Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:17][CH:16]=2)[C@H:11]([CH3:35])[O:10][C:9]1([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[C@H:11]([CH3:35])[O:10][C:9]1([CH3:36])[CH3:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of (4S,5S)-4-{2-[4-(benzhydrylidene-amino)-phenyl]-ethyl}-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.23 g) in methanol (50 ml) was added ammonium formate (6.13 g). The reaction mixture was degassed by bubbling argon through the mixture for several minutes. 10% Pd/C (207 mg) was added and the reaction mixture was stirred at 60° C. for 1 hour. TLC showed the reaction was complete. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 100% EtOAc in hexane) to afford (4S,5S)-4-[2-(4-amino-phenyl)-ethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow oil (1.76 g, 81%). MS (ISP): 335.2 ([M+H), 235.2 ([M-C4H8—CO2]+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[OH:13].[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCOC(C)=O>C1COCC1>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[O:13][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ccc1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
To a ice cooled suspension of sodium hydride (60%, 1.3 g, 78.3 mmol) in THF (100 mL) is added a solution of 2-hydroxy-5-methylbenzoic acid methyl ester (10 g, 60 mmol) in THF (20 mL) and it is stirred at 0° C. Then a solution of methanesulfonyl chloride (8.2 g, 72 mmol) in THF (20 mL) is added dropwise. The reaction mixture is stirred at RT for 18 h. Then the reaction mixture is cooled in an ice bath and slowly ice is added to quench the reaction. EtOAc is used to extract. Brine is added to the aqueous phase and re-extracted with EtOAc. The combined organic phase is washed with water, brine, dried over NaSO4 and MgSO4, and concentrated to give the title compound as an oil. It is used directly in the next step.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:29][CH2:28][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:27])[CH2:14][CH2:13]2)=[O:8])=[C:5]([N+:32]([O-])=O)[CH:4]=1.CO.[H][H]>[Ni].O>[OH2:8].[ClH:1].[NH2:32][C:5]1[CH:4]=[C:3]([F:2])[CH:31]=[CH:30][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:29][CH2:28][C:15]2([N:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][NH:17][C:16]2=[O:27])[CH2:14][CH2:13]1)=[O:8]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(F)ccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1

Procedure:
A mixture of 8 parts of 4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}-2-nitrobenzamide hydrochloride, 120 parts of methanol and 25 parts of water is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from methanol. The product is filtered off and recrystallized from ethanol, yielding 1 part of 2-amino-4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}benzamide hydrochloride hydrate; mp. 223.5° C.
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=O)[CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:21][OH:22]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=[N:21][OH:22])[CH2:8]2)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)N1C2CCCC1CC(=O)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)N1C2CCCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 9-isopropyl-9-aza-bicyclo[3.3.1]nonan-3-one (CAS no: 56258-85-6) (5.0 g, 28 mmol) in ethanol (125 mL) and pyridine (3.3 mL, 41 mmol) with hydroxylamine hydrochloride (2.03 g, 29 mmol) was refluxed for 6 h. Cooled to 23° C., the precipitate was filtered off, washed with diethyl ether leaving a solid, which was partitioned between dichloromethane and sodium carbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a white solid. (4.43 g, 82%); MS: m/e=197.1 (M+H−).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(#N)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(F)cc2)[nH]c1-c1ccncc1

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate and 4-fluorobenzylamine were dissolved in acetonitrile (80 ml). The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-(4-fluorophenyl)-5-(4-pyridyl)imidazole-4-carboxylate.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH:34]([OH:38])[CH:35]([CH3:37])[CH3:36])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:38][CH:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCC(O)C(C)C)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)CCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.3 ml of concentrated sulphuric acid in 2.8 ml of methanol with 140 mg (0.31 mmol) of 7-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methylhept-6-en-3-ol in 2.8 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), a white powder (m=80 mg; Y=77%) is obtained. m.p.=51-60° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[C:24]([CH3:40])=[CH:23][C:21]=1[NH2:22]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([CH3:40])[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 26).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH:16](O)[CH2:17][CH2:18]CCC3C=CC=CC=3)[C:6](=[O:28])[N:5]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:4]=2[N:3]=1.BrCCCC[N:39]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40]1=[O:51].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][N:39]3[CH2:43][CH2:42][CH:41]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:40]3=[O:51])[C:6](=[O:28])[N:5]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CC(O)CCCCc1ccccc1)c(=O)n2CCCCC
Reactant: O=C1C(Cc2ccccc2)CCN1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCCN1CCC(Cc3ccccc3)C1=O)c(=O)n2CCCCC
Temperature: 50 °C
Yield: 86 %

Procedure:
Prepared as with 8-chloro-1-(2-hydroxy-6-phenylhexyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione using 1-(4-bromobutyl)-3-(phenylmethyl)-2-pyrrolidinone as the alkylating agent, potassium carbonate as base and heating at 50° C. for 18 h. Yield 86%.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:14])=O.CN(C=O)C>>[Cl:14][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(S)oc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Oc1ccc2nc(Cl)oc2c1
Temperature: 80 °C
Yield: 68 %

Procedure:
2-Mercapto-benzoxazol-6-ol (1 eq) was dissolved in thionyl chloride (10 eq). DMF (0.6 eq) was slowly added to this solution at room temperature. The mixture was heated to 80° C. and refluxed for 15 minutes. The reaction mixture was cooled to room temperature and the solvent was removed. The resulting solid was azeotroped three times with xylenes. The solid was dissolved in a 10% solution of THF in ethyl acetate and washed once with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with anhydrous sodium sulfate, filtered, and the solvent removed. The solid was triturated with acetonitrile to yield pure product with a 68% yield. MH+=170.0.
Reaction SMILES: [OH:1]O.[Br:3][CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1(B(O)O)[F:10].O>COC(C)(C)C>[Br:3][C:4]1[C:5]([F:10])=[C:6]([OH:1])[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)C1(F)C=CC=CC1Br
Reactant: OO
Solvent: COC(C)(C)C
Solvent: O
Product: Oc1cccc(Br)c1F

Procedure:
125 ml of a 35% strength aqueous solution of hydrogen peroxide are added dropwise at room temperature to the crude 2-bromo-1-fluorophenylboronic acid (80 g) dissolved in 300 ml of tert-butyl methyl ether; during this addition, the temperature rises to 55° C. When the addition is complete, the mixture is refluxed for a further 2 hours. After the mixture has been cooled, 100 ml of water are added, and the organic phase is extracted by shaking twice with saturated sodium sulfite solution. After the solvent has been removed by distillation under reduced pressure, vacuum distillation (90° C.; 4 mbar) gives 54 g of 3-bromo-2-fluorophenol as an oil which soon crystallizes. 1H-NMR (CDCl3): 6.9-7.1 (m; 3H); 5.1 (br; 1H), 19F-NMR (CDCl3): −135 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][OH:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27](O)=[O:28]>CO.[Pd]>[C:27]([O:23][CH2:22][CH2:21][N:20]([CH2:19]/[CH:18]=[CH:17]\[C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH2:24][CH3:25])(=[O:28])[CH3:26]
Reactant: CC(=O)O
Reactant: CCN(CC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCO
Agent: [Pd]
Solvent: CO
Product: CCN(C/C=C\c1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCOC(C)=O
Yield: 69.9 %

Procedure:
75 mg (0.2 mmol) 2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanol in 2 ml MeOH with 0.012 ml (0.2 mmol) AcOH were hydrogenated in the presence of 7 mg Pd/C10% (16 h), filtration over decalite and evaporation yielded 58 mg (66%) Z-2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-allyl}-ethyl-amino)-ethanol acetate as light brown oil, MS: 373 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:13][C:14]1[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:13][C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(NC(=O)c2ccc(C#N)cc2)nc1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 82.6 %

Procedure:
A mixture of 4-cyanobenzoyl chloride (166.5 g), ethyl 2-amino-4-methylthiazole-5-carboxylate hydrochloride (224.0 g) and pyridine (2000 ml) was stirred at room temperature for 70 minutes. The precipitated crystals were collected by filtration, and washed with 3% hydrochloric acid and water to give ethyl 2-(4-cyanobenzoylamino)-4-methylthiazole-5-carboxylate (262.0 g).
Reaction SMILES: [CH2:1]([C:4]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH2:2][CH3:3].[CH:32]1[C:45]2[C:36](=[N:37][C:38]3[C:43]([C:44]=2[NH:46][C:47]2[CH:48]=[C:49]([NH:55][C:56](=[O:60])[CH:57]([NH2:59])[CH3:58])[CH:50]=[C:51]([CH2:53][OH:54])[CH:52]=2)=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[CH:34][CH:33]=1>>[CH:42]1[C:43]2[C:38](=[N:37][C:36]3[C:45]([C:44]=2[NH:46][C:47]2[CH:48]=[C:49]([NH:55][C:56]([CH:57]([NH:59][C:6]([C:5]4[CH:9]=[C:10]([NH:15][C:16]([N:18]5[CH2:23][CH2:22][N:21]([C:24]6[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=6)[CH2:20][CH2:19]5)=[O:17])[C:11]([O:13][CH3:14])=[N:12][C:4]=4[CH2:1][CH2:2][CH3:3])=[O:7])[CH3:58])=[O:60])[CH:50]=[C:51]([CH2:53][OH:54])[CH:52]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:39]=[CH:40][CH:41]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)O
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 42.3 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-propyl-5-{[4-(3,5-dimethylphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
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:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][CH2:37][C@@H:38]([OH:40])[CH3:39]>>[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:35])=[C:14]([C:30]([NH:36][CH2:37][C@@H:38]([OH:40])[CH3:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (d, J=5.90 Hz, 3 H), 1.64-1.80 (m, 6 H), 2.19 (t, J=5.69 Hz, 2 H), 3.16-3.27 (m, 4 H), 3.34-3.49 (m, 2 H), 3.78-3.84 (m, 1 H), 4.16-4.25 (m, 4 H), 4.96 (d, J=4.84 Hz, 1 H), 7.11-7.19 (m, 2 H), 7.38-7.45 (m, 2 H), 8.00 (s, 1 H), 8.56 (s, 1 H), 10.43 (t, J=5.48 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:31][C:32]1[C:33]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48](Cl)=[C:43]3[CH:42]=[N:41]2)=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[N:40]1[C:44]2=[N:45][CH:46]=[N:47][C:48]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:43]2[CH:42]=[N:41]1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (0.116 g, 2.89 mmol) was added to (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ2) (0.595 g, 1.45 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (0.438 g, 1.31 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane to afford the product (0.590 g, 67.5%). 1H NMR (400 MHz, CDCl3) δ 0.98-1.08 (21H, m), 1.12-1.17 (3H, m), 2.54 (3H, s), 3.59-3.78 (3H, m), 4.21-4.26 (1H, m), 4.29-4.36 (1H, m), 6.02-6.06 (1H, m), 7.60-7.65 (1H, m), 7.78-7.81 (1H, m), 7.85-7.87 (1H, m), 8.11-8.13 (1H, m), 8.50 (1H, d), 8.61 (1H, d), 8.71 (1H, d), 9.44 (1H, t); m/z (ES+) M+=665.26; HPLC tR=4.02 min.
Reaction SMILES: O[N:2]=[C:3]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[H][H]>C(O)(=O)C.[Pd]>[NH2:2][CH:3]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[OH:5]
Reactant: COc1ccc(C(=O)C(CC(C)C)=NO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(C(O)C(N)CC(C)C)cc1
Yield: 82.1 %

Procedure:
2-Hydroxyimino-1-(4-methoxyphenyl)-4-methyl-pentane-1-one (8.72 g; 37.1 mmol) was dissolved in acetic acid (88 ml). The solution was added with 5% palladium-charcoal (0.87 g) and the reactant was catalytically hydrogenated at normal pressure and at 80° C. until hydrogen was absorbed in a molar amount of three times that of the reactant. After removal of the catalyst by filtration, the acetic acid was removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid (80 ml). The solution was washed twice with ether (30 ml) and the aqueous layer was basified with a 20% aqueous solution of sodium hydroxide. The aqueous layer thus treated was extracted three times with chloroform and the extracts were combined together and then washed once with brine. The resulting extract was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure to give light-yellowish crystals (6.80 g). The crystals were recrystallized from benzene and hexane to obtain 5.24 g of the intended compound as white crystals (yield: 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[BrH:19].BrBr>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[Br:19]
Reactant: Br
Reactant: CSc1ccc(CC(=O)c2ccccc2F)cc1
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reaction time: 0.83 h

Procedure:
A 100 mL three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with 1-(2-fluorophenyl)-2-(4-methylthiophenyl)ethanone from Step 2, (4.36 g, 16.7 mmol), acetic acid (30 mL) and 33% HBr in acetic acid (0.5 mL). The solution was stirred and treated with bromine (17 mL, 16.8 mmol, 1.0M in acetic acid) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca, 15 min. After an additional 50 minutes at room temperature, the solution was concentrated in vacuo to give a brown oil. The crude haloketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone as an oil that solidified upon standing (4.83 g, 85%): mp 58°-63° C. 1H NMR (CDCl3) 300 MHz 7.87 (td, J=7.6, 1.8Hz, 1H), 7.52 (m, 1H), 7.39 (d, J=8.3Hz, 2H), 7.27-7.03 (m, 4H), 6.34 (s, 1H), 2.45 (s, 3H). 19F NMR (CDCl3) -108.51 (m). Mass spectrum M+ =338.
Reaction SMILES: [C:1]([C:4]1[O:32][C:7]([CH2:8][C:9]2[CH2:10][S:11](=O)[C@@H:12]3[C@H:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18](=[O:30])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(Cl)(=O)C>CN(C)C=O>[C:1]([C:4]1[O:32][C:7]([CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:18](=[O:30])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cc3ccc(C(=O)O)o3)CS(=O)[C@H]12
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cc3ccc(C(=O)O)o3)CS[C@H]12
Reaction time: 2 h

Procedure:
To a mixture of 1.3 g of crude 3-(5-carboxy-furfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid 1-oxide and 1.7 g of tin-II-chloride in 20 ml of dimethylformamide are added dropwise under anhydrous conditions 6 ml of acetic acid chloride, the temperature being maintained at 0°-5°. The reaction mixture is subsequently stirred for 2 hours and worked up in a conventional manner for free acids (see Example 78). Chromatography of the crude product (silica gel, washed with hydrochloric acid; elution with a 4:1-mixture of methylene chloride and ethyl acetate) and subsequent crystallisation from methyl acetate yield the 3-(5-carboxy-furfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid, m.p. 183°-186°; thin-layer chromatogram (silica gel); Rf = 0.24 (system: n-butanol/ethanol/water 40:10:50) and Rf = 0.55 (system: chloroform/methanol 1:1); infrared absorption spectrum (in mineral oil): characteristic bands at: 2,96μ, 3,18μ, 5,65μ, 5,73μ and 5,90μ.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: CCC(Br)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(C(CC)CC)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 3-bromopentane.