Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19]>>[CH3:12][N:13]1[CH:17]=[C:16]([N+:8]([O-:11])=[O:9])[CH:15]=[C:14]1[C:18]([OH:20])=[O:19]
Reactant: Cn1cccc1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
Acetic anhydride (8 ml, 85 mmol) was treated with nitric acid (1.020 ml, 15.98 mmol) (heating occurred upon addition); the mixture was cooled to RT and slowly added to a suspension of 1-methyl-1H-pyrrole-2-carboxylic acid (2 g, 15.98 mmol) in acetic anhydride (12 ml, 127 mmol) cooled to −30° C. The reaction was stirred at −30° C. for 0.5 hours, then at RT for 20 minutes. The mixture was cooled again to −30° C. to precipitate the desired product. The solid was quickly filtered in a frit funnel cooled in dry ice; after a few minutes at room temperature, the solid became deliquescent and resulted in a thick slurry/solution that was collected in a separate flask. The slurry was cooled at −30° C. and washed twice with a mixture of hexane (5 ml) and (iPr)2O (1 ml). The obtained solid was dried under vacuum, then treated with 2N NaOH till complete dissolution (10 ml) and precipitated again by addition of 37% HCl (20 ml). The solid was filtered, washed with water (10 ml) and finally dried under vacuum for 3 days to yield 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid (Int. 15) (540 mg, 3.17 mmol, MS/ESI+ 170.9 [MH]+).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH2:18]([O:20][C:21]([CH2:23][O:24][C:25](=[C:31](OC)N(C)C)[C:26](OCC)=[O:27])=[O:22])[CH3:19]>C1(C)C(C)=CC=CC=1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[C:26](=[O:27])[C:25]([O:24][CH2:23][C:21]([O:20][CH2:18][CH3:19])=[O:22])=[CH:31][N:17]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccnc(N)c2)n1
Reactant: CCOC(=O)COC(C(=O)OCC)=C(OC)N(C)C
Solvent: Cc1ccccc1C
Product: CCOC(=O)COc1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Yield: 25.3 %

Procedure:
4-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-aminopyridine (100 mg) and ethyl 2-ethoxycarbonylmethoxy-3-methoxy-3-dimethylaminopropenoate (150 mg) were heated at 140° C. in xylene (1 ml) for 7 hours with stirring. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (41 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27]1([CH:33]=[CH:34][C:35](Cl)=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:35](=[O:36])[CH:34]=[CH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Yield: 83.8 %

Procedure:
To a stirred and cooled (0° C.) mixture of 14.6 parts of 4-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]benzenamine, 60.9 parts of benzene and 6.86 parts of pyridine was added a solution of 10.6 parts of 3-phenyl-2-propenoyl chloride in 17.4 parts of benzene under a nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was basified and extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from dichloromethane. The product was filtered off and dried, yielding 17.7 parts (83.8%) of N-[4-[(4-chlorophenyl) (1H-imidazol-1-yl)methyl]phenyl]-3-phenyl-2-propenamide; top. 244° C.(interm. 50).
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][C:20](=[O:24])[NH:21][CH2:22][CH3:23])[CH:16]=[CH:15][C:14]=1[Cl:25])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[Cl:25][C:14]1[CH:15]=[CH:16][C:17]([CH2:19][C:20]([NH:21][CH2:22][CH3:23])=[O:24])=[CH:18][C:13]=1[CH2:12][NH:8][CH:9]1[CH2:10][CH2:11]1
Reactant: CCNC(=O)Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)Cc1ccc(Cl)c(CNC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
HCl (4M in dioxane, 29 m-L) was added to a sol. of (2-chloro-5-ethylcarbamoylmethyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (2.94 g, 8.01 mmol) in CH2Cl2 (29 mL) at 0° C. The mixture was stirred for 2 h at 0° C., and was carefully neutralized with aq. 1M NaOH. The layers were separated, and the aq. layer was extracted with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (1.90 g, 89%) that was used further without purification. LC-MS: tR=0.58 min; ES+: 308.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Br.BrBr.[Br:22]C(Br)=O>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[Br:22])=[CH:6][CH:7]=1
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: O=C(Br)Br
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
A 1 L three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with the intermediate from Step 2, (55.5 g, 0.21 mol), acetic acid (250 mL) and 33% HBr in acetic acid (120 mL). The solution was stirred and treated with bromine (11.1 mL, 0.21 mol) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca. 15 minutes. After an additional 10 minutes at room temperature, the solution was filtered through a Buchner funnel and the filtrate concentrated in vacuo to give an orange solid. The crude bromoketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 68.8 g of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone as a yellow solid which was used directly without further purification. The crude bromoketone was dissolved in 300 mL acetone and 150 mL of water and heated to reflux for 2.5 hours. The solution was concentrated in vacuo and the residue taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and reconcentrated in vacuo to give a light yellow solid that was crystallized from a mixture of dichloromethane and isooctane to provide 37.8 g (65%) of pure 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-hydroxy-ethanone: mp 90-92° C.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([NH2:6])[CH:3]([NH2:7])[CH2:2]1.Cl.N=[C:10](OC)[C:11]1[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>C(O)C>[CH3:21][C:14]1[CH:13]=[C:12]([CH3:22])[C:11]([C:10]2[NH:7][CH:3]3[CH2:2][O:1][CH2:5][CH:4]3[N:6]=2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=N)c1cc(C(=O)OC)c(C)cc1C
Reactant: NC1COCC1N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C2=NC3COCC3N2)c(C)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Into around-bottom flask, was placed a solution of tetrahydrofuran-3,4-diamine (compound 466.3, 140 mg, 1.17 mmol, 1.00 equiv, 85%) in ethanol (6 mL). Methyl 5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride (compound 466.4, 300 mg, 0.930 mmol, 1.00 equiv) and triethylamine (140 mg, 1.38 mmol, 1.00 equiv) were added and the resulting solution was stirred overnight at 80° C., then concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) as the eluent to obtain the title compound as a brown oil (120 mg, 34%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[N:8][CH:9]=1
Reactant: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1ncc2cc(Oc3ccc(N)cn3)ccc21
Reaction time: 3 h
Yield: 131.7 %

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1-methyl-1H-indazole (0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 5-(5-Amino-pyridin-2-yloxy)-1-methyl-1H-indazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:28]Br>C(O)(=O)C>[Br:28][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([S:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)(=[O:11])=[O:12])[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2C)cc1F
Yield: 74 %

Procedure:
The title compound was prepared from 5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (1.15 g, 3.0 mmol), bromine (0.61 mL, 12.0 mmol), and acetic acid (30 mL) according to the procedure and in the same manner as described in Example 4, step a. The crude product was purified by re-crystallization from ethyl acetate to yield 2-bromo-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (1.03 g, 2.22 mmol, 74%);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.B(OB=O)=O.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[OH:21][C:22]1[CH:23]=[C:24](/[CH:25]=[CH:13]/[C:12](=[O:14])[CH2:11][C:10](=[O:15])/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(=O)CC(=O)C=Cc1ccc(O)cc1
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCN
Product: COc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1O
Reaction time: 1 h
Yield: 86.2 %

Procedure:
6-(4-Hydroxyphenyl)hex-5-ene-2,4-dione (17.5 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 3-hydroxy-4-methoxybenzaldehyde (16 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol) in 0.7 mL of ethyl acetate. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution of 1N HCl and brine, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (24.8 mg, 86%) as a solid.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(NC=NN)cc3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NN=CNc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.08 g (0.2 mmol) of the ester from Example 64 were dissolved in 30 ml ethanol followed by addition of 0.4 ml aqueous 2 N sodium hydroxide solution. The mixture was stirred at room temperature for two days, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water, and the solution was neutralized with acetic acid, while the title acid precipitated. It was filtered with suction, washed with water, and dried in vacuo.
Reaction SMILES: N.[OH:2][CH2:3][C:4]([O:6][C:7]([CH3:19])([CH2:9][CH2:10][C:11]([O:14][C:15](=[O:18])[CH2:16][OH:17])([CH3:13])[CH3:12])[CH3:8])=[O:5].[C:20]([Cl:31])(=[O:30])[C:21]1[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([Cl:26])=[O:25])[CH:22]=1.C([O:35][C:36]1[CH:37]=[C:38]([C:45]([Cl:47])=[O:46])[CH:39]=[C:40]([CH:44]=1)[C:41]([Cl:43])=[O:42])(=O)C>O1CCCC1>[OH:2][CH2:3][C:4]([O:6][C:7]([CH3:19])([CH2:9][CH2:10][C:11]([O:14][C:15](=[O:18])[CH2:16][OH:17])([CH3:12])[CH3:13])[CH3:8])=[O:5].[C:24]([Cl:26])(=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([Cl:31])=[O:30])[CH:22]=1.[OH:35][C:36]1[CH:44]=[C:40]([C:41]([Cl:43])=[O:42])[CH:39]=[C:38]([CH:37]=1)[C:45]([Cl:47])=[O:46]
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: CC(C)(CCC(C)(C)OC(=O)CO)OC(=O)CO
Agent: N
Agent: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(O)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
To a solution of methanolic ammonia (20 mL, 1 N), polymer (118) dissolved in 5 mL tetrahydrofuran was added and the solution was stirred for two hours. The polymer was then precipitated in 100 mL of cold 1 N hydrochloric acid and collected by filtration. The polymer was then dried under high vacuum and was found to have a molecular weight of ˜7,000 g/mol by GPC.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25]([O:33][CH:34](Cl)[CH3:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:35][CH2:34][O:33][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)O
Reactant: CC(Cl)OC(=O)c1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)OCCOC(=O)c1ccccc1
Yield: 76.9 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (12) (3.0 g, 7.9 mmol) dissolved in 30 mL of anhydrous toluene was reacted with 4.4 g (23.7 mmol) of 1-chloroethyl benzoate (23) in the presence of 2.6 g (9.5 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 3.2 g of a mixture of the title compound (39a) and (3R/S)-4,4-dimethyl-3-(phenylmethoxy)-3,4,5-trihydrofuran-2-one (2a). MS (ESI) m/z 548.97 (M+Na)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH2:16][CH2:15]1)=[O:13].[CH3:24][C:25](OC(C)=O)=[O:26].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:25]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([C:12](=[O:13])[CH2:11][S:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:15][CH2:16]1)(=[O:26])[CH3:24]
Reactant: O=C(CSc1nc2ccccc2s1)N1CCNc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)CSc2nc3ccccc3s2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
To a 0° C. solution of compound 41 (0.41 g, 1.20 mmol) in dry CH2Cl2 (20 mL) were added Ac2O (1.12 mL, 12.0 mmol) followed by dropwise addition of Et3N (1.12 mL, 8.00 mmol), and DMAP (10 mg) The reaction was stirred for 18 h under N2 at room temperature. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (CH2Cl2/EtOAc 1:1), and triturated from CH2Cl2/hexanes to afford 48 as a yellow solid (0.24 g, 52%); MS m/z: 384 (M+H)+. Anal. Calcd. For, C19H17N3O2S2.0.1H2O: C, 59.23; H, 4.92; N, 10.91; S, 16.64. Found: C, 58.84; H, 4.55; N, 10.55; S, 16.32.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:43])=[C:5]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH:20][C:21]3[C:26]([C:27]4[N:35]=[CH:34][N:33]=[C:32]5[C:28]=4[N:29]=[CH:30][N:31]5C4CCCCO4)=[CH:25][CH:24]=[CH:23][N:22]=3)[C:14]=2[F:42])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>>[N:35]1[C:27]([C:26]2[C:21]([NH:20][C:15]3[C:14]([F:42])=[C:13]([NH:12][S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=4[CH3:43])(=[O:11])=[O:10])[CH:18]=[CH:17][C:16]=3[F:19])=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Agent: Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F
Reaction time: 2 h
Yield: 86 %

Procedure:
1M aqueous hydrochloric acid solution was added into the 3-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-methylbenzenesulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 15 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3-chloro-2-methylbenzenesulfonamide (percentage yield: 86%), was obtained.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.[CH:23](O)(C)C>C(N(CC)CC)C>[CH:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])([CH3:23])[CH3:1]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)O
Agent: FB(F)F
Solvent: CCN(CC)CC
Product: CC(C)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
Using the procedure of Step A of Example 8, 27.2 g of 7-amino-cephalosporanic acid, 170 ml of the etherate of boron trifluoride, 134 ml of isopropanol and 125 ml of triethylamine were reacted to obtain 16.25 g of raw product which was purified by two successive treatments with hot hydrochloric acid and ammonium hydroxide to obtain 5.8 g of 3-isopropoxymethyl-7-amino-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[S:19][C:20]2[C:26]([CH:27]=O)=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.O>O1CCCC1>[CH3:17][C:18]1[S:19][C:20]2[C:26](/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: Cc1nc2cccc(C=O)c2s1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nc(C)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
Under nitrogen atmosphere, to a suspension of 60% sodium hydride (1.26 g, 31.5 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (7.06 g, 31.5 mmol) in tetrahydrofuran (50 mL) at 0° C. and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl-1,3-benzothiazole-7-carbaldehyde (4.60 g, 26.0 mmol) in tetrahydrofuran (100 mL), and the mixture was warmed to room temperature over 2 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.50 g, yield 98%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33]>O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1

Procedure:
To a mixture of ethyl 4-hydroxy-3-methoxybenzoate (15.00 g), potassium carbonate (11.63 g) and N,N-dimethylformamide (2.00 mL) was added 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (17.45 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave a pale-brown solid (25.45 g, yield 91%). melting point: 103-104° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[CH2:20][CH2:19][CH:15]3[CH2:14][CH2:13]4)[C:10]=2[O:21]C(=O)C(C)(C)C)=[C:4]([CH3:28])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH3:28])[C:5]([CH:9]2[C:10](=[O:21])[CH:11]3[CH:16]([CH:15]4[CH2:19][CH2:20][CH:12]3[CH2:13][CH2:14]4)[C:17]2=[O:18])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(O)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3CCC(CC3)C2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(O)cc(C)c1C1C(=O)C2C3CCC(CC3)C2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-dimethylpropionic acid 2-(4-hydroxy-2,6-dimethylphenyl)-3-oxo-3a,4,5,6,7,7a-hexahydro-3H-4,7-ethanoinden-1-yl ester (1.3 g, 0.0034 mol) in methanol (50 ml) is added potassium carbonate (2.35 g, 0.017 mol), and the suspension is stirred at room temperature for 2 hours. The reaction mixture is carefully acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organics are separated, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to afford 2-(4-hydroxy-2,6-dimethylphenyl)hexahydro-4,7-ethanoindene-1,3-dione as a white solid.