Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24]>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.C(N(CC)CC)C>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
A mixture of 4.6 g of 2-benzyl-3-iodo-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine, 1.7 g of (3R)-3-ethynyl-3-quinuclidinol, 130 mg of tetrakis(triphenylphosphine)palladium(0), 110 mg of cuprous iodide and 3.1 ml of triethylamine was stirred for 5 hours at room temperature in a nitrogen atmosphere. The reaction solution was extracted with aqueous dilute ammonia-ethyl acetate, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to NH-silica gel column chromatography using 0-5% methanol/ethyl acetate, to give 4.0 g of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.O.[Fe]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reaction time: 72 h
Yield: 74.6 %

Procedure:
A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under a stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) Rf 0.27; 1H NMR (DMSO-d6) δ 5.14 (br s, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8.4 Hz, 1H), 11.02 (s, 1H); HPLC ES-MS m/z 255 ((M+H)+, 100%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:28][C:25]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:23])[O:21]2)=[CH:16][CH:15]=1>CN(C=O)C.O>[CH3:26][C:25]1([CH3:27])[C:22]([CH3:23])([CH3:24])[O:21][B:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4]3)=[CH:19][CH:18]=2)[O:28]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2ccc(Cn3ccc4ccccc43)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
To NaH (78 mg, 1.94 mmol) in anhydrous DMF (4 mL) under N2, at 0° C. was added indole (227 mg, 1.94 mmol) in anhydrous DMF (5 mL). The reaxtion mixture was maintained at this temperature for 10 min. 4-bromomethylphenylboronic acid pinacol ester (523 mg, 1.76 mmol) in anhydrous DMF (8 mL) was added and the reaction stirred at RT for 18 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2 (×2). The organic phases were combined, washed with brine, dried (phase separation cartridge) and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with isohexane and increasing the polarity to 5% EtOAc/isohexane. The compound was further purified by reverse phase preparative HPLC-MS to afford 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indole as an off-white solid (120 mg, 10%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][N:19]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:22]2[CH2:23][C@@H:18]3[CH2:24][C@H:21]2[CH2:20][N:19]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(N)ncn1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.222 g, 1.71 mmol) and diisopropylethylamine (0.222 g, 1.71 mmol) were suspended in n-butanol. tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 16-1 (0.34 g, 1.71 mmol) was then added. The reaction was stirred at 150° C. for 18 hours and then the product was purified on a silica column. 1H-NMR (DMSO): 7.91 ppm (s, 1H); 6.18 ppm (s, 2H); 5.33 ppm (s, 1H); 4.72 ppm (s, 1H); 4.41 ppm (d, 1H); 3.40 ppm (t, 1H); 3.27 ppm (m, 1H); 3.12 ppm (m, 2H); 1.86 ppm (m, 2H); 1.40 ppm (s, 4H); 1.36 ppm (s, 5H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][S:2]([C:5]1[C:15]([CH3:16])=[CH:14][C:8]([O:9][CH2:10][C:11]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])=[CH:7][C:6]=1[CH3:17])(=[O:4])=[O:3]
Reactant: Cc1cc(OCC(=O)Cl)cc(C)c1S(=O)(=O)Cl
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
Referring to FIG. 37, to a solution of 2-(4-(chlorosulfonyl)-3,5-dimethylphenoxy)acetyl chloride (6 g, 20.3 mmol) in THF (60 mL) were added dropwise a solution of BnOH (2.2 g, 20.3 mmol), Et3N (3.44 mL, 24.3 mmol) and DMAP (25 mg, 0.2 mmol) in THF (30 mL) at −78° C. The reaction mixture was stirred for 5 h at −78° C. and then poured into HCl solution (1 N, 100 mL). The resulting mixture was extracted with ethyl acetate (100 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=60:1) to give product as a white powder (1.2 g, 16% yield). 2-(4-(Chlorosulfonyl)-3,5-dimethylphenoxy)acetyl chloride (2.0 g) was recovered. 1H NMR (CDCl3, 300 MHz): δ 7.42-7.32 (m, 5H), 6.67 (s, 2H), 5.32 (s, 2H), 4.74 (s, 2H) 2.72 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+].C1COCC1>CO.C(#N)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:25])[CH3:9])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cscn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cscn1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethanone (6.0 mg, 0.021 mmol), ammonium acetate (20 mg, 0.2 mmol) and 1.0 M sodium cyanoborohydride in THF (0.053 mL, 0.053 mmol) in methanol (0.05 mL)/acetonitrile (0.05 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the crude product, which was used in the next step directly. LCMS calculated for C13H13ClNOS (M−NH2)+: m/z=266.1. found: 266.0.
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:11]=1[F:24])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:24][C:11]1[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:19])=[O:20])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[C:9]([OH:25])=[O:8]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reaction time: 0.25 h

Procedure:
To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester (44, 2.0 g, mmol) in methanol (30 mL) was added 20% palladium hydroxide on carbon (100 mg). The reaction was stirred under hydrogen at 1 atm for 15 minutes. The reaction was filtrated and concentrated to give white solid 45 that was used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:13]2[CH2:15][CH2:14]2)=[CH:7][CH:6]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C2CC2)cc1
Temperature: 100 °C
Yield: 69.9 %

Procedure:
To a solution of methyl(4-iodophenyl)acetate (1.5 g, 5.4 mmol), cyclopropylboronic acid (607 mg, 7.06 mmol), potassium phosphate (4.04 g, 29.7 mmol) and tricyclohexylphosphine (152 mg, 10 mol %) in 25 mL toluene under nitrogen was added water (1.25 mL) and palladium acetate (61 mg, 5 mol %). The mixture was heated to 100° C. for 10 hours. After cooling to room temperature, water and ethyl acetate were added and the mixture was filtered through a Celite® pad to remove insoluble material. The layers were separated and the water layer was washed 2× with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Solvent removal gave 1.5 g of a dark yellow paste which was purified by silica chromatography on an ISCO (Teledyne Corp., Thousand Oaks, Calif.) column, eluting with a gradient 0/100 to 30/70 ethyl acetate/heptanes, to give methyl(4-cyclopropylphenyl)acetate as a yellow semi-solid (718 mg, 69%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([C:38]([CH3:40])=[CH2:39])=[CH:26][C:22]=1[C:23](O)=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][CH:57]=2)[CH2:54][NH:53][CH2:52]3)[CH2:44][CH2:43]1>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]([C:38]([CH3:40])=[CH2:39])=[CH:26][C:22]=1[C:23]([N:53]1[CH2:52][C:51]2[C:55](=[CH:56][CH:57]=[C:49]([CH2:48][N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)[CH:50]=2)[CH2:54]1)=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=C(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN1CCN(Cc2ccc3c(c2)CNC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(CN4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.3 %

Procedure:
1,1′-Carbonyldiimidazole (4.82 Kg, 29.8 mol) was added to a solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (10.58 Kg, 28.3 mol, step 5) in DMF (21.2 L) at 25° C. After 20 mins at 25° C. a solution of 5-(4-Methyl-piperazin-1-ylmethyl)-2,3-dihydro-1H-isoindole (7.2 Kg, 31.1 mol, step 10) in DMF (7.2 L) maintaining a temperature below 35° C. and the solution stirred at 25° C. for a minimum of 12 h. The solid which had formed was removed by filtration, washed with isopropyl acetate (2×21.6 L) and dried at 35° C. to constant weight to give the title compound 8.7 Kg (77% yield, purity by hplc 97.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:20])[N:18]([CH3:19])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(C2C=CC3N(C(C)C)C(=O)NC=3C=2)=NC=C(C(F)(F)F)C=1.C([CH:52]1[O:54][CH2:53]1)Br>>[Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:22])[CH3:23])[C:17](=[O:20])[N:18]([CH2:19][CH:53]4[O:54][CH2:52]4)[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reactant: BrCC1CO1
Agent: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Product: CC(C)n1c(=O)n(CC2CO2)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Yield: 83 %

Procedure:
In a similar manner to the preparation of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)-3-methyl-1-(1-methylethyl)benzimidazol-2-one described above, 2.5 g of 5-(3-chloro-5-trifluoromethyl-pyridin-2yl)-1-(1-methylethyl)benzimidazol-2-one and 1.0 g of epibromohydrin gave 2.4 g of colorless crystals. Yield: 83%; m.p.: 110-111° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)(=[O:12])=[O:11])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
N-(2-Morpholin-4-yl-ethyl)-4-nitro-benzenesulfonamide (0.14 g, 0.45 mmol) was suspended in a 5:1 mixture of ethanol and water (3 ml). To this solution was added iron powder (0.13 g, 2.25 mmol) followed by saturated ammonium chloride solution (0.1 ml) and the mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.1 g, 78% yield) as a brown solid. Tr=0.35 min, m/z (ES+) (M+H)+ 285.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1.O>[CH3:20][S:21]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])=[O:22]
Reactant: Brc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccnc1
Reaction time: 2 h

Procedure:
To a solution of 3-bromopyridine (20 g, 127 mmol) in THF (200 ml) at room temperature is added a solution of 2M isopropylmagnesium chloride in THF (64 ml, 127 mmol). The resulting mixture is stirred for 2 hours, treated with triethylamine (20 ml), immediately followed by methanesulfonylchloride (10 ml, 127 mmol) and the resulting mixture stirred for 18 hours at room temperature. The mixture is diluted with water (200 ml) and extracted with EtOAc (3×100 ml). The mixture is concentrated in vacuo and purified on Silica gel (eluting with 50/50 Hexane/EtOAc). 1H-NMR (CDCl3) δ: 9.17 (s, 1H), 8.90 (d, 1H), 8.25 (dd, 1H), 7.55 (m, 1H), 3.12 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[ClH:31].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:39]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=4)=[O:40])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 32.8 mg (0.21 mmol) of 4-chlorophenyl isocyanate. After 16 h at room temperature, the mixture is concentrated in vacuo. The residue is dissolved in a 1:1 mixture of water and acetonitrile and purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 29 mg (55.2% of theory) of the title compound are obtained.
Reaction SMILES: [OH-].[Na+].[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([C:18](=[C:35]([CH3:40])[CH2:36][O:37]C=O)[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:15]1=[O:41])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>C1COCC1>[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([C:18](=[C:35]([CH3:40])[CH2:36][OH:37])[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:15]1=[O:41])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(COC=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CO)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To 6 ml of 0.1 N aqueous sodium hydroxide at 0° was added a solution of 338 mg (0.6 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-formyloxy-2-butenoate in 10 ml of cold THF. After 30 minutes, ethyl acetate was added. The organic layer was separated, washed with dilute acid and brine, dried, and evaporated in vacuo to dryness to provide 250 mg of a multi-component mixture. Separation by preparative thin layer chromatography (silica gel plates developed with 3:1/ethyl acetate:hexane) provided 35 mg of the title product: nmr (CDCl3) δ 2.28 (s, 3, CH3), 4.72 (s, 2, --CH2OH), 3.60 (m, 2, C4 --H), 5.02 (m, 1, C3 --H), 4.55 (s, 2, side chain CH2), and 7.2 (b, ArH).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][C:25]=3[C:34]([O:36]C)=[O:35])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=3[C:34]([OH:36])=[O:35])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)[nH]4)ccc3c2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)[nH]4)ccc3c2)c(C(=O)O)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of dimethyl 4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalate (230 mg, 0.468 mmol), prepared in the previous step, and 1 N NaOH (2.81 mL, 2.81 mmol) in 30 mL of THF plus 20 mL of methanol plus 5 mL of water was refluxed under nitrogen for 7 h. The reaction was filtered, cooled to room temperature, acidified by the addition of 5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure at 60° C. to give the title compound (204 mg, 94%) as a yellow solid, mp 289–291° C. Elemental Analysis for C29H21NO5.0.40 C4H8O.0.22 H2O Calc'd: C, 74.06; H, 5.00; N, 2.82. Found: C, 73.83; H, 5.19; N, 2.70.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30]C3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:36][O:37]CC(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:36][O:37][CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:10][CH2:11]2)=[O:5])=[N:26][N:27]=1
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: COCC(=O)NN
Agent: NNC(=O)CC1CCOC1
Product: COCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-methoxyacetohydrazide (compound 190.6) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 430 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]([O:11]/[N:12]=[C:13](/[C:44]1[N:45]=[C:46]([NH:49]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:47][CH:48]=1)\[C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:27])=[C:21]([CH2:24]I)[CH2:22][S:23][C@H:18]12)=[O:15])([CH3:10])[CH3:9])=[O:7])(C)(C)C.[CH3:69][O:70][C:71]1[S:75][CH:74]=[N:73][C:72]=1[CH3:76]>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH2:49][C:46]1[S:47][CH:48]=[C:44](/[C:13](=[N:12]/[O:11][C:8]([C:6]([OH:7])=[O:5])([CH3:9])[CH3:10])/[C:14]([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[C:20]([C:26]([O-:28])=[O:27])=[C:21]([CH2:24][C:74]4[S:75][C:71]([O:70][CH3:69])=[C:72]([CH3:76])[NH+:73]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[N:45]=1
Reactant: COc1scnc1C
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1sc(CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)/C(=N\OC(C)(C)C(=O)O)c4csc(N)n4)[C@H]3SC2)[nH+]c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Silver tetrafluoroborate (100 mg, 0.5 mmole) was added to a mixture of diphenylmethyl 7-[(Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-4') (577 mg, 0.5 mmole) and 5-methoxy-4-methylthiazole (146 mg, 1 mmole) [prepared according to the procedure described by D. S. Tarbell et al., J. Am. Chem. Soc., 72, 3138 (1950)] in methylene chloride (50 ml). The mixture was stirred for 20 minutes at room temperature and filtered. The filtrate was washed with water, evaporated under reduced pressure and the residue was triturated with ether to give the quaternized salt, which was collected by filtration (yield, 475 mg). The quaternized product was dissolved in cold TFA (2 ml), stirred for 1 hour at room temperature and evaporated under reduced pressure below 30° C., and the residue was triturated with ether. The crude TFA salt was collected by filtration (yield, 281 mg) and purified by HPLC (Column: Lichrosorb RP-18, Solvent: 0.01M NH4H2PO4 (pH 7):CH3OH=85:15). The fractions containing the desired compound were combined and concentrated under reduced pressure below 30° C. The concentrate was acidified to pH 2 (dilute HCl), chromatographed on a column of HP-20 (1.3×10 cm) and eluted with water and then with water-methanol (1:1). The fractions containing the desired product were combined, evaporated under reduced pressure and freeze-dried to give the title compound [Ii] as an amorphous powder. Yield, 61 mg (20%).