecular sieves (ca. 1 g) for 7 hours under an ambient atmosphere. Reaction mixture filtered through diatomaceous earth was washed with DCM (×3). Filtrate concentrated in vacuo, taken up in ethyl acetate and washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate, saturated brine and dried (MgSO4). Filtered, filtrate concentrated in vacuo and chromatographed (0-50% ethyl acetate/isohexane) to give a brown oil (210 mg, 39%).
Reaction SMILES: [S:1]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH2:4][CH:3]=[CH:2]1.S1[C@@H]2CC(=[O:18])N2C=CC1>>[S:1]1(=[O:18])[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH:4]=[CH:3][CH2:2]1
Reactant: O=C1C[C@H]2SCC=CN12
Reactant: O=C1C[C@H]2SC=CCN12
Product: O=C1C[C@@H]2N1C=CCS2=O

Procedure:
A ceph-2-em or ceph-3-em reaction product may also be oxidised to yield the corresponding ceph-3-em 1-oxide, for example by reaction with a peracid, e.g. peracetic or m-chloroperbenzoic acid; the resulting sulphoxide may if desired, subsequently be reduced as described hereinafter to yield the corresponding desired ceph-3-em sulphide.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:7])C.Cl>O.O1CCOCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]2[O:10][C:9]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[C:8]([C:5]([OH:1])=[O:7])[C:12]=2[CH:13]=1)#[N:18]
Reactant: [OH-]
Reactant: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(C)=O)cc1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCc2oc3ccc(C#N)cc3c2C(=O)O)cc1
Yield: 34.6 %

Procedure:
5.2 g of sodium hydroxide was dissolved in 30 ml of water, and the solution was cooled to a temperature of 0° C. or below. With stirring, to this were added dropwise 2.7 ml of bromine and then 40 ml of a dioxane solution containing 4.14 g of 3-acetyl-2-[2-(4-methoxyphenyl)ethyl]-5-benzofurancarbonitrile obtained in the above step d). The resulting mixture was stirred at 0° C. for 45 minutes with ice cooling for 1 hour. The resulting reaction solution was mixed with water, adjusted to pH 2 with concentrated hydrochloric acid, and then extracted with chloroform. The resulting organic layer was washed with water and dried to distill off the solvent. Thereafter, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an eluant, thereby obtaining 1.44 g of 5-cyano-2-[2-(4-methoxyphenyl)ethyl]-3-benzofurancarboxylic acid.