Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]CC)=O.C[O-].[K+].Cl[CH2:16][C:17]#[N:18]>CO>[C:17]([C:16]1[S:1][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]=1[OH:6])#[N:18]
Reactant: CCCC(=S)CC(=O)OCC
Reactant: N#CCCl
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CCCc1cc(O)c(C#N)s1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 4.6 %

Procedure:
A mixture of 77 g of ethyl 3-thioxo-hexanoate, 300 ml of methanol and 28 g of potassium methylate was stirred at 20° C. for 15 minutes and after the addition of 30.2 g of chloroacetonitrile thereto, the mixture was stirred for another 15 minutes at 20° C. The mixture was refluxed for 4 hours and the solvent was then evaporated. The residue was dissolved in ether and the ether phase was washed with methylene chloride, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The solution was then treated with activated carbon, was dried and evaporated to dryness. The residue was dissolved in toluene and the solution was iced and vacuum filtered. The recovered crystals were crystallized from a 3-1 petroleum ether-benzene mixture to obtain 3.1 g of 2-cyano-3-hydroxy-5-n-propyl-thiophene melting at 78° C.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:48][C@@H:49]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)[C:50]([NH:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C.C(OCC)C>[CH2:65]([O:64][C:61]1[CH:62]=[CH:63][C:58]([CH2:57][C@H:49]([NH:48][C:12]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:14])[C:50](=[O:51])[NH:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[CH:59][CH:60]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C1(c2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
1-Phenyl-1-cyclopentanecarboxylic acid (0.171 g, 0.899 mmol) was dissolved in dry DMF (3 mL) under a nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added in succession N,N-diisopropylethylamine (0.310 mL, 1.80 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.341 g, 0.899 mmol, Novabiochem, La Jolla, Calif.). The resulting reaction mixture was stirred at 0° C. for 30 minutes, (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (0.293 g, 0.899 mmol) was then added. After an additional 60 minutes stirring at 0° C. the reaction mixture was mixed with 60 mL of diethyl ether. The resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution and brine, and was dried over Na2SO4. The solution was concentrated in vacuo, and an oil was obtained. The crude residue was purified by chromatography (silica gel, 60% ether in hexanes) to give the title compound as a white foam (0.20 g, 45%); mp 40-50° C.
Reaction SMILES: CC1C=CC(S([CH2:11][N:12]=[CH2:13])(=O)=O)=CC=1.[C:14]([O:24][CH3:25])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1CCCC1.[H-].[Na+]>O>[C:17]1([C:16]2[C:15]([C:14]([O:24][CH3:25])=[O:23])=[CH:11][NH:12][CH:13]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c[nH]cc1-c1ccccc1
Temperature: 25 °C

Procedure:
p-Tosylmethyl isocyanide (1 g., 5 mmoles) and methyl cinnamate (0.8 g., 5 mmoles) were combined in 50 ml. of tetrahydrofuran and dissolved by stirring at room temperature. The solution was cooled to -50° C. and sodium hydride (57% dispersion in oil, 210 mg., 5 mmoles) added. After stirring for 15 minutes at -50° C., the reaction was warmed to room temperature and stirred for approximately 16 hours. Water (20 ml.) was added and the product extracted into 35 ml. ether. The ether was back-washed with 20 ml. of water, evaporated to dryness, the residue triturated with ether and methyl 4-phenylpyrrole-3-carboxylate (230 mg., m.p. 182°-185° C., m/e 201) recovered by filtration. The product was recrystallized from acetone/hexane (210 mg., m.p. 184°-187° C.).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: Oc1cccc(O)c1
Product: Oc1cccc(NCc2ccccc2)c1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Resorcinol (22 g) and 21.4 g of benzylamine were heated under an air condenser in a nitrogen atmosphere at 175°-185° C. for 5.5 hr. Then the air condenser was removed, and the temperature raised to 200°-203° where it was held for 1.5 hr. The red, viscous mass was cooled and boiled with 250 ml of 3:2 benzene-cyclohexane to form a solution. The solution was cooled several days at 5° C. to allow for the separation of oily material. The supernatant was decanted and evaporated to leave 12.0 g (30%) of pale-orange, viscous liquid 3-benzylaminophenol which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[C:19]#[N:20])[CH:16]=3)[N:11]=[C:10]([NH:28][NH2:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C1COCC1.[N:36]([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[C:19]#[N:20])[CH:16]=3)[N:11]3[N:36]=[N:29][N:28]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(c1ccc(I)cc1)c1ccc2nc(NN)nc(-c3cccc(Cl)c3)c2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 5 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Intermediate (41) (0.0121 mol) was added at 5° C. to a mixture of HCl 1N (60 ml) and THF (60 ml). A solution of sodium nitrite (0.0133 mol) in water (20 ml) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour then brought to room temperature, stirred at room temperature for 5 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc; 70/30; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 3.8 g (60%) which were crystallized from 2-propanone/CH3CN. The precipitate was filtered off and dried till dryness, yielding 3.5 g (55%) of 5-(3-chlorophenyl)-α-(4-iodophenyl)-tetrazolo[1,5-α]quinazoline-7-acetonitrile (intermediate 42).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:18])=[C:11]([CH3:17])[C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.Cl.[N:20](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[OH:21].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:17][C:11]1[C:12](=[O:16])[O:13][C:14]2[C:9]([C:10]=1[CH3:18])=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][C:22](=[N:20][OH:21])[CH2:23][CH2:24]1)[CH:15]=2
Reactant: Cc1c(C)c2ccc(OCCCBr)cc2oc1=O
Reactant: ON=C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)c2ccc(OCCCN3CCC(=NO)CC3)cc2oc1=O

Procedure:
By the reaction of 7-(3-bromopropoxy)-3,4-dimethylcoumarin with 4-oximino-piperidine hydrochloride in dioxane solution in the presence of a Hunig base, there is obtained 3,4-dimethyl-7-[3-(4-oximino-piperidino)-propoxy]-coumarin (m.p. 198°-200° C.), from which, by catalytic hydrogenation over Raney nickel in ammoniacal methanol, there is obtained 7-[3-(4-amino-piperidino)-propoxy]-3,4-dimethyl-coumarin; m.p. 92°-94° C.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=O.Cl>CO.O1CCCC1.C(=O)(O)[O-].[Na+]>[NH2:3][C:4]1[S:5][C:6]([CH2:9][C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(NC=O)s3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(N)s3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-5-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylic acid (4.67 g) and conc. hydrochloric acid (4.67 g) in methanol (93 ml) and tetrahydrofuran (46 ml) was stirred at 30° C. for 4 hours. After the organic solvent was removed by evaporation, to the residue was added water (70 ml), followed by adjusting to pH 6 to 7 with 10% aqueous solution of sodium hydroxide. After the insoluble substance was removed by filtration, the filtrate was adjusted to pH 3.0 with 10% hydrochloric acid under cooling, followed by stirring at the same temperature for 20 minutes. The precipitated substance was collected by filtration, washed with water and dried to give a residue, which was dissolved in an aqueous solution of sodium bicarbonate and then chromatographed on alumina (12 ml) using 5% aqueous sodium acetate as an eluent. The fractions containing the desired compound were collected and acidified to pH 3.1 with 10% hydrochloric acid, and the precipitated substance was collected by filtration and then dried to give 7-[2-(2-aminothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (1.52 g), mp>290° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H+].[B-:13]([F:17])([F:16])([F:15])[F:14].CC(C)CCO[N:23]=O.C(OCC)C>O1CCCC1>[F:14][B-:13]([F:17])([F:16])[F:15].[N:1]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]#[N:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CCON=O
Reactant: Nc1ccc2ncccc2c1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#[N+]c1ccc2ncccc2c1
Reaction time: 1 h

Procedure:
To a solution of quinolin-6-yl amine (2.88 g, 20 mmol) and HBF4 aqueous solution (48% W/W, 11 mL) in tetrahydrofuran (100 mL) was added 3-methyl-1-nitrosooxy-butane (10.7 mL, 60 mmol) dropwise under nitrogen atmosphere at from −10° C. to −15° C., then, the mixture was stirred for 1 hour. At from −10° C. to −15° C., diethyl ether (200 mL) was added dropwise, the precipitated solid was collected by filtration, washed with diethyl ether, dried, and quinolin-6-diazonium tetrafluoroborate (6.85 g) was obtained as a yellow-red solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][N:13]([C:19]3[CH:28]=[C:27]4[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]4[CH:29]4[CH2:31][CH2:30]4)=[CH:21][C:20]=3[F:36])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C.[CH3:49][S:50]([OH:53])(=[O:52])=[O:51]>ClCCl.C(O)C>[CH3:49][S:50]([OH:53])(=[O:52])=[O:51].[CH:29]1([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:36])=[C:19]([N:13]4[CH2:14][C:15](=[N:16][O:17][CH3:18])[C:10]5([CH2:11][NH:8][CH2:9]5)[CH2:12]4)[CH:28]=3)[C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25]2)[CH2:30][CH2:31]1
Reactant: CON=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C(=O)OC(C)(C)C)C2
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CON=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CNC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.5 %

Procedure:
7-[2-(t-butoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cyclo propyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolincarboxylic acid was dissolved in 5 ml of dichloromethane and thereto 1 ml of trifluoroacetic acid was added by dropping. The resulting mixture was stirred at room temperature for 18 hours, and thereto 10 ml of ethylether was added. The resulting precipitate was filtered and dried. Thus obtained solid was dissolved in 2 ml of diluted NaOH and neutralized with diluted hydrochloric acid, and the resulting precipitate was filtered and dried. The solid thus obtained was added to 2 ml of 1N-methanesulfonic acid in ethanol and stirred at room temperature for 3 hours. The precipitate was filtered and dried to give 35 mg of the titled compound (yield: 28.5%).
Reaction SMILES: [CH3:1][C:2]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][CH:16]=2)([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C([O-])=O.[NH4+]>C1COCC1.O.[Pd]>[NH2:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:2]([CH3:12])([CH3:1])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[CH:21]2
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C)(C)c1cc2cc(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
To a solution of tert-butyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propylcarbamate (80 mg, 0.24 mmol) in THF (9 mL) and water (2 mL) was added ammonium formate (60 mg, 0.96 mmol) followed by 10% Pd/C (50 mg). The mixture was stirred at room temperature for 45 minutes. Pd/C was filtered off and the organic solvent was removed by evaporation. The remaining aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated to give tert-butyl 2-(5-amino-1H-indol-2-yl)-2-methylpropylcarbamate (58 mg, 80%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]=2[C:21]([NH2:23])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:21]([C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[CH:19]=[CH:20][C:11]=1[NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])#[N:23]
Reactant: NC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Reaction time: 3 h

Procedure:
2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid amide (Intermediate 2, 1.2 g) was dissolved in dry DCM (20 mL) and phosphorous pentachloride (0.9 g) was added. The mixture was stirred for 3 hours then saturated aqueous sodium hydrogencarbonate was added carefully and the products were extracted into ethyl acetate. The organic solution was dried with magnesium sulfate, filtered and the solvent was removed by evaporation. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and the solvent was evaporated to give the title compound as an off-white solid.
Reaction SMILES: [NH:1]([C:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH3:17])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:10]1[C:11]([CH3:17])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)(=[O:20])[CH3:19]
Reactant: COC(=O)c1c(Nc2ccccc2)n[nH]c1C
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1c(Nc2ccccc2)nn(C(C)=O)c1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
23 g of 3-anilino-4-methoxycarbonyl-5-methylpyrazole is dissolved in 51 g of acetic anhydride and brought to the boil. After 15 minutes' boiling the mixture is allowed to cool, poured into ice water and stirred for 30 minutes. The solid which separates is isolated and recrystallized from methanol; m.p. 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)CCCC.[Cu].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([OH:21])=[O:20])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: Nc1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloro-1-fluoro-2-nitrobenzene (20 g, 114 mmol) and anthranilic acid (17.4 g, 127 mmol) in pentanol (250 mL) was heated to 120° C. in a Dean-Stark apparatus. Copper (126 mg, 2 mmol) was added, followed by potassium carbonate (12.7 g, 92 mmol). The resulting reaction mixture was stirred at 120° C. for 0.5 h and at 140° C. for 2 h. Subsequently, water and 1N (aq.) NaOH were added to dissolve the product. Then, the pH was adjusted to pH 5 and the water layer was extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried and evaporated. Ethanol was added to the obtained product. The title compound (14.4 g, 43%) was collected by filtration of the ethanol mixture.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21].O>CC(N(C)C)=O>[CH3:17][O:18][CH2:19][C:20]([NH:1][C:2]1[C:10]([I:11])=[C:6]([C:7]([Cl:9])=[O:8])[C:5]([I:12])=[C:4]([C:3]=1[I:16])[C:13]([Cl:15])=[O:14])=[O:21]
Reactant: COCC(=O)Cl
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 5 °C

Procedure:
5-Amino-2,4,6-triiodoisophthaloyl chloride prepared in Example 1 (59.6 g, 0.1 g-mole) is dissolved in DMAc (100 ml). The solution is cooled to 5° C. and methoxyacetyl chloride (21.7 g 0.2 g-mole) is added slowly keeping the temperature at 5°-10° C. When the addition is complete, the reaction mixture is allowed to warm to room temperature and stirred until the reaction is complete. The solution is cooled to room temperature and poured slowly into 1 L of cold water (0°-5° C.) with stirring to precipitate the product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21]Cl)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCCl)Cc1cccc(CC(=O)OC)c1
Reactant: C1COCCN1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN1CCOCC1)Cc1cccc(CC(=O)OC)c1

Procedure:
The title compound was prepared by the method of example 11 step (x) using the product from example 11 step (ix) (627 mg) and morpholine (1 ml) to give product as a white solid 165 mg.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][C:15]([CH2:18][OH:19])=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:18]([C:15]1[N:16]=[CH:17][N:11]2[C:10]([C:8]3[CH2:9][C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:33](=[O:34])[N:6]4[C:7]=3[C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[CH:14][S:13][C:12]=12)=[O:19]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4c(CO)ncn34)C[C@H]12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4c(C=O)ncn34)C[C@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution 428 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate in 30 ml of dichloromethane was added 1.03 g of manganese dioxide, and the mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue thus obtained was washed with diethyl ether to give 202.8 mg of 4-nitrobenzyl (5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][C:5]=1[CH:6]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOc1ccc(OCC)c(C=O)c1
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cc(OCC)ccc1OCC)C(=O)OCC
Yield: 91.9 %

Procedure:
2,5-Diethoxybenzaldehyde (24 g., 0.124 mole) and diethyl malonate (20 g., 0.125 mole) are added to a solution of piperidine (3.0 g.) and glacial acetic acid (6 ml.) in benzene (160 ml.). The mixture is heated under reflux utilizing a Dean-Stark water separater until water ceased to be separated. After 8 hours of distillation 2.3 ml. of water out of a theoretical yield of 2.23 ml. are obtained and the reaction mixture cooled. The cooled reaction mixture is washed with aqueous hydrochloric acid (6 N, 70 ml.) water (70 ml.) and aqueous sodium bicarbonate (5% w/w, 50 ml.). The organic layer is separated, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield a yellow oil (42.7 g., 0.127 mole, 100%). Trituration with petroleum ether yields diethyl 2,5-Diethoxybenzylidenemalonate (38.4 g., 0.114 mole, 92%) m.p. (from petroleum ether) 52°-53° C. I.R.: 1720 cm- 1 mass spec m/e 336.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH:6]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[C:20]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([CH3:32])[CH:21]=1.Cl.C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:20]1[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[C:22]([CH3:32])[CH:21]=1)[CH:7]([CH3:12])[CH:6]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CCOC(=O)CC1c2cc(OC)ccc2NC1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1c2cc(OC)ccc2N(c2cc(C)nc(-c3ccccc3)n2)C1C

Procedure:
A mixture of ethyl 5-methoxy-2-methylindolin-3-ylacetate (2.0g.), 6-chloro-4-methyl-2-phenylpyrimidine (1.76g.) and concentrated hydrochloric acid (0.5ml.) in ethanol (50ml.) was heated under reflux for 5 hours. The solution was cooled, saturated sodium acetate solution (3ml.) was added, and the mixture was concentrated in vacuo. The residue was diluted with water (30ml.) and extracted with ethyl acetate (3 × 30ml.). The combined exracts were washed with water and then dried (Na2SO4), and the solvent was evaporated in vacuo at ca 50° C. to give ethyl 5-methoxy-2-methyl-1-(4-methyl-2-phenylpyrimidin-6-yl)indolin-3-ylacetate as a syrup. This was shown to be pure by TLC (System A) and by NMR spectroscopy (OCH3 at 6.23τ).