Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)#[CH:23]>>[O:11]=[C:9]1[CH2:8][C:7]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[N:6][C:5]2[CH:20]=[CH:21][C:2]([C:23]#[C:22][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[CH:3][C:4]=2[NH:10]1
Reactant: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Reactant: C#Cc1cccs1
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4cccs4)cc3NC(=O)C2)c1
Yield: 82.8 %

Procedure:
Prepared from 3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 50) (185 mg, 0.48 mmol) and 2-ethynylthiophene (78 mg, 0.72 mmol) [prepared from 2-thiophenecarboxaldehyde according to J. Org. Chem. 1982, 47, 2201–2204] according to the general procedure F. Obtained as a light yellow solid (146 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=2)[C:6]([O:17][CH3:18])=[CH:5]1)(=O)C.O.[OH-].[Li+]>C1COCC1.O>[CH3:18][O:17][C:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)[NH:4][CH:5]=1
Reactant: COC(=O)c1ccc2c(OC)cn(C(C)=O)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c[nH]c2cc(C(=O)O)ccc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of methyl 1-acetyl-3-methoxyindole-6-carboxylate (74 mg, 0.3 mmol) in THF (10 ml) and water (2 ml) was added lithium hydroxide hydrate (63 mg, 1.5 mmol). The reaction mixture was warmed to 50° C. and stirred for 3 h. The THF was removed under reduced pressure and the pH of the aqueous phase adjusted to 3. Extraction of the aqueous layer with ethyl acetate, drying and concentration gave the acid (50 mg, 87%);
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27]C(O)=O)=[CH:23][CH:22]=1)([O-:20])=[O:19].N1CCCCC1>O>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:24]2[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: -30 °C

Procedure:
A mixture of 5.00 g (21 mmol) of 4-dibutylaminobenzaldehyde, 4.27 g (24 mmol) of 4-nitrophenylacetic acid, 1.80 g (21 mmol) of piperidine, and 50 mL of xylenes was heated with stirring at reflux of 20 hours with continuous removal of water using a Dean-Stark apparatus. The mixture turned dark red. Approximately half the xylenes was distilled, 20 mL of heptane was added, and the residue was cooled to -30° C. Red crystals separated which were collected and then recrystallized from toluene/heptane. Yield: 2.81 g (37%), mp 117-119 (lit2 182°-182.5° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23](S(C)(=O)=O)[CH:22]([N:28]=[N+:29]=[N-:30])[C:21]1=[O:31])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Cl:35])(=O)C>>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23]([Cl:35])[CH:22]([N:28]=[N+:29]=[N-:30])[C:21]1=[O:31])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1S(C)(=O)=O)OCCC(=O)OCc1ccccc1
Product: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1Cl)OCCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
1-(Benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-methylsulfonyl-2-azetidinone (0.446 g.) is dissolved in acetyl chloride (5 ml.). The mixture is allowed to stand for 10 minutes and the acetyl chloride is removed under reduced pressured to afford 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-chloro-2-azetidinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]=[CH:37][C:36]=3[CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[O:39]1[C:35]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][CH:14]5[CH2:17][N:16]([C:18]([CH:20]6[CH2:22][CH2:21]6)=[O:19])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:23])=[CH:4][CH:3]=3)=[CH:40][C:36]=2[CH:37]=[CH:38]1
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 22 h
Yield: 40.6 %

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (83 mg, 0.220 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.5 mL, 1.00 mmol) was stirred at 100° C. in an oil bath for 22 h. Additional 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmol) were added and the reaction mixture was heated at 100° C. in an oil bath for 20 h. The reaction was cooled to room temperature, poured into water (50 mL), and adjusted to pH˜4.5 with 1N aq HCl. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate, then 0-10% methanol/ethyl acetate) followed by a second purification by reverse phase HPLC (20-70% acetonitrile/water+0.1% NH4OH) provided the title compound as an ivory solid (37 mg, 38%). MS(ES)+ m/e 415.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[O-:13][C:14]#[N:15].[K+]>Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[O:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2500 mg (13.957 mmol) of 4-fluoro-3-(trifluoromethyl)aniline were dissolved in 15 ml of 1 N hydrochloric acid, and 1132 mg (13.957 mmol) of potassium cyanate were added. The suspension was stirred at room temperature overnight and then diluted with ethyl acetate such that a clear two-phase solution was formed. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed on a rotary evaporator, and the crude product was then chromatographed on silica gel (mobile phase: dichloromethane/methanol 80:1, then 10:1). This gave 2180 mg (70% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>C(O)(=O)C.O>[I:9][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Cc1ccnc(N)c1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)ncc1I
Temperature: 80 °C
Yield: 389.6 %

Procedure:
To a stirred solution of 4-methyl-pyridin-2-ylamine (30 g, 278 mmol, 1 eq) in acetic acid (167 mL) was added periodic acid (12.7 g, 55.6 mmol, 0.2 eq) followed by addition of sulphuric acid (4.8 mL, 90.8 mmol, 0.34 eq), water (33.3 mL) and iodine (28.7 g, 111.1 mmol, 0.4 eq) at room temperature. Resulting reaction mixture was heated at 80° C. for 6 hours. After complete consumption of starting material, reaction mixture was cooled and poured into sodium thiosulfate solution (200 mL), reddish oil was settled down at the bottom. Reaction mixture was decanted from reddish oil and filtrate was basified with 50% sodium hydroxide solution (100 mL), yellow colored solid was formed. Resulting solid was extracted with diethyl ether (2×200 mL) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown semi solid (60 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 15% EtOAc in hexane to get title compound as faint brown solid (50.7 g, 78%). 1H NMR (400 MHz, CDCl3) δ: 2.27 (s, 3H), 4.46 (bs, 2H), 6.44 (s, 1H), 8.24 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(O)CCC>[C:8]1([C:5]2[N:6]=[N:7][C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=4)[CH2:33][CH2:32]3)=[C:3]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nnc(-c2ccccc2)nc1Cc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: CCCCO
Product: Clc1cccc(N2CCN(c3nnc(-c4ccccc4)nc3Cc3ccccc3)CC2)c1
Temperature: 120 °C

Procedure:
Suspend 2 mmol (570 mg) of 6-chloro-5-benzyl-3-phenyl-1,2,4-triazine obtained in Step A of Example 57 in 40 ml of butanol, and add 4 equivalents of 1-(3-chlorophenyl)piperazine. Heat for 12 hours at 120° C., concentrate the solution, take up in ether, filter the resulting precipitate and recrystallise it from ethanol.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].C(O)(=O)C>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])/[CH:1]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(/C=C/c1ccccc1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 70.2 %

Procedure:
In a 500 mL flask, 99.4 g (0.50 mol) of 4-bromoacetophenone and 53.0 g (0.5 mol) of benzaldehyde were initially charged and dissolved in 50 g of methanol. The mixture was admixed with 6.7 g (0.025 mol) of 15% strength aqueous sodium hydroxide solution carefully added dropwise at 20-25° C. and subsequently stirred for 3 h. The reaction mixture was neutralized with glacial acetic acid and filtered and the solid was dried in vacuo to obtain 107 g (351 mmol) of (2E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1.[H-].[Na+].I[CH3:24]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:24])[C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1
Reactant: CI
Reactant: CSc1nc(-c2ccccc2F)c2ccc(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(-c2ccccc2F)c2ccc(=O)n(C)c2n1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (120 mg, 0.42 mmol) in 20 mL of anhyd THF was added NaH (50 mg, 1.2 mmol, 60% dispersion in mineral oil, 3 eq) followed by iodomethane (74 μL, 1.2 mmol, 3 eq). The reaction mixture was stirred 1 h at 23°, quenched with saturated aq NH4Cl. (20 mL), Et2O (100 mL) was added and the layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and evaporated. The yellow residue was then purified by Flash chromatography to afford 100 mg (92% yield) of 4-(2-Fluoro-phenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 2.68 (s, 3H), 3.81 (s, 3H), 6.61 (d, 1H, J=9.8 Hz), 7.22 (m, 3H), 7.50 (m, 3H). LC MS (m/e)=302 (MH+). Rt=2.17 min.
Reaction SMILES: C1([C:7]2[CH:17]=[CH:16][CH:15]=[C:9]3[C:10]([NH:12][C:13](=[O:14])[C:8]=23)=[O:11])C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[N:36]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:29]2[N:30]=[C:31]([C:34]#[N:35])[N:32]=[CH:33][C:28]=2[CH:27]=1>CN(C=O)C>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][N:36]1[C:29]2[N:30]=[C:31]([C:34]#[N:35])[N:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[CH2:25][N:12]1[C:13](=[O:14])[C:8]2[C:9](=[CH:15][CH:16]=[CH:17][CH:7]=2)[C:10]1=[O:11]
Reactant: O=C1NC(=O)c2c1cccc2-c1ccccc1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)c3ccccc3C2=O)cc2cnc(C#N)nc21
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of 500 mg (1.63 mmoles) of phenylphthalimide in 20 ml of DMF, 315 mg (2.28 mmoles) of K2CO3 and 500 mg (1.63 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 2 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=2:1) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 68% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]([SH:7])[CH3:6])C.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:33]=[CH:34][CH:35]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[CH3:1][O:3][C:4](=[O:8])[CH:5]([S:7][CH2:10][C:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:6]
Reactant: BrCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Reactant: CCOC(=O)C(C)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(C)SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1

Procedure:
Ethyl-2-mercaptopropionate (31 mg, 0.29 mmol) was added to a stirred suspension of 4-(3′-bromomethyl-biphen-3-yl)-dibenzofuran (100 mg, 0.24 mmol) and cesium carbonate (198 mg, 0.6 mmol) in 5 ml DMF. diluted with diethyl ether (30 mL) and washed with water (2×) and brine (3×). The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 30% ethyl acetate in hexane as eluent, afforded the title compound; methyl-2-(3′-dibenzofuran-4-yl-biphen-3-ylmethylsulfanyl)-propionate, as a colorless oil (105 mg, 94).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][OH:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH:31]([CH3:33])[CH3:32])(=O)=O>O1CCOCC1>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][O:11][CH:31]([CH3:33])[CH3:32])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CO
Reactant: CC(C)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1COC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
The product from Example 28A (50 mg, 0.14 mmol) in dioxane (5 mL) was treated with NaH (60%) (7 mg, 0.17 mmol) stirred at rt for 10 min and treated with isopropyl methanesulfonate (78 mg, 0.56 mmol). The reaction was heated at 85° C. for 12 hrs, quenched with H2O, the mixture was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 5.2 mg (9%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (d, J=6.14 Hz, 6 H) 1.81 (s, 9 H) 3.75-3.83 (m, 1 H) 4.12 (s, 3 H) 4.92 (s, 2 H) 7.10 (d, J=9.21 Hz, 1 H) 7.63 (dd, J=9.21, 2.76 Hz, 1 H) 8.18 (d, J=2.45 Hz, 1 H) 9.28 (s, 1 H); MS (DCI/NH4+) m/z 397 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3COCO3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3COCO3)CS[C@H]12)c1csc(N)n1
Yield: 83.7 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3-dioxolan-4-yl)methylthio-3-cephem-4-carboxylate (87 mg) as prepared in Example 29(b) was reacted with iodomethyl pivalate (80 mg) similarly to Example 28 for the esterification reaction. The resulting reaction solution was post-treated and the produced compound was recovered and purified similarly to Example 28 to give the titled compound (86 mg; 84%) .
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15]1>C1COCC1.CCCCCC>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:24])=[CH:15]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: OCCN1CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCCN1CCCC1)c1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a dry THF solution of 2-(1-pyrrolidinyl)ethanol (1.10 g, 9.6 mmol) was dropwise added under ice-cooling a 1.5M hexane solution of n-BuLi (6.4 ml, 9.6 mmol) over a period of 10 min. followed by stirring for 30 min. The solvent was removed under reduced pressure. To the residue was added dry THF (20 ml). To the resulting pale yellow suspension was added a dry THF solution (5 ml) of indole-3-carboxylic acid chloride (1.00 g, 5.6 mmol) with stirring at room temperature over a period of 10 min. After stirring overnight, a reaction solution was then concentrated under reduced pressure. The residue was extracted with diluted hydrochloric acid followed by washing with ether. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and again extracted with ether. The organic layer was washed successively with water and saturated aqueous sodium chloride, then dried (MgSO4) and concentrated under reduced pressure to give 1.10 g of the title compound as colorless plates. m.p. 145°-146° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:23][C:24](C)=[O:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]([OH:25])=[O:23])=[CH:11][C:10]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(C)=O
Product: O=C(O)c1ccc(OCc2ccccc2)c(OC(F)(F)F)c1

Procedure:
4-Benzyloxy-3-trifluoromethoxybenzoic acid was prepared from 4-benzyloxy-1-bromo-3-trifluoromethoxybenzene by following Method M. The crude product was purified by crystallization using a mixture of EtOAc and hexanes as a solvent (19% yield of desired product from the first crop).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]3[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=3[C:9]3[N:10](COCC[Si](C)(C)C)[C:11]([CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[N:12][C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])O.[Na+]>CO.Cl.O>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]3[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=3[C:9]3[NH:10][C:11]([CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[N:12][C:13]=3[C:4]=2[CH:3]=1
Reactant: CN(C)CCOCc1nc2c(n1COCC[Si](C)(C)C)-c1ccccc1Sc1ccc(Cl)cc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)CCOCc1nc2c([nH]1)-c1ccccc1Sc1ccc(Cl)cc1-2
Temperature: 25 °C

Procedure:
To a solution of {2-[5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-dimethyl-amine (0.21 mmole) in methanol (6.0 ml), 0.5 M hydrochloric acid in methanol (2.0 ml) was slowly added. The reaction mixture was heated under reflux for 3 hours, then it was cooled to room temperature, neutralized with a saturated aqueous solution of sodium hydrogencarbonate, diluted with water and extracted with dichloromethane. The organic extract was washed with an aqueous sodium chloride solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure. After purification by chromatography on a silica gel column, [2-(5-chloro-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine in the form of an oily product was obtained;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].CN(C)CCN(C)C.C([Li])CCC.[I:24]I.S(=O)(=O)(O)O>CCCCC.C1COCC1>[I:24][C:7]1[CH:8]=[C:9]([CH3:10])[C:2]([CH3:1])=[CH:3][C:4]=1[CH2:5][OH:6]
Reactant: II
Reactant: Cc1ccc(CO)cc1C
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cc(I)c(CO)cc1C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
A solution, cooled to 0° C., of 6.81 g of 3,4-dimethylbenzyl alcohol and 11.62 ml of N,N,N′,N′-tetramethyl-ethylenediamine in 150 ml of pentane was treated with 62.5 ml of n-butyllithium solution (1.6M in hexane). The reaction mixture was boiled at reflux for 11 hrs. Then, 12.69 g of iodine in 50 ml of THF were added dropwise at −30° C. The mixture was stirred for 15 min. at −30° C. and then left to warm to room temperature. The reaction mixture was added to 100 ml of 10% sulphuric acid. The crude product was isolated by extraction and purified by chromatography on silica gel. There were obtained 2.95 g of (2-iodo-4,5-dimethyl-phenyl)-methanol as a light yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([NH:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[OH:17])[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([OH:2])[CH:19]=[CH:18][C:6]=2[N:7]=1
Reactant: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.2 %

Procedure:
To a solution of (1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (1.06 g, 3.81 mmol) in 16 mL of DCM was added 1 M boron tribromide in DCM (8 mL, 8 mmol) slowly at 0° C. The reaction solution was stirred at room temperature for 2 hours. After removal of all solvent in vacuo, the mixture was quenched with water (30 mL) and diluted NaHCO3 solution, and extraction with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4 and subsequent removal of EtOAc in vacuo yielded the desired product (1.16 g) as a pink solid. The residue was purified by flash column chromatography to give the title compound (1.0 g, 3.78 mmol) as a brown solid. ES/MS m/z 265.1 (H+).