Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:23](I)[CH3:24]>CN(C=O)C>[CH2:23]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=2)[CH:6]=[N:7]1)[CH3:24]
Reactant: CCI
Reactant: COC(=O)c1cc([N+](=O)[O-])c2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncc2c([N+](=O)[O-])cc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a solution of methyl 4-nitro-1H-indazole-6-carboxylate (D197) (500 mg, 2.3 mmol, 1 equiv) in DMF (10 ml) at room temperature was added K2CO3 (346 mg, 2.5 mmol, 1.1 equiv) then ethyl iodide (200 μl, 2.5 mmol, 1.1 equiv). The resulting suspension was stirred at room temperature for 15 min then at 40° C. for 30 min, cooled to room temperature and partitioned between AcOEt and a 2N aqueous HCl solution. The two layers were separated and the organic phase dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 2/1) gave methyl 1-ethyl-4-nitro-1H-indazole-6-carboxylate (D198) (200 mg, 35%) as a pale yellow solid. [M+H]+=250.1, RT=3.11 min.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[NH2:28]>>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]2[N:19]=[C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[NH:28][C:21]=2[CH:22]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COc1ccc(N)c(N)c1
Agent: [Na+]
Product: COc1ccc2nc(Cc3nc(N4CCOCC4)cc(=O)[nH]3)[nH]c2c1
Yield: 2.3 %

Procedure:
The product is prepared according to the procedure described in Stage 3 of Example 1, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 166 mg of 1,2-diamino-4-methoxybenzene in place of the 1,2-diamino-4-fluorobenzene. After purification by silica gel column chromatography, elution being carried out with a gradient of pure CH2Cl2 to CH2Cl2/MeOH: 85/15, 8 mg of 2-[(6-methoxy-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one being obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[CH:22]/[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:20][CH2:19][CH:18](/[CH:21]=[CH:22]/[C:23]([C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[O:24])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C/C1CCNCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
3 ml of trifluoroacetic acid was added to 2.52 g of (E)-4-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzene dissolved in 20 ml of methylene chloride, and the mixture was stirred at room temperature for 3 hours. Subsequently, 7 ml of trifluoroacetic acid was further added to the mixture, and the mixture was stirred for 3 hours. Then, the solvent was removed by distillation, and a saturated sodium hydrogen carbonate solution was added to the residue. After the mixture was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate and condensed. The obtained solid was washed with methylene chloride to obtain 0.7 g of the title compound as pale yellow powder.
Reaction SMILES: B(O)(O)O.O[CH:6]([CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH2:7][C:8](=[O:10])[CH3:9]>C1(C)C=CC=CC=1>[F:22][C:20]([F:21])([F:23])[C:17]1[CH:18]=[CH:19][C:14]([S:13][CH2:12][CH2:11][CH:6]=[CH:7][C:8](=[O:10])[CH3:9])=[CH:15][CH:16]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Yield: 95.9 %

Procedure:
0.85 Gram of boric acid was added to 80 ml of toluene, and the resulting mixture was refluxed for 3 hours with stirring. Thereafter, a solution of 6.00 g of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone in 20 ml of toluene was added dropwise thereto at the same refluxing temperature as the toluene solution of boric acid had been refluxed. And the mixture was further refluxed for 8 hours with stirring. The reaction mixture was washed three times with hot water and dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 5.40 g of 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =38.8 : 1) (purity: 99.4). The yield was 95.4%.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:24]([NH:26][C@@H:27]([CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C@@H:28]([OH:43])[C:29]1[N:30](COCC2C=CC=CC=2)[CH:31]=[CH:32][N:33]=1)=[O:25])[CH2:9][C:10]1[N:14](COCC2C=CC=CC=2)[CH:13]=[N:12][CH:11]=1)=O)C.[H][H]>[OH-].[OH-].[Pd+2].CO.Cl>[CH:45]1([CH2:44][C@H:27]([NH:26][C:24](=[O:25])[C@H:8]([CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)[NH2:7])[C@@H:28]([OH:43])[C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cncn1COCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)c1nccn1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)c1ncc[nH]1
Reaction time: 2 h

Procedure:
A mixture of [(1,1-dimethylethoxy)carbonyl]-N-[(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-2-[1-[(phenylmethoxy)methyl]-1H-imidazol-2-yl]ethyl]-N3 -[(phenylmethoxy)methyl]-L-histidinamide (1.46 g., 2.0 mmole) [prepared as set forth in Example 11 (d)], 20% palladium hydroxide on carbon catalyst (350 mg.), and 1.0 N hydrochloric acid (4 ml., 4 mmole) in methanol (15 ml.) is hydrogenated under a slow stream of hydrogen for 20 hours at 25°, after which it is filtered and concentrated to dryness. The residue (1.1 g.) is dissolved in acetic acid (30 ml.) and dry HCl gas is bubbled through the solution for 30 minutes at 25°. The mixture is then stirred at 25° for 2 hours, after which is is concentrated in vacuo. The residue is triturated with acetonitrile to give 833 mg. of a white solid. The solid is dissolved in excess 1N hydrochloric acid and concentrated to dryness. The process is repeated three times to give N-[(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethyl]-L-histidinamide as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14]([NH:18][C:19]([C:21]1[N:22]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:24][NH:25][CH:26]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:18][C:19]([C:21]1[N:22]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:24][N:25]([C:1](=[O:3])[CH3:2])[CH:26]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCNC=C1C(=O)NC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1C=C(C(=O)NC(C)(C)C)N(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
16.7 g (163 mmol) of acetic anhydride and 12.4 g (157 mmol) of pyridine were added to 20.00 g (88.8 mmol) of 1-acetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide and the mixture was stirred for 4 hours at 25° C. 100 ml of water was then added and the pH was adjusted to 6 with 30 ml of sodium hydroxide solution (20%). Extraction was then carried out by shaking with three times 100 ml of methyl ethyl ketone. The combined organic extracts were dried over magnesium sulfate, toluene was added and the mixture was concentrated. The vigorously foaming crude product crystallized and 11.40 g (48%) of the title compound was isolated in the form of a light brown solid. The melting point of the title compound was: 138.0° to 139.2° C. Other data concerning the title compound was:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31](O)=[O:32])=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.C1C=CC2N(O)N=[N:43]C=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O.CCOCC.C1COCC1>[C:31]([C:30]1[CH:29]=[C:28]([CH:36]=[CH:35][CH:34]=1)[CH2:27][N:22]1[C:23]2[C:19](=[C:18]([NH:17][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:16])[CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:21]1)(=[O:32])[NH2:43]
Reactant: On1nnc2ccccc21
Reactant: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(C(=O)O)c3)cnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(C(N)=O)c3)cnc2c1
Reaction time: 0.25 h
Yield: 15 %

Procedure:
To a vial was added 3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoic acid (0.020 g, 0.0412 mmol), HOBT (0.00612 g, 0.0453 mmol) and EDCI (0.00869 g, 0.0453 mmol) followed by THF (0.500 mL). Diisopropylethylamine (0.00789 mL, 0.0453 mmol) was added and the mixture was stirred for 15 minutes. Ammonium carbonate (0.0119 g, 0.124 mmol) was added in one portion and the mixture was stirred vigorously overnight. The mixture was diluted with water and the resulting precipitate was isolated by vacuum filtration and washed with water. The solid was isolated and slurried in Et2O and filtered and the solid was washed with Et2O and hexanes, then dried under vacuum (0.025 g). The crude solid was purified by preparative TLC (10% MeOH/CH2Cl2) which provided 0.003 g (15%) of the desired product. MS (ES+APCI) m/z=485 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:6]#[N:7].N(CCO)(CCO)CCO.C[Si]([N:45]=[N+:46]=[N-:47])(C)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6]1[NH:47][N:46]=[N:45][N:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCN(CCO)CCO
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2Cl)c2nnn[nH]2)cc(C(F)(F)F)c1
Yield: 85 %

Procedure:
A solution of 5 gm of the compound from Step C, 50 mL of 2-methyl THF 5 mL, triethanolamine and 2.5 mL of trimethyl silyl azide was heated at 50° C. until reaction completion. When the reaction was judged complete, the reaction mixture was cooled and 50 mL of 1 N sodium hydroxide added, The layers were separated and the organic layer washed with 50 mL of 10% citric acid. The organic layer was concentrated and triturated with hexane to yield 4.6 of the desired compound. 85% yield. 1H NMR (400 MHz, CDCl3) 7.84 (s, 2H), 7.74 (m, 3H), 4.90 (s, 4H)C, H, N, Calculated, (found) 42.92 (42.98), 2.20 (1.97), 13.90 (13.54)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1O
Yield: 92 %

Procedure:
4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution. Ethyl acetate was added to the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92%) as white crystals. Methyl 4-fluorosalicylate (10.0 g, 58 mmol) and N,N-dimethylthiocarbamoyl chloride (9.6 g, 77 mmol) were dissolved in DMF (100 ml), and 1,4-diazabicyclo[2.2.2]octane (8.5 g, 75 mmol) was added thereto. The reaction mixture was stirred at room temperature for 7 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethylacetate-hexane (1:5, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (12.1 g, 80%) as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.O>O1CCOCC1.ClCCl>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3F)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 25 mg (0.05 mmol) 6-{[6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 1.0 ml dioxan and add 0.16 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.17 ml 1 N hydrochloric acid and then 2 ml water and 5 ml dichloromethane. Separate the organic phase, dry over sodium sulphate, filter, and concentrate by evaporation. 23 mg (92% of theor.) of the target compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:23])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1ccc(Br)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(=S)Nc1ccc(Br)cc1
Temperature: 120 °C
Yield: 136.1 %

Procedure:
In a 500 mL three-neck flask were put 18 g (74 mmol) of N-(4-bromophenyl)isobutyramide obtained in Step 1, 15 g (37 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), and 120 mL of toluene, and the mixture was heated and refluxed at 120° C. for 3 hours. After that, toluene was distilled off to give a yellow oily substance. This oily substance was purified by silica gel column chromatography. Toluene was used as a developing solvent. The resulting fraction was concentrated to give a yellow solid. The resulting solid was collected by suction filtration, and the collected solid was washed with a small amount of methanol to give 13 g of a white solid of N-(4-bromophenyl)isobutyrthioamide in a yield of 70%. The reaction scheme of Step 2 is shown in (b-2) below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]([C:19](OC)=[O:20])=[CH:17][S:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]([CH2:19][OH:20])=[CH:17][S:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cscc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cscc2CO)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A solution of 4-(4-methoxycarbonylthiophen-3-yl)-piperidine-1-carboxylic acid t-butyl ester (100 mg, 310 μmol, 1.0 eq.) in THF (5 mL) was combined with a solution of LiAlH4 (23 mg) under nitrogen. The resulting solution was stirred for 30 minutes while the temperature was maintained at 0-5° C. in an ice/salt bath. The reaction was then quenched by the addition of water (50 μL) and aqueous NaOH (150 μL). The solids were filtered and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:10) to yield the titled compound (50 mg) as a colorless oil. MS m/z: [M+H]+ calcd for C15H24NO3S, 298. found 298.
Reaction SMILES: [Si]([N:8]1[CH:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10][C:9]1=[O:22])(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH2:31]([O:34][C:35]([N:37]1[CH2:41][C@@H:40]([S:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][C@H:38]1[CH2:62]I)=[O:36])[CH:32]=[CH2:33]>>[CH2:31]([O:34][C:35]([N:37]1[CH2:41][C@@H:40]([S:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][C@H:38]1[CH2:62][CH:10]1[CH2:11][C@@H:12]([CH2:13][OH:14])[NH:8][C:9]1=[O:22])=[O:36])[CH:32]=[CH2:33]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1C[C@@H](CO)NC1=O
Yield: 20.4 %

Procedure:
The same procedure as in Reference Example 22-1 was carried out by using N-tert-butyldimethylsilyl-5-tert-butyldimethylsiloxymethyl-2-oxopyrrolidine (10.67 g, 31.6 mmol), lithium diisopropylamide (2.1M tetrahydrofuran solution, 15.1 ml, 31.6 mmol) and (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (10 g, 17.6 mmol) to obtain (2R,4S)-N-allyloxycarbonyl-2-[(5S)-5-hydroxymethyl-2-oxopyrrolidin-3-ylmethyl]-4-tritylthiopyrrolidine (2 g, yield: 21%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][O:29][CH:30]([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][CH2:28][O:29][CH:30]([CH3:32])[CH3:31])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)OCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-aminoethylisopropylether employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.72 (1H, br s), 10.88 (1H, br s), 10.06 (1H, br s), 8.18 (1H, s), 7.30-7.25 (3H, m), 7.16-7.11 (2H, m), 3.98 (2H, br s), 3.57-3.54 (1H, m), 3.50-3.38 (4H, m), 1.08 (6H, d, J=5.7 Hz); HRMS calcd for C21H22FN3O4+H+: 400.1667. Found 400.1673.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([OH:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2nnc(CC(O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(-c2nnc(CC(=O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 47.4 %

Procedure:
The title compound was prepared from 36 (22 mg, 0.052 mmol) following general procedure B. Flash chromatography (SiO2, 5% MeOH—CH2Cl2) afforded the title compound (10.2 mg, 47%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.39 (d, 1H, J=7.8 Hz), 8.25 (d, 1H, J=7.8 Hz), 8.02 (t, 1H, J=7.8 Hz), 7.59-7.54 (m, 4H), 7.44 (t, 2H, J=7.8 Hz), 7.36-7.30 (m, 2H), 4.19 (s, 2H), 4.02 (s, 3H), 3.93 (s, 2H); 13C NMR (CDCl3, 150 MHz) δ 199.1, 164.7, 164.1, 162.1, 148.5, 143.5, 140.5, 140.4, 138.4, 131.4, 129.9, 128.7, 127.7, 127.4 (2C), 127.1, 127.0 (2C), 126.1, 53.2, 49.4, 38.9; HRMS-ESI-TOF m/z 414.1460 ([M+H]+, C24H19N3O4 requires 414.1448).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:18])[CH3:17]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 4-aminobenzophenone (10.0 g, 50.8 mmol), acetic anhydride (5.74 mL, 60.9 mmol), and triethylamine (9.5 mL, 68.5 mmol) in toluene (30 mL). Heat to reflux. After 2 hours, cool to ambient temperature and pour the reaction mixture into water. Stir to give a solid. Collect the solid by filtration, rinse with water, and dry. Recrystallize from acetonitrile to give the title compound. Rf =0.35 (silica gel, ethyl acetate).
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Br:28])=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:29]>>[ClH:29].[NH2:3][C:4]1[S:5][C:6]([Br:28])=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Br

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.) was treated with conc. hydrochloric acid (0.4 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 700 mg.).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH:19]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:20][NH2:21]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH3:12])[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCCC2C)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCCC2C)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].[CH:10]1([C:13](=[N:15]O)[NH2:14])[CH2:12][CH2:11]1>C1(C)C(C)=CC=CC=1>[CH:10]1([C:13]2[N:15]=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[O:8][N:14]=2)[CH2:12][CH2:11]1
Reactant: O=C(Cl)c1cnccn1
Reactant: NC(=NO)C1CC1
Solvent: Cc1ccccc1C
Product: c1cnc(-c2nc(C3CC3)no2)cn1

Procedure:
To a mixture of 28.7 g. of pyrazinoyl chloride in 100 ml. of xylene is added slowly a solution of 20 g. of cyclopropanecarboxamidoxime in 100 ml. of xylene. This mixture is heated under reflux for 3 hours, concentrated under reduced pressure and the residue mixed with aqueous sodium hydroxide. The mixture is filtered and the filtrate is extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give crude crystals, which are recrystallized from cyclohexane to give light yellow crystals, melting point 61°-64°C.