Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][CH2:23]4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Cs+].[Cs+]>CCO.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>[CH3:15][C:14]1[N:13]=[C:12]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][CH2:23]3)=[N:17]2)[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)[CH:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-n2nc(C3(C(F)(F)F)CCC3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: Cc1nc(-n2nc(C3(C(F)(F)F)CCC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 4.9 %

Procedure:
To a suspension of 1-(5((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5(4H)-one (0.240 g, 0.564 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), Cs2CO3 (0.500 g, 1.535 mmol) and Pd(PPh3)4 (0.030 g, 0.026 mmol) in EtOH (20 mL) was heated at 100° C. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer saturated with solid sodium chloride and extracted with DCM (2×20 mL). The combined organics were dried, concentrated in vacuo, and purified by silica gel chromatography (0-40% THF/EtOAc) to provide 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(1-(trifluoromethyl)cyclobutyl)-1H-1,2,4-triazol-5(4H)-one (0.013 g, 4.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.48 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.61 (m, 4H), 2.35 (s, 3H), 2.03 (t, J=8.2 Hz, 2H); MS (ESI) m/z: 472.2 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[O:9][C:10]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:12]=1.Cl>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([O:6][CH:4]([CH3:5])[CH3:3])[O:9][C:10]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:15]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.60 g) was added to 2-propanol (20 ml), and stirred at room temperature for 10 minutes. To the reaction mixture was added 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), and stirred under reflux for 30 minutes. Next, water was added to the resulting reaction mixture, which was then acidified with 2 N hydrochloric acid, and the crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-isopropoxy-5-oxazolepropionic acid (1.35 g, 87%). This was recrystallized from isopropyl ether to give colorless prisms. mp 116-117° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[O:18][CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:13][C:12]=3[O:18][CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(O)ccc1-c1nc2ncc(C)cc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncc(C)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 6-methyl-2-(2'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[C:8](Cl)([Cl:10])=[O:9]>C1C=CC=CC=1>[Cl:10][C:8]([O:7][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][CH3:1])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: CCCC(O)CC
Solvent: c1ccccc1
Product: CCCC(CC)OC(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
20.4 G. (0.2 moles) of 3-hexanol is added dropwise under anhydrous conditions to 345 ml. (0.4 moles) of 12.5% phosgene in benzene with stirring and cooling in an ice bath. The addition is complete in 2 hours and 15 minutes and the temperature is allowed to warm to room temperature and the reaction mixture is stirred overnight. Gaseous nitrogen is passed through the solution for several hours to remove the excess phosgene and hydrogen chloride. The reaction mixture is then evaporated to dryness in vacuo affording 28.3 g. (86%) of a colorless oil which infrared analysis indicates to have a strong carbonyl band and no hydroxy band. The oil is used as is in subsequent reactions.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:10](OS(C)(=O)=O)[CH2:9][CH2:8][C:7]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:6]1)=[O:4].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:8][CH2:9][CH:10]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CC2(CCCCC2)CC[C@H]1OS(C)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)C1=CCCC2(CCCCC2)C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a solution of trans-3-methanesulfonyloxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (3.0 g) obtained in Step 5 in tetrahydrofuran (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.65 mL), followed by stirring the reaction mixture at 70° C. for 6 hours. After cooling down to room temperature and adding 2N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated to give spiro[5.5]undec-2-ene-2-carboxylic acid methyl ester (1.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=O)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.[NH4+:36]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:36][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:16][N:15]=2)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Yield: 72.3 %

Procedure:
The mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbarnoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g, 4 mmol), acetic acid (24 up, and ammonium acetate (1.54 g, 20 mmol) in xylene (20 ml) was heated at 140° C. for 20 hours. The mixture was quenched with saturated sodium carbonate solution, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.21 g). m/z: 417.9 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:15][S:14][C:9]2[C:10]([O:12][CH3:13])=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]([CH3:15])[CH:8]=2)=[CH:6][CH:11]=1
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 1-bromo-2,4-dichloro-benzene. MS m/z 479 (M+2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc2nc(Cl)nc(Cl)c2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2nc(Cl)nc(N3CCOCC3)c2c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
2,4-Dichloro-6-nitro-pyrido[2,3-d]pyrimidine (5.8 g; 23.8 mmol) was dissolved in dichloromethane (100 mL), and chilled in a dry ice bath. To the cold solution was added morpholine (2.07 g; 23.8 mmol), and diisopropylethylamine (3.07 g; 23.8 mmol) and it was allowed to warm gradually to room temperature. The solution was washed with a saturated ammonium chloride solution (2×50 mL), dried over magnesium sulfate, and evaporated to give 2-chloro-4-morpholino-6-nitro-pyrido[2,3-d]pyrimidine (6.7 g.).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:17]=[CH:18][C:8]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[CH:9][CH:10]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCOc1ccc(-n2ccnc2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A mixture of 2.04 g of 3-[4-(1H-imidazol-1-yl)phenoxy]propanamine dihydrochloride (Example 92) in 70 ml of methylene chloride is treated with 21 ml of 1N NaOH followed by 1.54 g of 4-bromobenzoyl chloride with stirring at room temperature for 18 hours. Additional methylene chloride and 5 ml of 1N NaOH is added and the organic layer separated, washed with water and filtered. The organic layer is evaporated in vacuo to a residue which is washed with ether and dried to give 1.3 g of off-white solid, m.p. 183°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.CI.[CH2:26](N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([N:17]([CH3:26])[S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(c1ccc(Cl)cc1)c1cc(Br)ccc1N)S(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid [(2-amino-5-bromo-phenyl)-(4-chloro-phenyl)-methyl]-amide (9.73 g, 0.024 mmol) solved in 150 mL DMF is added LiHNDS (1.06M, 24.5 mL) at −30° C. After 1 h, methyl iodide (3.4 g, 0.024 mol) and triethylamine (33.5 mL, 0.24 mol) is added. The mixture is stirred at RT for 2 h. The mixture is then quenched with H2O, extracted with CH3O(CH3)3, dried over Na2SO4, concentrated. This produces the desired compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][NH2:1])[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [H][H]
Reactant: CC(C)Cn1c(CN=[N+]=[N-])nc2c(N)nc3ccccc3c21
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c(CN)nc2c(N)nc3ccccc3c21

Procedure:
2-Azidomethyl-1(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.2 g, 0.0108 mol, Example 11) was added to ethanol (300 mL) and 5% Pd/C (about 1 g) was added to the mixture. The mixture was hydrogenated on a Parr apparatus until hydrogen uptake stopped. Hydrogen was removed and the mixture was flushed with hydrogen to regenerate the catalyst. Hydrogenation was resumed. This procedure was repeated until no more hydrogen was absorbed. The catalyst was filtered from the mixture and the filtrate was evaporated. The residue was recrystallized several times from ethanol to give yellowish crystals m.p. 287-291° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)c(F)cc1F
Reaction time: 24 h

Procedure:
To a solution of methyl 5-amino-2,4-difluorobenzoate (252 mg, 1.35 mmol) and pyridine (0.13 mL, 1.61 mmol) in 5 mL CH2Cl2 was added methanesulfonyl chloride (0.12 mL, 1.48 mmol). After 24 h at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 2,4-difluoro-5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 264 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2,4-difluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 250 (M−H)), which was used without further purification.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:28])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:28])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
A mixture of 7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (3.0 g) and conc. hydrochloric acid (3 ml) in methanol (50 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was adjusted to pH 5-6 with an aqueous solution of sodium bicarbonate and then concentrated under reduced pressure. The precipitated crystals in the concentrate were collected by filtration to give 7-[(2-aminothiazol-4-yl)glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (1.1 g).
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH2:37][CH2:36][C:31]6(OCC[O:32]6)[CH2:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[C:13]=2[CH3:38])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH2:37][CH2:36][CH:31]([OH:32])[CH2:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[C:13]=2[CH3:38])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCC(O)CC3)cc12

Procedure:
A mixture of Example 27 (450 mg, 0.832 mmol) and TFA (6 ml) in DCM (30 ml) was stirred at r.t. for 6 hrs. The solvents were removed in vacuo and the crude product was purified by flash chromatography (silica gel, EtOAc/MeOH/NH4OH gradient) to yield Intermediate 19.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][C:3]=1C(O)=O.C1(C)C=CC=CC=1.Cl>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([CH2:12][CH2:13][CH3:14])[CH:9]=[C:10]([Cl:11])[C:5]=2[O:4][CH:3]=1
Reactant: CCCc1cc(Cl)c2oc(C(=O)O)c(C)c2c1O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCc1cc(Cl)c2occ(C)c2c1O
Yield: 74.6 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-propyl--7-chlorobenzofuran carboxylic acid (0.93 gm; 3.7 mmoles), toluene (25 mL), 6N hydrochloric acid (20 mL), 10N HCl (100 mL) and acetic acid (30 ml) was refluxed for a period of 18 hours. The two phases were separated and the organic phase was dried (Na2SO4), and concentrated in vacuo to yield 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.62 gm; 80%), identical to the product obtained from the cyclisation reaction described above in Step C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:11][C:12]#[N:13].C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:11][C:12]1[NH:13][C:17](=[O:26])[C:18]2[C:19]([CH:25]=1)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: C[C@H]1CCCN(CCC#N)[C@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@H](C)[C@@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using cis-2-hydroxymethyl-3-methylpiperidine described in J. Heterocycl. Chem., sol. 9, pp. 875-878 (1972), 3-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-(Cis-2-hydroxymethyl-3-methylpiperidin-1-yl)propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-[2-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27]([C:41]4[CH:46]=[CH:45][C:44](C(OC(C)(C)C)=O)=[CH:43][C:42]=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[NH2:60])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:63]1([CH3:73])[CH:68]=[CH:67][C:66]([S:69]([OH:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1.C(#[N:76])C>>[C:63]1([CH3:73])[CH:64]=[CH:65][C:66]([S:69]([OH:72])(=[O:70])=[O:71])=[CH:67][CH:68]=1.[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27]([C:41]4[CH:42]=[CH:43][C:44]([NH2:76])=[CH:45][CH:46]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[NH2:60])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(N)=O)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(N)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
3.3 g of 7β-[(2S)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 100 ml of acetonitrile with 1.46 g of p-toluenesulphonic acid monohydrate in the manner described in Example 22. 7β-[(2S)-2-(4-Aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =+27°±1° (0.954% in CH3OH);
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14](C)=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:31][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methyl-2-thienyl)-2-naphthalenyl]ethynylbenzoate (Compound 33) (35.0 mg, 0.082 mmol) in 2 ml of EtOH and 1 ml THF at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was stirred at room temperature overnight and then acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.03 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.54-7.48 (3H, m), 6.89 (1H, m), 6.18 (1H, t, J=4.7 Hz), 2.49 (3H, s), 2.35 (2H, d, J=4.7 Hz), 1.32 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[CH2:21](Br)C#C.CO.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:21])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
3.50 g (11.81 mmol) of (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 4A]) and 1.97 ml (17.71 mmol) of propargyl bromide were dissolved in 60 ml of acetonitrile and 3 ml of MeOH and treated with 6.62 g (14.17 mmol) Cs2CO3. After vigorous stirring for 3 h at ambient temperature and filtration, the solvent was evaporated and the residue redissolved in EtOAc. The organic phase was washed with aqueous 1N NaOH (two times) and aqueous 10% NaCl. After extraction of the water phases with EtOAc (two times), the organic phase was dried (Na2SO4) and evaporated to give 3.48 g of the title compound as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl:36][C:37]([Cl:47])([O:39][C:40](=O)[O:41]C(Cl)(Cl)Cl)[Cl:38]>ClCCl>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[O:39][C:37]([Cl:47])([Cl:38])[Cl:36])=[C:7]([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:8]=1)=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(Cl)(Cl)Cl)c(-c3ccnn3C)c2)c1

Procedure:
N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (80.0 mg, 194 μmol), triethylamine (277 μl, 10 eq) and triphosgene (64.8 mg, 1.1 eq) were dissolved in 5 mL of dichloromethane and stirred under reflux for 5 mins. The solvent was removed under vacuum and 4 mL of ethyl acetate was added. It was divided in two and used immediately in the preparation of compound 5 and 7 without purification. LCMS m/z (%)=528 (M+H, 100).