Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[OH-].[Na+].O=O.C(=O)([O-])[O-:18].[Na+].[Na+]>O>[O:7]=[C:6]([OH:8])[C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:18])[OH:11])[OH:10])[OH:9]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=C([O-])[O-]
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
50.0 g of gluconolactone is dissolved in 950 ml demineralised water. The pH is adjusted to 6.0 with 25 g of a 45% wiw sodium hydroxide solution.The solution is heated to 55° C. under nitrogen, until no more oxygen is detected. 6.35 g of the prepared Pb/Pt/C catalyst (ratio Pt/Pb 5/2) is added and the suspension is stirred at 1300 rpm for another 10 minutes under nitrogen. The reaction is started by switching from nitrogen to oxygen (maximum 10% oxygen in the mixture). The pH is kept at 6.0 by controlled addition of 26 ml 0.4 M sodium carbonate. The reaction is stopped after 1.5 hours reaction time reaching a selectivity of 89.9%.
Reaction SMILES: C(C1C=CC=CC=1C(NCC[O:11][C:12]([C:14]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:18]([C:29]([O:31][CH2:32][CH2:33][NH:34][C:35](=[O:45])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([OH:44])=[O:43])=[O:30])=[C:17]([CH3:46])[NH:16][C:15]=1[CH3:47])=[O:13])=O)(O)=O>O>[CH3:46][C:17]1[NH:16][C:15]([CH3:47])=[C:14]([C:12]([OH:13])=[O:11])[C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:18]=1[C:29]([O:31][CH2:32][CH2:33][NH:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]([OH:44])=[O:43])=[O:30]
Reactant: CC1=C(C(=O)OCCNC(=O)c2ccccc2C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2ccccc2C(=O)O)=C(C)N1
Solvent: O
Product: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2ccccc2C(=O)O)=C(C)N1
Reaction time: 48 h
Yield: 41.3 %

Procedure:
To the culture liquor was added a solution of 100 mg of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridine-3,5-dicarboxylic acid bis[2-(2-carboxybenzoyl)aminoethyl] ester in 0.75 ml of deionized water, and shaked for continuous 2 days at 28° C. to obtain 30 mg of (4R)-1,4-dihydro-2,6-dimethyl-3-[2-(2-carboxybenzoyl) aminoethyl]oxycarbonyl-4-(3-nitrophenyl)pyridine-5-carboxylic acid by the same procedures as of Example 9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[CH:11](C)[NH:10]2)=[CH:5][CH:4]=1.COC1C=CC(N2C(=O)C(=O)C(C3C=CC=C(OC)C=3)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(C3C=CC=CC=3)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(C3C=CC(Cl)=CC=3)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(C3C=CC(OC)=CC=3)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(C3C=CC=C([N+]([O-])=O)C=3)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(OC)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(OCC)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(N(C)C)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(N(CC)CC)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(NC(=O)C)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(C(O)=O)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(C(OC)=O)N2)=CC=1.COC1C=CC(N2C(=O)C(=O)C(C(OCC)=O)N2)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2NC(C)C(=O)C2=O)cc1
Agent: CCN(CC)C1NN(c2ccc(OC)cc2)C(=O)C1=O
Agent: CCOC(=O)C1NN(c2ccc(OC)cc2)C(=O)C1=O
Agent: CCOC1NN(c2ccc(OC)cc2)C(=O)C1=O
Product: COc1ccc(N2NCC(=O)C2=O)cc1

Procedure:
1-(4′-methoxyphenyl)-3-methyl-4,5-pyrazolinedione; 1-(4′-methoxyphenyl) -3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-phenyl-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-(4′-chlorophenyl)-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-(3′-nitrophenyl)-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-methoxy-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-ethoxy-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-dimethylamino-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-diethylamino-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-acetamido4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-carboxy-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-methoxycarbonyl-4,5-pyrazolinedione; 1-(4′-methoxyphenyl)-3-ethoxycarbonyl-4,5-pyrazolinedione;
Reaction SMILES: [CH:1]([CH:4]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]([CH3:15])[CH:7]=[CH:6][CH2:5]1)([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.C1CC=CC=C1>C(Cl)(Cl)(Cl)Cl>[CH:1]([CH:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[CH:7]=[CH:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1C(C)C=CCC1C(C)C
Agent: O=C1CCC(=O)N1Br
Solvent: C1=CCCC=C1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(C)C=CCC1C(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 10.5 g (0.05 mol) of ethyl 6-isopropyl-2-methyl-3-cyclohexene-1-carboxylate (mixture of isomers obtained according to Example 1) and 9.8 g (0.055 mol) of N-bromosuccinimide dissolved in 75 ml of CCl4 was stirred for 3 hours under reflux. After cooling the reaction mixture was filtered and the filter cake was washed with some cold CCl4. The filtrate was evaporated down and the evaporation residue dissolved in 50 ml of dimethylformamide. 1.2 g of LiF and 3.4 g of Li2CO3 were added to this solution and the mixture was heated at 120° C. with continuous stirring for 1 hour. After cooling, 150 ml of water were added and the mixture was extracted 3 times with 50 ml of petroleum ether 40`-60. The extract was washed with water, dried and evaporated down, after which the residue was distilled. 8.1 g were obtained of a mixture, 60% of which consisted of the 2,4-cyclohexadiene isomer and the rest of the 1,3- and 2(exocyclic), 3-isomers of said compound. b.p.: 85°-88° C./0.6 kPa; NMR (data of the 2,4-isomer): 0.87 (3H, d, J=7 Hz); 0.90 (3H, d, J=7 Hz); 1.24 (3H, t, J=7 Hz); 1.6 (1H, m); 1.77 (3H, broad s); 2.54 (1H, m); 2.86 (1H, d, J=7 Hz); 4.07 (2H, k, J=7 Hz); 5.3-5.9 (3H).
Reaction SMILES: I[CH2:2][C@@H:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[CH:5]=[CH:4]1.[CH2:15]([O:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:24]=1[N:30]1[S:34](=[O:36])(=[O:35])[N:33]([CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:32](=[O:43])[CH2:31]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[N:30]1[CH2:31][C:32](=[O:43])[N:33]([CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[S:34]1(=[O:35])=[O:36])[CH2:2][C@@H:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[CH:5]=[CH:4]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C1N[C@@H](CI)C=Cc2ccccc21
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@H]3C=Cc4ccccc4C(=O)N3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from (R)-3-iodomethyl-2,3-dihydrobenzo[c]azepin-1-one and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([NH:50][C:51]([CH:53]3[CH2:58][O:57][CH2:56][CH2:55][O:54]3)=[O:52])[CH:47]=[CH:48][CH:49]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:51]([CH:53]5[CH2:58][O:57][CH2:56][CH2:55][O:54]5)=[O:52])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)C3COCCO3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6COCCO6)c5)nc43)cc2)CCC1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,4-dioxane-2-carboxamide (68 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (44 mg, 66%).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][OH:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][OH:17])[CH2:9]1
Reactant: OCCNCC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCCNCC1CCNC1
Yield: 57.5 %

Procedure:
A mixture of 32.32 g of 2-[[[1-(phenylmethyl)-3-pyrrolidinyl]-methyl]amino]ethanol, 330 ml of methanol and 3 g of 20% palladium on charcoal was shaken in an atmosphere of hydrogen at about 4.5×105Pa and at room temperature for 18 hours. The solvents were then removed at reduced pressure. The residue was distilled under vacuum (bp 129°-131° C., 1.5 mm Hg) to give 11.43 g of 2-[(3-pyrrolidinylmethyl)amino] ethanol.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C]=O.[C:10](OC=C)(=O)[CH3:11]>[Ru]>[C:1]([O:7][CH:10]=[CH2:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)O
Reactant: C=COC(C)=O
Agent: [Ru]
Agent: [C]=O
Product: C=COC(=O)C(C)(C)C
Yield: 96 %

Procedure:
Vinyl pivalate (91 pounds) was prepared in two, 20 gallon-batch runs in a 30 gallon stainless steel reactor. In two batches, pivalic acid (75.5 lbs, 10 gallons) and vinyl acetate (77.9 lbs, 10 gallons) were transvinylated in the presence of 300 ppm ruthenium catalyst, described in the preceeding paragraph, at 145° C. using a 50 psig carbon monoxide reaction atmosphere for 5 hours. Reaction product was removed from the reactor by vacuum distillation (60°-130° C., 240 mm Hg) from the ruthenium catalyst without difficulty. Based on gas chromatographic analysis, 90.4% and 94.7% of the vinyl pivalate respectively formed in the two reaction batches, could be accounted for after distillation. This demonstrates that reequilibration of vinyl pivalate (and acetic acid) to vinyl acetate (and pivalic acid) was successfully controlled during distillation within 9.6% (batch 1) and 5.3% (batch 2), respectively. Mass balances for all components were better than 98%.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C@@:10]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]4)[CH:22]=3)[CH:17]=2)[CH2:14][O:13][C:12](=[O:15])[NH:11]1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[I:1][C:22]1[C:21]([O:26][C@H:27]2[CH2:28][CH2:29][C@H:30]([C:33]([F:36])([F:34])[F:35])[CH2:31][CH2:32]2)=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:24]=[CH:25][C:16]([C@:10]1([CH3:9])[CH2:14][O:13][C:12](=[O:15])[NH:11]1)=[CH:17]2
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O[C@H]4CC[C@H](C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Iodosuccinimide (588 mg, 0.00261 mol, Acros) and zirconium tetrachloride (98 mg, 0.00042 mol, Strem) was added to a solution of repurified (R)-4-methyl-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one (786 mg, 0.00200 mol) in methylene chloride (30 mL, Acros) and were stirred at room temperature for 30 min. Silica gel was added and the reaction was evaporated to dryness. The residue was purified by silica gel chromatography using 0-100% ethyl acetate in hexanes as eluent. Cis and trans isomers were fully resolved and isolated was 822 mg (79%) of pure trans product (Rf=0.31 in 1:1 hexanes/ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:13]([C:15]1[CH:16]=[C:17]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:18]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:20]=1)=[O:14]>C(OCC)C.CCCCCC>[OH:14][CH:13]([C:15]1[CH:20]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:18]=[C:17]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:16]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C#N)c1cc(C=O)cc(C(C)(C)C#N)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C#N)c1cc(C(O)c2cccnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromopyridine (0.31 g) in diethyl ether was stirred and cooled to -70° while a solution of n-butyl-lithium in hexane (1.6M, 1.33 ml) was added, followed by 2,2'-(5 formyl-1,3-phenylene)di(2-methylpropiononitrile), (0.48 g). The mixture was allowed to warm to room temperature and was then extracted with 2N aqueous hydrochloric acid (10 ml). The acid extract was separated, basified with 10N aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography, eluting with ethyl acetate, to give 2,2'-[5-(1-hydroxy-1-(3-pyridyl]methyl)-1,3-phenylene]di(2-methyl propiononitrile), mp. 117°-120°.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)(O)[O-].[Na+].OO>O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: NC(N)=O
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CCCCCCCCCCCC
Product: c1ccc(C2CO2)cc1
Yield: 45 %

Procedure:
To a mechanically stirred solution of styrene (0.01 mol), dodecane (0.001 mol), urea (0.208 mol), sodium bicarbonate (0.003 mol) and nickel (II) acetate (0.15 mmol) in 10.0 ml of water at 30° C. is added 30% aqueous hydrogen peroxide (0.45 mol) in three equal portions over a period of 3 hours. After 8 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded styrene oxide in 45% yield with selectivity 68%.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:16][C:15](=[O:25])[N:14]([CH2:26][CH3:27])[C:13]=2[N:28]=1)[CH3:8].C(OCC)(=O)C>CN(C)C=O>[C:1]([S:3][CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[N:16][C:15](=[O:25])[N:14]([CH2:26][CH3:27])[C:13]=2[N:28]=1)[CH3:8])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)Br)nc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)SC(C)=O)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Potassium thioacetate (0.54 g, 48 mmol) was added to 7-(1-bromoethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.57 g, 40 mmol) dissolved in dimethylformamide (16 ml), followed by stirring at room temperature for 2 hours. The reaction solution was mixed with ethyl acetate, washed with water and with brine, and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 7-(1-acetylthioethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.13 g, 73%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]=[C:8]=[O:9])=[CH:2]1.[N+:10](=[C:12]1[N:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11]>CS(C)=O>[O:9]=[C:8]1[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:11]=[N:10][C:12]2=[C:13]([C:17]([NH2:19])=[O:18])[N:14]=[CH:15][N:16]12
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: O=C=NCc1ccsc1
Solvent: CS(C)=O
Product: NC(=O)c1ncn2c(=O)n(Cc3ccsc3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophen-3-ylmethyl isocyanate (0.306 g, 2.2 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) removed by filtration, washed with water and ethyl acetate and air dried. Yield: 0.235 g, 42%. IR vmax/cm−1 3094, 1728, 1688, 1604. 1H NMR δH (DMSO-d6) 5.50 (2H, s, CH2Ar), 7.17 (1H, dd, J 4.9, 1.3, ArH), 7.55-7.58 (2H, m, ArH), 7.70 (1H, br s, NH), 7.83 (1H, br s, NH), 8.85 (1H, s, 6-H). δC (DMSO-d6) 48.0, 124.4, 127.3, 128.0, 129.5, 131.4, 134.9, 136.7, 139.5, 162.0.
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:8]1[N:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:11][CH:12]=1)=[CH:5]\[CH2:6][CH3:7].[OH-].[Na+].Cl>C(O)(C)C.O>[C:17]([O:16][C:14]([NH:13][C:10]1[S:11][CH:12]=[C:8](/[C:4](=[CH:5]/[CH2:6][CH3:7])/[C:3]([OH:21])=[O:2])[N:9]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC/C=C(\C(=O)OC)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC/C=C(\C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
To a solution of (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl) -2-pentenoic acid methyl ester (425 mg : 1.4 mMol.) in isopropanol (1.3 ml) and water (3.7 ml) is added sodium hydroxide (163 mg : 4.1 mMol.), and the mixture is stirred at 65° C. for 90 minutes. The reaction mixture is adjusted to pH 4.7 with 35% hydrochloric acid and kept at 20° C. for 1 hour. The separating crystals are collected by filtration, washed with isopropanol, and dried to give (Z)-2-(2-t-butoxycarbonylaminothiazol-4- yl) -2-pentenoic acid (325 mg).Yield: 86%. mP. 187° C. (decomposition). NMR δ (CDC13) ppm: 1.09(t, J=7.6Hz, 3H), 1.55(s, 9H) 2.64(qd, J=7.6Hz, 2H), 6.69(t, J=7.6Hz, 1H), 6.96(s, 1H).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[C:15]([F:16])=[CH:14][C:13]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:12][C:11]=1[F:28])=[O:5])=[N-]>ClCCCl.C1(C)C=CC=CC=1>[F:28][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[C:15]([F:16])[C:10]=1[C@H:9]1[C@H:3]2[C@@H:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: [N-]=[N+]=CC(=O)OC/C=C/c1c(F)cc(NC(=O)OCc2ccccc2)cc1F
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1cc(F)c([C@@H]2[C@H]3COC(=O)[C@H]32)c(F)c1)OCc1ccccc1

Procedure:
A solution of (2E)-3-{2,6-difluoro-4-[(benzyloxycarbonyl)amino]phenyl}prop-2-enyl diazoacetate (9.7 g, 25.04 mmol) in 100 mL of 1,2-dichloroethane was added dropwise over 14 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato)copper(II) (0.52 g, 1.25 mmol, prepared as described by R. G. Charles, J. Org. Chem. 1957, 22, 677) in toluene (1000 mL). After the addition was complete, the reaction mixture was heated for another hour at reflux, then cooled, filtered and concentrated. The crude oil was purified by column chromatography (0-1% methanol-dichoromethane) to provide the title compound as a racemate.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([CH:19]([OH:22])[CH:20]=[CH2:21])[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC(O)c1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C=CC(=O)c1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 57.9 %

Procedure:
1-{5'-[3"-(t-Butyldimethylsilyloxy)propyloxy]-2'-nitrophenyl}-2-propen-1-ol (4.98 g) is dissolved in chloroform (140 ml), and thereto is added active manganese dioxide (36 g), and the mixture is heated with stirring for six hours. The insoluble materials are removed by filtration, and the filtrate is concentrated, and the residue is purified by silica gel column chromatography to give 1-{5'-[3"-(t-butyidimethylsilyloxy)propyloxy]-2'-nitrophenyl}-2-propen-1-one (2.87 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]([C:14]2[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[O:19])=[CH:16][CH:15]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH:12]([C:14]2[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[O:19])=[CH:16][CH:15]=2)[CH3:13])[C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:32][CH:33]=2)=[O:39])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Nc1ccc(C(C)(C)C)cc1)c1ccc(C(=O)Nc2nn[nH]n2)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: CC(c1ccc(C(=O)Nc2nn[nH]n2)cc1)N(C(=O)Nc1ccc(OC(F)(F)F)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Yield: 6.3 %

Procedure:
4-[1-(4-tert-Butylphenylamino)ethyl]-N-(2H-tetrazol-5-yl)benzamide (100 mg, 0.28 mmol) and 4-trifluoromethoxyphenyl isocyanate (70 mg, 0.30 mmol) was dissolved in DMF (0.6 mL) and the solution was heated to 80° C. for 3 hours. The mixture was cooled to room temperature and subsequently taken to dryness using rotary evaporation. The residual oil was dissolved in a minimum of DMF/acetonitrile (1:1), and submitted to preparative HPLC purification. Pure fractions were pooled and concentrated to dryness to afford 10 mg (8%) of the title compound.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)NC[CH2:66][C:67]([NH:69][CH:70]2[CH2:73]N[CH2:71]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:69]([CH2:67][CH3:66])[CH:70]([CH3:71])[CH3:73])([CH3:31])[CH3:4]
Reactant: O=C(CCNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (909 mg) in anhydrous acetonitrile (13 ml), N,N-carbonyldiimidazole (346 mg) was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, N,N-diisopropylethylamine (338 μl) and a solution of the compound (1.68 g), which had been obtained in (2), in anhydrous acetonitrile (15 ml) were added and the mixture was stirred overnight at room temperature. Dichloromethane was added to the reaction mixture. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate-methanol), whereby 1.88 g of the title target compound were obtained as a colorless amorphous substance.