Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.[OH-].[Na+]>O1CCOCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:46]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH:43]=[CH:44][CH:45]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C(NCc1ccccc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 18.1 %

Procedure:
To a stirred solution of (3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-N-benzylcarboxamide (0.232 g, 0.322 mmol) was added dioxane (10.0 mL) and aqueous 6 N hydrochloric acid (10.0 mL) and the mixture heated at 50° C. for 24 h. The mixture was cooled and aqueous 6 N sodium hydroxide (20 mL). Neutralization of the aqueous layer to pH=7 with aqueous 6 N hydrochloric acid followed by extraction with ethyl acetate, drying of the organic extracts over anhydrous sodium sulfate, filtration and evaporation gave crude product. Purification by preparative HPLC (15–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0230 g, 18% yield). 1H NMR (CD3OD) δ 8.78 (s, 1H), 8.49 (t, 1H), 8.21 (dt, 1H), 8.11 (br d, 1H), 7.93 (dt, 1H), 7.69 (t, 1H), 7.65 (d, 1H), 7.40 (dd, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 4.64 (s, 2H). ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].B(F)(F)F.[CH3:17][CH2:18]OCC>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:17][CH3:18])=[O:11]
Reactant: Nc1ccc(CC(=O)O)c(F)c1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1F

Procedure:
A solution of 8.2 g. of 2-fluoro-4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 2-fluoro-4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 2-fluoro-4-(hexadecylamino)phenylacetate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([N:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])=[O:4].[CH3:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:21][N:14]([C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:3](=[O:4])[CH2:2][NH:1][C:38]([NH:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[CH:32]=1)=[O:39])=[O:13])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN(C(=O)c1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)N(C)c2ccccc2)c1
Yield: 57.4 %

Procedure:
Using a procedure similar to that described in Example 27, but starting with tert-butyl 2-{2-amino-N-[2-(N-methylanilino)carbonylphenyl]acetamido}acetate (2.5 g) and 3-methylphenyl isocyanate (0.83 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-[2-(N-methylanilino)carbonylphenyl]-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.9 g), m.p. 145° C., is obtained.
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>C(O)C>[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([CH2:20][N:6]2[CH2:7][CH2:8][N:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)N1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCN(Cc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
Sodium borohydride (500 mg) was added to a mixture of 1.6 g of ethyl 1-piperazinecarboxylate, 1.3 g of p-tolualdehyde and 30 ml of ethanol, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 50 ml of water was added, and the resultant mixture was extracted with ethyl acetate. The ethyl acetate extract was then extracted with diluted hydrochloric acid. The diluted hydrochloric acid extract was washed with ethyl acetate, made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous potassium carbonate and concentrated under reduced pressure to give 0.8 g of ethyl 4-p-tolylmethyl-1-piperazinecarboxylate as an oil. This was deprived of the carboethoxy group by the method described in Reference Example 38 to give 0.36 g of 1-ptolylmethylpiperazine as an oil.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].C(N([CH2:19][CH3:20])CC)C>CO.O>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:10]3[C:19]4[C:20](=[CH:1][CH:3]=[CH:4][CH:13]=4)[CH2:6][C@H:11]3[OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2]
Reactant: CCN(CC)CC
Reactant: Cc1nc2c(O)cccn2c1C=O
Solvent: CO
Solvent: O
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1C=O

Procedure:
12 g (68 mmol) of 3-formyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine, 18 g (136 mmol) of 1,2-indenoxide and 9,6 ml (68 mmol) of triethylamine are stirred in 95 ml methanol/water (4:1) for 14 hours at 40° C. The mixture is evaporated at 50° C. in the rotary evaporator, mixed with 200 ml icewater, rendered alkaline with sodium hydroxide solution (approximately pH 13), and the precipitate is filtered off. The filtrate is shaken out with dichloromethane and the organic phase made up to 250 ml with dichloromethane, combined with the precipitate, dried with magnesium sulfate and purified with active charcoal. 250 ml of toluene is added, dichloromethane is distilled off, the mixture is purified at the boiling point with bleaching earth (e.g. Tonsil®), evaporated to half its volume and allowed to crystallize in the refrigerator. The yield of the titel compound m.p. 200°-202° C. is 17.6 g (84%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21]N(C=O)C.[OH-].[K+].IC>C1COCC1>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[C:11]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: CN(C)C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCC1=O
Reaction time: 0.12 h

Procedure:
To a suspension of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (20 g, 67.2 mmol) in THF (130 mL)/DMF (130 mL) was added KOH (powder, 7.64 g, 136 mmol) at room temperature. The reaction mixture was stirred for 5-10 min, then added iodomethane (4.62 mL, 73.9 mmol) dropwise. The reaction mixture was further stirred for 3 h at room temperature and then quenched with water. The aqueous phase was extracted with diethyl ether twice. The organic phases were combined and washed with water, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-20% EtOAc/heptanes) to provide ethyl 1-benzyl-3-methyl-4-oxopiperidine-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.45 (m, 5H), 4.00-4.21 (m, 2H), 3.66 (d, J=13.39 Hz, 1H), 3.47 (d, J=13.39 Hz, 1H), 3.30 (dd, J=2.78, 11.62 Hz, 1H), 2.96-3.08 (m, 1H), 2.77 (ddd, J=6.69, 11.68, 14.46 Hz, 1H), 2.36-2.45 (m, 1H), 2.27-2.35 (m, 1H), 2.14 (d, J=11.37 Hz, 1H), 1.15 (t, J=7.07 Hz, 3H), 1.09 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([NH2:18])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[F:27].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[F:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[NH:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Nn1ccc2cc(OCc3ccccc3)ccc21
Reactant: Fc1cnccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1cnccc1Nn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To 250 ml 1-methyl-2-pyrrolidinone was added 5-phenylmethoxy-1H-indol-1-amine (27.3 g), and the mixture was heated to 80° C. Then, 4-chloro-3-fluoropyridine hydrochloride (22 g) was added, and the mixture was heated at 80° C. for two hours. After cooling, the mixture was poured into 1 liter of ice-water, stirred for five minutes, and adjusted to pH 9 with milled K2CO3. The product was extracted with ethyl acetate (3×). The organic layer was washed with water (2×) and dried (saturated NaCl, anhydrous MgSO4). After filtration, the filtrate was concentrated to give an oil, 46 g of which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to give an oil, which solidified on cooling, 32.2 g, m.p. 140° C. A sample of this material was recrystallized from ether, m.p. 157°-159° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][C:14]1[N:15]([C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:16]=[CH:17][N:18]=1>O1CCOCC1>[CH3:13][C:14]1[N:15]([C:19]2[CH:20]=[C:21]([NH:22][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:17][N:18]=1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Cc1nccn1-c1cccc(N)c1
Solvent: C1COCCO1
Product: Cc1nccn1-c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C
Yield: 70.1 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (39 mg, 0.215 mmol) in dioxane was added 3-(2-methyl-1H-imidazol-1-yl)aniline (90 mg, 0.520 mmol). The mixture was heated in microwave (200 W) for 50 minutes at 120° C. The solid formed was isolated by filtration and air dried to yield 48 mg 5-(3-(2-methyl-1H-imidazol-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (70% yield). LCMS (M+1=319)
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1>CCO.C(O)(=O)C>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([N:12]=[C:4]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:1][C:2]3=[O:3])[CH:21]=2)[CH:17]=[N:18]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C1=Nc1ccc2cn[nH]c2c1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a mixture of isatin (147 mg, 1 mmol) and 6-aminoindazole (133 mg, 1 mmol) in EtOH (5 mL) was added 2 drops of acetic acid. The resulting mixture was capped and microwaved 60 min at 120° C. After cooling to rt, the precipitate was collected by suction filtration to give 135 mg (48%) of title compound as yellow solid. 1H NMR indicated a 85:15 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H, NH), 11.00 (s, 1H, NH), 8.09 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.89 (t, J=8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 6.66 (t, J=7.6 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.S(OC)(O[CH3:21])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4'-hydroxy-2-nitrobiphenyl (10.4 g), dimethyl sulphate (9.15 g) in acetone (350 ml) and anhydrous potassium carbonate (22 g) was heated at reflux for 10 hours to get an oil which was purified by column chromatography on silica gel (150 g, 100-200 mesh) eluted with hexane to give 4'-methoxy-2-nitrobiphenyl (m.p. 55°-56° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=O>C(O)C.N1CCCCC1>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (40.6 mg, 38%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:44](=[O:45])[N:12]2[CH:13]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[C:14]([CH:17]([O:24][C:25](=[O:27])[CH3:26])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][S:16][C@H:11]12)=[O:8].C(O)(C)C.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:44](=[O:45])[N:12]2[C:13]([C:28]([O:30][CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:29])=[C:14]([CH:17]([O:24][C:25](=[O:27])[CH3:26])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)OC(C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1)c1ccccc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of stereoisomer A of diphenylmethyl 7-(2-thienylacetamido)-3-(α-acetyloxybenzyl)-2-cephem-4-carboxylate (468 mg) in a mixture (10 ml) of methylene chloride and isopropanol (1:1) is added a solution of 80% m-chloroperbenzoic acid (205 mg) in a mixture (2 ml) of methylene chloride and isopropanol (1:1) at 0° C. After 30 minutes, the reaction mixture is diluted with methylene chloride (120 ml), washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and evaporated. From the residue are obtained the crystalline 1β-oxide and 1α-oxide of the stereoisomer A of diphenylmethyl 7-(2-thienylacetamido)-3-(α-acetyloxybenzyl)-3-cephem-4-carboxylate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].Cl.[N:13]([O-])=O.[Na+]>O>[F:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH:5][NH2:13]
Reactant: O=N[O-]
Reactant: COc1ccc(N)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
To a vigorously stirred suspension of 2-fluoro-4-methoxyaniline hydrochloride (665 mg, 3.7 mmol) in cone. HCl (5.5 mL) cooled to 0° C. was added a cold solution of NaNO2 (312 mg, 4.5 mmol) in H2O (1 mL). The mixture was stirred at 0° C. for 90 min. A cold solution of SnCl2-2H2O (3.4 g, 15.0 mmol) in cone. HCl (5.5 mL) was then added slowly to the solution of diazonium salt. The reaction was allowed to warm to room temperature, stirred for 30 min and the reaction was filtered. The collected precipitate was washed on the filter with several large portions of ether and dried under vacuum. The solid was dissolved in DCM and washed saturated NaHCO3, extracted and dried using a phase separator. Evaporation gave (2-fluoro-4-methoxyphenyl) hydrazine (220 mg 38%), which was used in the next step without further purification. The procedure was adapted from J. Med. Chem. 2000, 43, 4701.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccnc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccnc(Cl)c1CBr
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a solution of 2,4-dichloro-3-methylpyridine (1.0 g, 6.17 mmol) in carbon tetrachloride (25 mL) was added NBS (1.09 g, 6.17 mmol) and a catalytic amount of benzoyl peroxide (0.15 g, 0.617 mmol). The reaction mixture was heated to reflux for 4 hours, and then cooled to room temperature and filtered. The filtrate was evaporated to afford 3-(bromomethyl)-2,4-dichloropyridine as a syrup (1.41 g, 95% yield), which was used in the next reaction without any further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:4][C:5]([CH2:8]Cl)=[CH:6][N:7]=1.O.C(=O)([O-])[O-:12].[Na+].[Na+].Cl>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[S:4][C:5]([CH2:8][OH:12])=[CH:6][N:7]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1cnc(Cl)s1
Temperature: 80 °C

Procedure:
2-Chloro-5-chloromethylthiazole hydrochloride (100 g, 0.49 mole), and water (100 mL) were charged to a flask. The mixture was stirred and heated to 80° C. for 2.5 hours. The reaction mixture was cooled to about 15° C. and sodium carbonate (51.5 g) was added (to raise the pH to about 8-9). The product was extracted with ethyl acetate (1×500 mL and 1×250 mL). The combined organic extracts were stirred for 20 minutes with 3 g of decolorizing carbon (Norit® SA3 about 100 mesh) and filtered through celite. The celite and flask were washed with an additional 100 mL of ethyl acetate and combined with the filtrate. The filtrate was concentrated under reduced pressure to provide a yellow-orange oil. The oil was dissolved in 500 mL of ethyl acetate and cooled to -10° C., under a nitrogen atmosphere. A solution of HCl (17.82 grams, 1 eq.) in ethyl acetate was slowly added. The temperature was maintained below -5° C. After the addition was complete the slurry formed was stirred for 30 minutes. The product was filtered under vacuum and the flask and product washed with ethyl acetate(100 mL). The title compound, an off white powder, was purged with nitrogen gas until dry. Yield: 63.3 g; 69.6%.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][OH:20].CC(C)([O-])C.[K+]>C1COCC1>[CH3:23][O:22][C:18](=[O:21])[CH2:19][O:20][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Br)nc1
Reactant: COC(=O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 70 °C
Yield: 65.7 %

Procedure:
A suspension of 6-bromo-N-(4-fluorophenyl)nicotinamide (1.0 g, 3.4 mmol), methyl glycolate (1.6 mL, 19 mmol), and potassium tert-butoxide (1.5 g, 13.6 mmol) in THF (10 mL) was heated in a sealed tube at 70° C. After 3 h the reaction mixture was poured onto ice and the solids isolated by filtration. Purification on silica gel by column chromatography using 30% ethyl acetate in hexanes gave 0.68 g (65%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s 1H), 8.66 (m, 1H), 8.22 (m, 1H), 7.73 (m, 2H), 7.16 (m, 2H), 7.04 (m, 1H), 4.98 (s, 2H), 3.65 (s, 3H); MS (EI) m/z 303.13 (M−H)−.
Reaction SMILES: Cl[CH:2]([CH2:15][CH3:16])[C:3]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:15]([C@H:2]1[O:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:3]1=[O:4])[CH3:16]
Reactant: CCC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H]1OC[C@@H](c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]butanamide from Step A (2.75 g, 11.4 mmol) in THF (200 mL) at 0° C. was added NaH (983 mg of a 60% dispersion in oil, 24.6 mmol) and the mixture was stirred at ambient temperature for 18 h. Saturated aqueous NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (3×40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-75:25 to 0:100, to give the title compound. MS: m/z=206 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1[OH:16])[C:5]([CH2:7][C:8](OCC)=[O:9])=O.O.[NH2:21][NH2:22]>C(O)C>[OH:9][C:8]1[NH:22][N:21]=[C:5]([C:4]2[CH:3]=[C:2]([OH:1])[C:15]([OH:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cc(O)[nH]n2)cc(O)c1O
Reaction time: 0.08 h

Procedure:
2.0 g of ethyl (3,4-dihydroxy-5-nitrobenzoyl)acetate are suspended in 50 ml of ethanol. After treatment with 0.4 g of hydrazine hydrate the mixture is held at the reflux temperature for 16 hours. After distillation of the solvent, the residue is held at the boiling temperature for 5 minutes with 50 ml of ethyl acetate. The separated precipitate is filtered under suction and the filtrate is concentrated to 10 ml. The crystals, which separate in the cold, are filtered under suction. There is obtained 5-(5-hydroxypyrazol-3-yl)-3-nitropyrocatechol in form of orange crystals of m.p. 228° (dec.).
Reaction SMILES: N[C:2]1([NH2:16])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]1=[N:4][CH:5]=[N:6]2.C([O-])([O-])=O.[K+].[K+].[O:23]1[CH:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1>CN(C=O)C>[NH2:16][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:24][CH:25]([OH:23])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COCCOC1=NC(N)(N)C2=NC=NC2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(CC(O)COc3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a suspension of 6-amino-2-(2-methoxyethoxy)adenine (300 mg, 1.43 mmol) in DMF (3 ml) was added K2CO3 (200 mg, 1.43 mmol). Then 1,2-epoxy-3-phenoxy-propane (321 mg, 2.14 mmol) was added. The reaction mixture was stirred at 70° C. overnight. The solvent was removed and the residue was taken up in CH2Cl2 and washed with water. The aqueous phase was extracted with DCM. The organic layer was dried over NaSO4, filtered, concentrated, and purified by silica gel chromatography, using linear gradient of MeOH in DCM as eluent to give 350 mg product. 1H NMR (CDCl3): δ 3.43 (s, 3H), δ 3.74 (t, 2H), δ 3.90-4.06 (m, 2H), δ 4.30-4.35 (m, 1H), δ 4.30-4.50 (m, 4H), δ 6.00 (bs, 2H), δ 6.88-7.01 (m, 3H), δ 7.27-7.32 (m, 2H), δ 7.70-7.73 (m, 1H); MS: 360.2 (M+1).