Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33](Cl)=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1>CC(N(C)C)=O.C(OCC)(=O)C>[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCOC2)c1
Yield: 82.5 %

Procedure:
A solution of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (2.5 g, 10.5 mmol), potassium carbonate (2.9 g, 21.0 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.9 g, 12.6 mmol) in DMA (25 mL) was heated at 120° C. for 5 hours. The solution was diluted with ethyl acetate (150 mL), washed with water (3×50 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with 20-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (3.75 g). 1H NMR δ (CDCl3): 2.13-2.29 (m, 2H), 2.38 (quin, 2H), 3.85-4.04 (m, 4H), 3.90 (s, 3H), 4.19-4.37 (m, 4H), 4.96-5.00 (m, 1H), 6.91 (t, 1H), 7.42-7.45 (m, 2H), 8.14 (d, 1H), 8.25 (d, 1H); m/z 433 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[OH-].[Na+].C([CH:14]1[O:16][CH2:15]1)Cl.C[Si](O[Si](C)(C)C)(C)C>O>[CH2:1]([O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6])[CH:15]1[O:16][CH2:14]1
Reactant: ClCC1CO1
Reactant: COC(=O)C(C)(C)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: O
Product: CC(C)(CO)C(=O)OCC1CO1
Reaction time: 3 h

Procedure:
132 parts by wt. (1 mole) hydroxypivalic methyl ester, 48 parts by wt. (1.2 mole) sodium hydroxide solution and 250 ml water were heated for 1 hour at 100° C. in a 0.5-liter three-neck flask equipped with stirrer, thermometer and reflux cooler. The temperature was reduced to 50° C. To the mixture were added 276 parts by wt. (3 mole) epichlorohydrin (ECH) and 50 parts by wt. Dowex (Fluka AG, 1×8). The water was removed azeotropically at a temperature of 50° C. and at reduced pressure (200 mbar), the ECH being supplied back to the reaction mixture. The total reaction time was 3 hours. The salt formed was filtered off and washed twice with 20 ml ECH The excess ECH was removed by means of rotary film evaporation. Thus 167 parts by wt. hydroxypivalic glycidyl ester were obtained in the form of a light yellow liquid with an epoxide content of 5.5 meq/g and a hydroxy content of 307 mg KOH/g.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]=[N:7]1)=[S:5])[CH3:2].I[CH3:14]>CO>[CH3:14][S:5][C:4]([N:6]1[CH2:10][C:9]([CH3:11])([CH3:12])[CH:8]=[N:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CI
Reactant: CCNC(=S)N1CC(C)(C)C=N1
Solvent: CO
Product: CCN=C(SC)N1CC(C)(C)C=N1
Temperature: 50 °C
Yield: 7.8 %

Procedure:
15 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide was dissolved in 300 mL methanol, 50.4 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 3 hours. Volatiles were removed in vacuo. The residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to give 15.5 g (96%) N-ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.3 Hz, 3H), 1.20 (s, 6H), 2.45 (s, 3H), 3.49 (s, 2H), 3.53 (q, J=7.3 Hz, 2H), 6.66 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:4][CH2:3][CH:2]([NH:1][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH3:5]
Reactant: C=C1CC(=O)O1
Reactant: CC(N)CO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC(C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
19 ml (0.24 mol) of 2-amino-1-propanol were added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 27.12 g (0.17 mol, 71% yield) of a colorless oil.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: NCCO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and monoethanolamine comparable as in Example A. A viscous, syrupy substance was obtained.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:3]([CH:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[O:5])[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: O=C(O)[C@@H]1CCCN1
Product: CN1CCN(C(=O)C2CCCN2)CC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-tert-butoxycarbonyl)-L-proline was reacted with 1-methylpiperazine to give (2S)-1-tert-butoxycarbonyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7–2.05 (m, 4H), 2.1–2.25 (m, 1H), 2.32 (s, 3H), 2.35–2.5 (m, 4H), 2.6–2.7 (m, 1H), 2.8–2.9 (m, 1H), 3.3–3.7 (m, 8H), 4.15 (br s, 1H); Mass Spectrum: M+H+ 242.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([CH2:33][O:34][CH3:35])[CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:14]([CH:22]=[CH:23][CH:24]=1)[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]([CH2:26][CH2:25][C:13]1[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]2[CH:3]=[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)[CH:32]=[C:31]([CH2:33][O:34][CH3:35])[CH:30]=2)=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([OH:29])=[O:28]
Reactant: COCc1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COCc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cncnc2)c1
Yield: 69.8 %

Procedure:
A similar procedure as described in step 3, method B was used, starting from 4-[3-[6-(3-bromo-5-methoxymethyl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (209 mg, 0.38 mmol), 5-pyrimidinylboronic acid (94 mg, 0.76 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg, 0.07 mmol), and cesium carbonate (492 mg, 1.51 mmol) to obtain 4-[2-(2-carboxy-ethyl)-3-[6-(3-methoxymethyl-5-pyrimidin-5-yl-phenoxy)-hexyl]-phenoxy]-butyric acid (146 mg, 70%) as a light brown paste: ES(+)-HRMS m/e calcd for C31H38N2O7 (M+H)+ 551.2752. found 551.2748.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18](=[O:26])[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=1.Cl>C1COCC1.CO>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:17][C:18](=[O:26])[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]c(-c2ccc(CO)cc2)cc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under nitrogen, lithium aluminiumhydride (22.8 mg, 0.60 mmol) is added to a suspension of 4-(1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoic acid methyl ester (83.8 mg, 0.301 mmol) (for preparation see previous example) in THF (3 ml). The reaction mixture is stirred at ambient temperature for 16 hours. A few drops of methanol and then HCl (2 N aqueous solution, 0.5 ml) are added slowly to the reaction mixture. It is then filtered over a pad of celite. The filtrate is evaporated and the residue is triturated with tert-butyl methylether to afford 3-(4-hydroxymethyl-phenyl)-2H-isoquinolin-1-one as brown powder; HPLC/MS 1.55 min (A), [M+H] 252;
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=3[CH:3]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2ccc(OC(=O)Cc3ccc(Cl)cc3)cc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (1.15 g., 0.005 mole) triethylamine (0.7 ml, 0.005 mole) and 4-dimethylaminopyridine (5 mg, catalyst) in dimethylformamide (10 ml) is added 2-(4-chlorophenyl)acetyl chloride (0.8 ml). The reaction mixture is stirred for 2 hours, poured into ice water, acidified with hydrochloric acid and extracted with ether. The organic extract is washed with water and dried over magnesium sulfate. The ether is distilled at reduced pressure and the residue chromatographed on silica gel as eluant (130 g, 70-230 mesh) using ethylacetatehexane (1:1) to give 2-sulfamoyl-6-benzothiazolyl 2-(4-chlorophenyl)acetate which melts at 206°-208° C. after recrystallization from benzene.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].N12CCCN=C1CCCCC2.[CH2:24]([O:26][C:27]1[CH:28]=[N:29][C:30]([N:33]2[C:38](=[O:39])[C:37]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=4[C:49](=[N:51][OH:52])[NH2:50])=[N:45][CH:46]=3)=[C:36]([CH2:57][CH2:58][CH3:59])[N:35]=[C:34]2[CH:60]([CH3:62])[CH3:61])=[N:31][CH:32]=1)[CH3:25].Cl>O1CCCC1.ClCCl>[CH2:24]([O:26][C:27]1[CH:28]=[N:29][C:30]([N:33]2[C:38](=[O:39])[C:37]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=4[C:49]4[NH:50][C:1](=[O:2])[O:52][N:51]=4)=[N:45][CH:46]=3)=[C:36]([CH2:57][CH2:58][CH3:59])[N:35]=[C:34]2[CH:60]([CH3:62])[CH3:61])=[N:31][CH:32]=1)[CH3:25]
Reactant: CCCc1nc(C(C)C)n(-c2ncc(OCC)cn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nc(C(C)C)n(-c2ncc(OCC)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
Process 6: 1,1′-Carbonyldiimidazole (130 mg, 0.80 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (122 mg, 0.80 mmol) were added to dichloromethane (4 mL) and tetrahydrofuran (4 mL) mixture solution of 2-{5-{[1-(5-ethoxypyrimidin-2-yl)-2-isopropyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (212 mg, 0.40 mmol) and stirred for 3 hours at room temperature. Once the reaction is completed, 1 M hydrochloric acid solution was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (chloroform/methanol=20:1) to give 3-{2-{5-{[1-(5-ethoxypyrimidin-2-yl)-2-isopropyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one (201 mg, 91%) as white amorphous.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](SC)=[N:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)CCC.[F-].[Cs+].C(Cl)Cl>CN(C)C=O.[Cu](I)I.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>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[N:8][C:6]=2[N:7]=1
Reactant: CSc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(-c3cscn3)nc2n1

Procedure:
5-Chloro-2-(methylthio)-7-morpholinothiazolo[4,5-d]pyrimidine was combined with 4-(tributylstannyl)thiazole (1.1 eq), cesium fluoride (2 eq), copper iodide (2 eq), tetrakis(triphenylphosphine)palladium (0.1 eq) in dimethylformamide and microwaved 110° C. for 15 minutes. Methylene chloride was added the solution was filtered through silica washing with methanol. The organic layer was evaporated to dryness and the resulting residue was purified by silica gel chromatography to yield 5-chloro-7-morpholino-2-(thiazol-4-yl)thiazolo[4,5-d]pyrimidine as a pale yellow solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.[CH3:10][C:11]1([CH3:17])[CH2:15][NH:14][C:13](=[O:16])[NH:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[F:8][C:7]1[C:2]([N:14]2[CH2:15][C:11]([CH3:17])([CH3:10])[NH:12][C:13]2=[O:16])=[N:3][CH:4]=[C:5]([I:9])[CH:6]=1
Reactant: Fc1cc(I)cnc1F
Reactant: CC1(C)CNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC1(C)CN(c2ncc(I)cc2F)C(=O)N1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
2,3-Difluoro-5-iodopyridine (300 mg, 1.24 mmol) was dissolved in 2 ml toluene. (140 mg, 1.24 mmol, 1 equiv.) 4,4-Dimethylimidazolidin-2-one (CAS 24572-33-6) and cesium carbonate (650 mg, 1.99 mmol, 1.6 equiv.) were added and the mixture was heated to 100° C. for 4 hours. The reaction mixture was loaded directly onto a silica gel column and purified by flash chromatography eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (205 mg, 49% yield) was obtained as a white solid, MS: m/e=336.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][C@@H:18]([C:20]([O:22]C)=[O:21])[CH3:19])=[O:16])=[C:5]2[OH:24].[OH-].[Na+].O.Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][C@@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16])=[C:5]2[OH:24]
Reactant: COC(=O)[C@@H](C)NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O)C(=O)O
Reaction time: 3 h

Procedure:
Methyl N-((6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)-D-alaninate (75 mg, 213 μmol) was dissolved in THF (2132 μL). 5N NaOH in water (2132 μL, 10660 μmol) was added at ambient temperature, and the reaction was stirred for 3 hours. The reaction mixture was acidified with 3N HCl, diluted with 50 mL of EtOAc, added to a separatory funnel, washed 2 times with 20 mL of brine (saturated, aqueous), separated, dried over Na2SO4, and concentrated to give the title compound as a white amorphous solid. MS m/e 338 (M+H)+. Calculated for C16H16ClNO5 337.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1Oc1cncc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1Oc1cncc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
To a solution of methyl 5-chloro-2-[(5-fluoropyridin-3-yl)oxy]benzoate (80 mg, 0.28 mmol) in methanol (2 mL) was added 2 M sodium hydroxide aqueous solution (2 mL) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was acidified with 2 M hydrochloric acid (2.5 mL). The precipitate was collected by filtration to afford 61 mg (80%) of the title compound: 1H-NMR (CDCl3) δ 8.24 (1H, br.s), 8.19 (1H, br.s), 8.07 (1H, d, J=2.6 Hz), 7.56 (1H, d, J=8.8, 2.6 Hz), 7.06 (1H, d, J=8.8 Hz), 6.98 (1H, td, J=9.4, 2.2 Hz).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 26.6 %

Procedure:
A solution of (2Z,4E)-5-(benzothiophen-2-yl)-2-methoxy-2,4-pentadienoic acid (53 mg, 0.20 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (34 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole hydrate (27 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) in DMF (1 ml) was stirred at RT for 6 hours. After the same work up as seen in example 3 pure title compound was obtained (22 mg, 0.054 mmol, yield 26.6%) as white crystals, m.p.=240°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[C:20]([CH:29]=O)[CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:29][C:20]2[CH:19]=[C:18]([CH3:17])[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=2)[CH2:12][CH2:13]1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1
Yield: 87.4 %

Procedure:
Compound 61 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:45]2[C@H:46]([CH3:69])[C@H:47]3[C@@H:64]([C@H:65]([OH:67])[CH3:66])[C:63](=[O:68])[N:48]3[C:49]=2[C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)=[O:51])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:16]([NH:15][CH2:14][C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:45]3[C@H:46]([CH3:69])[C@@H:47]4[C@@H:64]([C@H:65]([OH:67])[CH3:66])[C:63](=[O:68])[N:48]4[C:49]=3[C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH2:8]2)[S:10][CH:11]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CNC(=O)c5ccccc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 3-acetylthio-1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]azetidine (698 mg, 2.01 mmol) (obtained as described in Reference Example 64) in dimethylformamide (20 ml) was added hydrazine acetate (222 mg, 2.41 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.43 g, 2.41 mmol) in acetonitrile (40 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.40 ml, 8.94 mmol). The mixture was stirred for 2.5 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (20:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (851 mg, yield 65%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[N:4]=1.[OH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[C:13]([C:5]1[N:4]=[C:3]([CH2:2][O:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: N#Cc1cc2ccccc2c(CBr)n1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OCc2nc(C#N)cc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 1-(bromomethyl)isoquinoline-3-carbonitrile (0.150 g, 0.607 mmol) in DCM (6 mL) was added (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.114 g, 0.607 mmol) and AgOTf (0.016 g, 0.061 mmol). The suspension was stirred for 15 minutes at RT and then heated at 45° C. overnight. The reaction mixture was subsequently cooled, absorbed onto silica and eluted with a gradient of 0-5% MeOH in DCM. The enriched fractions were concentrated in vacuo to give the title compound as a yellow residue which was used without further purification (54.6 mg, 25.4%). ESI-MS m/z [M+H-tert butyl]+ 298.6.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12>CN(C=O)C>[CH:7]1[C:3]2[C:4]([O:6][C:1](=[O:11])[C:2]=2[CH:10]=[C:9]2[C:4]([O:6][C:1](=[O:11])[C:8]=12)=[O:5])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12

Procedure:
A polyamic acid of PMDA/ODA in DMF was prepared at 97% stoichiometry and 23.5% solids by weight. The amic acid was end-capped with phthalic anhydride at 0.04% by weight. (need to confirm)