Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=O)=[O:15])=[C:9]([C:25](=[O:42])[NH:26][C:27]3[CH:31]=[CH:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)[N:28]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Br:52]CC1C=C(C=CC=1)C(Cl)=O>O1CCCC1>[Br:52][CH2:19][C:18]1[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=1)[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8][C:9]=1[C:25]([NH:26][C:27]1[CH:31]=[CH:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=2)[N:28]=1)=[O:42])=[O:15]
Reactant: O=C(Cl)c1cccc(CBr)c1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 111 %

Procedure:
Into a 50-mL round bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (60 mg, 0.47 mmol, 2.00 equiv). To this was added 3-(bromomethyl)benzoyl chloride (75 mg, 0.32 mmol, 1.39 equiv), in portions at 0° C. The resulting solution was stirred for 2.5 h at room temperature. The reaction progress was monitored by LCMS/TLC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water, extracted with 3×10 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 160 mg (88%) of product as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]1)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6](=[O:24])[NH:5]2.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:32](=[O:33])[NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6](=[O:24])[NH:5]2
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c(Cl)cc2[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Yield: 56.6 %

Procedure:
To a suspension of the compound (100 mg, 287 μmol) of Example 41 in ethyl acetate (3 ml) were added phenyl isocyanate (68.4 mg, 574 μmol) and triethylamine (58.1 mg, 574 μmol), and the mixture was refluxed for 24 hours. After cooling, the insolubles were filtered off and solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [ethyl acetate], thereby obtaining 76.0 mg of title compound as light brown powder. Yield 57%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:7]4[NH:6][C:5](=[O:27])[C:4]5[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=5[O:2][CH3:1])[N:8]=4)=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(Cc5ccc(F)cc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.55 mmol) in DMF (5 mL) was added 4-fluorobenzyl bromide (0.07 mL, 0.55 mmol) and K2CO3 (0.15 g, 1.10 mmol). The reaction was stirred at room temperature for 2 hours then diluted with H2O and the solids filtered off to afford the title compound (0.17 g, 65%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6): δ 11.76 (br s, 1H), 8.09 (d, J=8.1 Hz, 2H), 7.26-7.52 (m, 2H), 7.08-7.25 (m, 2H), 7.00 (d, J=8.0 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 2H), 3.08-3.41 (m, 4H), 2.23-2.68 (m, 4H). APCI MS m/z 475 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH2:17]([NH2:27])[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:27][CH2:17][C:18]2[CH:26]=[CH:25][C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Yield: 82.4 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of piperonylamine (0.23 g, 1.52 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.47 g, 81%) as a white solid, 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 3.96 (2H, d, J=6.4 Hz); 5.94 (2H, s); 6.66-6.85 (3H, m); 6.71 (1H, d, J=16.4 Hz); 7.49-8.07 (5H, m); 8.14 (1H, br t, J=6.4 Hz).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([C:11]#[N:12])[CH2:9][OH:10]>C1(C)C=CC=CC=1>[C:11]([CH2:8][CH2:9][O:10][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])#[N:12]
Reactant: N#CCCO
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: N#CCCOC(=O)CCC(=O)O
Yield: 101.8 %

Procedure:
5.00 g (50 mmol) of succinic anhydride, 3.55 g (50 mmol) of ethylene cyanohydrin and 61 mg (0.5 mmol) of N,N-dimethylaminopyridine were dissolved in 40 mL of toluene, and heated under reflux for 10 hours. After the reaction, the reaction liquid was concentrated under reduced pressure to give 8.71 g of 4-(2-cyanoethoxy)-4-oxobutanoic acid as a mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31].O>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH2:30][CH3:31])[CH:20]=2)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:23])[CH:3]=1
Reactant: CCI
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (354 mg) in N,N-dimethylacetamide (4.7 ml) were added powdered potassium carbonate (131 mg) and ethyl iodide (141 mg). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (324 mg) as a light yellow oil. MS (m/e)=438.2 [M+H+].
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5](=[O:7])[NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][SiH:16]([CH3:18])Cl>O1CCCC1>[CH3:15][SiH:16]([CH3:18])[N:4]1[CH2:3][CH:2]([CH3:1])[O:6][C:5]1=[O:7]
Reactant: C[SiH](C)Cl
Reactant: CC1CNC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CN([SiH](C)C)C(=O)O1

Procedure:
A 3-dimethylsilyl-5-methyl-2-oxazolidinone was prepared in accordance with the following procedure. A stirred mixture of 60.6 grams of 5-methyl-2-oxazolidinone and 62.4 grams of triethylamine was prepared in a tetrahydrofuran solvent. To this mixture, 67.5 ml of dimethylchlorosilane was added dropwise over a period of 90 minutes.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)([OH:27])[CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:22]1([CH2:21][C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[OH:27])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(O)(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 2.6 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethanol (5.1 g, 9.4 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 20 mL, 20 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-methanesulfonyl-phenyl)-ethanol (100 mg) as a white solid: LC/MS m/e calcd for C21H23FN2O3S [M+H]+ 403.49, observed 403.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (br. s., 1H), 7.95-8.00 (m, J=8.3 Hz, 2H), 7.88-7.94 (m, J=8.6 Hz, 2H), 7.77 (dd, J=9.1, 2.3 Hz, 1H), 6.60 (s, 1H), 3.16-3.23 (m, 3H), 2.54-2.64 (m, 2H), 1.83-1.98 (m, 2H), 1.43-1.71 (m, 5H), 1.25-1.40 (m, 1H), 1.05-1.15 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(N(CC)CC)C.[Cl:14][C:15]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[C:21]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])=[O:22]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CCCN1C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidin-2-one (7.60 grams; 0.02 mol), triethylamine (2.0 grams; 0.02 mol) and toluene (50 mol) were placed in a three-necked, glass reaction flask equipped with stirrer, thermometer, addition funnel and drying tube. 3-(2-Chloro-4-trifluoromethylphenoxy)-6-nitrobenzoylchloride (7.60 grams; 0.02 mol) in toluene (10 ml) was added to the mixture in the flask. The mixture, after being stirred overnight at room temperature, was washed with water, dried over sodium sulfate and evaporated to give a dark oil. The oil was chromatographed using silica gel into two fractions, the first using toluene as eluant and the second fraction using an equal mixture of toluene and ethyl acetate gave the desired product as a brown oil which solidified upon standing. Trituration with isopropyl ether resulted in white crystals, melting point 88° C. This product analyzed as follows:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].Cl[C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26](=[O:34])[NH:25][CH2:24][CH2:23][C:22]2[CH:21]=[CH:20][CH:19]=[CH:36][CH:35]=2)=[CH:32][CH:31]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccccc3)cc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.122 g), N-(4-chlorophenethyl)-4-hydroxybenzamide (0.150 g), and potassium carbonate (0.086 g) was dissolved in 2 ml of DMSO and stirred at 90° C. After 1 day, the reaction was cooled, loaded onto a silica gel samplet and product eluted with a solvent system gradient of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane to give tert-butyl 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetate (0.120 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]/[C:7](O)=[O:8])[CH3:2].[C:11]([OH:15])([CH3:14])([CH3:13])[CH3:12].C1CCC(N=C=NC2CCCCC2)CC1.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:7](=[O:8])/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C=C/C(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of fumaric acid mono-ethyl ester (721 mg, 5 mmol) and tert-butanol (0.938 mL, 10 mmol) in 10 mL of DCM was added DMAP (122 mg, 1 mmol) followed by DCC (2.06 g, 10 mmol). The resulting mixture was stirred at rt for 16 h, taken to dryness under reduced pressure, stirred overnight with 50 mL acetone and filtered to remove DCU. The resulting filtrate was concentrated under reduced pressure, and the residue taken up in EtOAc. The EtOAc was washed twice with 30 mL 0.1 M KHSO4, and once with 30 mL saturated NaHCO3 and once with 30 mL of brine. The resulting EtOAc solution was treated with charcoal and dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel flash chromatography using a gradient of 0–15% EtOAc in hexanes as eluent to give essentially pure (one peak on HPLC) 4-1 (350 mg, 35% yield).
Reaction SMILES: C1C=CC(CC(NC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=O)=CC=1.[CH3:23][C:24]1([CH3:45])[S:28][C@@H:27]2[C@H:29]([NH:32]C(CC3C=CC=CC=3)=O)[C:30](=[O:31])[N:26]2[C@H:25]1[C:42]([O-:44])=[O:43].[K+]>O>[CH3:23][C:24]1([CH3:45])[S:28][C@@H:27]2[C@H:29]([NH2:32])[C:30](=[O:31])[N:26]2[C@H:25]1[C:42]([OH:44])=[O:43]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [K+]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 38 °C

Procedure:
330 g of carrier-bound penicillinacylase produced according to Example 1, having an enzymatic activity of 3,410 U (NIPAB test) and 129 g of potassium penicillin G are successively added to 2,000 ml of water and stirred at 38°C. and pH 7.8 as described in Example 14. The penicillin G is completely split to 6-APA and phenylacetic acid over the course of 2 hours. The 6-APA is isolated as described in Example 14. The carrierbound penicillinacylase is employed 20 times in succession. Even after the twentieth splitting, the reaction time does not have to be extended to achieve complete splitting.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:13]=1)[C:5](N(OC)C)=[O:6].Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([CH3:29])[CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)=[O:6])[CH:11]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Br)cc(OCC(F)(F)F)c1
Reactant: COc1ccc(Br)cc1C
Product: COc1ccc(C(=O)c2cc(Br)cc(OCC(F)(F)F)c2)cc1C
Yield: 75 %

Procedure:
In analogy to the procedure described for the preparation of the Building Block AU, the reaction of the 3-bromo-N-methoxy-N-methyl-5-(2,2,2-trifluoro-ethoxy)-benzamide and 4-bromo-1-methoxy-2-methyl-benzene, beforehand transformed to the Grignard reagent, yielded the title compound as a white solid (yield: 75% of theory). Mass (calculated) C17H14BrF3O3 [402]; (found) [M]+=403, 405.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:10](=[N:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccccc1
Product: Clc1ccc(N=Cc2ccccc2)cc1Cl

Procedure:
Equimolar amounts of 3,4-dichloroaniline and benzaldehyde are stirred together at room temperature to give a nearly quantitative yield of N-benzylidene-3,4-dichloroaniline that melts at 62°-5° C. upon recrystallization from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][S:25][CH2:26]Cl.O>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:24][S:25][CH3:26])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCl
Reactant: O=C(OCc1ccccc1)N1CCc2ccc(O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCOc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (2.5 g) in dimethylformamide (25 ml) was added 60% sodium hydride (390 mg) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 30 min. Then, chloromethyl methyl sulfide (0.96 ml) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) and dried under reduced pressure to give the title compound (2.7 g).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl)oxy]benzonitrile (D76) (150 mg), acetic acid (0.044 mL) and sodium acetate (63 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (175 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (204 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D83) (188 mg). The crude product was used for next step without further purification. MS (ES): C28H31N3O3S requires 489. found 490.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:38]([OH:40])=[O:39])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]3[C:30]4[C:29](=[O:31])[CH2:28][C:27]([CH3:33])([CH3:32])[CH2:26][C:25]=4[O:24][C:23]4[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]3=4)[C:10]=2[CH3:37])=[CH:7][CH:8]=1)#[CH:2].[H][H].ClCCl>CO.[C].[Pd]>[CH2:1]([C:3]1[C:4]([C:38]([OH:40])=[O:39])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]3[C:30]4[C:29](=[O:31])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26][C:25]=4[O:24][C:23]4[CH2:22][C:21]([CH3:34])([CH3:35])[CH2:20][C:19](=[O:36])[C:18]3=4)[C:10]=2[CH3:37])=[CH:7][CH:8]=1)[CH3:2]
Reactant: C#Cc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Yield: 36.1 %

Procedure:
A suspension of the 3-ethynyl-6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 12-3 (100 mg, 0.19 mmol) and 10% palladium carbon (wet) (100 mg) in methanol (2 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at the same temperature as above under a hydrogen atmosphere for 2.5 hours. Thereafter, a solid was removed from the reaction solution by filtration, and the solvent was then distilled away from the filtrate thus obtained under reduced pressure. The residue thus obtained was purified by silica gel thin-layer chromatography (methanol:dichloromethane=1:10, v/v) to obtain the title compound (37.3 mg, yield: 37%).
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]CC)=O)=[N:5][C:4]([C:12]([O:14]CC)=O)=[N:3][C:2]=1[C:17]([O:19]CC)=O.[NH2:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:41])([CH3:40])[CH2:24]1>>[CH2:32]([O:31][N:26]1[C:27]([CH3:29])([CH3:30])[CH2:28][CH:23]([NH:22][C:17]([C:2]2[N:1]=[C:6]([C:7]([NH:22][CH:23]3[CH2:28][C:27]([CH3:29])([CH3:30])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:40])([CH3:41])[CH2:24]3)=[O:9])[N:5]=[C:4]([C:12]([NH:22][CH:23]3[CH2:28][C:27]([CH3:29])([CH3:30])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:25]([CH3:40])([CH3:41])[CH2:24]3)=[O:14])[N:3]=2)=[O:19])[CH2:24][C:25]1([CH3:40])[CH3:41])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)c2nc(C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(C(=O)NC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of triethyl 1,3,5-triazine-2,4,6-tricarboxylate and 4-amino-1-octyloxy-2,2,6,6-tetramethylpiperidine.