Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21].O>C1COCC1>[C:20]([O:23][CH2:24][C:25]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12])=[O:26])(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)NCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl N-(3-aminopropyl)carbamate (1.00 g, 5.74 mmol) in THF (10 mL) were added triethylamine (1.6 mL, 11.5 mmol) and acetoxyacetyl chloride (0.678 mL, 6.31 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (30 mL), and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:4) to give the title compound (1.35 g, 86%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15])[CH:8]=2)=[O:4].[OH-].[K+].Cl>C1COCC1.O>[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15])[CH:8]=2)([OH:4])=[O:2]
Reactant: COC(=O)c1cc2ccc(C(=O)NCCc3ccccn3)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1ccccn1)c1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 82.6 %

Procedure:
A mixture of 2-(methoxycarbonyl)-N-[2-(2-pyridinyl)-ethyl]indole-6-carboxamide (326 mg, 1.01 mmol) and KOH (68 mg, 1.21 mmol) in THF (20 mL) and H2O (3 mL) was stirred at 20° C. for 15 h then at 65° C. for 3 h, cooled and neutralised with 2N HCl (0.61 mL, 1.2 mmol). The THF was evaporated, the aqueous residue allowed to cool, and the solid filtered off and dried to give 2-carboxy-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide as a white solid (258 mg, 83%), mp 198-199° C. 1H NMR [(CD3)2SO] δ13.14 (br s, 1H, CO2H), 12.07 (s, 1H, indole NH), 8.59 (t, J=5.6 Hz, 1H, amide NH), 8.54-8.51 (m, 1H, H-6'), 7.95 (s, 1H, H-3 or H-7), 7.71 (td, J=7.7, 1.7 Hz, 1H, H-4'), 7.68 (d, J=8.5 Hz, 1H, H-4), 7.53 (dd, J=8.5, 1.4 Hz, 1H, H-5), 7.29 (d, J=7.8 Hz, 1H, H-3'), 7.23 (ddd, J=7.4, 4.7, 0.8 Hz, 1H, H-5'), 7.13 (d, J=1.2 Hz, 1H, H-3 or H-7), 3.64 (q, J=6.8 Hz, 2H, NHCH2CH2 py), 3.02 (t, J=7.4 Hz, 2H, NHCH2CH2 py); 13C NMR δ166.7 (CONH), 162.5 (CO2H), 159.2 (C-2'), 136.5, 130.6, 130.5, 128.7 (C-2,6,8,9), 149.0, 136.4, 123.1, 121.4, 118.7, 112.2, 107.0 (one peak doubled or not observed, C-3,4,5,7,3',4',5',6'), 39.3, 37.3 (NHCH2CH2 py). Anal. (C17H15N3O3) C,H,N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:50]5[CH:49]=[N:48][N:47]([CH2:46][C:45]6[CH:61]=[CH:62][CH:63]=[C:43]([F:42])[CH:44]=6)[CH:51]=5)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(I)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Yield: 18.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 50) (150 mg, 0.215 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (78 mg, 0.258 mmol) using sodium carbonate (68 mg, 0.645 mmol) and Pd(PPh3)2Cl2 (8 mg, 0.0107 mmol) in toluene/ethanol/water (5/2.5/1 ml) to afford 30 mg (18.7% yield) of titled compound after purification by preparative TLC (Silicagel-1000 micron) using 1% methanol in DCM as eluent.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:10]=[C:9]([CH3:11])[S:8][C:7]=1[CH3:12].Cl[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>ClCCl>[Br:5][C:6]1[C:10]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH3:11])[S:8][C:7]=1[CH3:12]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc(Br)c(C)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Under a nitrogen atmosphere, aluminium chloride (1.46 g, 11 mmol) was added per portions at 0° C. to a solution of 3-bromo-2,5-dimethylthiophene (17b) (1.05 g, 5.49 mmol) and ethyl chlorooxoacetate (614 μL, 5.5 mmol) in dichloromethane (12 mL). After 2 hours of vigorous stirring, the reaction mixture was slowly hydrolyzed at 0° C. with water. The organic layer was separated, washed with hydrochloric acid aqueous solution 1N, brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5)) to afford the desired keto-ester (17c) as a orange solid (630 mg, 2.16 mmol, 39%).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](O)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>N1C=CC=CC=1>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])=[O:29])([OH:28])=[O:27]
Reactant: O=C(O)CCCCC(=O)O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2[C@]2(C(=O)CCCCC(=O)O)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 500 mg of guanosine in anhydrous pyridine was added adipic acid (5 mol eq) and bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOPDC) (1.0 mol eq.). The mixture was allowed to stir at room temperature for 18 h, then the solvent was removed in vacuo. The residue was added to 100 mL of ice-cooled water and the aqueous layer adjusted to pH 3.0 and then extracted three times with 60 mL of ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on a silica gel column and eluted with a mixture of chloroform-ethanol, whereupon the eluate was evaporated in vacuo.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([CH3:19])[C:16](O)=[O:17])(=[O:13])=[O:12].C1C=CC=CC=1.S(Cl)([Cl:28])=O>CCCCCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([CH3:19])[C:16]([Cl:28])=[O:17])(=[O:13])=[O:12]
Reactant: C[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)Cl
Reaction time: 18 h

Procedure:
2 g of (S)-2-(2-naphthylsulfonylamino)propionic acid are added to 50 ml of anhydrous benzene, and 2.04 ml of thionyl chloride are added thereto. The mixture is stirred at 40° to 50° C for 18 hours. The reaction mixture is condensed to dryness under reduced pressure, and the residue is recystallized from a mixture of benzene and n-hexane. 1.6 g of (S)-2-(2-naphthylsulfonylamino)propionyl chloride are obtained.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:1]([CH:2]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(C)O)nn1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccccc2)nn1
Reaction time: 18 h
Yield: 70.4 %

Procedure:
To a solution of methyl 6-(1-hydroxyethyl)pyridazine-3-carboxylate (100 mg, 0.55 mmol), phenol (78 mg, 0.8 mmol), triphenylphosphine (216 mg, 0.8 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (166 mg, 0.8 mmol) at room temperature. The mixture solution was stirred for 18 hours. Then tetrahydrofuran was removed in vacuo. The residue was purified by column chromatography (silica-gel, petroleum/ethyl acetate=5:1) to give methyl 6-(1-phenoxyethyl)pyridazine-3-carboxylate as a colorless oil (100 mg, 70%). 1H NMR (300 MHz, DMSO-d6): δ 8.20 (d, J=9 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 7.20-7.25 (m, 2H), 6.87-6.94 (m, 3H), 5.87-5.90 (m, 1H), 3.94 (s, 3H), 1.68 (d, J=6 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.CO.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])[CH3:15].N1CCCCC1>CC(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:15]/[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])=[CH:2]1
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCNCC1
Product: O=C(/C=C/c1c[nH]c2ccccc12)c1ccccn1

Procedure:
Indole-3-carboxaldehyde (200 mg, 1.38 mmol) was added to a dried 100 mL round bottom flask under argon and anhydrous methanol (8 mL) was added. 2-Acetyl-pyridine (232 μL, 2.07 mmol) and piperidine (69 μL, 0.7 mmol) were added and the reaction was stirred under reflux for 24 hours, after which still no precipitate had formed (AcOH did not lead to precipitation). The crude reaction mixture was concentrated and directly applied to a silica column for chromatography (ethyl acetate:hexanes 1:1). The product was partially separated from the aldehyde starting material (some product coeluted with aldehyde and was discarded), and 80 mg (23%) of purified product was isolated. NMR: 1H NMR (600 MHz, d6-DMSO): δ 11.989 (s, 1H, N—H), 8.831-8.819 (m, pyr-H2), 8.220-8.194 (d, J=15.6, 1H, C═CH), 8.154-8.105 (m, 3H, C═CH, indole-H2, pyr-H3), 8.052-8.027 (m, 1H, pyr-H4), 7.976-7.962 (m, 1H, indole-H4), 7.679-7.656 (m, 1H, pyr-H5), 7.522-7.508 (m, 1H, indole-H7), 7.285-7.262 (m, 2H, indole-H5,6). 13C NMR (150 MHz, d6-DMSO): δ 188.2, 154.3, 149.1, 139.3, 137.7, 137.6, 134.2, 127.1, 125.1, 122.3, 122.2, 121.4, 120.1, 114.3, 113.1, 112.7. Melting Point: 141-145° C. TLC: (ethyl acetate:hexanes 4:1) Rf=0.40. Elemental analysis calculated for C16H12N2O.0.1C4H8O2: C, 76.62; H, 5.02; N, 10.90. found: C, 76.41; H, 5.03; N, 10.80.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:37][C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:36][CH:35]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 8 h

Procedure:
In the same manner as described in Referential Example 13, 3.0 g of p-dodecyloxybenzoic acid chloride and 2.0 g of p-benzyloxyphenol were dissolved in 50 ml of tetrahydrofuran, 1.5 g of triethylamine was added to the solution, and reaction was carried out at room temperature overnight. The obtained 4-benzyloxyphenyl 4-dodecyloxybenzoate was isolated, and reduction was carried out under a hydrogen pressure of 25 kg/cm2 by using Pd/C as the catalyst to obtain 2.3 g of 4-hydroxyphenyl 4-dodecyloxybenzoate.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:30]([CH3:32])[CH3:31])[C:12]([O:14][CH:15](Cl)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)=[O:13])=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:30]([CH3:32])[CH3:31])[C:12]([O:14][CH:15]([C:1]#[N:2])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: CC(C)C(C(=O)OC(Cl)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
1.5 g of potassium cyanide were added to a mixture of 80 ml of acetonitrileand the solution obtained in Example 9 and the mixture was stirred at 20° C. for 72 hours. Ether was added to the mixture which was then filtered to remove insolubles. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 95-5 cyclohexane-acetone mixture yielded 6.5 g of RS α-cyano-3-phenoxy-benzyl 2-(p-chlorophenyl)-2-isopropyl-acetate.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:25]2[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=2)[CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>>[CH3:24][C:10]1[CH:9]=[C:8]([C:25]2[N:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[O:27][N:26]=2)[CH:7]=[C:6]([CH3:5])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:4][N:3]=[C:1]([CH3:2])[CH:23]=1
Reactant: CC=NO
Reactant: C#CCCCCCCCCCOc1c(C)cc(-c2noc(C(F)(F)F)n2)cc1C
Product: Cc1cc(CCCCCCCCCOc2c(C)cc(-c3noc(C(F)(F)F)n3)cc2C)on1

Procedure:
Following Procedure 1 and using equivalent amounts of acetaldehyde oxime and 3-[3,5-dimethyl-4-(9-ethinylnonyloxy)phenyl]-5-trifluoromethyl-1,2,4-oxadiazole, there can be obtained 5-{9-[2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]nonyl}-3-methylisoxazole [I; R1 =CH3, Y=(CH2)9, R2 and R3 =2,6-(CH3)2, R4 =CF3 ].
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:12][C:11]2[CH:13]=[C:14]([CH:17]([OH:25])[CH2:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=[CH:16][C:10]=2[O:9]1.[OH-].[Li+].Cl>O.C1COCC1>[OH:25][CH:17]([C:14]1[CH:15]=[CH:16][C:10]2[O:9][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[O:12][C:11]=2[CH:13]=1)[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Temperature: 23 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of (±)-methyl-5-[[6-(1-hydroxy-3-(2-thienyl)propyl-1,3-benzodioxolyl]pentanoate (Compound 73, 35 mg, 0.093 mmol) and lithium hydroxide (0.37 ml of a 0.5N solution in H2O, 0.186 mmol) in THF (0.74 mL) was stirred at 23° C. for 16 hours. The mixture was acidified with 1N HCl and extracted with EtOAc. The organic portion was dried (MgSO4) filtered and concentrated in vacuo. Flash column chromatography (silica gel, 100% EtOAc) afforded 33.3 mg (99%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 12.0 (brs, 1H), 7.14 (d, J=5.1 Hz, 1H), 7.00 (s, 1H), 6.93 (dd, J=3.3, 5.1 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.59 (s, 1H), 5.91 (s, 2H), 4.87-4.92 (m, 1H), 2.97 (t, J=5.4 Hz, 2H), 2.43-2.47 (m, 2H), 2.32 (t, J=6.9 Hz, 2H), 1.86-2.18 (m, 2H), 1.44-1.64 (m, 5H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:29][C:30]([O:32][CH2:33]I)=[O:31])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:33][O:32][C:30]([O:29][CH2:27][CH3:28])=[O:31])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCOC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.2 %

Procedure:
In the same manner as in Example 81, 203 mg of the title compound was prepared from 214 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 146 mg of ethoxycarbonyloxymethyl iodide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C([O-])(C)C.[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:18])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (2.00 g, 8.54 mmol) in DMF (30 mL) was added KOtBu (1.54 g, 13.7 mmol) under Ar. The resulting solution was stirred at room temperature for 15 min and cooled to 0° C. MeI (0.85 mL, 14 mmol) was then added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. DMF was removed in vacuo and the residue was chromatographed on silica (5-50% EtOAc:hexane) to obtain the title compound (1.40 g, 66%). 1H-NMR (CDCl3; 400 MHz): δ 7.32 (m, 5H), 5.13 (s, 2H), 4.13 (s, 2H), 3.70 (m, 2H), 3.34 (m, 2H), 2.97 (s, 3H)
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[O:37])[N:22]([CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:30]1=[O:36])[C:23]2=[O:28]>CCOCC.CO.C1COCC1>[O:36]=[C:30]1[CH:29]([N:22]2[C:21](=[O:37])[C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[NH:18][C:4](=[O:6])[CH2:3][S:2][CH3:1])[C:23]2=[O:28])[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CSCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 3 h
Yield: 69.2 %

Procedure:
To a solution of (methylthio)acetic acid (0.77 mL, 8.9 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.02 mL) at room temperature. After 3 h, 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and THF (40 mL) was added to the mixture. Then the mixture was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (10 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methylsulfanyl-acetamide as a white solid (1.0 g, 69% yield): mp, 228-230° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H, CHH), 2.18 (s, 3H, CH3), 2.46-2.65 (m, 2H, CH2), 2.82-2.95 (m, 1H, CHH), 3.53 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.63 (d, J=7.2 Hz, 1H, Ar), 7.86 (t, J=7.5 Hz, 1H, Ar), 8.61 (d, J=8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 15.62, 21.96, 30.93, 37.99, 48.94, 116.69, 118.46, 125.28, 131.44, 136.31, 166.67, 167.88, 168.63, 169.78, 172.75; Anal Calcd for C16H15N3O5S: C, 53.18; H, 4.18; N, 11.63. Found: C, 53.26; H, 4.17; N, 11.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:59][CH3:60])=[C:31]([C:33]2[C:42]3[C:37](=[CH:38][C:39]([S:43](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:45])=[O:44])=[CH:40][CH:41]=3)[C:36](=[O:58])[NH:35][N:34]=2)[CH:32]=1>C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:59][CH3:60])=[C:31]([C:33]2[C:42]3[C:37](=[CH:38][C:39]([S:43]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=4)[C:9]4[S:10][CH:11]=[CH:12][N:13]=4)(=[O:45])=[O:44])=[CH:40][CH:41]=3)[C:36](=[O:58])[NH:35][N:34]=2)[CH:32]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (63.5 mg, 0.288 mmol) and THF (1.60 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (1M in THF, 961 μl, 0.961 mmol) was added drop wise to give a light yellow solution. The mixture was stirred for 15 min. Then, a solution of perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (128 mg, 0.240 mmol) in THF (1.60 mL)) was added drop wise. LCMS after 1 h showed a complete conversion of SM to mainly product. The reaction was quenched with saturated aqueous ammonium chloride (0.5 mL) at −78° C. and then warmed to rt. The product was extracted with EtOAc. The organic layers was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 20-50% EtOAc/heptanes) to give 1-(5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (56 mg, 41.0% yield) as an off-white solid. m/z (ESI) 569.0 (M+H)+.
Reaction SMILES: [CH:1]1([C@@H:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1>CCO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C@@H:4]([CH:1]2[CH2:2][CH2:3]2)[OH:18])=[C:8]([O:16][CH3:17])[CH:9]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OC[C@H](O)C1CC1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1OC[C@H](O)C1CC1

Procedure:
To a solution of (R)-1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol (20.90 g, 83 mmol), prepared in Part C, in EtOH (546 ml) was added 5% Pd/C, dry basis, Degussa type 50% water content (3.0 g, 0.705 mmol). The suspension was hydrogenated (1 atm. H2, balloon) at 20° C. for 2.5 h; whereupon, LC/MS analysis revealed the reaction to be complete. After filtration of the reaction mixture through CELITE® pad and subsequent washing of the cake with EtOH, the filtrate was concentrated under vacuum using a rotary evaporator to yield (R)-2-(4-amino-2-methoxyphenoxy)-1-cyclopropylethanol as a brown solid. M.P. 71° C. (18.34 g, 100%). 1H NMR (400 MHz, CDCl3): δ ppm 0.18-0.27 (m, 1H), 0.38-0.43 (m, 1H), 0.45-0.61 (m, 2H), 0.82-0.92 (m, 1H), 3.21 (ddd, J=8.8, 8.8, 2.6 Hz, 1H), 3.80 (s, 3H), 3.86 (dd, J=10.1, 8.8 Hz, 1H), 4.09 (dd, J=10.1, 2.6 Hz, 1H), 6.21 (dd, J=8.3, 2.7 Hz, 1H). 6.29 (d, J=2.7 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ ppm 151.2, 142.1, 140.8, 118.7, 106.9, 100.5, 76.5, 74.4, 55.7, 12.9, 2.5, 1.6. HPLC: 6.28 min retention time, 98.5% API; ZORBAX® column SB C18 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 100% A:0% B to 0% A:100% B for 8 min (Solvent A: 10% MeOH−90% H2O=0.2% H3PO4; Solvent B: 90% MeOH−10% H2O+0.2% H3PO4) Detection at 220 nm. LC/MS: m/e 224.5 (M+H); 4 min gradient.