Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.[Cl-].[NH4+].C(O)C>[Fe].O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Temperature: 80 °C
Yield: 72.5 %

Procedure:
6-Bromo-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (6 g, 18.40 mmol), iron filings (3.29 g, 58.9 mmol) and ammonium chloride (0.492 g, 9.20 mmol) were weighed to a 250 ml round-bottomed flask and ethanol (60 ml) then water (18 ml) was added. The reaction was heated to 80° C. for 2.5 hr. The reaction mixture was cooled. 100 ml Ethyl acetate and 50 ml water was added. There was no visible separation of layers so the reaction was evaporated to remove the ethyl acetate and ethanol. 250 ml Ethyl acetate was then added and the organic layer was washed with a further 50 ml water, before passing through a hydrophobic frit. The organic layer was evaporated to dryness to give 6 g crude material. The aqueous layer was further extracted with DCM and then ethyl acetate. The DCM extract was evaporated to dryness to give a small amount of impure product that was discarded. The 6 g batch of crude material was purified by column chromatography on silica (120 g silica column, ISCO companion technology) eluting with a gradient of 1-2% methanol in DCM over 25 minutes. Fractions containing desired material were combined and evaporated to dryness to afford the title compound (3.95 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH3:10])=[CH:4][N:3]=1.[CH3:20][C@H:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:29]([NH:28][C@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:20])=[O:30])[CH3:10])=[CH:4][N:3]=1
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)cc1
Reactant: C[C@H](N=C=O)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)N[C@@H](C)c2ccccc2)C(C)c2cnc(Cl)nc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of [1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine (378 mg, 1.27 mmol) (from Example 1d supra) and (S)-(−)-α-methylbenzyl isocyanate (205 mg, 1.39 mmol) (Aldrich) in toluene (5 mL) was stirred at 100° C. for 16 hours. After cooling to room temperature the reaction mixture was purified by passing through silica gel and eluting with hexanes-ethyl acetate (1:1) to give 1-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-1-(4-methoxy-phenyl)-3-[1-(S)-phenyl-ethyl]-urea as two separable diastereomers. Less polar diastereomer (thin layer chromatography in hexanes-ethyl acetate, 1:1) (Yield 270 mg, 47.8%) and more polar diastereomer (Yield 284 mg, 50.3%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[CH2:9][NH:10][C:11](=[O:12])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1]
Reactant: O=C=NCc1ccccc1Cl
Reactant: CNCCO
Solvent: C1CCOC1
Product: CN(CCO)C(=O)NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 2-(methylamino)ethanol (600 mg, 7.99 mmol) in THF (5.0 mL) was added 2-chlorobenzylisocyanate (0.75 mL, 6.66 mmol). The reaction was stirred at rt for 30 min. The mixture was concentrated, re-dissolved in MeOH, filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (950 mg, 49%). LRMS (M+H+) m/z 243.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:49])[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:49])[CH:32]([C:34]1[CH:39]=[CH:38][C:37]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[CH3:25])=[CH:36][CH:35]=1)[CH3:33])[CH3:29]
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2F)ccc1Br
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2C)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-3-methyl-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-2′-methyl-biphenyl-4-yl)-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19]C)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([OH:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:32][CH:33]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 12, 950 mg, 1.77 mmol) in dry dichloromethane (30 mL) at −78° C. was added a solution of boron tribromide (1.7 mL, 17.7 mmol) in dry dichloromethane (10 mL). The mixture was then warmed to room temperature and stirred for 1 h. The solution was poured into ice-water and neutralized with a 2.5M aqueous sodium hydroxide solution (pH ˜6). The mixture was extracted with ethyl acetate (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (925 mg, 100%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C27H26N2O5S2 [M+H]+ 523.65, observed 523.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10](=O)OC(C)(C)C.[Cl:24][CH2:25]C([O-])=O.[Na+]>Cl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]([CH2:25][Cl:24])=[N:1][C:2]=2[CH:7]=1
Reactant: O=C([O-])CCl
Reactant: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)c1ccc(Cl)cc1N
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A mixture of tert-butyl 2-amino-4-chlorophenyl(3-(methylsulfonyl)propyl)carbamate (320 mg, 0.92 mmol) and sodium chloroacetate (130 mg, 1.1 mmol) in 4 N HCl was heated to 100° C. After overnight stirring, the reaction solution was cooled to RT and concentrated. The residue was diluted with DCM (100 mL) and washed with sat. NaHCO3 (50 mL). The organic layer was dried and concentrated under vacuum. The residue was purified by prep-TLC (DCM/EtOAc=3:1) to give 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole (130 mg, yield: 44%) as pale solid. MS obsd. (ESI+) [(M+H)+]: 321.0.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:27])[NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19]1)[CH2:9][CH2:10][N:11]1[N:15]=[CH:14][CH:13]=[N:12]1)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[NH2:7][CH:8]([CH2:9][CH2:10][N:11]1[N:15]=[CH:14][CH:13]=[N:12]1)[C:16]([NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:27]
Reactant: CC(C)(C)OC(=O)NC(CCn1nccn1)C(=O)NC1(c2ncccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(CCn1nccn1)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the [1-(1-pyrimidin-2-yl-cyclopropyl-carbamoyl)-3-1,2,3-triazol-2-yl-propyl]-carbamic acid tert-butyl ester (143 mg, 0.37 mmol) in CH2Cl2 (5 mL) was added TFA (0.14 mL, 1.85 mmol) and the mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and 106 mg of crude 2-amino-N-(1-pyrimidin-2-yl-cyclopropyl)-4-1,2,3-triazol-2-yl-butyramide trifluoroacetate. The title compound was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([N:28]1[CH2:33][C:32](=O)[O:31][C:30](=[O:35])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:21]([N:28]1[CH2:33][C:32](=[O:31])[N:1]([C:2]2[CH:3]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][N:7]=3)[CH:17]=[CH:18][C:19]=2[F:20])[C:30](=[O:35])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CN(Cc2ccccc2)CC(=O)O1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1CN(Cc2ccccc2)CC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (2.51 g, 9.3 mmol; prepared in a manner similar to that described in Example 23), 4-benzylmorpholin-2,6-dione (2.3 g, 11.2 mmol) and toluene (15 ml) was heated under reflux for 20 hours, then the solvent was removed in vacuo. The residue was dissolved in dimethylacetamide (15 ml) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (3 g, 9.3 mmol) and diisopropylethylamine (1.63 ml, 9.3 mmol) were added sequentially. The mixture was stirred at ambient temperature for 2 hours, then it was added dropwise to stirred, ice-cold water (300 ml). The resulting solid was collected by filtration and dried in vacuo to give 4-benzyl-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperazine-2,6-dione (4.01 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.6 (s, 4H) (2×ring CH2) 3.75 (s, 2H) (NCH2Ph), 4.35 (s, 2H) (ArCH2—), 7.17–7.5 (m, 8H) (8×ArH), 7.75–8.0 (m, 3H) (3×ArH), 8.25 (d, 1H) (ArH), 12.6 (s, 1H) (CONH); m/z (M+H)+ 457, 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:9]([CH2:10][C:11]=1OS(C(F)(F)F)(=O)=O)[CH2:8][CH2:7]2)=[O:4].[OH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:9]([CH2:10][C:11]=1[C:32]1[CH:33]=[CH:34][C:29]([OH:28])=[CH:30][CH:31]=1)[CH2:8][CH2:7]2)=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(O)cc1
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: [Na+]
Solvent: COCCOC
Product: COC(=O)C1=C(c2ccc(O)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a sol. of compound A1 (10.0 g, 24.1 mmol) and 4-hydroxybenzeneboronic acid (3.42 g, 24.1 mmol) in DME (171 mL) was added aq. 2 M Na2CO3 (86 mL). The mixture was stirred at rt for a few minutes, and Pd(PPh3)4 (1.39 g, 1.20 mmol) was added. The mixture was heated rapidly to 80° C., and stirred at this temperature for 60 min. The mixture was partitioned between EtOAc and water, and the aq. layer was extracted with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 6:4) yielded the title compound (7.70 g, 89%). LC-MS: tR=0.95 min, ES+: 360.18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([C:24](O)=[O:25])=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.O=S(Cl)Cl.O[NH:41][C:42](=[NH:44])[CH3:43].CCN(CC)CC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([C:24]4[O:25][N:44]=[C:42]([CH3:43])[N:41]=4)=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:34])[CH3:35])=[CH:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(-c2nc3c(c(C(=O)O)nn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: CC(=N)NO
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2nn(-c3ccccc3)c3nc(-c4ccc(C(C)C)cc4)n(-c4ccc(Cl)cc4)c(=O)c23)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid (15 mg, 0.031 mmol) is treated with SOCl2 (0.5 mL) at 80° C. for 1 h. and cooled down to room temperature. SOCl2 is removed under vacuum and the residue is dissolved in anhydrous dichloromethane (0.5 mL). N-hydroxy-acetamidine (9 mg, 0.12 mmol) is added followed by Et3N (0.02 mL). The mixture is stirred at room temperature for 1 h and then poured into water (5 mL). The mixture is extracted with EtOAc(3×3 mL). After the combined extracts is concentrated and dried under vacuum for 5 h., the residue is dissolved in anhydrous dioxane (0.5 mL) followed by the addition of NaOAc (15 mg). The mixture is stirred at 80° C. for 24 h to complete the conversion. After cooling down to room temperature, the mixture is treated with water and extracted with EtOAc. The combined extracts is concentrated and the residue is purified by preparative LC/MS to provide the title compound 5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (CDCl3) δ (ppm) 8.21(d, 2H), 7.54(t, 2H), 7.42(t, 1H), 7.32 (d, 2H), 7.29(d, 2H), 7.12(m, 4H), 2.87(m, 1H), 2.55(s, 3H), 1.20(d, 6H). HPLC-MS calculated C29H23ClN6O2 (M+1+): 523.2. Found: 523.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:18])([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CC(C)(C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CC(C)(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-dimethyl-3-phenyl-butyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC1N(C)CC[NH+]1C.[OH:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([NH2:52])([CH2:45]3)[CH2:43]1)[CH2:49]2>ClCCl>[OH:41][C:42]12[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][C:44]([NH:52][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[N:3]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:4]=4[CH3:10])=[O:9])([CH2:45]3)[CH2:43]1)[CH2:49]2
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: Cc1nc(C(=O)O)c(C)n1-c1ccccc1
Agent: CN1CC[NH+](C)C1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)NC23CC4CC(CC(O)(C4)C2)C3)c(C)n1-c1ccccc1
Yield: 67.1 %

Procedure:
To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.66 gram, 0.00306 mol) in dichloromethane (35 ml) was successively added diisopropylethylamine (DIPEA) (3.1 ml), CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate). (2.55 gram) and 3-hydroxyadamantane amine (0.612 gram, 0.00366 mol). The resulting mixture was reacted at 20° C. for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with 5% aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichoromethane/methanol=98/2 (v/v)) to give N-(3 hydroxyadamant-1-yl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (0.75 gram, 67% yield). Rf (silica gel/dichoromethane/methanol=98/2 (v/v))˜0.6. Melting point: 215-220° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Li]CCCC.CN([CH:21]=[O:22])C>O1CCCC1>[CH:21]([C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:22]
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)O)cc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a stirred solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 5 g, 18.11 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) under nitrogen at −78° C. was added n-BuLi (2.5 M in THF, 18 mL, 2.50 equiv) dropwise. After stirring at −78° C. for 1 h, DMF (5 g, 68.4 mmol, 3.80 equiv) was added dropwise. The resulting mixture was stirred at −78° C. for an additional 0.5 h and then carefully quenched by slow addition of 50 mL of water. The pH was then adjusted to ˜3-4 using aqueous HCl (aq., 6 M). The mixture was extracted with 3×200 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue thus obtained was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:5) as gradient to yield 2.4 g (74%) of the title compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:28][CH3:29])[C:26](=[O:27])[N:12]2[CH:13]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[C:14]([CH3:17])=[CH:15][S:16][C@H:11]12)=[O:8].[Se](=O)=O>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:28][CH3:29])[C:26](=[O:27])[N:12]2[CH:13]([C:18]([O:20][CH2:21][C:22]([Cl:24])([Cl:25])[Cl:23])=[O:19])[C:14]([CH2:17][O:20][C:18](=[O:19])[CH3:13])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)=CS[C@@H]21
Agent: O=[Se]=O
Solvent: CC(=O)O
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(COC(C)=O)=CS[C@@H]21
Reaction time: 2 h

Procedure:
To a solution of β,β,β-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-methyl-2-cephem-4-carboxylate 0.94 (mg., 2 mmole) in acetic acid (10 ml.) is added selenium dioxide (0.111 g., 1 mmole) keeping the reaction temperature at about 25°C. The reaction mixture is stirred for two hours, filtered, diluted with water (30 ml.) and extracted with chloroform. The chloroform extracts are washed successively with water, sodium bicarbonate and water. The solvent is removed under vacuum to afford a residue which is chromatographed on silica gel using chloroform and ethyl acetate (95:5) to afford substantially pure β,β,β-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl-2-cephem-4-carboxylate.
Reaction SMILES: [C:1]1([S:7]([CH2:9][C@@H:10]2[NH:13][C:12](=[O:14])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:22]=[C:23]=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([N:13]1[C:12](=[O:14])[CH2:11][C@@H:10]1[CH2:9][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1C[C@H](CS(=O)c2ccccc2)N1
Reactant: O=C=NCc1ccccc1
Product: O=C1C[C@H](CS(=O)c2ccccc2)N1C(=O)NCc1ccccc1

Procedure:
Following the same procedure as in example 4, step D, but using 4(R)-(benzenesulfinylmethyl)azetidin-2-one and benzylisocyanate as the starting material, gave 2(R)-benzenesulfinylmethyl-4-oxoazetidine-1-carboxylic acid benzyl amide.
Reaction SMILES: C([NH:5][C:6](=[O:41])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)=[O:26])[CH2:21]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:38][C:36]([F:37])([F:39])[C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[C:29]([NH:28][CH2:27][C:25](=[O:26])[NH:24][CH:22]1[CH2:21][N:20]([CH:17]2[CH2:16][CH2:15][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:6]([NH2:5])=[O:41])=[CH:9][CH:10]=3)[CH2:19][CH2:18]2)[CH2:23]1)=[O:40]
Reactant: CC(C)(C)NC(=O)Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
N-[(1-{4-[4-(3-tert-Butyl-ureido)-phenyl]-cyclohexyl}-azetidin-3-ylcarbamoyl)-methyl]-3-trifluoromethyl-benzamide (prepared as described in Example 18, 50 mg, 0.087 mmol) was treated with TFA (1 mL) at room temperature overnight. The reaction was quenched with saturated NaHCO3. The reaction solution was extracted with a chloroform/IPA “cocktail” (˜3:1, v/v). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compound as white solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.C(O)(=O)C>C1COCC1>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 158A (6.31 g, 21.7 mmol) and 30% aqueous acetic acid (100 mL) in THF (50 mL) was stirred at 95° C. for 6 hours, cooled to room temperature, concentrated, treated with water, and extracted with dichloromethane. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 248 (M+H)+.