Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C@@H:9]([CH2:35][C@H:36]1[CH2:41][CH2:40][CH2:39][O:38][CH2:37]1)[CH2:10][NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[O-:26])[CH2:15]1)=[O:13])(OC(C)(C)C)=O.C(Cl)Cl.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>>[OH:51][C:45]([C:47]([F:50])([F:49])[F:48])=[O:46].[NH2:8][C@@H:9]([CH2:35][C@H:36]1[CH2:41][CH2:40][CH2:39][O:38][CH2:37]1)[CH2:10][NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[OH:27])[CH2:15]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)[O-])c2cccc(Cl)c2)C1)C[C@H]1CCCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)O)c2cccc(Cl)c2)C1)C[C@H]1CCCOC1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
The 2-((R)—((R)-1-((S)-2-(Boc-amino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate (5 mg, 0.008 mmol) was dissolved in DCM/TFA (3/1 mL). The solution was stirred for 30 min and concentrated. The crude mixture was purified on preparative HPLC to afford 2-((R)—((R)-1-((S)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate TFA salt 2.8 mg, yield 54%. 1H NMR (CD3OD) δ 7.36-7.32 (m, 3H), 7.23 (d, J=7.6 Hz, 1H), 4.20 (br d, J=13.6 Hz, 1H), 4.04 (d, J=8.8 Hz, 1H), 3.89-3.78 (m, 3H), 3.64 (s, 3H), 3.48-3.42 (m, 2H), 3.37 (m, 1H), 3.28-3.24 (m, 5H), 3.15 (dd, J=10.8, 9.2 Hz, 1H), 2.92 (m, 2H), 1.97 (m, 1H), 1.78 (m, 2H), 1.68-1.54 (m, 4H), 1.45-1.07 (m, 5H). MS ESI+ve m/z 511 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)[C:8](=[O:22])[CH:7]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:28][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])=[CH:7][C:8]2=[O:22])=[CH:15][CH:16]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 250 mg (0.71 mmol) 4-(2-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 9.1a) in 4.0 mL of DCM is added 100 μL (1.06 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous phase is extracted three times with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1C=C[CH:27]=[CH:26][CH:25]=1.IC1C=C2C(=CC=1)C(=O)NC(=O)C2=COC.NCC1C=CC(CCCC)=C(O)C=1>>[CH2:24]([C:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])=[CH:7][C:2]=1[OH:1])[CH2:25][CH2:26][CH3:27]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: CCCCc1ccc(CN)cc1O
Agent: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Product: CCCCc1ccc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Yield: 65 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (85 mg, 0.26 mmol) and 5-Aminomethyl-2-butyl-phenol (54 mg, 0.3 mmol) in 65% yield: MS (ESI): 475.2 (M−1)−1.
Reaction SMILES: [CH2:1]([C:4]1([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O1CCOCC1>CO>[CH2:1]([C:4]1([C:17]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:26])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1COCCO1
Solvent: CO
Product: C=CCC1(C(=O)Nc2cccc(Cl)c2)CCNCC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-allyl-4-(3-chlorophenylcarbamoyl)piperidine-1-carboxylate from step A (0.172 g, 0.453 mmol) in MeOH (10 mL) was added 4 MHCl in dioxane (0.340 mL, 1.36 mmol). The reaction was heated at 50° C. for 30 min, and then concentrated under vacuum, re-dissolved in MeOH and re-concentrated twice to give the title compound as the hydrochloride salt. MS (ES+) [M+H]+=279.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:26]([O-])([OH:28])=[O:27].O>C[N+]([O-])=O>[C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[C:17]([N+:26]([O-:28])=[O:27])[CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3CO
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)OC(C)(C)C)CC3CO
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 45.4 %

Procedure:
A warm solution of 55 (447 mg, 1.29 mmol) in CH3NO2 (50 mL) was cooled in an ice bath. As the starting material began to precipitate (internal temperature ca. 5° C.) c.HNO3 (0.16 mL, 2.6 mmol) was added dropwise, giving an orange-red mixture. The suspension was stirred at 0° C. for 40 min, then poured into cold H2O and extracted with CH2Cl2 (×3). The extracts were washed with aq. NaHCO3, dried (Na2SO4), and evaporated. The residue was recrystallized from MeOH to give methyl 3-(t-butyloxycarbonyl)-1-hydroxymethyl-5-nitro-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (29) as an orange powder (229 mg, 45%), mp 200° C. (dec.). The mother liquor was purified by chromatography (40% EtOAc-petroleum ether) to give more 29 (70 mg, 14%). 1NMR [(CD3)2SO] δ 11.22 (d, J=1.5 Hz, 1 H, NH), 8.72 (br, s, ca. 0.8 H, H-4 major rotamer), 8.42 (br s, ca. 0.2 H, H-4 minor rotamer), 7.47 (d, J=2.0 Hz, 1 H, H-8), 5.02 (t, J=5.2 Hz, 1 H, OH), 4.14 (t, J=10.5 Hz, 1 H), 3.95 (dd, J=11.2, 4.7 Hz, 1 H), 3.92 (s, 3 H, CO2Me), 3.89-3.80 (m, 1 H), 3.73 (t, J=5.2 Hz, 2 H), 1.54 (s, 9 H, t-Bu). Anal. Calculated for C18H21N3O7 : C, 55.2; H, 5.4; N, 10.7. Found: C, 55.4; H, 5.4; N, 10.7%.
Reaction SMILES: [C:1]1([C@@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@@H](C)c3ccccc3)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (S)-1-phenyl-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-methyl-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: Br[CH2:2][C@@:3]([OH:16])([CH3:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4]([C@:3]2([CH3:15])[CH2:2][O:16]2)=[O:5])=[CH:8][CH:9]=1
Reactant: COc1ccc(NC(=O)[C@@](C)(O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)[C@]2(C)CO2)cc1
Yield: 96 %

Procedure:
(R)-3-bromo-2-hydroxy-N-(4-methoxyphenyl)-2-methylpropanamide (6b) (5.80 g, 20.13 mmol) and K2CO3 (5.56 g, 40.26 mmol) were placed in a 500 mL round-bottomed flask fitted with a stirring bar. 150 mL of acetone was added at room temperature. The reaction solution was heated to reflux for 3 hours. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, (S)—N-(4-methoxyphenyl)-2-methyloxirane-2-carboxamide, 4.00 g, 96.0% yield.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:47]([C:43]2[N:42]([CH3:41])[CH:46]=[CH:45][N:44]=2)(=[O:49])=[O:48])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1ccnc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2nccn2C)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.13 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 1-methyl-1H-imidazole-2-sulfonyl chloride (136 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 229 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[C:33]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:32]=[CH:31][C:30]=2[C:42]([F:43])([F:44])[F:45])[N:8]=1)=[O:5]
Reactant: FC(F)(F)c1ccc(Oc2ccccc2)cc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2cc(Oc3ccccc3)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(100 mg, 0.448 mmol) in dry THF (6.0 ml) under nitrogen at ambient temperature was added 1.0 M lithium bis(trimethylsilyl)amide (0.45 ml, 0.45 mmol) dropwise and then the solution stirred for approximately 30 min. To the solution was added a solution of crude 2-(bromomethyl)-4-(phenyloxy)-1-(trifluoromethyl)benzene (0.135 g) in dry THF (2.5 ml) and stirred for 7 h. The solvent was removed using a stream of nitrogen. To the residue was added saturated aqueous sodium bicarbonate (approximately 7 ml) and then the residue extracted three times with chloroform. The combined organic extracts were filtered through a hydrophobic frit. The solvent was removed in vacuo and the residue purified on MDAP (Method B). The appropriate fractions were combined and solvent evaporated in vacuo. The residue was dried under high vacuum at 45° C. to give the title compound as a white solid (85 mg); LCMS: (System 4) MH+=474, tRET=3.30 min.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:14]([O:16]C)=[O:15].Cl>>[NH2:3][CH2:12][CH:13]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:14]([OH:16])=[O:15]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccsc1
Agent: Cl
Product: NCC(C(=O)O)c1ccsc1

Procedure:
To methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45) was added 6 N HCl, and the solution was refluxed for 4 hours. The solvents were evaporated to give 3-amino-2-(thiophen-3-yl)propanoic acid (E46).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].[OH-].[Na+].Cl>CO>[O:14]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Reaction time: 16 h
Yield: 86 %

Procedure:
To a stirred suspension at room temperature of 4-formylbenzoic acid (2.58 g, 17 mmol) and acetophenone (2.0 ml, 17 mmol) or acetophenone derivatives (1.0–1.1 equiv.) in MeOH (100 ml) was added a solution of NaOH (34 ml, 1N in H2O). After 16 h, the reaction mixture was acidified with conc. HCl (pH=1–2), filtered off, rinsed with H2O and dried to afford the title compound XXIIIa (3.73 g, 14.6 mmol, 86% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl>[Cl:1][C:2]1[C:3]([CH3:9])=[N+:4]([O-:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(C)c(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Cl)c(C)[n+]([O-])c1
Yield: 98.8 %

Procedure:
3-Chloro-2,5-dimethylpyridine (1.10 g) was dissolved in dichloromethane (30 mL). m-Chloroperbenzoic acid (1.61 g) was added with stirring under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was washed with 1 N sodium hydroxide, and the organic layer dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.21 g, 99%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.F[B-](F)(F)F.O=[N+:18]=O>ClCCl>[CH3:8][C:6]1[C:7]([NH2:18])=[C:2]([CH3:1])[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]=1[CH3:9]
Reactant: Cc1cc(C)c(C)c(C)c1C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1c(C)c(C)c(N)c(C)c1C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of pentamethylbenzene (5 g, 33.8 mmol) in dichloromethane (250 mL) at 0° C. was quickly added nitronium tetrafluoroborate (5 g). The mixture was stirred for 4 h before it was quenched with cold water. The organic layer was concentrated and the residue was reduced (Example 14, procedure C) to give pentamethylaniline in 52% yield.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([O:26]CC3C=CC([N+]([O-])=O)=CC=3)=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(O)(=O)C>[C].[Pd].O>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 69.8 %

Procedure:
4-Nitrobenzyl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer, 6.8 g), methanol (60 ml) tetrahydrofuran (60 ml), acetic acid (6 ml), water (10 ml) and 10% palladium carbon (3.5 g) were treated in a similar manner to that of Example 3 to give 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 3.8 g).
Reaction SMILES: CCCCC.C([Li])CCC.[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=O)=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:60])([CH3:59])[CH3:58])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:58])([CH3:60])[CH3:59])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A pentane solution (2.6 ml, 4.2 mmol) of 1.6M n-butyllithium was added dropwise to a solution of n-heptyltriphenylphosphonium bromide (1.84 g, 4.2 mmol) in tetrahydrofuran (10 ml) under a nitrogen atmosphere. After stirring the mixture at room temperature for 30 min, a solution of 5-benzyloxy-4-tert-butyl-2-formylbenzofuran (1.0 g, 3.2 mmol) in tetrahydrofuran (10 ml) was added dropwise. Subsequently, the mixture was stirred at room temperature for 30 min, poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica Gel chromatography (chloroform) to afford 5-benzyloxy-4-tert-butyl-2-(1-octenyl)benzofuran [1.14 g (yield, 91%)].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15](=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[NH2:30])[CH:17]=1>CCO>[CH3:13][O:14][C:15](=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[NH:30][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:17]=1
Reactant: COC(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: COC(=O)c1cccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)c1
Temperature: 80 °C

Procedure:
The product from Example 1d (175 mg, 0.979 mmol) and the product from Example 208b (272 mg, 0.979 mmol) were dissolved in 2 mL of abs EtOH and heated to 80° C. for 16 hrs. At this time the reaction mixture was cooled and solvent removed yielding the title compound as a brown foam that was taken forward without purification (410 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([O:16][CH2:17][CH3:18])=[N:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:25]C(F)(F)C(F)(F)Br.[Cl-].[NH4+]>C(O)(=O)C.CCCCCC.C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([O:16][CH2:17][CH3:18])=[N:10][N:11]2[C:15]([Br:25])=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CCOc1nn2ccsc2c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 62.3 %

Procedure:
To a THF (150 mL) solution of (6-ethoxy-pyrazolo[5,1-b][1,3]thiazol-7-yl)-carbamic acid tert-butyl ester (16.5 g, 61.4 mmol), was added a 2.77M n-hexane solution of n-butyllithium (15.9 mL, 44 mmol) while stirring at −78° C. The mixture was stirred at −78° C. for one hour, and then 1,2-dibromotetrafluoroethane (2.61 mL, 22 mmol) was added, and the mixture was stirred while heating to room temperature for three hours. A saturated aqueous solution of ammonium chloride was added and acetic acid was added, and the mixture was extracted with ethyl acetate and washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate: 0% then 30%) to obtain 4.95 g (13.7 mmol) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH2:13][Si](C)(C)C)[CH:12]=2)[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[N:3]=1
Reactant: C[Si](C)(C)Cn1cc(-c2cccc(Br)n2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-6-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}pyridine (550 mg, 1.77 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 5.30 mL, 5.30 mmol). The reaction was stirred at room temperature for 2 h. It was subsequently diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (20-100% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[NH:29]([C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9]([CH3:12])([CH3:13])[N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:21][CH:22]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)COC1(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Nc3ccccc3)cc2)COC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of tert-butyl (S)-4-(4-aminobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.0 g) in dichloromethane (10 ml) was added dropwise phenyl isocyanate (0.39 ml). The mixture was stirred at the same temperature for 1 hour and partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give tert-butyl (S)-4-[4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.48 g) as colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:12]1=[O:28].[OH-].[Na+]>>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[C:12]2=[O:28])=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(C)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Cn2c(=O)n(CCCCCCCC(=O)O)c3ccccc32)cc1

Procedure:
The product is produced as described in example 22 from 7.3 g. of 8-[3-(4-methylbenzyl)-2-oxo-benzimidazolin-1-yl]-caprylic acid methyl ester and 1.5 g. of NaOH.