Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[F:11].C([Li])CCC.C([O:19][B:20](OCC)[O:21]CC)C>CCCCCC.O1CCCC1>[F:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[B:20]([OH:21])[OH:19]
Reactant: CCOB(OCC)OCC
Reactant: Cc1ccc(Br)c(F)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)c(F)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a 500 mL three-necked round-bottomed flask equipped with septum and N2 inlet were added 10.0 g (52.9 mmol) 4-bromo-3-fluorotoluene and 100 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 25.4 mL (63.5 mmol) of a 2.5 M solution of butyl lithium in hexane was added slowly so the temperature did not exceed −60° C. The clear solution was stirred at −70° C. for 1 hour, then treated with 10.8 mL (63.5 mmol) triethylborate. The reaction was stirred for 2 hours at −70° C., then warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, adjusted to pH 1-2 with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 6.1 g (75%), as a mixture of monoaryl and diaryl boronic acids.
Reaction SMILES: C(OC(=O)C[C:6]1[C:15]([C:16]([OH:18])=[O:17])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)C.O=P(Cl)(Cl)[Cl:22].CN(C=O)C>ClCCl>[Cl:22][C:6]1[C:15]([C:16]([OH:18])=[O:17])=[N:14][C:13]2[C:8]([N:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1nc2ccccc2nc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1nc2ccccc2nc1Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
From crude 16d, with a changed ratio of 1 g 16d: 0.8 mL POCl3: 1.6 mL DMF. The reaction mixture was heated, with moisture exclusion, at 75° C. for 16 h, then cooled, diluted with cold dichloromethane, and kept at −18° C. for 1 h. The brick red solid was filtered and washed exhaustively, with thorough stirring, with cold dichloromethane to give the dione (22% from 3-chloroquinoxaline-2-carboxylic acid), mp 133-139° C. 1H NMR (d6-DMSO): δ 3.27 (s, 3H, NCH3), 3.57 (s, 3H, NCH3), 7.66 (ddd, J=8.3, 6.6, 1.6 Hz, 1H), 7.81-7.92 (m, 2-H), 8.04 (d, J=7.8 Hz, 1H), 8.66 (s, 1H, ═HCNMe2). 13C NMR (d6-DMSO): δ 45.0 (CH3), 48.3 (CH3), 87.0 (C), 127.2 (CH), 128.3 (CH), 130.3 (CH), 133.3 (C), 133.7 (CH), 139.4 (C), 143.2 (C), 150.3 (C), 157.6 (C), 159.7 (C), 161.1 (CH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(aminomethyl)phenylamino]-1-phenyl-methylidene}-2-indolinone, N-tert.butoxycarbonyl-glycine, TBTU, HOBt and N-ethyl-N,N-diisopropylamine in DMF.
Reaction SMILES: Cl.[N:2]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>CO>[CH3:24][O:23][C:19](=[O:22])[CH2:20][CH2:21][N:5]1[CH2:6][CH2:7][N:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: CO
Product: COC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate hydrochloride, (200 g, 0.82 mol) in methanol (1 L) was added methyl acrylate (214 g, 2.46 mol) with stirring at approximately 25° C. under N2 atmosphere, and the reaction mixture was refluxed at 70° C. for 48 hours. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (1.2 L) and water (2 L). The organic layer was separated and washed with water (1 L×2) and brine (500 mL), dried over Na2SO4, filtered and concentrated. The crude obtained was purified by column chromatography over silica gel using 30-40% ethyl acetate in petroleum ether to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 9H), 2.20-2.34 (m, 1H), 2.35-2.46 (m, 1H), 2.48 (t, 2H, J=7.2 Hz), 2.76-2.90 (m, 1H), 2.90-3.12 (m, 2H), 3.12-3.30 (m, 1H), 3.32 (t, 1H, J=4.5 Hz), 3.35-3.44 (m, 1H), 3.67 (s, 3H), 3.71 (s, 3H) 3.83-3.94 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]#[CH:45])[CH2:39][CH2:38]1)[CH3:36]>>[CH2:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]#[C:45][C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([N:19]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:39][CH2:38]1)[CH3:36]
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CCN1CCN(CC)CC1
Product: CCN1CCN(CC#Cc2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)CC1
Yield: 9.6 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 50 mg, 0.0845 mmol) and 1-ethyl-4-(prop-2-ynyl)piperazine (Example 18, Step A, 32.2 mg, 0.211 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.67), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (5 mg, 10%). HPLC: 100% purity (220 nm); LRMS (APCI−): 100% purity, 220 nm, m/z 614 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.49 (d, J=5 Hz, 1H), 8.31 (br s, 1H), 7.75 (m, 1H), 7.58 (s, 1H), 7.43 (m, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 6.52 (d, J=5 Hz, 1H), 3.64 (m, 2H), 3.61 (s, 2H), 2.4-2.8 (m, 8H), 1.80 (m, 2H), 1.62 (m, 2H), 1.12 (m, 3H).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].[NH2:26][C@H:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13]([NH:26][C@H:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: N=C(NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OCc1ccccc1

Procedure:
Equimolar quantities of Z-D-Arg(NO2)-OH and H-Phe-OtBu were dissolved in DMF and coupled by adding DCC and HOBt under the conditions described in Example 1(2), DCU was filtered off, and the organic EtOAc layer of the filtrate was then extracted successively with acid, base and water, dried and crystallized from EtOAc-hexane mixture. The peptide subsequently purified with the aid of an SiO2 column has an Rf of 0.52 in To/EtOH (4:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13][NH:14][OH:15])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1.C[Si]([N:28]=[C:29]=[S:30])(C)C.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8]([CH2:13][N:14]([OH:15])[C:29]([NH2:28])=[S:30])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CNO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CN(O)C(N)=S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-3-(hydroxyamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran in tetrahydrofuran was added dropwise trimethylsilyl isothiocyanate at room temperature. The reaction mixture was stirred at room temperature for two hours. Water was added, and the organic layer separated, dried and evaporated. The residue was triturated with diethyl ether to give 0.18 g of 6-bromo-2,2-dimethyl-3-(N-hydroxythioureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 219° C.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(O)=O.Cl>C(N(CC)CC)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 90 °C

Procedure:
After weighing 14.4 g (0.1 mol) of Meldrum's acid and 16.6 g (0.1 mol) of veratraldehyde to 50 ml of the mixture of formic acid and triethylamine prepared according to Example 1, the reaction mixture was heated to 90° C. during 1 hour and maintained at 90° C. for 2 hours. After cooling down to room temperature 200 ml of ice-water were added to the reaction mixture, the pH value was adjusted to 1 by adding concentrated hydrochloric acid and the mixture was let stand at 5° C. for 16 hours. After filtration the precipitate was washed 3 times on the filter and dried at 40° C. under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[S:39][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:40]([O:43][CH2:44][CH2:45]P(OCC)(OCC)=O)(=[O:42])[CH3:41].[H-].[Na+].O>C1COCC1>[C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:7]2[C:6]3[S:39][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=3[C:10](=[O:11])[N:9]([CH2:12]/[C:13](/[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:41]/[C:40]([O:43][CH2:44][CH3:45])=[O:42])[C:8]2=[O:23])=[CH:30][CH:29]=1)#[N:38]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(/Cn1c(=O)c2cc(CC)sc2n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.0 g), (diethoxyphosphoryl)ethyl acetate (0.56 ml) in THF (20 ml) was added NaH (0.1 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl (2E)-4-[1-[(2′-cyanobiphenyl-4-yl)methyl]-6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]-3-(4-methoxyphenyl)but-2-enoate (1.0 g, 88%). This was dissolved in dimethyl sulfoxide (5 mL), and the mixture was added to a mixture of hydroxylammonium chloride (1.15 g), sodium hydrogencarbonate (1.40 g) and dimethyl sulfoxide (20 mL), which had been stirred at 40° C. for 30 min in advance. The reaction mixture was stirred at 90° C. for 16 hr, diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.078 g, 13%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(F)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 3-fluorophenol (6.00 g, 53.5 mmol), ethyl 4-bromobutanoate (15.70 g, 80.5 mmol) and Cs2CO3 (26.20 g, 80.4 mmol) in DMF (25 mL) under N2 was refluxed overnight. The mixture was then cooled to rt and 150 mL of water was added. The resulting mixture was extracted with DCM (100 mL×2) and the combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as colorless oil (12.0 g, 99%).
Reaction SMILES: C(OC([N:8]([CH2:17][CH:18]([NH:25][CH2:26][C:27]([O:29]C)=O)[CH2:19][CH2:20][N:21]([O:23][CH3:24])[CH3:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[CH2:17][CH:18]([CH2:19][CH2:20][N:21]([O:23][CH3:24])[CH3:22])[NH:25][CH2:26][C:27]2=[O:29])=[CH:15][CH:14]=1
Reactant: COC(=O)CNC(CCN(C)OC)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)CCC1CN(Cc2ccc(F)cc2)C(=O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl N-{1-{[(tert-butoxycarbonyl)-(4-fluorobenzyl)amino]methyl}-3-[methoxy(methyl)amino]propyl}glycinate (1.63 g, 3.82 mmol) in CH2Cl2 (41 mL) was treated with TFA (12.6 mL) at 0° C. The mixture was stirred at ambient temperature under inert atmosphere for 2 h and then concentrated in vacuo. The resulting oil was suspended in water (46 mL) and treated, portion-wise, with solid K2CO3 (3.1 g). The reaction was heated to 100° C. for 30 min. After cooling to ambient temperature, the mixture was saturated with NaCl and extracted into CH2Cl2 three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield the title compound as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.29-7.23 (m, 2H), 7.05-6.99 (m, 2H), 4.63 (d, J=14.8 Hz, 1H), 4.47 (d, J=14.8 Hz, 1H), 3.62 (dt, J=17.2, 38.8 Hz, 2H), 3.47 (s, 3H), 3.12-3.10 (m, 1H), 3.08-2.94 (m, 2H), 2.71-2.62 (m, 2H), 2.55 (s, 3H), 1.82 (br s, 1H), 1.63 (dd, J=6.4, 12.4 Hz, 2H). ES MS (M+1)=296.4.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH:14]=2)[C:9]2[N:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)([OH:3])=[O:2].[CH2:35](O)[CH3:36]>>[CH2:35]([O:2][C:1]([CH2:4][CH2:5][C:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[O:21])[CH:14]=2)[C:9]2[N:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1)=[O:3])[CH3:36]
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)O)nc3cccnc32)c1
Reactant: CCO
Product: CCOC(=O)CCc1nc2cccnc2n(-c2cccc(NC(=O)Nc3ccccc3OC)c2)c1=O

Procedure:
To a suspension of 2-(2-carboxyethyl)-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (0.15 g) in ethanol (9 ml) was added conc. sulfonic acid (0.9 ml) and the mixture was refluxed for 30 minutes. After cooling, the reaction mixture was neutralized and ethanol was evaporated. Crystalline materials formed were collected, washed with water and dried to give 2-(2-ethoxycarbonylethyl)-3-oxo-4-[3-[3-(2-methoxyphenyl)-ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (0.12 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(=O)(O)[O-].[Na+].O.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:27]([NH:1][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)S[C@@H]2C(NC(=O)CN)C(=O)N2C1c1nnn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)S[C@@H]2C(NC(=O)CNC(=O)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a stirred solution of 0.80 g. (2.7 mmole) of 6-(2-aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.453 g. (5.4 mmole) of sodium bicarbonate in 21 ml. of water and 15 ml. of acetone at 0°-5° C. is added 0.32 ml. (2.8 mmole) of benzoyl chloride. Starting is continued for a further 20 minutes at ca. 0° C., and then the acetone is removed in vacuo. The aqueous residue is extracted with ethyl acetate and the extracts are discarded. The pH of the aqueous phase is adjusted to 2.0, and the product is extracted into ethyl acetate. The solvent is dried (Na2SO4), and then concentrated in vacuo to give 150 mg. (37% yield) of the title compound, m.p. 85°-93° C. IR (KBr disc): 1785 cm-1 (β-lactam) and 1695 cm-1 (amide I). NMR (in D2O): 7.90 ppm (m, 2 H), 7.50 ppm (m, 3H), 5.82 ppm (s, 1H), 5.58 ppm (s, 1H), 5.19 ppm (s, 1), 4.25 ppm (m, 2H), 1.67 ppm (s, 3H), 1.67 ppm (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1>CC(C)=O>[C:3]([O:2][CH2:1][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1)(=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(=O)OC
Reactant: COc1cc(CO)ccc1O
Solvent: CC(C)=O
Product: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
This compound was synthesized by the method described in Kobata et al. (Biosci. Biotechnol. Biochem., 66(2), 319-327, 2002). Decanoic acid methyl ester (2.13 mL, 10.5 mmol), vanillyl alcohol (1.62 g, 10.5 mmol), molecular sheaves 4 Å (10 g), and Novozyme 435 (2.5 g) were added to acetone (50 mL) and stirred for 2 hours at room temperature. The reaction solution was filtered through cellite and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography, yielding 2.25 g (7.30 mmol, 73.0 percent) of vanillyl decanoate in the form of a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[C:12]([Cu])#[N:13]>CN(C=O)C.CCOC(C)=O>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:12]#[N:13])=[CH:3][C:4]=2[O:8]1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1
Temperature: 175 °C
Reaction time: 6 h

Procedure:
To a solution of 6-bromo benzoxazolinone (2 g, 9.4 mmol) in DMF (20 mL) was added CuCN (16.79 g, 188 mmol), and the reaction was stirred at 175° C. for 6 h. The reaction progress was monitored by TLC (100% EtOAc). The reaction was diluted with EtOAc (10 mL) and filtered through Celite® brand filter agent. The organic layer was concentrated and purified by column chromatography (silica gel, 0-50% EtOAc in hexanes) to give the title compound. MS (ESI pos. ion) m/z: 158.9 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].Cl.Cl[CH:13](OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15].[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5]/[N:6]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: NNCc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)/C=N/NCc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Fluorobenzyl)hydrazine (1.00 g, 7.14 mmol) is suspended in water (3 ml), and the mixture is brought to pH 4 with 4N hydrochloric acid. It is then cooled in an ice bath, and a solution of ethyl chloro(ethoxy)acetate (1.37 g, 8.21 mmol) in dioxane (10 ml) is added. The mixture is stirred at RT for 1 h, then made weakly alkaline (pH 8) with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate. The crude product is purified by chromatography on silica gel (eluent: dichloromethane with increasing methanol content). 1.40 g (88% of theory) of the desired compound are obtained.
Reaction SMILES: [Li]CCCC.[Se:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[Se:12][CH:13]=[CH:14][CH:15]=1.CN(CCN(C)C)C.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26]>C1COCC1.CC#N>[CH3:24][Sn:25]([CH3:27])([CH3:26])[C:10]1[Se:6][C:7]([C:11]2[Se:12][C:13]([Sn:25]([CH3:27])([CH3:26])[CH3:24])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1c[se]c(-c2ccc[se]2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Sn](C)(C)c1ccc(-c2ccc([Sn](C)(C)C)[se]2)[se]1
Temperature: 17 °C
Reaction time: 0.33 h

Procedure:
A solution of BuLi in hexanes (10.6 ml of a 1.6 M solution, 17 mmol) is added dropwise to a cooled (−78° C.) solution of 2,2′-biselenophene (2.00 g, 7.7 mmol) in THF (50 ml) and TMEDA (1.98 g, 17 mmol). On addition of the BuLi an immediate colour change is observed (dark red). After stirring for 20 min, the reaction mixture appeared dark yellow. The mixture is stirred for 6 h allowing to warm to 16-18° C. While warming the reaction mixture changed appearance to a green suspension. The reaction mixture is then cooled to −70° C. Trimethylstannyl chloride (3.38 g, 17 mmol) is added as a solid to the reaction mixture. After 10 min, the reaction mixture appeared brown. The reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with water (100 mL) and the mixture stirred for 1 h. Ethylacetate (100 mL) is added to the mixture. The layers are separated. The combined organic extracts are washed with water, brine and then dried (Na2SO4). After filtration the crude product is concentrated to yield a brown oil. MeCN is added and the mixture is stirred for 5 min. The mixture is recrystallized three times from acetonitrile. The material is used without further purification. MS (EI) 588 (M+).