Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+](C1C=CC([O:40][C:41](=O)[O:42][CH:43]2[CH:50]3[CH:46]([O:47][CH2:48][CH2:49]3)[O:45][CH2:44]2)=CC=1)([O-])=O.C(N(C(C)C)CC)(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:25]#[C:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C@@H:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:41]([O:42][CH:43]1[CH:50]2[CH:46]([O:47][CH2:48][CH2:49]2)[O:45][CH2:44]1)=[O:40])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCN
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCC12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCNC(=O)OC1COC2OCCC12
Reaction time: 1 h

Procedure:
A mixture of crude 3-[[3-Amino-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester in ACN (3.0 mL) was treated with carbonic acid hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester (0.11 g, 0.375 mmol) followed by diisopropylethyl amine (0.1 mL, 0.625 mmol) and DMAP (cat). The reaction was stirred for 1 h and quenched with CH3OH (1 mL). Solvent was removed under reduced pressure and the crude material was partitioned between EtOAc, and ½ sat NaHCO3(aq). The organics were dried over Na2SO4, solids filtered and solvent removed under reduced pressure. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[3-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-1-(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was isolated by reverse phase HPLC and carried forward wet to the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(Cl)Cl.CO>[NH2:23][CH2:22][C@@H:7]1[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:10])[N:6]1[CH2:5][C:4]1[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2C(=O)c3ccccc3C2=O)c(OC)c1
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN)c(OC)c1
Reaction time: 16 h

Procedure:
To a solution of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((1,3-dioxoisoindolin-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (4.40 g, 8.31 mmol) in DCM:MeOH (5:1, 60 mL) was added hydrazine hydrate (1.50 g, 25.0 mmol). After stirring for 16 h the precipitate was filtered off and the filtrate was concentrated, affording title compound (quantitative) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1B(O)O)[CH3:15].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:17]2[C:18]([CH2:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:14][CH3:15])=[N:6][CH:5]=1
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: COC(=O)c1cnc(Cl)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)cn1
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-4-methoxy-nicotinic acid methyl ester (4.0 g, 19.8 mmol), 2,6-diethylphenyl boronic acid (7.0 g, 39.3 mmol), Na2CO3 (2M in H2O, 39 mL) and Pd(PPh3)4 (2.0 g, 1.7 mmol) in toluene (200 mL) is heated overnight at 80° C. under argon. On cooling, hexane (200 mL) is added and the organic layer separated. The organic layer is washed with 1N NaOH and water, dried (Na2SO4) and concentrated. The residue is purified by silica gel column (hexane/EtOAc 4:1) to give 6-(2,6-diethyl-phenyl)-4-methoxy-nicotinic acid methyl ester. 1H NMR (CDCl3) 8.99 (s, 1H), 7.30 (m, 1H), 7.15 (d, 2H), 6.89 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.34 (m, 4H), 1.06 (t, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].NC1C=C(C=CC=1[F:35])C(N)=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([F:35])=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(F)c(N)c1
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)cc1OC
Yield: 55 %

Procedure:
19C was prepared in a procedure similar to that of 1A using 19B, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 55%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.78 (s, 3H) 3.81 (s, 3H) 5.15 (s, 1H) 6.90 (d, J=7.91 Hz, 1H) 7.01-7.08 (m, 2H) 7.12 (d, J=1.76 Hz, 1H) 7.13-7.17 (m, 2H), LCMS: 349 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9]>C(Cl)Cl>[N:1]1([C:8]([O:10][CH2:11][Cl:12])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Product: O=C(OCCl)N1CCOCC1
Reaction time: 0.25 h

Procedure:
Morpholine (1 equiv.) is slowly added to a 0.1M solution of chloromethyl chloroformate (10 equiv.) in methylene chloride at low temperature. After 15 min at low temperature and a suitable time at 25° C. the reaction mixture is filtered and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography giving chloromethyl morpholine-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:13])[CH2:12][N:11]([CH2:21][CH3:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCI
Reactant: OC1(c2cc(F)cc(Cl)c2)CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCN1CC(O)(c2cc(F)cc(Cl)c2)C1
Temperature: 120 °C
Yield: 60.1 %

Procedure:
A mixture of 3-(3-chloro-5-fluorophenyl)azetidin-3-ol (0.41 g, 2.03 mmol), potassium carbonate (0.56 g, 4.06 mmol) and iodoethane (0.31 g, 2.03 mmol) in acetonitrile (5 ml) was heated at 120° C. under microwave irradiation for 10 min. Water (50 ml) and ethyl acetate (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the crude product. Purification by flash column chromatography on silica gel (ethyl acetate) gave 0.28 g (60%) of the title compound. The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 166-168° C. MS m/z (relative intensity, 70 eV) 229 (M+, 1), 172 (23), 130 (24), 109 (33), 58 (bp).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N+:26]#[C-:27])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CO.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:26]=[CH:27][O:35][C:28]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: [C-]#[N+]C(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: c1ccc(COc2ccc(-c3ncoc3-c3ccncc3)cc2)cc1
Yield: 61.2 %

Procedure:
A mixture of 1-((4-(Benzyloxy)phenyl)isocyanomethylsulfonyl)4-methylbenzene (4.3 g, 11.4 mmol), isonicotinaldehyde (1.34 g, 12.5 mmol) and K2CO3 (3.15 g, 22.8 mmol) in methanol (96 mL ) and DME (30 mL) was heated at reflux for 5 h. After removal of solvent, the residue was purified by silica gel chromatography (2:1 hexane/EtOAc) to provide 2.29 g (84%) of a white solid. 1H NMR (400 MHz, CDCl3) δ: 5.12v (s, 2H), 7.03 (d, 2H), 7.46 (m, 6H), 7.56 (d, 2H), 7.61 (d, 2H), 8.02 (s, 1H), 8.58 (d, 2H). MS m/z: 329 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])[CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])O.[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[CH:14][C:13]=2[F:19])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
4-(4-amino-2-fluorophenoxy)pyridine-2-carboxylic acid methyl ester (11.5 g) was dissolved in acetone (340 ml) and water (170 ml). To the reaction mixture was added sodium hydrogencarbonate (17.3 g), then benzyl chloroformate (9.79 ml) while stirring in an ice water bath, followed by stirring for 15 min. The reaction mixture was allowed to warm up to room temperature, then stirred for 2 hr. To the reaction mixture cooled in an ice water bath was further added benzyl chloroformate (2.45 ml), followed by stirring for 18 hr. The reaction mixture was concentrated under reduced pressure, and to the resultant residue were added ethyl acetate (500 ml) and brine (200 ml), and liquid-liquid separation was carried out. The separated organic layer was washed with water (100 ml) and brine (200 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the resultant solid was suspended in ethyl acetate (50 ml) and hexane (30 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as a pale yellow solid (9.6 g, 70.6%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:20])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[C:6]([CH2:18][CH3:19])([CH2:12][CH2:13][C:14](=[O:17])[CH2:15][CH3:16])[CH2:5]2.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.Cl.CCOC(C)=O>[NH2:1][C:2]1[C:3]([Br:20])=[C:4]2[C:8]([C:7]3[C:6]([CH2:18][CH3:19])([CH2:5]2)[CH2:12][CH2:13][C:14](=[O:17])[C:15]=3[CH3:16])=[CH:9][CH:10]=1
Reactant: CCC(=O)CCC1(CC)Cc2c(ccc(N)c2Br)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC12CCC(=O)C(C)=C1c1ccc(N)c(Br)c1C2
Temperature: 80 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
The crude diketone (1.17 g) from step 3 was dissolved in acetic acid (14 mL) and the solution was diluted with aqueous 6N HCl (14 mL). The resulting mixture was stirred and heated in an oil bath at 80° C. for 5 hours and then kept at room temperature for 3 days. The mixture was diluted with EtOAc (100 mL) and carefully basified with aqueous K2CO3 (200 mL). The organic portion was washed with brine, dried over MgSO4 filtered, and evaporated under vacuum. The residue was lyophilized from benzene to afford crude 7-amino-8-bromo-9a-ethyl-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.0 g) as an amorphous solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14]1.C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH:13]1[CH2:14][N:15]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(ON2C(=O)c3ccccc3C2=O)CN1C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(ON)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of di-tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]pyrazolidine-1,2-dicarboxylate 142 (1.81 g, 4.18 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.240 mL, 4.18 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 143 (1.04 g, 83%) as a white foam.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)=[CH:7][CH:6]=1.[O-:29][C:30]#[N:31].[K+]>C(O)(=O)C>[CH3:25][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][NH:3][C:30]([NH2:31])=[O:29])=[CH:6][CH:7]=3)[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: N#C[O-]
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nc(Nc3ccc(CNC(N)=O)cc3)ncc2C(N)=O)c1
Reaction time: 6 h
Yield: 32.3 %

Procedure:
A 20 ml acetic acid-10 ml THF mixed solution containing 500 mg of 2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide dihydrochloride was mixed with 5.76 g of potassium cyanate, which was added by dividing into 6 portions, at room temperature, followed by stirring for 6 hours. The reaction mixture was concentrated and then poured into water, and the precipitated solid was collected by filtration and washed with acetonitrile. The resulting solid was purified by a silica gel column chromatography (chloroform:methanol) to obtain 150 mg of 4-[(3-methylphenyl)amino]-2-[(4-ureidomethylphenyl)amino]pyrimidine-5-carboxamide as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:27][CH2:26]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(CCc2ccc(Cl)cc2)CC1

Procedure:
The 1-(4-nitrobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine is prepared from 4-nitrobenzoic acid and 1-[(4-chlorophenyl)ethyl]piperazine in N,N-dimethylformamide in the presence of N,N-carbonylimidazole. It melts at 109°-110°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52](O)=[O:53].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:52](=[O:53])[CH2:51][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[F:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1ccccc1F
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccccc1F)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-fluorophenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The reaction mixture was stirred at room temperature overnight and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), and the solution was washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (eluent: EtOAc: CH2Cl2=4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(2-fluoro-phenyl)-acetamide (0.7 g, 79%) as a white solid: mp 172-174° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.87 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.94 (m, 1H), 3.61 (s, 2H), 4.75 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.12-7.38 (m, 4H), 7.68-7.86 (m, 3H), 8.70 (t, J=6.0 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 35.20, 37.87, 48.83, 114.83 (115.12), 121.88, 122.95 (123.17), 124.14 (124.19), 127.10, 128.60 (128.71), 131.51, 131.85 (131.91), 133.11, 134.68, 139.15, 158.96 (162.20), 166.90, 167.44, 169.59, 169.78, 172.73; Anal. Calcd. for C22H18N3O5F: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.65; H, 4.25; N, 9.95; F, 4.62.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])CCC.CCCCCC.[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][CH:52]1[CH2:57][CH2:56][CH2:55]CO1>O1CCCC1.CCOCC>[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][CH2:52][CH:57]=[CH:56][CH:55]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: CCCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC=CC=CCOC1CCCCO1
Temperature: 0 °C

Procedure:
Tridecyltriphenyl phosphonium bromide (0.3 mole) was dissolved in 900 ml of tetrahydrofuran and cooled to 0° C. in an ice-salt bath while stirring under argon. A 2.2N solution of n-butyllithium in hexane (0.36 mole) was added dropwise over a period of 30 minutes. The mixture was stirred for an additional 20 minutes and then cooled to -70° C. in a dry ice-acetone bath. The 4-hydroxybut-2(E)-ene-1-al tetrahydropyranyl ether (0.3 mole) in 225 ml of tetrahydrofuran was added dropwise over a period of 35 minutes and the mixture stirred for an additional hour at -70° C. The mixture was then poured into 6.25 liters of ether and stirred for 20 minutes. The resulting mixture was filtered through glass fiber filter paper. The filtrate was evaporated and the residue triturated with hexane, filtered and evaporated to give a ~3:1 mixture of trans:cis isomers of the desired compound.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:18]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[C:3]([NH:1][NH2:2])(=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCC(=O)OC
Reactant: NN
Solvent: CO
Product: CCCCCCCCCCCCCC(=O)NN
Yield: 43.9 %

Procedure:
Hydrazine (1.9 mL, 0.058 mol) was added to a solution of methyl tetradecanoate (13.96 g, 0.058 mol) in methanol (300 mL) and the solution refluxed for 3 days. The mixture was allowed to cool and filtered to yield 6.17 g of a crystalline solid, m.p. 107°-111° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].NCP(=O)(O)[OH:9].[OH-].[Na+].[C:14]([O-:18])(=[O:17])[CH2:15][OH:16]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:15]([OH:9])(=[O:16])[C:14]([OH:18])=[O:17]
Reactant: NCP(=O)(O)O
Reactant: O=C([O-])CO
Reactant: O=C(O)CO
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: -80 °C
Reaction time: 11 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.500M), aminomethylphosphonic acid (0.375M), flavin mononucleotide (0.01 mM), and no added HPLC internal standard (pH 8.3, adjusted with 50% NaOH), and the solution cooled to 5° C. Frozen (-80° C.) Aspergillus nidulans FT17SYCSL/OL (26 g, 124 IU glycolate oxidase and 57,800 IU catalase) were allowed to thaw at 5° C., then washed with 4×100 mL of KH2PO4 (50 mM, pH 7.0)/FMN (0.01 mM) buffer at 5° C. and the washed cells added to the reactor with 1.4×106 units of Aspergillus niger soluble catalase (Sigma). The resulting mixture was stirred at 400 rpm and 5° C. under 120 psig of oxygen while bubbling oxygen through the mixture at 50 mL/min. After 11 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 89%, 4.5%, and 2.0%, respectively, with complete conversion of glycolic acid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][O:12][C:11]2=[O:16])[CH2:4][CH2:3]1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([CH2:18][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]3[C:14](=[O:15])[CH2:13][O:12][C:11]3=[O:16])[CH2:4][CH2:3]2)=[CH:24][CH:23]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: O=C1COC(=O)N1CCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1COC(=O)N1CCC1CCN(Cc2ccc(-c3ccccc3)cc2)CC1

Procedure:
A solution of 0.40 g (1.61 mmol) of 3-(2-piperidin-4-ylethyl)-1,3-oxazolidine-2,4-dione hydrochloride, prepared in step 1.1., 0.326 g (1.61 mmol) of 4-(chloromethyl)biphenyl and 0.51 g (4.82 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at reflux for 17 hours. It is left to return to ambient temperature and filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in dichloromethane and water and the aqueous phase is separated off and extracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 97/3 then 95/5 mixture of dichloromethane and methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=S)[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COc1cccc(N=C=S)c1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add 3-methoxy phenyl isothiocyanate (69 uL, 0.512 mmol) and stir for 1.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 50 min. Upon cooling to room temp, dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and suspend the solid in 1 N NaOH. Collect the solid wash with water and Et2O, Suspend the solid in boiling toluene/EtOAc. Cool the suspension to 4° C. and filter. Wash the solid with Et2O. Again suspend the solid in 1 N NaOH and stir for 1 hr. Collect the solid and wash with water and Et2O. Dry to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (s, 3H) 6.61 (dd, J=8.15, 1.83 Hz, 1H) 7.14-7.19 (m, 1H) 7.28 (t, J=8.15 Hz, 1H) 7.34 (t, J=2.15 Hz, 1H) 7.64 (dd, J=9.35, 6.69 Hz, 1H) 7.70 (s, 1H) 7.84 (br. s., 2H) 7.72 (d, J=1.89 Hz, 1H) 8.11 (br. s., 1H) 10.67 (br. s., 1H) 13.29 (br. s., 1H); MS m/z=452.1 (M+1).