Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si:29]([CH3:32])([CH3:31])[CH3:30])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2cc(Br)cnc2n1S(=O)(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a well stirred solution of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (6.0 g, 17.8 mmol) in dry THF (60 mL) was added LDA (2M in THF; 16.0 mL, 32 mmol) at −78° C. slowly over 15 min. The reaction mixture was stirred at −70° C. for 1 h and then cooled back to −78° C. Chlorotrimethylsilane (4.1 mL, 32 mmol) was added slowly, and the reaction mixture was allowed to warm to ambient temperature over 4 h (TLC monitoring: 20% ethyl acetate in hexanes). Solvent was removed under reduced pressure keeping temperature below 40° C. to give a residue. It was extracted with ethyl acetate (2×50 mL) and washed with water (40 mL), followed by brine (10 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield a brown solid which was purified by column chromatography using 10% ethyl acetate in hexanes to yield the title compound as a white solid (4.8 g, 66%). 1H NMR (CDCl3, 300 MHz): δ=0.51 (s, 9H), 6.72 (s, 1H), 7.47-4.59 (m, 3H), 7.91 (d, J=2.1 Hz, 1H), 8.09-8.12 (m, 2H), 8.37 (d, J=2.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH2:17]Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:14][C:12]([CH:11]1[CH2:17][NH:1][C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[O:9]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(Br)CBr
Reactant: Nc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(Br)ccc2O1
Yield: 78.2 %

Procedure:
A mixture of 2-amino-4-bromophenol (5.00 g, 26.6 mmol), ethyl 2,3-dibromopropionate (7.84 g, 29.2 mmol), and potassium carbonate (10.3 g, 81.8 mmol) in acetone (55 mL) was heated at reflux for 16 h. After evaporation of volatile material, the residue was partitioned between dichloromethane and water. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient produced 6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (5.95 g, 78%). Orange solid, MS (ISP)=286.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:8][C:9]1(C)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])([CH3:4])([CH3:3])[CH3:2].C(C(C)=O)CCC>>[C:21]([C:18]1[CH:17]=[C:7]([CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:19]=1[OH:20])[CH2:8][CH:9]([C:10]([CH3:11])=[O:15])[CH2:14][CH2:13][CH3:12])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC1(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCCCC1=O
Solvent: CCCCC(C)=O
Product: CCCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)=O
Yield: 60 %

Procedure:
If, in this example, the 2-methylcyclohexanone is replaced by an equivalent quantity of methyl n-butyl ketone, an otherwise identical procedure gives methyl [1-(3,5-ditert.-butyl-4-hydroxybenzyl)-n-butyl] ketone, which boils at 120° C. at 0.01 mm Hg and is an oil, in a yield of 60%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:28]=[N:29][C:24]([N:23]([CH3:22])[CH3:41])=[CH:25][CH:26]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:34][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)nc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)nc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 78.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.54 g) as starting materials, 5-benzyloxy-N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) was obtained.
Reaction SMILES: C1COCC1.O.[CH3:7][O:8][C:9](=[O:32])[C:10]1[CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.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>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[C:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)=[O:32]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
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: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Temperature: 130 °C
Yield: 90.8 %

Procedure:
To a mixture of THF/H2O (5 mL, v/v=4:1) in a microwave vial was added 3-benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (100 mg, 0.256 mmol), phenylboronic acid (34 mg, 0.281 mmol), potassium carbonate (71 mg, 0.512 mmol), and Pd(PPh3)4 (15 mg, 0.02 mmol). The reaction vessel was sealed and subjected to microwave heating for 5 min at 130° C. After cooling, it was diluted with diethyl ether and washed with brine, dried (MgSO4), and evaporated. The residue was subjected to chromatography on silica gel using an ethyl acetate-hexane gradient to afford 74 mg (90%) of 5-benzyloxybiphenyl-3-carboxylic acid methyl ester: LCMS m/z=319.4 [C21H18O3+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:22]=2)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C1CC1
Temperature: 150 °C
Yield: 97.8 %

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (66 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (35 mg) and DBU (0.027 mL) in DMA (1 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (52 mg). LC-MS ESI+: 449 (M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[CH:3]=[N:2]1.O.[OH-].[Li+]>O1CCCC1.CO.O>[NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
4.2 g of methyl 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoate and 50 ml of a tetrahydrofuran/methanol/water 2/1/1 mixture are introduced into a 250 ml round-bottomed flask equipped with a magnetic stirrer and placed in an ice bath. 1.63 g of lithium hydroxide monohydrate are added and the reaction mixture is stirred at ambient temperature for 18 h. After evaporating the organic solvents, citric acid is added up to pH 5. The precipitate is filtered off and dried under vacuum. 3.87 g of 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoic acid are obtained.
Reaction SMILES: [CH2:1]1[C:4]2[CH:5]=C[C:7](C(C3C=CC=CC=3)(C3C=CC=CC=3)O)=[CH:8][C:3]=2[CH2:2]1.[C:23]([Cl:26])(=O)[CH3:24].[C:27]1(C)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:26][C:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24]1[CH:7]=[CH:8][C:3]2[CH2:2][CH2:1][C:4]=2[CH:5]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccc2c(c1)CC2
Reactant: Cc1ccccc1
Reactant: CC(=O)Cl
Product: ClC(c1ccccc1)(c1ccccc1)c1ccc2c(c1)CC2

Procedure:
(1,2-dihydrocyclobutabenzen-4-yl)diphenylmethanol (0.8 g, 2.8 mmol) and acetylchloride (20 ml, 280 mmol) was refluxed in 30 mL of toluene for 2 hours. The solvent was then evaporated under reduced pressure. The residue was used for the next step without purification. 0.8 g of the product was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:16]([O:18]CC)=[O:17])=[C:6]1[S:15][CH2:14][CH2:13][N:7]12.C(O)C.O.C(O)(=O)C>[OH-].[Na+]>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:16]([OH:18])=[O:17])=[C:6]1[S:15][CH2:14][CH2:13][N:7]12
Reactant: CCOC(=O)c1c2n(c3ccc(Cl)c(Cl)c3c1=O)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c2n(c3ccc(Cl)c(Cl)c3c1=O)CCS2
Yield: 63.3 %

Procedure:
Ethyl 6,7-dichloro-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylate (1.0 gram, 2.9 mmol) obtained in Example 3 was suspended in a mixture of 2.0 grams of sodium hydroxide, 140 ml of ethanol and 60 ml of water, the mixture was heated to reflux for thirty minutes, acidified with acetic acid when it was still hot, crystals separated out were collected by filtration, washed with water, and dried and recrystallized from dimethyl formamide to give 580 mg (62.8 percent) of the title compound. Melting point 305° to 310° C. (decomposition). Elementary analysis calculated as C12H7Cl2NO3S: C 45.59, H 2.23, N 4.43; Found: C 45.85, H 2.19, N 4.37.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C.O>[Cl:11][C:10]1[C:3]2[C:2]([NH:23][CH:21]([C:18]3[CH:19]=[CH:20][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=3)[CH3:22])=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Clc1csc2ncnc(Cl)c12
Reactant: CC(C)c1ccc(C(C)N)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(C)Nc2ncnc3scc(Cl)c23)cc1
Yield: 87.2 %

Procedure:
A mixture of 4,5-dichlorothieno[2,3-d]pyrimidine (prepared as taught in EP 447,891) (775 mg, 3.8 mmol), 1-(4-isopropylphenyl)ethanamine (compound 95) (734 mg, 4.5 mmol), and triethylamine (767 mg, 7.6 mmol) in DMF (20 mL) was allowed to react for 24 hours at 20° C. The reaction mixture was diluted with water and extracted thrice with Et2O. The organic portions were combined, washed with brine, and dried (Na2SO4). The mixture was filtered through silica gel, and the solvent was removed in vacuo. The residue was purified by flash chromatography (15 percent Et2O in pentane), yielding 1.1 g of oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CCN(C(C)C)C(C)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[N+:12]([C:4]1[CH:3]=[C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
Dissolve 1-bromo-3-nitro-5-(trifluoromethyl)benzene (270 mg, 1 mmol) and DIEA (258 mg, 2 mmol) in DMF (5 mL), add morpholine (174 mg, 2 mmol). Stir the reaction at 120° C. overnight. Cool to room temperature; remove the volatiles under reduced pressure to give a crude residue. Purification of the residue by chromatography (silica gel, EtOAc:PE=1:5) affords the product (138 mg, 50%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[N:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])C.C1COCC1.O.[OH-].[Li+].O>>[CH2:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:30]=[N:29][N:28]=2)=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: CCCn1cc(C(=O)OCC)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1cc(C(=O)O)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 40 h
Yield: 99.3 %

Procedure:
1-Propyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1H-imidazole-4-carboxylic acid ethyl ester (400 mg, 607 μmol) was dissolved in THF (12.0 mL, 148 mmol). A solution of lithium hydroxide monohydrate (127 mg, 3.0 mmol) in water (4.0 mL, 222 mmol) was then added and the mixture was stirred at 40° C. for ˜40 hours to yield the title compound (380 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C=O)C>[CH2:31]([C:30]1[N:38]=[C:13]([CH:12]=[CH:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:15][N:29]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N=C(Cc1ccccc1)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=Cc2nc(Cc3ccccc3)no2)cc1OC
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 2.0 g, 9.6 mmol) was dissolved in DMF (20 mL) to which 1,1′-carbonyldiimidazole (CDI) (1.71 g, 10.56 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-2-phenyl-acetamidine (1.58 g, 10.56 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After the completion of the reaction, additional CD (1.71 g, 10.56 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 8 h to effect cyclodehydration. DMF was evaporated and the residue obtained was cooled to room temperature followed by addition of water (15 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[NH:10][C:11](=O)[NH:12][C:13](=O)[C:8]=3[O:7][C:6]=2[N:16]=1.P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)[Cl:25].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[Cl:25][C:11]1[N:12]=[C:13]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:8]2[O:7][C:6]3[N:16]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:9]=2[N:10]=1
Reactant: C1COCCN1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(n1)oc1c(=O)[nH]c(=O)[nH]c12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Product: Cc1ccc2c(n1)oc1c(N3CCOCC3)nc(Cl)nc12
Temperature: 115 °C
Yield: 30 %

Procedure:
To a mixture of 7-methyl-1H-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-2.4-dione (1.6 g, 4.20 mmol, 1 eq) 17, and PCl5 (10.5 g, 50 mmol, 12 eq) was added at rt POCl3 (33.5 mL, 357 mmol, 85 eq) under Ar(g). The reaction mixture was refluxed at 115° C. overnight. Once cooled down to rt, the mixture was poured dropwise very slowly onto stirred crushed ice over 2 h, then warmed up to rt for 1 h. The resulting aqueous was extracted with EtOAc (3×100 mL) and CH2Cl2 (4×100 mL). The combined organics were dried over MgSO4 and the solvent was removed in vacuo. To this residue in dry MeOH (50 mL) was added at rt morpholine (0.92 mL, 10.5 mmol, 2.5 eq) under Ar(g). The reaction mixture was stirred for 3 h, then the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:1-0:1) to yield the product as a pale brown solid (384 mg, 30%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([O:12][CH2:13][CH2:14][CH:15]1[NH:18][C:17](=[O:19])[CH2:16]1)(=[O:11])[CH3:10]>CCN(CC)CC>[Si:1]([N:18]1[CH:15]([CH2:14][CH2:13][O:12][C:9](=[O:11])[CH3:10])[CH2:16][C:17]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OCCC1CC(=O)N1
Solvent: CCN(CC)CC
Product: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
Triethylauine (Et3N) (2.96 ml, 21.2 mmol) and t-butyldimethylsilyl chloride (3.059 g, 20.3 mmol) are added to an ice-cold stirring solution of 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g, 19.3 mmol) in anhydrous dimethylformamide(DMF) (20 ml). A white precipitate appears immediately. The cooling bath is removed and the mixture is stirred at 25° C. (room temperature) for 5 mins. The mixture is diluted with benzene (200 ml), washed with H2O (5×80 ml) and brine, dired with MgSO4, filtered, and evaporated under reduced pressure to afford N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (5.078 g) as an off white solid: ir(neat) 5.75, 8.08, 8.41, 11.92, and 12.18 cm-1 ; nmr(CDCl3) δ0.25 (s, 6), 0.98 (s, 9), 1.97 (m, 2), 2.05 (s, 3), 2.67 (dd, 1), 3.20 (dd, 1) 3.62 (m, 1), and 4.12 (t, 2); mass spectrum m/e 214 (M+ -57) and 172.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][C:30]([S:33]([C:36]2[N:37]=[CH:38][N:39]3[CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:41][C:40]=23)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:42]3[S:41][C:40]4=[C:36]([S:33]([C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)(=[O:35])=[O:34])[N:37]=[CH:38][N:39]4[CH:43]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)c3ccncc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)c5ccncc5)c4s3)[C@H](C)[C@H]12
Yield: 55.1 %

Procedure:
The procedure of Example 1a) was repeated, except that 503 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 808 mg of 7-(pyridin-4-yl)sulfonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 466 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)sulfonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[N:15][C:16]#[N:17])[N:10]([CH3:18])[CH2:9]2)=[CH:4][C:3]=1[C:19]1[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH:20]=1.[C:27]([C:29]1[N:30]=[C:31]([C:42](O)=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1(C2C=C(C3CC(=O)NC(=O)C3)C=CC=2NC(C2NC=C(C#N)N=2)=O)CCCCC=1>>[C:16]([N:15]=[C:11]1[N:12]([CH3:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:31]3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=3)=[O:43])=[C:3]([C:19]3[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH:20]=3)[CH:4]=2)[CH2:9][N:10]1[CH3:18])#[N:17]
Reactant: CN1CC(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CN(C)C1=NC#N
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CC(=O)NC(=O)C3)cc2C2=CCCCC2)n1
Product: CN1CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCC(C)(C)CC3)c2)CN(C)C1=NC#N

Procedure:
5-[4-Amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide (as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1) as described in Example 1, step (1) to obtain the title compound: Mass spectrum (ESI, m/z): Calcd. for C32H44N8O2Si, 601.3 (M+H). found 601.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]=1[CH2:10]Br)=[O:4].COC(C1SC(C2C=CC(F)=CC=2)=C(C2C=CC(SC)=CC=2)C=1CBr)=O.FC1C=CC(C=O)=CC=1.[C-:61]#[N:62].[K+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]=1[CH2:10][C:61]#[N:62])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)c(-c2ccc(SC)cc2)c1CBr
Reactant: [C-]#N
Agent: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(SC)cc2)c1CBr
Agent: O=Cc1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1sc(-c2ccccc2)c(-c2ccc(SC)cc2)c1CC#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 3-bromomethyl-4-(4-(methylthio)phenyl)-5-phenyl-thiophene-2-carboxylic acid methyl ester (1 g, prepared by using the same procedure described for 3-bromomethyl-5-(fluorophenyl)-4-(4-(methylthio)phenyl)thiophene-2-carboxylic acid methyl ester of Example 8, Step 2 but substituting benzaldehyde for 4-fluorobenz-aldehyde) in DMSO (25 mL) in an ice bath was added powdered KCN. The mixture was stirred for 15 minutes at R.T., then H2O was added and the mixture was extracted with Et2O (2X), the organic layers were combined, washed with brine, dried over MgSO4, filtered and the solvent was evaporated under vacuum. Purification by silica gel chromatography afforded the title compound.