Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH:33]([CH2:35][O:36][CH3:37])[O:32][C:31]2=[O:38])=[CH:26][CH:25]=1>CC(CC)=O>[OH:16][CH:14]([CH3:15])[CH2:13][CH2:12][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:34][CH:33]([CH2:35][O:36][CH3:37])[O:32][C:31]2=[O:38])=[CH:28][CH:29]=1
Reactant: COCC1CN(c2ccc(O)cc2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCC1CN(c2ccc(OCCC(C)O)cc2)C(=O)O1
Yield: 70 %

Procedure:
To a solution of 27.5 g (0.112 mol) of 1-tosyloxy-3-butanol in 250 ml of methylethylketone, are added 28.2 g (0.2 mol) of K2CO3 and 22.8 g (0.102 mol) of 3-(4-hydroxyphenyl)-5-methoxymethyl-2-oxazolidinone (code number MD 780232). The mixture is heated under reflux for 4 h 30. After filtration and concentration, the residue is taken up in 200 ml of CH2Cl2, the organic phase is washed with NaCl saturated water, dried over Na2SO4 and concentrated. After purification by flash chromatography (silica, eluent: CH2Cl2 :98;CH3OH:2), the aimed product is obtained with a 70% yield, m.p.: 58° C.;
Reaction SMILES: CC(O)=O.C([N:12]1[CH2:17][CH2:16][C:15]([OH:21])([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[OH:21][C:15]1([C:18]([NH2:20])=[O:19])[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)C1(O)CCNCC1
Reaction time: 14 h

Procedure:
Pd/C (150 mg) and HOAc (2 mL) are added to a solution of 1-benzyl-4-hydroxy-piperidine-4-carboxylic acid amide (2 g, 8.5 mmol) in MeOH. The mixture is shaken under H2 (40 psi) for 14 h. The catalyst is removed by filtration and the solvent is removed in vacuo to give the title product. 1H NMR (CD3OD) 2.96(m, 4H), 2.05(m, 2H), 1.49 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:10]=1.N1C=CC=CC=1.Cl[C:35]([C:37]1[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=1)[CH2:40][S:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:36]>O1CCCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:35]([C:37]2[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=2)[CH2:40][S:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:36])[CH:10]=1)=[O:22]
Reactant: Nc1ccccc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccccc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Yield: 63.3 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-aminophenyl)isonicotinamide (240 mg, 0.65 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and pyridine (77 mg, 0.97 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (194 mg, 0.71 mmol, 1.10 equiv) in tetrahydrofuran (5 mL) with stirring. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched with 30 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over magnesium sulfate. The resulting mixture was concentrated under vacuum to yield 250 mg (64%) of product as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(I)nc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)nc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (62 mg, 0.088 mmol, 0.05 equiv.) was dissolved in 5 ml THF. (500 mg, 1.76 mmol) 5-Bromo-2-iodopyridine and phenylacetylene (216 mg, 2.11 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (0.74 ml, 5.28 mmol, 3 equiv.) and copper(I)iodide (10 mg, 0.053 mmol, 0.03 equiv.) were added and the mixture was stirred for 16 hours at 60° C. The reaction mixture was evaporated to dryness and loaded directly to a silica gel column. The crude product was purified by flash chromatography on a silica gel column eluting with a heptane:ethyl acetate gradient 100:0 to 90:10. The desired 5-bromo-2-phenylethynyl-pyridine (354 mg, 78% yield) was obtained as a light yellow solid, MS: m/e=258.0/259.9 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH3:7])[CH2:5][C:4]([C:14]2[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:21].Cl.C[OH:24]>ClCCl>[CH3:1][N:2]1[CH:6]([CH3:7])[CH2:5][C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[OH:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3]1=[O:21]
Reactant: CO
Reactant: CC1CC(c2ccccc2)(c2ccc(O)cc2)C(=O)N1C
Agent: Cl
Solvent: ClCCl
Product: CC1CC(c2ccccc2)(c2ccccc2O)C(=O)N1C
Temperature: -60 °C

Procedure:
(+/-)-1,5-dimethyl-3-(p-hydroxyphenyl)-3-phenyl-2-pyrrolidone (from Example 1), 1.5 g, was dissolved in 30 mL dichloromethane. The flask was flushed with argon and chilled in an acetone/dry ice bath to -60° C. I M boron tribromide in dichloromethane, 10 mL, was then added drop-wise over 18 min with stirring. The reaction was allowed to come to room temperature and stirred for 22 h. Methanol, 10 mL, was then added slowly to quench the reaction. The resultant solution was rotary evaporated to give an oil redissolved in 10 mL methanol and rotary evaporated a second time. The oil was diluted with 20 mL water to give a precipitate. 6 N hydrochloric acid, 6 mL, was added followed by 50 mL dichloromethane. Mixing gave a biphasic solution. The phases were separated and the upper aqueous phase was reextracted twice with 25 mL portions of dichloromethane. The combined dichloromethane extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to give a foam residue.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:13])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[CH3:36][C:37]1([CH3:45])[C:39]([CH3:41])([CH3:40])[CH:38]1[C:42](O)=[O:43]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:13][C:42]([CH:38]2[C:39]([CH3:41])([CH3:40])[C:37]2([CH3:45])[CH3:36])=[O:43])[S:5][C:6]=1[N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Cc1nc(N)sc1N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)C2C(C)(C)C2(C)C)sc1N1CCOCC1

Procedure:
A mixture of 4-methyl-5-morpholin-4-yl-thiazol-2-ylamine (prepared using the method described in Christopher et al., Bioorganic and Medicinal Chemistry Letters 2004, 14(22), 5521-5525), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, and 2,2,3,3-tetramethylcyclopropanecarboxylic acid were processed using the method described in Example 58 to afford the title compound. MS (ESI+) m/z 324 (M+H)+.
Reaction SMILES: [O-2].[Nd+3:2].[O-2].[O-2].[Nd+3].[Nd].[CH2:7]([CH:9]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][O:11][P:12](=[O:23])([OH:22])[O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:8].CC1CCCCC1.Cl>O>[CH2:7]([CH:9]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][O:11][P:12]([O-:23])([O:13][CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH3:8].[Nd+:2]
Reactant: [Nd+3]
Reactant: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Agent: Cl
Agent: [Nd]
Agent: [O-2]
Solvent: CC1CCCCC1
Solvent: O
Product: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC
Product: [Nd+]
Reaction time: 3 h
Yield: 100 %

Procedure:
3.03 g of neodymium oxide containing 72.4% by weight of neodymium, 17.39 g of di(2-ethylhexyl)phosphoric acid (DEHPA), 80 g of methylcyclohexane (MCH) and 0.9 ml of hydrochloric acid at 1 mol/l are introduced into a reactor made inert beforehand with argon. This amount of hydrochloric acid corresponds to 0.06 molar equivalent of HCl relative to the neodymium. The mixture is stirred and brought to 80° C. for 3 h. The mixture is cooled. Three washes with 20 g of water are successively carried out in order to remove the residues of hydrochloric acid. Each wash comprises a step of stirring for 30 minutes and then a step of separating by settling out, also for 30 minutes, except for the final separating by settling out, which lasts 12 h. The water/MCH azeotrope is subsequently distilled with a Dean Stark apparatus. A clear solution of neodymium di(2-ethylhexyl)phosphate in MCH is thus obtained.
Reaction SMILES: FC1C=C([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)C=CC=1O.C(O)C.[OH-].[K+].CC(CC)CCCCBr>C1(C)C=CC=CC=1.O>[CH2:15]([C:12]1[CH:13]=[CH:14][CH:9]=[N:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc(-c2ccc(O)c(F)c2)nc1
Agent: CCC(C)CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCc1cccnc1
Reaction time: 4 h
Yield: 134.4 %

Procedure:
To this 2-(m-fluoro-p-hydroxyphenyl)-5-octylpyridine (2 g, 0.007 mol) were added ethanol (20 ml), KOH (0.4 g, 0.007 mol) and optically active 5-methylheptyl bromide (1.4 g, 0.007 mol), followed by heating the mixture under reflux with stirring for 4 hours, cooling, adding water and toluene, transferring the mixture into a separating funnel, washing the resulting organic layer with 2N-NaOH aqueous solution, washing with water, distilling off the solvent under reduced pressure and recrystallizing the residue in a freezer to obtain the objective optically active (S)-2-p-5-methyl-heptyloxy-m-fluorophenyl)-5-octylpyridine (1.8 g).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:36][C:37]1[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH2:41])=[O:40].C(O)(C)C>CN(C)C=O.N1C=CC=CC=1>[C:39]([C:38]1[C:37]2[N:36]=[C:17]([C:16]3[CH:15]=[CH:14][C:13]([CH:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:21][CH:20]=3)[NH:46][C:45]=2[CH:44]=[CH:43][CH:42]=1)(=[O:40])[NH2:41]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)cc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Reaction time: 0.5 h

Procedure:
N-Boc-4-pyrrolidin-2-ylbenzoic acid (0.29 g) in dimethylformamide (DMF, 1 mL) and pyridine (1 mL) at 40° C. was stirred for 10 minutes, treated with CDI (0.17 g) stirred for 30 minutes, treated with 2,3-diaminobenzamide dihydrochloride (0.22 g), stirred at ambient temperature for 3.5 hours, treated with isopropanol (2 mL), stirred at ambient temperature for 16 hours, treated with isopropanol (5 mL) and hexanes (40 mL) and decanted. The residue was stirred in water (3 mL) at ambient temperature with 2 drops 50% NaOH for 5 hours and filtered. The filtrant was stirred in acetic acid (3 mL) at reflux for 7.5 hours, cooled and concentrated. The concentrate was stirred in dichloromethane (5 mL) and hexane (15 mL) and filtered. 1H NMR (DMSO-d6) δ 13.35 (br, 1H), 9.35 (br, 1H), 8.18 (br d, J=7.8 Hz, 2H), 7.87 (d, J=7.4 Hz, 1H), 7.75 (br, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.40 (br d, J=8.5 Hz, 2H), 7.34 (t, J=7.8 Hz, 1H), 4.79 (brm, 1H), 3.55 (m, 2H), 2.36 (m, 1H), 1.80 (m, 3H), 1.41 (s, 4H), 1.12 (s, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[CH:9]N(C)C)[C:6](=O)[CH3:7])[CH3:2].Cl.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[N:22][N:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[C:6]=1[CH3:7])=[O:13])[CH3:2]
Reactant: NNc1ccncc1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2ccncc2)c1C
Yield: 76 %

Procedure:
Dissolve 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (0.550 g, 2.96 mmol), pyridin-4-yl-hydrazine hydrochloride (0.454 g, 3.12 mmol) and triethylamine (0.435 mL, 3.12 mmol) in ethanol (12 mL) and reflux for 2 hr. Evaporate the mixture then dilute with saturated sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate) the solution, filter and concentrate. Purify using silica gel chromatography, eluting with 50:50 ethyl acetate:hexane to give 5-methyl-1-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester as a tan solid (0.520 g, 76%). MS (ES): m/z=232 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH:4]([OH:5])=[O:3].[CH:28]1[C:19]2[CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH2:23][N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN2Cc3ccccc3Cc3ccccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN2Cc3ccccc3Cc3ccccc32)C1
Product: O=CO
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
The above ester (1.0 g, 2.4 mmol) was dissolved in ethanol (25 ml) and a 2 N aqueous sodium hydroxide solution (4.7 ml) was added. The mixture was heated at 50° C. with stirring for 2.5 h. The volatiles were evaporated in vacuo and dichloromethane (100 ml) was added to the residue. The mixture was cooled on an ice-bath and a concentrated aqueous hydrochloric acid solution (1.2 ml) was added dropwise with vigorous stirring. The phases were separated and the organic phase was dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue re-evaporated several times with acetone.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:18][C:19]([N:21]2C=CN=[CH:22]2)=[O:20])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.I.NC[CH2:29][C:30]([NH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:31]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:18][C:19](=[O:20])[NH:21][CH2:22][CH2:29][C:30]([NH:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:31])[S:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: NCCC(=O)Nc1cccnc1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(-n2cccn2)cc1
Agent: I
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)NCCC(=O)Nc2cccnc2)sc1-c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of imidazole-1-carboxylic acid [4-methyl-5-(4-pyrazol-1-yl-phenyl)-thiazol-2-yl]-amide (Intermediate A1) (0.1 g, 0.28 mmol) and 3-amino-N-pyridin-3-yl-propionamide hydroiodide (Intermediate B2) (0.083 g, 0.28 mmol) in dry DMF (1 ml) is treated with TEA. After stirring at room temperature for 1 hour, the solvent is removed in vacuo and purification of the crude residue by chromatography on silica eluting with EtOAc/EtOH (10:1 increasing to 5:1) affords a solid which is recrystallised from EtOAc/EtOH to yield the title compound. [MH+ 448.49]
Reaction SMILES: C([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[C:11]([F:17])[CH:10]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[F:17][C:11]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:18])=[O:5])[CH:14]=[CH:13][C:12]=1[CH:15]=[O:16]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1ccc(C=CC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.3 %

Procedure:
3-(3-fluoro-4-formyl-phenyl)-acrylic acid tert-butyl ester (2 g, 8 mmol) was dissolved in DCM (23 ml) and trifluoroacetic acid (6 ml). The mixture was stirred at room temperature for 6 h then the solvent was evaporated under vacuo giving 1.62 g of 3-(3-fluoro-4-formyl-phenyl)-acrylic acid
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[S:6](=[O:8])(=[O:7])[C@@H:5]2[C:9](Br)(Br)[C:10](=[O:11])[N:4]2[C@H:3]1[C:14]([OH:16])=[O:15].C(=O)(O)[O-].[Na+]>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[S:6](=[O:7])(=[O:8])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)N2C(=O)C(Br)(Br)[C@H]2S1(=O)=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Reaction time: 1 h
Yield: 58 %

Procedure:
The ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide from Preparation K was combined with 705 ml. of saturated aqueous sodium bicarbonate solution and 8.88 g. of 5% palladium-on-carbon catalyst. The mixture was shaken under an atmosphere of hydrogen, at a pressure of about 5 kg/cm2 for about 1 hour. The catalyst was removed by filtration, and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride. The layers were separated and the aqueous phase was extracted with further ethyl acetate (3×200 ml.). The combined ethyl acetate solutions were dried (MgSO4) and evaporated in vacuo to afford 33.5 g. (58% yield from 6-aminopenicillanic acid) of penicillanic acid 1,1-dioxide. This product was dissolved in 600 ml. of ethyl acetate, the solution was decolorized using activated carbon and the solvent was removed by evaporation in vacuo. The product was washed with hexane. This afforded 31.0 g. of pure product.
Reaction SMILES: C1COCC1.[H-].[Na+].[C:8]([O:12][CH3:13])(=[O:11])[CH2:9][OH:10].[F:14][C:15]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>O>[F:14][C:15]1[CH:20]=[C:19]([O:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cc(F)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To 20 ml of THF, 0.24 g (60 mmol) of 60% sodium hydride was suspended under cooling with ice, and 0.32 g (6.6 mmol) of methyl glycolate, was added thereto, followed by stirring for 15 minutes. To this mixture, 2 g (6.0 mmol) of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluormethyl-2(1H)-pyridone was added, followed by stirring at room temperature for 3 hours. The product was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. After distilling off ethyl acetate under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 1.57 g (yield: 65%) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.Br[CH2:23][CH2:24][N:25]=[C:26]=[O:27].[H-].[Na+].Cl>ClCCl>[O:27]=[C:26]1[NH:25][CH2:24][CH2:23][N:1]1[CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1
Reactant: O=C=NCCBr
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CN1CCNC1=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice-cooled solution of 302 mg (0.99 mmol) of the compound from Example 101A in 10 ml of dichloromethane was admixed dropwise with 99 μl (1.09 mmol) of 2-bromoethyl isocyanate. After 10 minutes, the ice bath was removed and the mixture was stirred for a further 5 min. All of the volatile components were removed on a rotary evaporator. The residue was taken up in 5 ml of anhydrous THF and admixed, with ice cooling, with 44 mg of sodium hydride (60% in mineral oil, 1.09 mmol). After 2 h, 1 ml of 1M hydrochloric acid was added and the reaction mixture was freed from the solvent on a rotary evaporator. The aqueous residue was dissolved in DMSO and purified by preparative HPLC [Method 23]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 210 mg (38% of theory) of the title compound.
Reaction SMILES: C(O)=O.[C:4]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.BrC[CH2:20][CH2:21][CH2:22][C:23]1C=[CH:32][CH:31]=[C:25]2[C:26]([NH:28][C:29](=[O:30])[C:24]=12)=O.C(N(CC)CC)C.O.[CH2:42]([OH:44])[CH3:43]>>[C:4]([N:12]1[CH2:17][CH2:16][N:15]([CH2:32][CH2:31][CH2:25][CH2:26][N:28]2[C:42](=[O:44])[C:43]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:24]3[C:29]2=[O:30])[CH2:14][CH2:13]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: O=C(c1ccccc1)N1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C

Procedure:
A solution of 5.0 g (21.16 mmol.) of 1-benzoylpiperazine formate, 5.97 g (21.16 mmol.) of 4-bromobutylphthalimide and 9.0 ml (64.57 mmol.) of triethylamine in ethanol (50 ml) was heated for 40 hours under reflux. The reaction mixture was cooled to room temperature, to which was added water. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, which was then dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure to leave a crude product. The crude product was purified by means of a column chromatography (methanol/ethyl acetate 5-10%). The solvent was distilled off under reduced pressure to give N-[4-(4-benzoylpiperazin-1-yl)butan-1-yl]phthalimide (6.99 g) as yellow oil. To a solution of 6.99 g of this compound in ethanol (50 ml) was added, at room temperature, 1.34 g (26.8 mmol.) of hydrazine monohydrate. The mixture was heated for 2 hours under reflux. The reaction mixture was cooled to room temperature. The resulting white solid substance was filtered off, and the filtrate was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure to leave crude 4-(4-aminobutan-1-yl)-1-benzoylpiperazine. To an ethanol solution of this compound was added, at room temperature, 5 ml (60 mmol.) of 12N hydrochloric acid. The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, to which was added diethyl ether. The resulting crystals were collected by filtration and washed with ethanol and diethyl ether to give the object compound as a white crystalline product. The yield was 2.92 g (41%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[C:14](/[CH:16]=[C:17](\[O-:19])/[CH3:18])#[N:15].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:16](/[C:17](=[O:19])[CH3:18])\[C:14]#[N:15]
Reactant: C/C([O-])=C/C#N
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 2.74 g (15.5 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 2.6 g (24.8 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate to yield 1.6 g (42% of th.) of the crude product which was used in the next step without further purification.