Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[Br:15])[N:11]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[C:19]1([S:16]([N:11]2[C:12]3[C:8](=[CH:7][C:6]([CH2:5][OH:4])=[C:14]([Br:15])[CH:13]=3)[CH:9]=[CH:10]2)(=[O:17])=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OCc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1ccc2cc(CO)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Under a nitrogen stream, a mixture of 1-benzenesulfonyl-6-bromo-1H-indol-5-ylmethyl acetate (257 mg, 0.63 mmol), potassium carbonate (15 mg, 0.11 mmol) and methanol (4 mL) was stirred for 1 hour at room temperature. To the resultant mixture was added 2 N hydrochloric acid (0.11 mL), and solvent was then removed by distillation under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (2:1)), to thereby obtain the titled compound (225 mg, 97%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:43])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH:30]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>CO>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:43])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][OH:34])[CH:30]=3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)n1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)n1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO)c2)n1
Yield: 83.7 %

Procedure:
3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide (142 mg, 0.23 mmol) in methanol (2 mL) was stirred with 3.5M hydrochloric acid (0.2 mL, 0.68 mmol) for 1 hour. The solution was neutralised with saturated sodium bicarbonate solution and the organic solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (3×10 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by chromatography on silica, eluting with 75-100% ethyl acetate in hexane, to give the required product as a white foam (99 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:38]([CH:35]4[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]4)=[O:39])[CH2:21][CH2:20]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(CCC1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.5 %

Procedure:
Under an inert atmosphere ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(2-piperidin-4-yl-ethyl)-propyl-amine (200 mg, 0.61 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (139 mg, 0.61 mmol), EDCl (117 mg, 0.61 mmol), HOBT (82 mg, 0.61 mmol), triethylamine (0.17 mL, 1.2 mmol), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in-vacuo. The residue was taken-up in EtOAc (50 mL) and washed with water (30 mL), 1 N NaOH (30 mL), brine (30 mL), and dried (MgSO4). The solution was filtered and concentrated to afford an oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (260 mg) which was deprotected with 10 mL trifluoroacetic acid, as described herein, to afford (4-{2-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-ethyl}-piperidin-1-yl)-piperidin-4-yl-methanone (200 mg) 116[M+H]+=478.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
3-Chlorophenylacetic acid (20.90 g, 122.51 mmol) and N-Bromosuccinimide NBS (23.50 g, 132.03 mmol) were dissolved in carbon tetrachloride (300 mL). Benzoyl peroxide BPO (300 mg) was added and the resulting reaction mixture was heated to reflux under a sunlamp for 5 hours, then cooled to room temperature, filtered and concentrated to give the desired α-bromo-3-chlorophenylacetic acid, component “A”. 10.00 g of this acid were dissolved in MeOH (100 mL) and 2 mL of sulfuric acid were added. The resulting reaction mixture was refluxed for 3 hours, and then concentrated. The residue was diluted with ether (150 mL) and washed with water, dried over sodium sulfate, and then concentrated to give the methyl ester. The methyl ester was reacted with the component “B”, 3,4-dimethylaniline (CAS 95-64-7) (6.89 g, 1.5 eq), and potassium carbonate (13.00 g, 2.5 eq) in methylethyl ketone and the mixture heated with stirring at 80° C. for 14 hours. After concentration, MeOH (50 mL) was added, followed by KOH (5.00 g). The reaction mixture was refluxed for 6 hours, acidified with concentrated HCl, and then concentrated. The resulting residue was diluted with ether and washed with water, then dried over sodium sulfate and concentrated to the 2-(3-chlorophenyl)-2-((3,4-dimethylphenyl)amino)acetic acid, which was used in the next step without further purification. Crude 2-(3-chlorophenyl)-2-(3,4-dimethylphenyl)amino)acetic acid reacted with 1,1′-carbonyldiimidazole (2.40 g, 14.81 mmol) and (Z)-N′-hydroxy-2-(methylamino) nicotinimidamide (1.80, 10.83 mmol) according to the protocols as outlined in general procedure described above to afford Compound 1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[S:8][C:9]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][C:14]([N+:20]([O-])=O)=[CH:15][CH:16]=4)[C:10]=3[N:11]=2)[N:3]=[CH:2]1.CO.[H][H]>[Ni].O1CCOCC1>[NH2:20][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][C:9]3[S:8][C:7]([CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)=[N:11][C:10]=32)=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2
Yield: 57 %

Procedure:
5.0 g of Raney nickel (wet) was added to a solution of 0.52 g of.2-(4-imidazolylmethyl)-8-nitro-4,5-dihydronaphtho[1,2-d]thiazole obtained in Example 23 in 1,4-dioxane (40 ml)-methanol (20 ml), and the mixture was stirred for 2 hours in an atmosphere of hydrogen (1 atm). After filtration of insoluble matter, the solvent was evaporated from the filtrate, and the residue was mixed with ethyl acetate to effect crystallization. The resultant crude crystals were washed with hot ethyl acetate to afford 0.27 g (57%) of 8-amino-2-(4-imidazolylmethyl)-4,5-dihydronaphtho[1,2-d]thiazole.
Reaction SMILES: [H-].[CH3:2][O:3][C:4](=[O:7])[CH2:5][OH:6].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1>CN(C)C=O>[CH3:2][O:3][C:4](=[O:7])[CH2:5][O:6][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[N:10]=1
Reactant: COC(=O)CO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(Br)n1
Yield: 80.2 %

Procedure:
A suspension of 178 mg of sodiura hydride (80% dispersion in mineral oil) in 4 ml of dimethylformamide is mixed under argon atmosphere, stirring and ice cooling with a solution of 361 mg of glycolic acid methyl ester in 2 ml of dimethylformaraide and stirred for 3 hours at room temperature. Then, a solution of 948 mg of 2,6-dibromopyridine in 2 ml of dimethylformamide is added under ice cooling and the mixture is stirred for 48 hours at room temperature. The reaction mixture is poured on ice and extracted with ethyl acetate. The organic phase is washed 4 times with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 790 mg of 2-(6-bromo-2-pyridyloxy)acetic acid methyl ester is obtained as oily crude product.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C1COCC1>[N:35]1([C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:6]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Product: Fc1ccc(Oc2nc(N3CCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F
Temperature: 60 °C

Procedure:
To a sealed tube fitted with a magnetic stirrer bar was added 2-methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (from Example 20) (30 mg, 0.06 mmol), 10 eq. of pyrrolidine and THF, flushed with nitrogen. The reaction was heated at 60° C. overnight in the sealed tube. The solvent was removed under reduced pressure. Flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate) afforded the title compound: HPLC/MS: m/e=532 (M++1); Rt=4.9 min. 1H-NMR 500 MHz (CDCl3): 1.91-2.00 (m, 4H), 3.23-3.40 (s, 2H1), 3.45-3.62 (s, 2H), 6.89-6.94 (m, 1H), 7.08-7.21 (m, 8H), 7.35 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:22])[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([OH:19])[C:13]=2[C:12](=[O:23])[N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]1=[O:33].C(N(CC)CC)C.Cl.CN(C)C.[C:46]1([CH3:56])[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(#N)C.CO>[CH3:56][C:46]1[CH:51]=[CH:50][C:49]([S:52]([O:19][C:18]2[C:13]3[C:12](=[O:23])[N:11]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:10](=[O:33])[N:9]([C:3]4[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=4[F:1])[C:14]=3[N:15]([CH3:22])[C:16](=[O:21])[C:17]=2[CH3:20])(=[O:54])=[O:53])=[CH:48][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(Cn2c(=O)c3c(O)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Under nitrogen atmosphere, to a solution of 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (41 g, 72.8 mmol) (Prepared as per reference WO2005121142) in acetonitrile (300 ml), triethylamine (30.4 ml, 218 mmol) and trimethylamine hydrochloride (3.48 g, 36.4 mmol) were added slowly followed by addition of p-toluensulfonylchloride (27.8 g, 146 mmol) in acetonitrile (300 ml) at 0° C., and the mixture was stirred under ice cooling for 1 hr, and then at room temperature for 24 h. To the reaction mixture was added methanol (220 ml), and the mixture was stirred at room temperature for 1 h. The precipitated crystals were collected by filtration, dried under vacuum to afford the titled compound (40.5 g, 78%)
Reaction SMILES: [N:1]([CH2:4][Si:5]([O:8][CH3:9])([CH3:7])[CH3:6])=[C:2]=[O:3].[C:10]1(=[O:17])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCOCC1>[CH3:9][O:8][Si:5]([CH2:4][NH:1][C:2]([N:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:17])=[O:3])([CH3:7])[CH3:6]
Reactant: CO[Si](C)(C)CN=C=O
Reactant: O=C1CCCCCN1
Solvent: C1COCCO1
Product: CO[Si](C)(C)CNC(=O)N1CCCCCC1=O
Reaction time: 4 h

Procedure:
A solution of 1.45 g of (isocyanatomethyl)methoxy-dimethylsilane and 1.13 g of ε-caprolactam in 25 ml of anhydrous dioxane was heated at reflux with stirring for 4 h. The solvent was subsequently removed under reduced pressure. This gave hexahydro-N-[(methoxydimethylsilyl)methyl]-2-oxo-1H-azepine-1-carboxamide in quantitative yield with a purity of >90% (analysis by 1H NMR).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)[CH:7]=4)=[C:14]([CH3:15])[N:13]=3)[N:17]=2)=[CH:23][CH:24]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(Cl)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: O
Solvent: C1COCCO1
Product: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 45.5 %

Procedure:
A suspension of Example A8 (0.300 g, 0.754 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), K2CO3 (0.200 g, 1.447 mmol) in a mixture of dioxane/water (10:1) (11 mL) was degassed for 5 minutes with argon purge. The reaction mixture was treated with Pd(PPh3)4 (0.020 g, 0.017 mmol) and heated at 100° C. under argon over night. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (30 mL) and water (30 mL). The organic layer separated and the aqueous layer extracted with dichloromethane (2×15 mL). The combined organics were dried and concentrated to a small volume and purified by silica gel chromatography (0-100% THF/DCM) to provide 3-(4-fluorophenyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.152 g, 45%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98-7.94 (m, 4H), 7.74 (d, J=8.8 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 7.23 (d, J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.37 (s, 3H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:54])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12][N:11]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:9])[CH2:4]1.[ClH:55]>O1CCCC1.O>[ClH:55].[CH3:54][N:2]([CH3:1])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][NH:11]2)=[O:9])[CH2:4]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](N(C)C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC[C@H](N(C)C)C4)C3)[C@H](C)[C@H]12

Procedure:
306 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-3-dimethylaminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 12 ml of a 2:1 by volume mixture of tetrahydrofuran and water, after which 0.38 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 600 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up and purified by the same procedure as described in Example 18(b), to give 19 mg of the title compound as a powder.
Reaction SMILES: [C:1]1(=[O:15])[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[C:3](=[O:14])O1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:18][C:19]#[N:20]>C(O)(=O)C>[O:15]=[C:1]1[C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=[CH:13][C:4]=2[C:3](=[O:14])[N:16]1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:18][C:19]#[N:20]
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CC#N)N2C(=O)c3ccc4ccccc4c3C2=O)ccc1OC
Yield: 48.8 %

Procedure:
A solution of naphtho[1,2-c]furan-1,3-dione (440 mg, 2.2 mmol) and 3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (490 mg, 2.2.mmol) in acetic acid (10 mL) was heated to reflux overnight. The solvent was removed in vacuo to give a solid, which was purified with chromatography (Silica Gel, CH2Cl2) to give 3-(1,3-dioxobenzo[e]isoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile as a yellow solid (430 mg, 48% yield): mp 163.0-165.0° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7 Hz, 3H, CH3), 3.34 (dd, J=7, 17 Hz, 1H, CHH), 3.80-3.92 (m, 1H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 5.67 (dd, J=7, 10.1 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.11-7.13 (m, 2H, Ar), 7.61-7.74 (m, 2H, Ar), 7.81 (d, J=8 Hz, 1H, Ar), 7.92 (d, J=7.9 Hz, 1H, Ar), 8.14 (d, J=8.3 Hz, 1H, Ar), 8.87 (d, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.66, 21.22, 50.97, 55.91, 64.48, 111.43, 112.19, 117.00, 118.46, 120.03, 124.79, 126.79, 127.96, 128.73, 128.94, 129.24, 129.66, 130.78, 135.37, 136.68, 148.56, 149.72, 168.37, 168.92. Analy. calculated for C24H20N2O4: C 71.99; H 5.03; N 7.00. Found: C 71.81; H 5.04; N 7.00.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23]CC)=[O:22].[O-]CC.[Na+]>C(O)C>[CH2:26]([C:19]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][C:12]([F:14])([F:13])[F:15])=[O:9])=[CH:16][CH:17]=2)[N:2]=[N:3][C:20]=1[C:21]([OH:23])=[O:22])[CH2:27][CH3:28]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-azido-N-(2,2,2-trifluoroethyl)benzamide (0.98 g) obtained in Example 46a) and ethyl 3-keto-n-hexanoate (0.77 ml) in ethanol (20 ml) was added 20% sodium ethoxide in ethanol solution (1.85 ml) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-brown amorphous solid (1.4 g, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C@@H:12]1[C@@H:16]([CH2:17][OH:18])[O:15][C:14](=[O:19])[CH2:13]1>C1COCC1>[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C@@H:12]([CH2:13][CH2:14][OH:19])[C@H:16]([OH:15])[CH2:17][OH:18]
Reactant: O=C1C[C@H](C2OCCO2)[C@@H](CO)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC[C@H](C1OCCO1)[C@H](O)CO
Reaction time: 4 h

Procedure:
To a solution of lithium aluminum hydride (76 mg, 1.98 mmols) in THF (10 ml) at 0° C. was added dihydrofuranone 15 (275 mg, 1.46 mmol) in THF (30 mL) dropwise. Upon completion of the reduction after 4 hours, the reaction was quenched with a saturated aqueous sodium sulfate solution at 0° C. The solvent then was decanted and the remaining residue was washed with THF (3×), EtOAc (3×), and CHCl3 (3×). The organic extracts were combined and the solvent was removed under reduced pressure, yielding a crude (2S,3S)-3-[1,3]dioxolan-2-ylpentane-1,2,5-triol, which was immediately used in the next reaction.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][N:7]=1.CN(C)C=O.[BH4-].[Na+]>C1C=CC=CC=1.O1CCOCC1.C([O-])(O)=O.[Na+]>[F:5][C:6]1[N:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(F)nc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: OCc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (0.29 mL, 4.08 mmol) was added to a slurry of 6-fluoronicotinic acid (13, 0.48 g, 3.40 mmol) and N,N-dimethylformamide (0.1 mL, catalytic amount) in benzene (40 mL) at room temperature under nitrogen, after which the mixture was heated at reflux for 3 h. The solvent was removed under reduced pressure to provide an amber oil that was dissolved in 1,4-dioxane (25 mL) under nitrogen. The solution was treated with sodium borohydride (0.26 g, 6.80 mmol) and the mixture was stirred at room temperature for 24 h. The suspension was diluted with sat. NaHCO3 solution (200 mL) and extracted with diethyl ether (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered and the solvents were removed under reduced pressure to provide the title compound as a colorless oil: 1H NMR (300 MHz) 8.20 (s, 1H), 7.87-7.81 (dt, J=8.0, 2.3 Hz, 1H), 6.97-6.93 (dd, J=8.4, 2.8 Hz, 1H), 4.73 (s, 2H), 2.04 (bs, 1H) ppm.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:34]>C1COCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][O:26][CH3:34])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg (0.112 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in 0.5 mL of THF was added 60% sodium hydride (8.96 mg, 0.244 mmol) at 0° C. After being stirred at 0° C. for 30 min, iodomethane (14.01 uL, 0.244 mmol) was added. The reaction was allowed to warm to 25° C., and stirred for an additional 2 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to provide the title compound.